Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].C[OH:22].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[CH2:23]([O:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[CH:1]=[O:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cccc(Cc2ccccc2)c1
Reactant: CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=Cc1cccc(OCc2ccccc2)c1

Procedure:
To a solution of 3-hydroxylbenzaldehyde 31 (5.0 g, 40 mmol) and K2CO3 (27.2 g, 197 mmol) in 200 ml CHCl3: 100 ml MeOH was added benzylbromide (5.9 ml, 49 mmol). The suspension was refluxed under nitrogen overnight. The solvent was removed by evaporation and the resulting oil was taken up in DCM and washed with water and brine and dried (Na2SO4). The crude product was purified by column chromatography to yield the product as a viscous oil which solidified upon sitting (8.48 g, 40 mmol, 98%). m.p. 46°. 1H NMR (500 MHz, CDCl3) δ 9.97 (s, 1H), 7.48-7.25 (m, 9H), 5.13 (s, 2H). 13C NMR (125 MHz, CD3OD) δ 191.8, 159.2, 137.8, 136.3, 130.0, 128.6, 128.1, 127.5, 123.41, 121.9, 113.3, 70.0. HRMS (EI) m/e calcd for C14H12O2: 212.08373, found: 212.0827.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([O:19][CH3:20])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:21]N(C=NC=[N+](C)C)C.[Cl-].C([O-])(=O)C.[Na+].C(O)(=O)C>O1CCOCC1>[CH2:12]([O:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:6][CH:21]=[N:1]2)=[CH:7][C:8]=1[O:19][CH3:20])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CN(C)C=NC=[N+](C)C
Reactant: COc1cc(C(N)=O)c(N)cc1OCc1ccccc1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Yield: 77 %

Procedure:
A mixture of 2-amino-4-benzyloxy-5-methoxybenzamide (10 g, 0.04 mol), (J. Med. Chem. 1977, vol 20, 146-149), and Gold's reagent (7.4 g, 0.05 mol) in dioxane (100 ml) was stirred and heated at reflux for 24 hours. Sodium acetate (3.02 g, 0.037 mol) and acetic acid (1.65 ml, 0.029 mol) were added to the reaction mixture and it was heated for a further 3 hours. The volatiles were removed by evaporation, water was added to the residue, the solid was collected by filtration, washed with water and dried. Recrystallisation from acetic acid gave 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (8.7 g, 84%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](N)[CH:7]=[CH:6][C:5]=1[Cl:11].[C:13]([Cu])#[N:14].[C-]#N.[K+]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([C:13]#[N:14])[CH:7]=[CH:6][C:5]=1[Cl:11]
Reactant: N#C[Cu]
Reactant: COC(=O)c1cc(N)ccc1Cl
Agent: [C-]#N
Agent: [K+]
Product: COC(=O)c1cc(C#N)ccc1Cl

Procedure:
5-Amino-2-chloro-benzoic acid methyl ester (10 g, 54 mmol) was diazotized followed by treatment with CuCN and KCN using the procedure described in example 165 to get the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([OH:24])([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)C.C(O)(=O)C.[OH-].[Na+]>[Pd].O>[OH:24][C:11]1([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: OC1(c2ccc(C(F)(F)F)cc2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: OC1(c2ccc(C(F)(F)F)cc2)CCNCC1

