Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[C:12]1([C:18]2[C:19]([C:23]#[N:24])=[CH:20][NH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+]>CN(C=O)C>[NH2:7][C:6]1[CH:8]=[C:2]([N:21]2[CH:22]=[C:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:19]([C:23]#[N:24])=[CH:20]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: N#Cc1c[nH]cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cn(-c2ccc([N+](=O)[O-])c(N)c2)cc1-c1ccccc1

Procedure:
Prepared from 5-chloro-2nitroaniline, 4-phenyl-pyrrole-3-carbonitrile [CAS-no. 40167-37-1] and NaH in DMF at 150° C. for 3 h according to the general procedure E (method b). Obtained as a dark red solid (168 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:14](I)[CH3:15].[BH4-].[Na+]>CN(C=O)C.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH:12]=[CH:11][CH2:10][N:9]2[CH2:14][CH3:15])=[CH:6][CH:7]=1
Reactant: CCI
Reactant: Brc1ccc(-c2ccccn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCN1CC=CCC1c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 29.4 %

Procedure:
To a solution of 2-(4-bromophenyl)pyridine (2.7 g, 11.5 mmol) in DMF (50 mL) was added ethyl iodide (1.9 mL, 23.1 mmol) and the reaction mixture was heated to 80° C. for 16 h. The mixture was cooled then evaporated and the resultant residue dissolved in methanol (100 mL) before addition of sodium borohydride (1.5 g, 39.2 mmol) portionwise. The reaction mixture was stirred at ambient temperature for 1 h then evaporated and saturated aqueous sodium carbonate solution was added. The mixture was extracted with ethyl acetate (2×100 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated then the residue was purified by flash chromatography (silica, Biotage 100 g column, 50% ethyl acetate in cyclohexane) to afford the title compound (0.9 g, 29%), which was used without further purification. 1H NMR (CDCl3, 300 MHz): 7.47-7.42 (m, 2H), 7.24-7.19 (m, 2H), 5.86-5.74 (m, 2H), 3.47-3.35 (m, 2H), 2.98-2.87 (m, 1H), 2.64-2.46 (m, 1H), 2.33-2.26 (m, 2H), 2.13-2.00 (m, 1H), 0.99 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:26](=[O:27])[CH2:25][C:22]2[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=2)[CH2:7]1
Reactant: Cc1ccc(CC(=O)O)cc1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: Cc1ccc(CC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)cc1

Procedure:
Example 9 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0055 g) and (4-methylphenyl)acetic acid (0.03 g) to give thetitle compound (0.024 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=2)[C:5]([Cl:8])=[N:6][CH:7]=1.B(Br)(Br)Br>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: COc1ccc(C(=O)Nc2cc(Br)cnc2Cl)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(Br)cnc1Cl)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.3 %

Procedure:
N-(5-Bromo-2-chloropyridin-3-yl)-4-methoxybenzamide (1.4 g, 81% purity, 3.32 mmol) was dissolved in 80 mL dichloromethane. A solution of boron tribromide (1M in dichloromethane, 16.6 ml, 16.6 mmol) was added dropwise and the reaction was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and washed with a solution of 4% sodium bicarbonate, water, brine and dried over sodium sulphate, filtered and evaporated under reduced pressure to give 1.2 g (100% yield) of the title compound as an orange solid. Purity 91%.
Reaction SMILES: [N+](C1C=CC([C:10]2[CH:22]=[C:21]([C:23]([O-])=[O:24])[C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:12]=3[C:11]=2[O:33][CH3:34])=CC=1)([O-])=O.[Cl:35][C:36]1[CH:37]=[N:38][CH:39]=[C:40]([Cl:43])[C:41]=1[NH2:42].[H-].[Na+].Cl>CN(C=O)C>[Cl:35][C:36]1[CH:37]=[N:38][CH:39]=[C:40]([Cl:43])[C:41]=1[NH:42][C:23]([C:21]1[C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:12]=2[C:11]([O:33][CH3:34])=[CH:10][CH:22]=1)=[O:24]
Reactant: COc1c(-c2ccc([N+](=O)[O-])cc2)cc(C(=O)[O-])c2c3ccccc3n(Cc3ccccc3)c12
Reactant: Nc1c(Cl)cncc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c3ccccc3n(Cc3ccccc3)c12
Reaction time: 8 h
Yield: 57.7 %

