Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][CH2:4][C:5](OCC)=[O:6].FC(F)(CCC1C=CC=CC=1)CO>>[F:1][C:2]([F:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][OH:6]
Reactant: CCOC(=O)CCC(F)(F)c1ccccc1
Agent: OCC(F)(F)CCc1ccccc1
Product: OCCCC(F)(F)c1ccccc1

Procedure:
Obtained from Intermediate 21 (0.9 g, 4.1 mmol) by the procedure described in Intermediate 2. The title compound was obtained as oil (0.65 g, 85%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([OH:20])[CH:18]=3)[C:13]([C:21]#[N:22])=[CH:12]2)=[CH:7][C:6]=1[O:23][CH2:24][O:25][CH3:26])[CH3:2].[CH2:28]([O:35][C:36](=[O:41])[NH:37][CH2:38][CH2:39]Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:39][CH2:38][NH:37][C:36]([O:35][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:41])[CH:18]=3)[C:13]([C:21]#[N:22])=[CH:12]2)=[CH:7][C:6]=1[O:23][CH2:24][O:25][CH3:26])[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c3ccc(O)cc32)cc1OCOC
Reactant: O=C(NCCBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-n2cc(C#N)c3ccc(OCCNC(=O)OCc4ccccc4)cc32)cc1OCOC
Temperature: 50 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
To a solution of 4-(3-cyano-6-hydroxyindol-1-yl)-2-methoxymethoxybenzoic acid ethyl ester (0.37 g) in N,N-dimethylformamide (10 mL) were added (2-bromoethyl)carbamic acid benzyl ester (0.39 g) and potassium carbonate (0.28 g), and this mixture was stirred at 50° C. overnight. This reaction mixture was poured into water, and the precipitated solid was collected by filtration. This solid was washed with methanol, and dried to give the title compound (0.40 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[N:8][C:9](=[O:11])O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1>>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:12][C:9]([N:8]=[C:3]1[NH:4][C:5](=[O:7])[CH2:6][N:2]1[CH3:1])=[O:11]
Reactant: CN1CC(=O)NC1=NC(=O)O
Reactant: Nc1ccccn1
Product: CN1CC(=O)NC1=NC(=O)Nc1ccccn1
Temperature: 90 °C

Procedure:
A mixture of 2.7 g (11.6 mM) of the phenyl ester of tetrahydro-1-methyl-4-oxo-1H-imidazol-2-ylidene carbamic acid 8 and 10.0 g (106 mM) of 2-aminopyridine was heated at 90° C. for 1 hr. The excess amine was removed by vacuum distillation and the residue triturated with 35 ml. ethanol, filtered and the collected solid recrystallized from ethyl acetate to give 1.1 g of the above urea as a cream colored solid, m.p. 218° C. (dec.).
Reaction SMILES: [C:1]1([CH:7]2[CH:15]3[CH2:16][CH2:17][C:18](=[O:19])[C:13]4[C:14]3=[C:9]([CH:10]=[CH:11][CH:12]=4)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(Cl)C(Cl)=C(Cl)C(=O)C(=O)C=1Cl.[OH-].[Na+]>O1CCCC1>[C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:18](=[O:19])[CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC2c3c(cccc31)NC2c1ccccc1
Agent: O=C1C(=O)C(Cl)=C(Cl)C(Cl)=C1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
A portion (3.3 g) of the compound obtained in Example 22 was dissolved in anhydrous tetrahydrofuran (THF; 400 ml) and to the solution was added o-chloranil (3.6 g). The resulting mixture was stirred for 30 minutes at room temperature. After adding 1N aqueous solution of sodium hydroxide, the reaction mixture was extracted twice with ethyl acetate. The organic layers were combined, washed twice with 1N aqueous solution of sodium hydroxide and once with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (methylene chloride) and further crystallized from an ether/hexane mixed solvent to yield 2.3 g (70%) of the titled compound as crystals.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].Br[C:16]1[CH:17]=[CH:18][C:19]([F:28])=[C:20]([N:22]2[CH2:26][CH2:25][CH2:24][C:23]2=[O:27])[CH:21]=1>>[F:28][C:19]1[CH:18]=[CH:17][C:16]([C:12]2[N:4]3[CH:5]=[CH:6][C:7]([C:8]([F:9])([F:10])[F:11])=[C:2]([F:1])[C:3]3=[N:14][CH:13]=2)=[CH:21][C:20]=1[N:22]1[CH2:26][CH2:25][CH2:24][C:23]1=[O:27]
Reactant: O=C1CCCN1c1cc(Br)ccc1F
Reactant: Fc1c(C(F)(F)F)ccn2ccnc12
Product: O=C1CCCN1c1cc(-c2cnc3c(F)c(C(F)(F)F)ccn23)ccc1F
Yield: 24 %

Procedure:
8-Fluoro-7-trifluoromethylimidazo[1,2-α]pyridine was coupled to 1-(5-bromo-2-fluorophenyl)pyrrolidin-2-one as described in Example 6 to give 1-[2-fluoro-5-(8-fluoro-7-trifluoromethylimidazo[1,2-α]pyridin-3-yl)-phenyl]pyrrolidin-2-one as a white solid (90 mg, 24%): m/z (ES+) 382 [MH+].
