Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[NH:7][C:8](=[O:16])[CH2:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:4].C(N(CC)CC)C.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:33](Cl)=[O:34]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[NH:7][C:8](=[O:16])[CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:30]([O:29][CH3:28])[CH:31]=2)[CH2:12][CH2:11]1)=[O:4]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: COC(=O)c1ccccc1NC(=O)CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccccc1NC(=O)CN1CCN(C(=O)c2ccc(OC)c(OC)c2)CC1
Reaction time: 1 h

Procedure:
6.5 Grams of o-methoxycarbonyl-α-(1-piperazinyl)acetanilide and 2.4 g of triethylamine were dissolved in 50 ml of methylene chloride, then a methylene chloride solution containing 5.4 g of 3,4-dimethoxybenzoyl chloride was added dropwise thereto under ice-cooled condition with stirring. The reaction was continued at the same temperature for 1 hour, then the reaction mixture was washed with water, 5%-sodium bicarbonate aqueous solution, next with potassium carbonate aqueous solution, and was dried. Methylene chloride was removed by distillation, the residue obtained was crystallized by adding ethyl acetate, the crystals formed were collected by filtration. Recrystallized from ethanol to obtain 7.5 g of o-methoxycarbonyl-α-[4-(3,4-dimethoxy-benzoyl)-1-piperazinyl]acetanilide in the form of colorless needle-like crystals. Melting point: 167.5°-169° C.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH2:14]1CCN2C(=NCCC2)CC1.IC.O>CN(C=O)C>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(O)c1ccc(I)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1ccc(I)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.8 %

Procedure:
To a solution of 4-iodo-2-nitrobenzoic acid (2.3 g, 7.9 mmol) in DMF (30 mL) was added DBU (2.4 mL, 16 mmol) followed by iodomethane (1.5 mL, 24 mmol). The reaction mixture was allowed to stir at 0° C. for 15 min, then slowly allowed to warm to rt and to stir overnight. After 12 h, the reaction mixture was poured into 200 mL of H2O and extracted with EtOAc (2×100 mL). The organic solutions were combined, washed with H2O (2×100 mL), dried over Na2SO4, filtered and concentrated to give methyl 4-iodo-2-nitrobenzoate (2.3 g, 96%).
Reaction SMILES: [N:1]1C=CC=C(CNC(C2(CC3C=CC=CC=3)CCNCC2)=O)C=1.Cl.C(OC([N:32]1[CH2:37][CH2:36][C:35]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)([C:38]([OH:40])=O)[CH2:34][CH2:33]1)=O)(C)(C)C.[CH2:49]([NH2:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>>[CH2:49]([NH:56][C:38]([C:35]1([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=2)[CH2:34][CH2:33][NH:32][CH2:37][CH2:36]1)=[O:40])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.[NH3:1]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(F)cc2)(C(=O)O)CC1
Reactant: NCc1ccccc1
Reactant: O=C(NCc1cccnc1)C1(Cc2ccccc2)CCNCC1
Agent: Cl
Product: N
Product: O=C(NCc1ccccc1)C1(Cc2ccc(F)cc2)CCNCC1