Procedure:
To a solution of 4-nitrophenyl-9-benzyl-1-methoxy-9H-4-carbazolecarboxylate (229 mg, 0.506 mmoles) and 3,5-dichloro-4-aminopyridine (82.53 mg, 0.506 mmoles) in dry DMF (10 ml), under N2 atmosphere, 60% sodium hydride (44.19 mg, 1.012 mmoles) was added at 25° C. and the reaction mixture was stirred overnight. The reaction mixture was poured into ice-cold water and neutralized with 1N HCl. The compound was extracted with chloroform (2×15ml), combined the organic layers and washed with water (3×15 ml) and with brine (15 ml). The organic layer was dried over anhydrous sodium sulphate and concentrated to give 200 mg of the crude compound which was purified by column chromatography to yield 139 mg of the title compound as light brown colored solid, m.p: 215-217° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6](=O)[C@H:7]([CH3:13])[C@H:8]([CH3:12])[CH2:9][CH2:10][CH3:11])[CH3:2].Cl.[O:17]([NH2:19])[CH3:18].C([O-])(=O)C.[Na+]>CCO>[CH2:1]([O:3][C:4](=[O:15])/[CH:5]=[C:6](\[NH:19][O:17][CH3:18])/[C@H:7]([CH3:13])[C@H:8]([CH3:12])[CH2:9][CH2:10][CH3:11])[CH3:2]
Reactant: CCC[C@@H](C)[C@@H](C)C(=O)CC(=O)OCC
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCC[C@@H](C)[C@@H](C)/C(=C/C(=O)OCC)NOC
Temperature: 25 °C
Yield: 99.6 %

Procedure:
A 2 L 3-necked round bottom flask, equipped with magnetic stirring and nitrogen inlet, was charged with 153 g (0.71 mol) of (4R,5R)-4,5-dimethyl-3-oxo-octanoic acid ethyl ester and 600 mL of anhydrous EtOH. The solution was cooled to 0° C.–5° C. with an ice bath and 65.6 g (0.79 mol) of methoxylamine hydrochloride was added, followed by 58.6 g (0.71 mol) of sodium acetate. This flask contents were slowly warmed to room temperature (about 2 hours) and the reaction mixture was stirred at room temperature for another 24 hours. The solvent (EtOH) was removed under reduced pressure and the mixture was charged with CH2Cl2 (2×300 mL), which was subsequently removed. The mixture was cooled to RT, diluted with CH2Cl2 (300 mL), stirred at room temperature for 0.5 hours, and filtered under 5 psig of nitrogen. The filter cake was washed with CH2Cl2 (150 mL). The filtrate was concentrated under vacuum (50° C.) to give 172 g (99% yield) of the titled compound as a light yellow oil: 1H NMR (400 MHz, CHLOROFORM-D) 0.87 (t, J=3.5 Hz, 5H), 0.89 (d, J=7.2 Hz, 3H), 1.08 (d, J=7.0 Hz, 3H), 1.24 (t, J=7.2 Hz, 4H), 1.3–1.55 (m, 2H), 2.25 (m, 1H), 3.15 (q, J=19.5 Hz, 2H) 3.81 (s, 3H), 4.14 (q, J=7.0 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]([CH3:13])([CH3:12])[C:3]1=[O:14].[N+:15]([O-])([OH:17])=[O:16].[OH-].[Na+]>OS(O)(=O)=O>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:15]([O-:17])=[O:16])=[CH:9][CH:10]=2)[NH:5][C:4]([CH3:12])([CH3:13])[C:3]1=[O:14]
Reactant: O=[N+]([O-])O
Reactant: CN1C(=O)C(C)(C)Nc2ccccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CN1C(=O)C(C)(C)Nc2cc([N+](=O)[O-])ccc21
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 93.6 %