Reaction SMILES: C([Mg]Br)(C)C.I[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11].[O:15]1[C:19]2([CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]2)[O:18][CH2:17][CH2:16]1>C1COCC1>[OH:25][C:22]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])[CH2:23][CH2:24][C:19]2([O:15][CH2:16][CH2:17][O:18]2)[CH2:20][CH2:21]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: N#Cc1cccc(I)c1
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: N#Cc1cccc(C2(O)CCC3(CC2)OCCO3)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of iso-propyl-magnesium bromide (Aldrich, 2.0 M in THF, 8 mL, 16 mmol) was slowly dropped into a solution of 3-iodo-benzonitrile (Aldrich, 3.25 g, 14.2 mmol) in THF (20 mL) at 0° C. After addition, the reaction was stirred for another 30 min. A solution of 1,4-dioxa-spiro[4.5]decan-8-one (2.22 g, 14.2 mmol) in THF (5 mL) was added to the reaction mixture at 0° C. The reaction was then stirred for additional 2 hours. The reaction was quenched with diluted NH4Cl solution and warmed to room temperature. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow solid, which was purified by silica gel column on a CombiFlash® system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:30])[C:6]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:7]2[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1.[CH3:31]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:26]([O:25][CH:19]([C:6]1[C:5]([CH3:30])=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[CH3:31])[C:7]=1[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH3:28])([CH3:27])[CH3:29]
Reactant: CB1OB(C)OB(C)O1
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2c(Br)cccc2c1-c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2c(C)cccc2c1-c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 36.9 %

Procedure:
To a solution of ethyl 2-(5-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate (100 mg, 0.204 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.086 mL, 0.61 mmol) in toluene:ethanol (2:1, 3 mL) and water (1 mL) was added potassium carbonate (282 mg, 2.04 mmol) and PdCl2(dppf) (15 mg, 0.02 mmol) and the reaction was degassed with argon for 10 minutes. The reaction was heated to 100° C. for 20 minutes in a microwave reactor. The crude reaction was purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a yellow oil (32 mg) 1H-NMR: 400 MHz, (CD3OD) δ: 8.08-7.87 (m, 2H), 7.87 (s, 1H), 7.65-7.35 (m, 1H), 7.26 (m, 2H), 7.15 (d, J=7.2 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H). 5.10 (s, 1H), 4.14 (m, 2H), 2.69 (s, 3H), 2.65 (s, 3H), 1.20 (t, J=6.8 Hz, 3H), 0.99 (s, 9H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([S:39][CH2:40][C:41]5[N:42]([CH2:46][CH2:47][CH3:48])[CH:43]=[CH:44][N:45]=5)=[CH:35][CH:34]=4)=[O:31])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.CSC.O>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:34]=[CH:35][C:36]([S:39]([CH2:40][C:41]5[N:42]([CH2:46][CH2:47][CH3:48])[CH:43]=[CH:44][N:45]=5)=[O:58])=[CH:37][CH:38]=4)=[O:31])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CCC)cc2)CCCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CSC
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CCC)cc2)CCCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a solution of 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-propylimidazol-2-yl]methyl]sulfanyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (400 mg) in dichloromethane (10 ml) was added dropwise a 70% solution of 3-chloro-per-benzoic acid (217 mg) in dichloromethane (10 ml) at −78° C. After stirring as such for 1 hour, dimethyl sulfide (0.1 ml) was added. The mixture was returned to room temperature and stirred for 30 minutes, after which water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous brine, and was dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was separated and purified by basic silica gel column chromatography (hexane:ethyl acetate=1:4→ethyl acetate) and recrystallized from diisopropyl ether→ethyl acetate to give 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-propylimidazol-2-yl]methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (245 mg) as yellow crystals (Compound 16).