Procedure:
In analogy to the procedure described for the synthesis of 4-benzyl-piperidine-4-carboxylic acid (pyridin-3-ylmethyl)-amide; hydrochloride (intermediate 1) the title compound was prepared from 4-(4-fluoro-benzyl)-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (commercially available) and benzylamine (commercially available) with subsequent cleavage of the protecting group under acidic conditions. The title compound was purified on silica eluting with a gradient formed from DCM and 2N NH3 and methanol. MS (m/e): 220.2/327.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:9]2[CH2:8][CH2:7][C:6]3[CH:22]=[CH:23][CH:24]=[CH:25][C:5]=3[C:4]=2[N:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.C(OCC)(=O)C>C1COCC1>[NH2:13][CH2:12][C:11]1[C:2]([NH2:1])=[N:3][C:4]2[C:5]3[CH:25]=[CH:24][CH:23]=[CH:22][C:6]=3[CH2:7][CH2:8][C:9]=2[C:10]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21]
Reactant: N#Cc1c(N)nc2c(c1-c1ccc(Cl)cc1Cl)CCc1ccccc1-2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NCc1c(N)nc2c(c1-c1ccc(Cl)cc1Cl)CCc1ccccc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an atmosphere of argon, a solution of 2-amino-4-(2,4-dichloro-phenyl)-5,6-dihydro-benzo[h]quinoline-3-carbonitrile (200 mg, 0.58 mmol) in THF (1 ml) is added slowly to a suspension of LiAlH4 (162 mg, 4.26 mmol) in THF (1 ml). After stirring for 2 h at room temperature, the reaction mixture is cooled to −20° C. and water (0.2 ml) is added. After 15 min, ethyl acetate is added and the mixture is filtered through Decalite. The organic phase is then separated, washed with water, and dried over sodium sulfate. Purification by flash chromatography (silica gel, methanol, dichloromethane) affords the title compound, MS: m/e=369.9 (M+H+), as a light yellow solid (53 mg, 26%).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([OH:32])=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][CH2:38][C@H:39]([OH:41])[CH3:40]>>[OH:41][C@H:39]([CH3:40])[CH2:38][NH:37][C:30](=[O:32])[C:29]1[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=1[S:27][CH2:26][C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=2[CH:23]=[CH:24][C:15]=1[O:14][C@@H:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C[C@@H](O)CN
Reactant: O=C(O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Product: C[C@@H](O)CNC(=O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 57.6 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and (R)-1-amino-2-propanol (23 mg, 0.30 mmol, 0.6M in DMF) were combined to give 32 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 556 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([F:23])=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1.CCCCCC>O1CCOCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:10]2[C:19]3[C:14](=[CH:15][C:16]([F:23])=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=[N+]([O-])c1cc2c(Cl)ncnc2cc1F
Solvent: C1COCCO1
Solvent: CCCCCC
Solvent: ClCCl
Product: O=[N+]([O-])c1cc2c(Nc3cccc(Cl)c3)ncnc2cc1F
Reaction time: 0.25 h

Procedure:
A solution of 2.76 ml of 3-chloroaniline in 7 ml of dioxan is added dropwise to 5.0 g of 4-chloro-7-fluoro-6-nitro-quinazoline in 40 ml of methylene chloride at 15° C. within 15 minutes. The reaction mixture is stirred for a further 15 minutes at this temperature before being poured onto 100 ml of n-hexane for working up. The mixture is stirred for about one hour while cooling with an ice bath, then the precipitate formed is filtered off. The hydrochloride thus obtained is suspended in 30 ml of methanol, made alkaline with triethylamine while cooling with an ice bath and combined with 100 ml of water. The precipitate formed is suction filtered and washed with water. The crude product is purified by chromatography on a silica gel column with methylene chloride/methanol (20:1) as eluant. Yield: 3.50 g (50% of theory), Melting point: 223-225° C. Mass spectrum (ESI*): m/z=319, 321 [M+H]*
Reaction SMILES: [N+]([O:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=[CH:17][C:10]=2[O:9][CH2:8]1)([O-])=O.[H][H].O>CO.[Pd]>[NH2:18][C:15]1[CH:16]=[CH:17][C:10]2[O:9][CH2:8][N:7]([CH2:6][CH2:5][OH:4])[C:12](=[O:13])[C:11]=2[CH:14]=1
Reactant: O=C1c2cc([N+](=O)[O-])ccc2OCN1CCO[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CO
Product: Nc1ccc2c(c1)C(=O)N(CCO)CO2
Yield: 97.4 %

Procedure:
A solution of 42 g (0.148 mole) of the compound of Example 1 in 6,300 ml of methanol was combined with 10% Pd/C, and the resulting mixture was placed in a hydrogen atmosphere having a head of water, at room temperature. At the end of the reaction, the suspension was filtered on celite and the solution obtained was evaporated under vacuum. The resulting crude product was taken up with ethyl ether and filtered under vacuum, thus yielding 30 g of 6-amino-2,3-dihydro-3-(2'-hydroxyethyl)-4H-1,3-benzoxazin-4-one. m.p. 94°-96° C. (ethyl ether).
Reaction SMILES: [CH2:1]([CH:8]1[O:12][C:11](=[O:13])[N:10]([CH2:14][CH2:15][CH:16](O)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O.O>ClCCl>[CH2:1]([CH:8]1[O:12][C:11](=[O:13])[N:10]([CH2:14][CH2:15][CH:16]([Cl:26])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1OC(Cc2ccccc2)CN1CCC(O)c1ccccc1
Solvent: ClCCl
Solvent: O
Product: O=C1OC(Cc2ccccc2)CN1CCC(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.1 %