Procedure:
In a 50-mL r.b. flask, a solution of 3,4-dihydro-1,3,3-trimethylquinoxalin-2(1H)-one (830 mg, 4.36 mmol) in 20 mL of conc. H2SO4 was cooled to −15° C. A solution of HNO3 (336 mg, 4.80 mmnol, 1.1 equiv) dissolved in conc. H2SO4 (1 mL) was then added dropwise via syringe in order to maintain a temperature below −5° C. After complete addition the reaction was allowed to stir at −15° C. for 15 min, warmed to rt, poured over NaOH (15 g) pellets and ice. After complete solution of the NaOH pellets, the red precipitate was filtered, redissolved in EtOAc (150 mL), washed with H2O (20 mL), brine (20 mL), dried (MgSO4), filtered, and concentrated to give a orange solid. No further purification is required to obtain 960 mg (94%) of 3,4-dihydro-1,3,3-trimethyl-6-nitroquinoxalin-2(1H)-one as an orange solid. Data for 3,4-dihydro-1,3,3-trimethyl-6-nitroquinoxalin-2 (1H)-one: 1H NMR (400 MHz, CDCl3) δ 7.76 (dd, J=8.8, 2.5, 1H), 7.55 (d, J=2.4, 1H), 6.96 (d, J=8.9, 1H), 4.04 (bs, 1H), 3.42 (s, 3H), 1.41 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([N+:11]([O-:13])=[O:12])[C:5]([O:9][CH3:10])=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[Ca+2].Cl[C:22]([O:24][CH2:25][CH2:26][Cl:27])=[O:23]>O1CCOCC1>[Cl:27][CH2:26][CH2:25][O:24][C:22]([NH:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([N+:11]([O-:13])=[O:12])[C:5]([O:9][CH3:10])=[C:6]([Cl:8])[CH:7]=1)=[O:23]
Reactant: COc1c(N)cc(Cl)c(OC)c1[N+](=O)[O-]
Reactant: O=C(Cl)OCCCl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Product: COc1c(Cl)cc(NC(=O)OCCCl)c(OC)c1[N+](=O)[O-]
Temperature: 90 °C

Procedure:
0.05 mole (11.7 g) of 5-amino-2,4-dimethoxy-3-nitrochlorobenzene was dissolved in 50 ml of dioxane. 5 g of calcium carbonate were added, then the temperature was raised to the region of 90° C. 0.05 mole (7.2 g) of β-chloroethyl chloroformate was then introduced with stirring. Upon completion of the addition, stirring was maintained for 30 additional minutes at 90° C. The inorganic salts present in the reaction mixture were removed by filtration while hot. After addition of iced water to the filtrate, the expected product crystallized. The product obtained was thoroughly drained and washed with water. After drying, it was recrystallized from ethanol. It melted at 93° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:13][CH:12]=[C:11]([C:23](O)=[O:24])[C:10]2=[O:26])=[O:5])[CH3:2].S(Cl)([Cl:29])=O>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:13][CH:12]=[C:11]([C:23]([Cl:29])=[O:24])[C:10]2=[O:26])=[O:5])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)Oc1cc2occ(C(=O)O)c(=O)c2cc1OC(=O)OCC
Solvent: c1ccccc1
Product: CCOC(=O)Oc1cc2occ(C(=O)Cl)c(=O)c2cc1OC(=O)OCC