Reaction SMILES: [CH3:1][C:2]1[S:24][C:5]2[NH:6][C:7]3[CH:21]=[CH:20][C:19]([CH2:22][NH2:23])=[CH:18][C:8]=3[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:32][O:33][C:34](=[O:47])[CH2:35][CH2:36][C:37](ON1C(=O)CCC1=O)=[O:38]>ClCCl>[CH3:32][O:33][C:34](=[O:47])[CH2:35][CH2:36][C:37]([NH:23][CH2:22][C:19]1[CH:20]=[CH:21][C:7]2[NH:6][C:5]3[S:24][C:2]([CH3:1])=[CH:3][C:4]=3[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[N:9][C:8]=2[CH:18]=1)=[O:38]
Reactant: COC(=O)CCC(=O)ON1C(=O)CCC1=O
Reactant: Cc1cc2c(s1)Nc1ccc(CN)cc1N=C2N1CCN(C)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCC(=O)NCc1ccc2c(c1)N=C(N1CCN(C)CC1)c1cc(C)sc1N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2-methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thieno[2,3-e][1,4]diazepin-7-yl)methanamine, prepared as described in Example 3, (40 mg, 0.12 mmol) in dichloromethane (2 mL) was added triethylamine (0.030 mL, 0.22 mmol) and succinic acid 2,5-dioxo-pyrrolidin-1-yl ester methyl ester, prepared as described in the previous step, (31 mg, 0.13 mmol). The solution was stirred at room temperature for 1 hour and concentrated. The crude was loaded onto a silica column, eluted with 3-5% methanol/dichloromethane containing ammonium hydroxide to give the title compound as a yellow solid. LC-MS: m/z 456 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]3[CH:24]=[CH:23][NH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:12][C:9]21[CH2:11][CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1C2CCC1CNC2)=O)(C)(C)C.C(OC(N1CCNCC21CC2)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH:9]2[CH2:10][CH2:11][CH:15]1[CH2:14][N:13]([C:16]1[C:17]3[CH:24]=[CH:23][NH:22][C:18]=3[N:19]=[CH:20][N:21]=1)[CH2:12]2)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Agent: CC(C)(C)OC(=O)N1C2CCC1CNC2
Agent: CC(C)(C)OC(=O)N1CCNCC12CC2
Product: CC(C)(C)OC(=O)N1C2CCC1CN(c1ncnc3[nH]ccc13)C2

Procedure:
Prepared in a way similar to Intermediate 1, using 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, instead of 4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:14][C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][CH:21]2[O:23][CH2:22]2)=[CH:17][CH:16]=1>C(O)(C)C>[Cl:14][C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][CH:21]([OH:23])[CH2:22][N:11]2[CH2:10][CH2:9][N:8]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[CH2:13][CH2:12]2)=[CH:17][CH:16]=1
Reactant: Clc1ccc(OCC2CO2)cc1
Reactant: Fc1cccnc1N1CCNCC1
Solvent: CC(C)O
Product: OC(COc1ccc(Cl)cc1)CN1CCN(c2ncccc2F)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
To 1-(3-fluoro-2-pyridyl)piperazine (453 mg, 2.5 mmol) in 5 ml of isopropanol stirred under nitrogen at 70° C. was added 4-chlorophenoxy-2,3-epoxypropane (476 mg, 2.5 mmol) portionwise and the solution stirred at 70° C. for 3 hours The solution was concentrated in vacuo and the residual oil chromatographed on silica gel eluting with 5% methanol-chloroform to yield 740 mg (81%) of 1-[3-(4-chlorophenoxy)-2-hydroxypropyl]-4-(3-fluoro-2-pyridyl]piperazine; m.p. 73°-76° C. Analysis satisfactory for C18H21ClFN3O2.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][CH:5]=[C:4]2[N:8]([C@@H:11]3[O:33][C@H:32]([CH2:34][O:35]C(=O)C4C=CC=CC=4)[C@@H:22]([O:23]C(=O)C4C=CC=CC=4)[C@@:12]3([CH3:44])[O:13]C(=O)C3C=CC=CC=3)[CH:9]=[N:10][C:3]=12.[NH3:45]>CO>[NH2:45][C:2]1[N:7]=[N:6][CH:5]=[C:4]2[N:8]([C@@H:11]3[O:33][C@H:32]([CH2:34][OH:35])[C@@H:22]([OH:23])[C@@:12]3([CH3:44])[OH:13])[CH:9]=[N:10][C:3]=12