Procedure:
5-Benzyl-3-(3-hydroxy-3-phenylpropyl)-1,3-oxazolidine-2-one (0.31 g, 1 mmol) prepared in the above (2) was dissolved in dichloromethane (3 ml). To the solution, thionyl chloride (0.08 ml, 1.1 mmol) was added and stirred at room temperature for 30 minutes. After water was added, the obtained solution was extracted with ethyl acetate. The organic portion was sequentially washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, and then dried over sodium sulfate. The solvent was then removed by distillation under reduced pressure to obtain 0.34 g of the titled compound as a colorless oil (yield: 100%).
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11]([O:18][C:19]([C:21]1[S:22][C:23]([CH3:27])=[C:24]([NH2:26])[CH:25]=1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1.C(OCC)C>[CH2:11]([O:18][C:19]([C:21]1[S:22][C:23]([CH3:27])=[C:24]([NH:26][C:9]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH:25]=1)=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C=NCc1ccccc1
Reactant: Cc1sc(C(=O)OCc2ccccc2)cc1N
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1sc(C(=O)OCc2ccccc2)cc1NC(=O)NCc1ccccc1
Reaction time: 0.33 h
Yield: 65.7 %

Procedure:
Benzyl isocyanate (0.29 g, 2.2 mmol) was added to a stirred solution of 5-methyl-4-amino-thiophene-2-carboxylic acid benzyl ester from Example 9, Step 2 (0.5 g, 2.0 mmol) in toluene (10-15 mL) at room temperature under an inert atmosphere. After 20 minutes, the mixture was heated to reflux for 10 minutes, allowed to cool, then diluted with an equal volume of diethyl ether. After 10 minutes, the precipitate was filtered off, rinsed with ether, and dried to afford 0.5 g of 4-(3-benzyl-ureido)-5-methyl-thiophene-2-carboxylic acid benzyl ester; mp 208-209° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:7].C(N(C(C)C)CC)(C)C.[Cl:37][C:38]1[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[C:39]=1[C:40](Cl)=[O:41]>ClCCl>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:40]([C:39]2[C:38]([Cl:37])=[CH:46][CH:45]=[CH:44][C:43]=2[Cl:47])=[O:41])=[CH:24][CH:25]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])[CH2:9][CH2:10][CH2:11][CH2:12]1)=[S:7]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=S)C1(CCNC(C)=O)CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=S)C1(CCNC(C)=O)CCCC1
Yield: 106.7 %

Procedure:
To a solution of 4-amino-N-[[1-[2-(acetylamino)ethyl]cyclopentyl]thioxomethyl]-L-phenylalanine methyl ester (195 mg, 0.498 mmol) and diisopropylethylamine (0.0950 mL, 0.548 mmol) in dichloromethane (1 mL) was added a solution of 2,6-dichlorobenzoyl chloride (110 mg, 0.523 mmol) in dichloromethane (1 mL). The resultant mixture was stirred overnight then was concentrated in vacuo and transferred to a separatory funnel containing ethyl acetate (50 mL) and water (10 mL). The separated aqueous layer back-extracted with ethyl acetate (1×25 mL). The combined organic layer was washed in turn sat. solution of Na2CO3 and brine, then was dried over MgSO4, filtered and concentrated in vacuo to provide crude N-[[1-[2-(acetylamino)ethyl]cyclopentyl]thioxomethyl]-4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester (300 mg).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][OH:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.Cl[C:24](OC1C=CC([N+]([O-])=O)=CC=1)=[O:25].[NH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>O>[CH:11]1[C:12]2[C:7](=[CH:6][C:5]3[C:14]([C:13]=2[CH2:15][O:16][C:24]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[O:25])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OCc1c2ccccc2cc2ccccc12
Reactant: C1CNCCN1
Solvent: O
Solvent: c1ccncc1
Product: O=C(OCc1c2ccccc2cc2ccccc12)N1CCNCC1

Procedure:
PAC is produced by adding 9-anthacenemethanol and pyridine to a solution of p-nitrophenyl chloroformate. Product is isolated to provide a crude anthrylmethyl p-nitrophenyl carbonate, which is then added to a solution of piperazine. The reacted mixture is poured into water and extracted with a solvent, preferably an organic solvent such as toluene. The product is washed and dried to provide 9-anthracenylmethyl-1-piperazinecarboxylate (PAC).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:10][S:11]([NH:14][C:15]1[CH:24]=[CH:23][C:18]([C:19](=[O:22])[CH2:20]Br)=[CH:17][CH:16]=1)(=[O:13])=[O:12].C(N(CC)CC)C>C(O)C>[CH3:10][S:11]([NH:14][C:15]1[CH:24]=[CH:23][C:18]([C:19](=[O:22])[CH2:20][N:2]([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH3:1])=[CH:17][CH:16]=1)(=[O:13])=[O:12]
Reactant: CNCc1ccccc1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CBr)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(CC(=O)c1ccc(NS(C)(=O)=O)cc1)Cc1ccccc1