Procedure:
6,7-Bis(ethoxycarbonyloxy)chromone-3-carboxylic cid (1.1 g) was dissolved in benzene (20 ml) and thionyl chloride (2 ml) was added dropwise at room temperature with stirring. Then, the mixture was refluxed with stirring. The reaction mixture was concentrated, and n-hexane was added to the concentrate to crystallize it. The resulting crystals were collected by filtration, washed with n-hexane and dired to afford the desired product (980 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:16][CH2:15][CH2:14][NH:13]2)[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.Br[C:18]1[CH:23]=[CH:22][N:21]2[N:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:20]2[CH:19]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:18]2[CH:23]=[CH:22][N:21]3[N:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:20]3[CH:19]=2)[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: Fc1cc2c(c(C3CCCN3)c1)OCCO2
Reactant: CCOC(=O)c1cnn2ccc(Br)cc12
Product: CCOC(=O)c1cnn2ccc(N3CCCC3c3cc(F)cc4c3OCCO4)cc12

Procedure:
The title compound (Int-65) was prepared by the method similar to that of Int-84 using 2-(7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pyrrolidine (Int-56B)) and Ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate to afford as pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([C:9]1[S:13][C:12]([C:14](O)=[O:15])=[CH:11][CH:10]=1)=[O:8].C(Cl)(=O)C([Cl:24])=O>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([C:9]1[S:13][C:12]([C:14]([Cl:24])=[O:15])=[CH:11][CH:10]=1)=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)s1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A stirring solution of (12(b)) (495 mg; 1.5 mmole) in dichloromethane (25 mL) was cooled in an ice bath and DMF (1 drop) and oxalyl chloride (0.175 mL; 2.0 mmole) added dropwise. The solution was stirred at ambient temperature under argon for 4 hours. The dichloromethane and excess oxalyl chloride were removed in vacuo. The residue was azeotroped uith toluene (2×15 mL) to give 5-(3,4-dichlorobenzyl-carbamoyl)-thiophene-2-carbonyl-chloride (12(c)) which was used crude in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[N:11]=1)[C:8](=[O:13])[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[CH3:16]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[N:11]=1)[C:8](=[O:13])[N:7]([CH3:16])[CH:6]=[CH:5]2
Reactant: CI
Reactant: O=c1[nH]ccc2cc(Cl)nc(Cl)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2cc(Cl)nc(Cl)c2c1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 6,8-dichloro-2,7-naphthyridin-1(2H)-one (215.0 mg, 1.0 mmol) in dry DMF (10 mL) was added NaH (100 mg, 60% in mineral oil, 2.5 mmol) at 0° C. under N2. After the reaction mixture was allowed to be warmed to room temperature and stirred for 20 minutes, CH3I (0.25 mL, 568.08 mg, 4.0 mmol) was added via syringe. The reaction mixture was stirred at room temperature for 18 hours and concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL), washed with saturated NH4Cl solution (2×50 mL), water (30 mL) and brine (20 mL), and concentrated to afford the crude title compound. ESI-MS m/z 229.0 (MH+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(C)(C)C.[K+]>CS(C)=O>[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]([NH:23][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:24][CH:25]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccccc1Nc1ccc(OCc2ccccc2)cc1
Temperature: 110 °C

Procedure:
To 600 μL of 2-fluoro-nitrobenzene, 6 mL of DMSO are added 1.7 g of 4-(benzyloxy)aniline (1.5 equivalents) and 1.02 g of potassium tert-butanolate (1.6 equivalents). The whole is heated to 110° C. for 1 h 30. The medium is then hydrolyzed and extracted several times with ethyl acetate. The organic phases are washed with a saturated solution of sodium chloride, dried on magnesium sulfate, filtered and then concentrated under reduced pressure. A silica gel chromatography of the residue (cyclohexane/ethyl acetate: 99/1) allows 754 mg of the desired product to be isolated.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]2[CH:9]=[CH:10][C:11]3[O:15][CH:14]=[N:13][C:12]=3[CH:16]=2)[CH2:7][CH2:6]1)=[O:4].[Al+3].[Cl-].[Cl-].[Cl-].O>CCS>[O:15]1[C:11]2[CH:10]=[CH:9][C:8]([C:5]3([C:3]([OH:4])=[O:2])[CH2:7][CH2:6]3)=[CH:16][C:12]=2[N:13]=[CH:14]1
Reactant: COC(=O)C1(c2ccc3ocnc3c2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: O
Product: O=C(O)C1(c2ccc3ocnc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 10.3 %