Reactant: C[C@@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cnc2c(Cl)nncc21
Reactant: N
Solvent: CO
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)nncc21

Procedure:
The compound from Step B (590 mg, 0.96 mmol) was added to a solution of ammonia in methanol and stirred in a steel bomb at 150° C. for 6 hours. The reaction mixture was evaporated to dryness to remove methanol. The crude product was purified on silica gel reverse-phase (C18) using water as eluant to give the title compound (35 mg) as a white powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH:14]([CH3:16])[CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:20]1[O:21][C:22]2[C:23](=[C:25]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:27][CH:28]=2)[N:24]=1>COCCOC>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:20]2[O:21][C:22]3[C:23](=[C:25]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:27][CH:28]=3)[N:24]=2)[C@@H:10]([CH:14]([CH3:16])[CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H]1CN(Cc2ccccc2)CCN1
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1cccc2oc(N3CCN(Cc4ccccc4)C[C@@H]3C(C)C)nc12
Reaction time: 1 h
Yield: 54.3 %

Procedure:
To a solution of (2S)-4-benzyl-2-isopropylpiperazine (363 mg, 1.66 mmol) in 1,2-dimethoxyethane (10 mL) at room temperature, was added NaH (80 mg, 1.66 mmol, 60% suspension in mineral oil) and the mixture was stirred for 1 h. Methyl 2-chlorobenzoxazole-4-carboxylate (351 mg, 1.66 mmol) was added to the reaction mixture and the reaction was stirred at room temperature for 17 h. The reaction mixture was quenched with CH3OH (10 mL), silica gel (15 mL) was added, and solvent removed under reduced pressure. The mixture was purified by column chromatography (silica gel, 0 to 100% EtOAc in hexanes) to afford (S)-methyl 2-(4-benzyl-2-isopropylpiperazin-1-yl)benzoxazole-4-carboxylate (355 mg, 54%) as a pale yellow oil. MS consistent.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:12]1[CH:16]=[C:15]([NH:17][C:18](=[O:26])OC2C=CC=CC=2)[N:14]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[N:13]=1)([CH3:11])([CH3:10])[CH3:9].[CH2:34]([C:36]1[N:41]=[C:40]([NH:42][C:43]2[CH:48]=[C:47]([CH2:49][O:50][C:51]3[C:60]4[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=4)[C:54]([NH:61]C(=O)OC(C)(C)C)=[CH:53][CH:52]=3)[CH:46]=[CH:45][N:44]=2)[CH:39]=[N:38][CH:37]=1)[CH3:35]>C1COCC1>[C:8]([C:12]1[CH:16]=[C:15]([NH:17][C:18]([NH:61][C:54]2[C:55]3[C:60](=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:51]([O:50][CH2:49][C:47]3[CH:46]=[CH:45][N:44]=[C:43]([NH:42][C:40]4[CH:39]=[N:38][CH:37]=[C:36]([CH2:34][CH3:35])[N:41]=4)[CH:48]=3)=[CH:52][CH:53]=2)=[O:26])[N:14]([C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)[N:13]=1)([CH3:10])([CH3:11])[CH3:9]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Reactant: CCc1cncc(Nc2cc(COc3ccc(NC(=O)OC(C)(C)C)c4ccccc34)ccn2)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1cncc(Nc2cc(COc3ccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C)cc4)c4ccccc34)ccn2)n1