Procedure:
N-Methylbenzylamine (22.43 g), 4-methanesulphonamidophenacyl bromide (50 g) (see J. Med. Chem. 1966, 9, 88) and triethylamine (17 g) in ethanol (500 ml) were stirred at room temperature for 18 hours. The solvent was removed, the residue was taken up in dilute hydrochloric acid, washed with ethyl acetate and the organic layer was discarded. The aqueous layer was neutralised with sodium bicarbonate and then extracted three times with ethyl acetate. The combined organic extracts were evaporated and the residue chromatographed on silica [Merck `Kieselgel 60` (Trade Mark)] eluting with hexane containing ethyl acetate (0% up to 100%). The title compound was obtained as an oil by collection and evaporation of appropriate fractions. The oil solidified when triturated with ether, yield of the title compound 32 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([S:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=[CH:4][N:5]=1)[C:10]#[C:11][CH3:12]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: Sc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC#CCOc1cc(Sc2ccccc2)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.3 %

Procedure:
To 5 ml of chloroform were added 0.57 ml of triethylamine and 0.5 g of 4-chloro-6-(2-butynyloxy)pyrimidine, to which 0.6 ml of a chloroform solution containing 0.33 g of thiophenol was slowly added dropwise, followed by stirring at room temperature for 8 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined. washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.22 g of 4-(2-butynyloxy)-6-(thiophenoxy)pyrimidine (the present compound (97)).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl-].[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[NH2:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41]([C:46]([NH:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([Cl:56])=[C:52]([O:57][C:58]3[CH:63]=[C:62]([C:64]#[N:65])[CH:61]=[C:60]([Cl:66])[CH:59]=3)[C:51]=1[F:67])=[O:47])=[CH:40]2.[N:68]1([CH2:74][CH2:75][C:76](O)=[O:77])[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[Cl:56][C:53]1[CH:54]=[CH:55][C:50]([CH2:49][NH:48][C:46]([C:41]2[NH:42][C:43]3[C:39]([CH:40]=2)=[CH:38][C:37]([NH:36][C:76](=[O:77])[CH2:75][CH2:74][N:68]2[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]2)=[CH:45][CH:44]=3)=[O:47])=[C:51]([F:67])[C:52]=1[O:57][C:58]1[CH:63]=[C:62]([C:64]#[N:65])[CH:61]=[C:60]([Cl:66])[CH:59]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(N)ccc4[nH]3)c2F)c1
Reactant: O=C(O)CCN1CCCCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(NC(=O)CCN5CCCCC5)ccc4[nH]3)c2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
BOP chloride (0.079 g, 0.309 mmol) was added to a solution of 5-amino-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-indole-2-carboxamide trifluoroacetate (0.060 g, 0.103 mmol), 3-(1-piperidinyl)propanoic acid (0.0162 g, 0.103 mmol) and diisopropylethylamine (0.090 mL, 0.514 mmol) in DMF (1 mL). The mixture was stirred at room temperature for 1 hr. The reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was purified by reverse phase HPLC (acetonitrile:water with 0.% trifluoroacetic acid) to give 0.032 g (43%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.56 (br. s., 1H), 10.01 (br. s., 1H), 9.01-9.18 (m, 1H), 8.97 (d, 1H), 7.92 (br. s., 1H), 7.68-7.84 (m, 1H), 7.40-7.56 (m, 2H), 7.27-7.41 (m, 2H), 7.15-7.28 (m, 1H), 7.08 (s, 1H), 4.36-4.68 (m, 2H), 3.22-3.48 (m, 4H), 2.67-2.98 (m, 4H), 1.72-1.87 (m, 2H), 1.48-1.71 (m, 3H), 1.20-1.43 (m, 1H). ES MS: m/z 608 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)=O)(C)(C)C.[ClH:21]>C1COCC1.O1CCOCC1>[ClH:21].[ClH:21].[CH3:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN1CCN(C(=O)OC(C)(C)C)CC1c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CN1CCNCC1c1ccccc1
Reaction time: 8 h