Procedure:
To a solution of 1-benzooxazol-5-yl-cyclopropanecarboxylic acid methyl ester (2.9 g) in EtSH (30 mL) was added AlCl3 (5.3 g, 40 mmol) in portions at 0° C. The reaction mixture was stirred for 18 hours at room temperature. Water (20 mL) was added dropwise at 0° C. The resulting mixture was extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 1:2) to give 1-(benzo[d]oxazol-5-yl)cyclopropanecarboxylic acid (280 mg, 11% over two steps). 1H NMR (DMSO, 400 MHz) δ 12.25 (brs, 1H), 8.71 (s, 1H), 7.70-7.64 (m, 2H), 7.40 (dd, J=1.6, 8.4 Hz, 1H), 1.49-1.46 (m, 2H), 1.21-1.18 (m, 2H). MS (ESI) m/e (M+H+) 204.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:50]([N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1)([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51]>>[C:53]([O:52][C:50]([N:57]1[CH2:62][CH2:61][N:60]([C:34](=[O:36])[C:33]2[CH:32]=[CH:31][C:30]([N:27]3[C:17]4[N:18]=[C:19]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[N:20]=[C:15]([C:12]5[CH:13]=[N:14][C:9]([N:8]([CH2:39][C:40]6[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=6)[CH2:7][C:6]6[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:49][CH:48]=6)=[N:10][CH:11]=5)[C:16]=4[CH2:29][CH2:28]3)=[CH:38][CH:37]=2)[CH2:59][CH2:58]1)=[O:51])([CH3:56])([CH3:54])[CH3:55]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cn2)cc1
Yield: 83.8 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (70.4 mg, 0.107 mmol) obtained in Step A in Example 1-D-19 and 1-Boc-piperazine (31.7 mg, 0.170 mmol) instead of 3-(aminomethyl)pyridine, in the same manner as Step B in Example 1-D-19, amidation was carried out, to obtain a crude product of 4-{4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-benzoyl}-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (74.2 mg), and then the PMB groups and BOC group were removed according to the above Deprotection method 3, to obtain the desired compound (D-112) as a colorless powder (41.4 mg, 80%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1.[Cl:14][C:15]([Cl:20])([Cl:19])[C:16](Cl)=[O:17].C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[N:3]=[C:4]([C:16](=[O:17])[C:15]([Cl:20])([Cl:19])[Cl:14])[N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1
Reactant: Clc1cccnc1-n1cnc(Br)c1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1nc(Br)cn1-c1ncccc1Cl)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1.0 g of 2-(4-bromo-1H-imidazol-1-yl)-3-chloropyridine in 5 ml of dichloromethane was added dropwise a solution of 0.45 ml of trichloroacetyl chloride in 5 ml of dichloromethane at room temperature. The resulting mixture was stirred at room temperature for 1 day. Thereto 0.57 ml of triethylamine was added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was subjected to silica gel chromatography to obtain 1.0 g of 1-[4-bromo-1-(3-chloro-2-pyridinyl)-1H-imidazol-2-yl]-2,2,2-trichloroethanone of the formula:
Reaction SMILES: [ClH:1].Cl.[CH:3]1([C:9]2[N:10]=[N:11][C:12]([O:28][CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl.[CH2:36](OCC)C>C(Cl)Cl>[ClH:1].[ClH:1].[CH:3]1([C:9]2[N:10]=[N:11][C:12]([O:28][CH:29]3[CH2:30][CH2:31][N:32]([CH3:36])[CH2:33][CH2:34]3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CCOCC
Reactant: c1cc(-c2cc(OC3CCNCC3)nnc2C2CCCCC2)ccc1OC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CN1CCC(Oc2cc(-c3ccc(OC4CCCCC4)cc3)c(C3CCCCC3)nn2)CC1