Temperature: 40 °C
Reaction time: 0.67 h

Procedure:
Triethylamine (0.013 mL, 0.093 mmol) was added to a solution of phenyl (3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)carbamate (Intermediate B) (0.042 g, 0.121 mmol) and N-(4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)-6-ethylpyrazin-2-amine (Intermediate D) (0.093 g, 0.250 mmol) in THF (1.5 mL) at 40° C. The reaction mixture was stirred at 40° C. for 40 min then cooled to RT and stirred for 3 days, and then concentrated in vacuo. The crude product was purified by silica gel chromatography (12 g column, 0 to 5% MeOH in DCM) to give an off white-brown solid. The product was re-purified by preparative HPLC (Gilson, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 45-75% MeCN in Water) to afford the title compound 1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea as an off white solid (0.029 g, 49%); Rt 2.26 min (Method 1); m/z 627 (M+H)+ (ES+), 625 (M−H)− (ES−); 1H NMR δ: 1.18 (3H, t), 1.28 (9H, s), 2.40 (3H, s), 2.63 (2H, q), 5.36 (2H, s), 6.36 (1H, s), 7.02 (1H, d), 7.07 (1H, dd), 7.37 (2H, m), 7.45 (2H, m), 7.56-7.67 (3H, overlapping m), 7.94 (1H, m), 7.99 (1H, s), 8.02 (1H, s), 8.30 (1H, d), 8.39 (1H, m), 8.60 (1H, s), 8.81 (1H, s), 8.92 (1H, s), 10.08 (1H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:13]1[C:25]2[CH:24]([CH2:26][O:27][C:28]([NH:30][CH2:31][CH2:32][OH:33])=[O:29])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:33][CH2:32][CH2:31][NH:30][C:28]([O:27][CH2:26][CH:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:25]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:29])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(NCCO)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCOC(=O)c1ccc([N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To a solution of 4-nitrobenzoylchloride (4.0 g, 21.6 mmoles) and N-(9-fluorenyl-methoxycarbonyl)ethanolamine (7.3 g, 25.9 mmoles) in 160 ml of methylene chloride is added triethylamine (3.1 ml, 22.6 mmoles). The mixture is stirred at room temperature for one hour, then is diluted with 400 ml of methylene chloride. The organic solution is washed with two portions of 200 ml of water and one portion of 200 ml of a saturated aqueous solution of sodium chloride. The organic phase is dried with Na2SO4, filtered and concentrated in vacuo. The resulting pale yellow solid is triturated in ethyl acetate. Filtration afforded 7.347 g of the title compound (79%). 400 MHz 1H NMR (DMSO-d6) δ: 8.32 (d, J=8.4 Hz, 2H), 8.20 (d, J=8.8 Hz, 2H), 7.87 (d, J=7.3 Hz, 2H), 7.66 (d, J=7.3 Hz, 2H), 7.61 (t, J=5.7 Hz, 1H), 7.39 (t, J=7.5 Hz, 2H), 7.28 (t, J=7.5 Hz, 2H), 4.4-4.3 (m, 4H), 4.20 (t, J=6.8 Hz, 1H), 3.45-3.35 (m, 2H). LCMS: 433 [M+H].