Procedure:
A mixture of 10.0 g. (0.03 mol) of 1-benzyl-4-hydroxy-4-(α,α,α-trifluoro-p-tolyl)piperidine and 1.0 g. of 10% Pd/C in 100 ml. of ethanol containing 2.0 ml. of acetic acid is shaken under hydrogen. The mixture is filtered and the filtrate is evaporated to give a white solid which is dissolved in 50 ml. of water and rendered alkaline by addition of 1N NaOH solution. Filtration gives white crystals, m.p. 136°-138°C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:3]1.[OH-].[K+].Br[CH2:21][CH2:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1>CS(C)=O.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:21][CH2:22][O:23][C:24]3[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)=[CH:3]1
Reactant: Cn1cc(CN2CCNCC2)c2ccccc21
Reactant: O=Cc1ccc(OCCBr)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cn1cc(CN2CCN(CCOc3ccc(C=O)cc3)CC2)c2ccccc21
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
A suspension of 1-(1-methylindole-3-ylmethyl)piperazine (1.3 g) in dimethylsulfoxide (15 ml) and potassium hydroxide (0.63 g) was stirred for 30 min under nitrogen at 22° C. and then a solution of 4-[2-bromoethoxy]benzaldehyde (1.3 g) was added and stirring was continued for further 4 h. The reaction mixture was diluted with water and extracted with ethyl acetate and the organic layer was washed with water, brine, dried (Na2SO4) and solvent was evaporated under reduced pressure. The crude product was chromatographed on silica gel using mixture of methanol: chloroform (1:9) as eluent to afford the pure product (0.76 g, 51%) as an oil.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].BrC[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=O.O.CN(C)[CH:41]=[O:42]>>[CH2:36]([O:35][C:33](=[C:41]=[O:42])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][N:11]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:9]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:8]=[C:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:37]
Reactant: CN(C)C=O
Reactant: c1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)cc1
Reactant: CCOC(=O)CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=C=O)CCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 41 %

Procedure:
2,4,5-Triphenylimidazole (1.3 g) was added to a suspension of sodium hydride (0.23 g) (50% dispersion in oil, washed with hexane) in dry dimethylformamide (40 ml) under nitrogen. The reaction was stirred at 45° C. for 1.5 h, cooled and ethyl 7-bromoheptanoate (1.1 g) in dry dimethylformamide (10 ml) was added. The reaction was stirred at 50° C. for 5 h, cooled and water was carefully added. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (100 ml). The organic solution was washed with saturated sodium chloride solution (150 ml), water (100 ml), dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. The residue was chromatographed on silica gel eluted with a dichloro-methane:ethanol gradient to give 1-(6-ethoxy-carbonylhexyl)-2,4,5-triphenylimidazole (0.81 g, 41%) as an oil. Found: C, 79.74; H, 7.32; N, 6.12%; C30H32N2O2 requires: C, 79.61; H, 7.13; N, 6.19%.
Reaction SMILES: [OH-:1].[K+].[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][N:12]1[C:16]2[CH:17]=[C:18]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:19]=[C:20]([C:21]#[N:22])[C:15]=2[N:14]=[C:13]1[CH3:29].OO>O.C1COCC1>[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][N:12]1[C:16]2[CH:17]=[C:18]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH:19]=[C:20]([C:21]([NH2:22])=[O:1])[C:15]=2[N:14]=[C:13]1[CH3:29]
Reactant: [OH-]
Reactant: Cc1nc2c(C#N)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1Cl
Agent: OO
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2c(C(N)=O)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1Cl
Temperature: 50 °C
Yield: 51.1 %

Procedure:
A solution of KOH (78 mg, 1.4 mmol) in water (10 mL) was added dropwise to solution of 1-[(2,3-dichlorophenyl)methyl]-2-methyl-6-(4-morpholinyl)-1H-benzimidazole-4-carbonitrile (280 mg, 0.7 mmol) and 30% H2O2 (3 mL) in THF (10 mL) at rt. The mixture was heated at 50° C. for 2 h. When TLC showed no starting material left, the pH of the mixture was acidified to pH ca. 5 and extracted with EtOAc (50 mL×3). The organic layer was washed with brine, dried over MgSO4, concentrated. The resulting residue was purified by silica gel chromatography eluted with EtOAc to give the product (150 mg, 51%), as a white solid. 1H NMR (300 Mhz, DMSO-d6) δ ppm 2.44 (s, 3H), 3.11 (t, 4H, J=4.8 Hz), 3.71 (t, 4H, J=4.8 Hz), 5.60 (s, 2H), 6.31 (d, 1H, J=8.1 Hz), 7.16 (br s, 2H), 7.25 (t, 1H, J=8.1 Hz), 7.35 (d, 1H, J=1.8 Hz), 7.41 (d, 1H, J=1.8 Hz), 7.60 (d, 1H, J=8.1 Hz); LC-MS: m/e=419 [M+1]+
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][CH:12]2[CH2:15][N:14]([C:16]3[S:17][C:18]([C:22]([O:24]CC)=[O:23])=[C:19]([CH3:21])[N:20]=3)[CH2:13]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].C1COCC1.O>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][CH:12]2[CH2:13][N:14]([C:16]3[S:17][C:18]([C:22]([OH:24])=[O:23])=[C:19]([CH3:21])[N:20]=3)[CH2:15]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(N2CC(NC(=O)c3nc(Cl)c(CC)[nH]3)C2)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCc1[nH]c(C(=O)NC2CN(c3nc(C)c(C(=O)O)s3)C2)nc1Cl
Temperature: 25 °C
Reaction time: 27 h
Yield: 92.4 %