Procedure:
To a solution of 3-cyclohexyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (0.079 mmol, 0.04 g) and aqueous formaldehyde (37%, 0.39 mmol, 0.035 mL) in dry DCM (1 mL) was added macroporous resin-bound triacetoxyborohydride (loading 2.36 mmol/gram, 0.47 mmol, 0.20 g). The mixture was shaken for 2 hours. The reaction was placed directly onto a 4 g SiO2 cartridge and the column was eluted with 4-6% (2N NH3 in MeOH) in DCM to give 3-cyclohexyl-4-(4-cyclohexyloxy-phenyl)-6-(1-methyl-piperidin-4-yloxy)-pyridazine. The neutral amine was treated with 2N HCl in diethyl ether (0.5 mL) and DCM (0.5 mL). The volatiles were removed under reduced pressure and the salt was triturated with diethyl ether and filtered to provide the title compound (0.04 g). LCMS: m/z 451 [M+1]. 1H NMR (400 MHz, CD3OD) δ 7.63-7.79 (1H, m), 7.38-7.43 (2H, m), 7.10-7.14 (2H, m), 5.33-5.57 (1H, m), 4.40-4.51 (1H, m), 3.66-3.69 (1H, m), 3.11-3.54 (3H, m), 2.94 (3H, s), 2.37-2.62 (2H, m), 2.20-2.30 (1H, m), 1.20-2.17 (22H, m).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:21])[N:4]([CH3:20])[C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[CH:15][N:14]=1)[CH:8]=[CH:7][CH:6]=2.NC1C(=O)NC2C(N=1)=C(OC1C=C([N:40]3[CH2:45][CH2:44][N:43]([C@H:46]([C:48]4[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=4)[CH3:47])[CH2:42][CH2:41]3)N=CN=1)C=CC=2>>[NH2:1][C:2]1[C:3](=[O:21])[N:4]([CH3:20])[C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17]([N:40]3[CH2:41][CH2:42][N:43]([C@H:46]([C:48]4[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=4)[CH3:47])[CH2:44][CH2:45]3)[N:16]=[CH:15][N:14]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: Cn1c(=O)c(N)nc2c(Oc3cc(Cl)ncn3)cccc21
Reactant: C[C@@H](c1ccc(F)cc1)N1CCN(c2cc(Oc3cccc4[nH]c(=O)c(N)nc34)ncn2)CC1
Product: C[C@@H](c1ccc(F)cc1)N1CCN(c2cc(Oc3cccc4c3nc(N)c(=O)n4C)ncn2)CC1

Procedure:
3-Amino-5-(6-chloropyrimidin-4-yloxy)-1-methylquinoxalin-2(1H)-one, Example 59(e), (80 mg, 0.26 mmol) was reacted with (S)-1-(1-(4-fluorophenyl)ethyl)piperazine (55 mg, 0.26 mmol, prepared as described in Example 27) under the conditions of Example 26(b) to give the title compound. MS (ESI, pos. ion.) m/z: 476 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27](O)=[CH:28][CH:29]=2)[O:24][C:23](=[O:32])[CH:22]=1)[CH3:19].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:27]2[CH:26]=[C:25]3[C:30]([C:21]([O:20][CH2:18][CH3:19])=[CH:22][C:23](=[O:32])[O:24]3)=[CH:29][CH:28]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCCN1CCN(Cc2ccccc2)CC1
Reactant: CCOc1cc(=O)oc2cc(O)ccc12
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCO
Product: CCOc1cc(=O)oc2cc(OCCCN3CCN(Cc4ccccc4)CC3)ccc12
Yield: 61.2 %

Procedure:
Condensation of 1-benzyl-4-(3-hydroxypropyl)piperazine (12.5 g) with 4-ethoxy-7-hydroxycoumarin (11 g) as described in Example 4(b) gave 13.8 g (52%) of the title compound as its dihydrochloride of m.p. (ethanol) 240°-241° C.; (Found; C, 59.89; H, 6.47; N, 5.68; Cl, 14.44; C25H30N2O4.2HCl requires; C, 60.60; H, 6.51; N, 5.66; Cl, 14.31%).