Reaction SMILES: [F:1][C:2]1[C:7](O)=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[NH:10]C(=O)OC.C1(C)C=CC(S([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)(=O)=O)=CC=1.[OH-].[K+].Cl>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([Cl:9])[C:5]([O:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)=[CH:4][C:3]=1[NH2:10]
Reactant: Cc1ccc(S(=O)(=O)OC2CCCCC2)cc1
Reactant: COC(=O)Nc1ccc(Cl)c(O)c1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Nc1cc(OC2CCCCC2)c(Cl)cc1F
Temperature: 80 °C
Reaction time: 4 h
Yield: 25.6 %

Procedure:
Methyl N-(2-fluoro-4-chloro-hydroxyphenyl)carbamate (2.03 g, 9.23 mmol), cyclohexyl p-toluenesulfonate (2.51 g, 9.85 mmol) and N,N-dimethylformamide (30 ml) were charged into a 100 cc round-bottom flask, and then potassium hydroxide (1.0 g, 17.8 mmol) in a powder form was added thereto. The mixture was stirred for 4 hours on an oil bath at 80° C. After completion of the reaction, the reaction solution was cooled to room temperature, 1N hydrochloric acid (100 ml) was added thereto, and the mixture was extracted with ethyl acetate (20 ml×8). The organic layers were combined, washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off under reduced pressure to obtain a crude product. The product was isolated and purified by silica gel column chromatography (development solvent: hexane/ethyl acetate=9/1) to obtain 2-fluoro-4-chloro-5-cyclohexyloxyaniline (574 mg, 2.36 mmol, 26% yield) and the unreacted starting material, methyl N-(2-fluoro-4-chloro-5-hydroxyphenyl)carbamate (1.22 g, 5.54 mmol, 60% recovery ratio). The spectral data and the like are as shown in Reference Example 11.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C(C)=CC=CN=1.C(O)(=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C=CCCCC.C1(C)C=CC=CC=1>>[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])[CH2:22][CH2:23][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=Cc1ccccc1
Reactant: O=C(O)c1ccccc1
Agent: Cc1cccnc1N
Solvent: C=CCCCC
Solvent: Cc1ccccc1
Product: CCCCCCC(=O)c1ccccc1
Temperature: 130 °C
Reaction time: 0.04 h

Procedure:
Under the same reaction procedure and conditions as in Example 1 (benzaldehyde 0.5 mmol, 2-amino-3-picoline 0.1 mmol, bezoic acid 0.03 mmol, 1-hexene 2.5 mmol, toluene 0.87 mmol), various kinds of amines 0.3 mmol as shown in the following table 5, were added to each 500 ml pressure reactor. The mixture was stirred at normal temperature for 2-3 minutes and then combined with Rh(PPh3)3Cl 0.01 mmol. While the reactor was stopped with a stopper, the reactants were heated at 130° C. for 1 hour with stirring. After completion of the reaction, column chromatography was conducted to determine the yields of heptanophenone, products according to various amines. The results are given in Table 5, below.
Reaction SMILES: [C:1]([C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Br:12]Br.O>C(O)C>[Br:12][CH2:2][C:1]([C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5]1)=[O:3]
Reactant: BrBr
Reactant: CCOC(=O)C1(C(C)=O)CC1
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1(C(=O)CBr)CC1
Temperature: 30 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
Ethyl 1-acetylcyclopropanecarboxylate (200 g, 1.28 mol) was dissolved in ethanol (1000 ml), and bromine (72.7 ml, 1.41 mol) was added dropwise while stirring and cooling with ice. After completion of dripping, the temperature of the reaction solution was raised to 30° C. and stirring was performed for 2 hours. After adding water (1000 ml) to the reaction solution while cooling with ice, it was concentrated under a reduced pressure was performed. After extracting the concentrate into ethyl acetate (750 ml×2), it was washed with a 10% aqueous sodium thiosulfate solution (500 ml×2) and saturated sodium bicarbonate water (500 ml×2) in that order and then dried over anhydrous sodium sulfate. After filtering and concentrating the filtrate under a reduced pressure, 291 g (97%) of the title compound was obtained as a yellow, oily substance.