Procedure:
Ethyl 2-(3-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}azetidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (218c) (145 mg, 0.36 mmol) was dissolved in methanol (3.6 mL). A 2 N aqueous lithium hydroxide solution (1.82 mL, 3.64 mmol) was added, and the mixture was stirred at room temperature for 27 hours. THF (2 mL) was added, followed by further stirring for 22 hours. Water was added to the reaction solution, and then the mixture was washed with ethyl acetate. A 1 N aqueous hydrochloric acid solution (4 mL) was added to the aqueous layer, followed by extraction with a chloroform/methanol mixed solvent. The combined organic layers were dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The resulting solid was suspended and washed in diethyl ether to obtain 123 mg of the title compound as a white solid (91%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.C(N(CC)CC)C.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl>[C:16]([Si:20]([CH3:23])([CH3:22])[O:8][CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][NH:1][CH2:2]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC1CCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCC1CCCNC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.5 %

Procedure:
To a solution of piperidin-3-ylmethanol (2.10 g, 0.018 mol) in CH2Cl2 (20 mL) is added triethylamine (5.53 g, 0.0547 mol) followed by t-butyldimethylchlorosilane (4.127 g, 0.0275 mol) and the reaction mixture is stirred at room temperature. After 24 hours, the reaction mixture is washed with water, saturated solution of NaHCO3, and brine. The combined organic layers are combined and dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) over a gradient using 0-10% MeOH in dichloromethane to afford the title compound (2.50 g, 60%). Mass spectrum (m/z): 231.2 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:9][CH2:8][C:6]=2[N:7]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1OC)[NH2:25].C[CH2:32][O:33]C(C)=O>C(O)(C)C>[CH3:32][O:33][C:27]1[CH:26]=[C:24]([NH:25][C:2]2[N:3]=[CH:4][C:5]3[CH2:11][N:10]([C:12]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)=[O:13])[CH2:9][CH2:8][C:6]=3[N:7]=2)[CH:23]=[C:22]([O:21][CH3:20])[CH:28]=1
Reactant: O=C(c1cccnc1)N1CCc2nc(Cl)ncc2C1
Reactant: COc1ccc(N)cc1OC
Reactant: CCOC(C)=O
Solvent: CC(C)O
Product: COc1cc(Nc2ncc3c(n2)CCN(C(=O)c2cccnc2)C3)cc(OC)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
A solution of (2-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(pyridin-3-yl)methanone, Intermediate 5 (0.025 g, 0.091 mmol) in isopropanol (0.1 mL) was treated with 3,4-dimethoxyaniline (0.015 g, 0.100 mmol). The resulting mixture was heated to 60° C. and allowed to stir overnight. After being allowed to cool to room temperature, EtOAc (10 mL) was added to the reaction mixture, and the resulting solution was then washed twice with brine (10 mL). The combined aqueous layers were washed once with EtOAc (10 mL). The organic layers were combined, then dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The resulting crude residue was then purified over silica using a MeOH/CHCl3 gradient. The desired product was obtained in 62% yield (0.022 g, 0.056 mmol).
Reaction SMILES: C([O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]3)[CH2:7][CH2:6]1)(=O)C.[Cl:22]N1C(=O)CCC1=O>>[Cl:22][C:20]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][C:16](=[O:21])[NH:17]2)=[CH:12][C:11]=1[N:8]1[CH2:9][CH2:10][CH:5]([OH:4])[CH2:6][CH2:7]1.[Cl:22][C:12]1[C:11]([N:8]2[CH2:9][CH2:10][CH:5]([OH:4])[CH2:6][CH2:7]2)=[CH:20][CH:19]=[C:18]2[C:13]=1[CH2:14][CH2:15][C:16](=[O:21])[NH:17]2
Reactant: CC(=O)OC1CCN(c2ccc3c(c2)CCC(=O)N3)CC1
Reactant: O=C1CCC(=O)N1Cl
Product: O=C1CCc2c(ccc(N3CCC(O)CC3)c2Cl)N1
Product: O=C1CCc2cc(N3CCC(O)CC3)c(Cl)cc2N1