Procedure:
To a mixture of tert-butyl 3-phenylpiperazine-1-carboxylate (288 mg, 1.1 mmol), and formaldehyde (185 mg, 6.16 mmol) in methanol (7 mL) was added sodium triacetoxyborohydride (949 mg, 4.48 mmol) at 0° C. After stirring for 3 h at room temperature, the reaction mixture was diluted with 10% sodium bicarbonate solution and ethyl acetate. The aqueous part was extracted with ethyl acetate and the combined organic part was dried over sodium sulfate, filtered, concentrated in vacuo. The residue was purified by flash chromatography (20/1 dichloromethane/methanol) to provide 4-methyl-3-phenyl-piperazine-1-carboxylic acid tert-butyl ester (307 mg, 101%). (M+H)+=277 m/e. To a solution of 4-methyl-3-phenyl-piperazine-1-carboxylic acid tert-butyl ester (307 mg, 1.11 mmol) in THF (3 mL) at 0° C. was added 4M HCl in dioxane (0.9 mL). The reaction mixture was stirred overnight and concentrated in vacuo. The residue was triturated with dichloromethane and filtered to provide 1-methyl-2-phenyl-piperazine dihydrochloride (290 mg), which was used as is for the next step.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].Cl.[CH2:10]([O:12][C:13](=N)[CH3:14])[CH3:11].C([O-])([O-])=O.[K+].[K+]>C(OCC)C>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][N:7]=[C:10]([O:12][CH2:13][CH3:14])[CH3:11])[CH3:3]
Reactant: CCOC(C)=N
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCOC(=O)CN=C(C)OCC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 71.5 %

Procedure:
17.140 g (0.123 mol) of aminoacetic acid ethyl ester hydrochloride and 15.175 g (0.123 mol, 1 eq) of acetimidic acid ethyl ester hydrochloride were stirred in solution in 300 mL ice cold water. 200 mL diethyl ether and then 16.97 g (0.123 mol, 1 eq) K2CO3 were added. The reaction mixture was stirred for 10 minutes. The organic phase was separated and dried over Na2SO4, filtered and evaporated to dryness to yield to 15.229 g (72%) of (1-ethoxy-ethylideneamino)-acetic acid ethyl ester as a light yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].Br[CH2:15]/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=1>C(OCC)(=O)C.CCCCCC>[CH:24]([C:21]1[CH:20]=[CH:19][C:18](/[CH:17]=[CH:16]/[CH2:15][O:1][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=2[CH3:13])=[CH:23][CH:22]=1)([CH3:26])[CH3:25]
Reactant: CC(C)c1ccc(/C=C/CBr)cc1
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(OC/C=C/c2ccc(C(C)C)cc2)c(C)c(C)c1NC=O
Yield: 59 %

Procedure:
By using N-(4-hydroxy-2,3,6-trimethylphenyl)formamide and 1-[(E)-3-bromo-1-propenyl]-4-isopropylbenzene, the title compound was synthesized according to Reference Example 17a. Yield: 59%. Melting point: 165-167° C. (Ethyl acetate-hexane).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[F:8][C:5]1[CH:4]=[N:3][C:2]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]2)=[N:7][CH:6]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: OCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: OCC1CCN(c2ncc(F)cn2)CC1
Temperature: 100 °C
Yield: 95.3 %

Procedure:
A solution of 2-chloro-5-fluoropyrimidine (1.1 g, 8.05 mmol) and 4-piperidinemethanol (1.14 g, 9.66 mmol) in DMSO (20 mL) was treated with K2CO3 (2.23 g, 16.10 mmol). The reaction mixture was heated at 100° C. overnight. The mixture was cooled to ambient temperature and poured into water and extracted with CH2Cl2 (60 mL×3). The organic extracts were combined and washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give crude product as a brown oil. The crude product was purified by chromatography on an ISCO silica gel column using 0 to 40% EtOAc/hexanes to give 1.62 g (95%) of [1-(5-fluoro-2-pyrimidinyl)-4-piperidinyl]methanol as a white solid upon standing. 1H NMR (400 MHz, CDCl3): δ 8.18 (s, 2H), 4.75-4.65 (m, 2H), 3.51 (d, 2H, J=6.1 Hz), 2.95-2.80 (m, 2H), 1.85-1.70 (m, 3H), 1.30-1.15 (m, 2H); LRMS (ESI), m/z 212 (M+H).