Procedure:
7-Chloro-6-(4-hydroxypiperidino)-3,4-dihydrocarbostyril and 5-Chloro-6 (4-hydroxypiperidino)- 3,4-dihydrocarbostyril were prepared from 6-(4-acetoxypiperidino)-3,4-dihydrocarbostyril in the same procedure as that described in Example 2, except using of N-chlorosuccinimide instead of N-bromosuccinimide.
Reaction SMILES: [C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].[Cl:11][C:12]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18](O)=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Cl:11][C:12]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([O:3][C@H:2]([CH3:4])[C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[CH:17][CH:16]=1
Reactant: C[C@H](O)C(=O)OC(C)(C)C
Reactant: Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 25 h

Procedure:
To a stirred solution of known tert-butyl L-(+)-lactate (0.88 g), 4-(2',4'-dichlorophenoxy)phenol (1.54 g) and triphenylphosphine (1.58 g) in dry tetrahydrofuran (58 ml) on an ice bath, diethylazodicarboxylate (0.95 ml) was added dropwise. After the addition, the ice bath was removed and the mixture was further stirred at room temperature for 25 hours. The reaction mixture was evaporated with a rotary evaporator. The residue thus obtained was purified by silica gel chromatography [silica gel 399 g, eluant:ethyl acetate-hexane (1:30)] to give tert-butyl (2R)-(+)-2-[4'-(2",4"-dichlorophenoxy)phenoxy]propionate as a colorless oily substance (0.98 g). This was left to stand at room temperature under high vacuum (0.25 Torr) for 2 hours and under atmosphere for several days to crystallize. A crystalline substance thus formed was washed with a small amount of hexane and filtered to give colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]3[CH2:15][CH2:16][CH2:17][C:12]3=[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26](OCC)=[O:27])=[CH:21][CH:20]=3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].NC1C=CC(CCO)=CC=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]3[CH2:15][CH2:16][CH2:17][C:12]3=[C:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][OH:27])=[CH:23][CH:24]=3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)Cc1ccc(Nc2cc(-c3ccc(F)c(Cl)c3)nc3c2CCC3)cc1
Agent: Nc1ccc(CCO)cc1
Product: Cl
Product: OCCc1ccc(Nc2cc(-c3ccc(F)c(Cl)c3)nc3c2CCC3)cc1
Yield: 13.5 %

Procedure:
Following General Procedure B2, ethyl 2-(4-((2-(3-chloro-4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-4-yl)amino)phenyl)acetate (0.110 g, 0.39 mmol) was reacted with 4-aminophenethyl alcohol (0.080 g, 0.58 mmol), followed by the formation of the hydrochloride salt to afford the title compound (0.011 g, 15%) as an off-white solid. MW=405.29. 1H NMR (DMSO-d6, 300 MHz) δ 14.04 (s, 1H), 9.74 (s, 1H), 8.18-8.01 (m, 1H), 7.81-7.72 (m, 1H), 7.64 (t, J=8.9 Hz, 1H), 7.38-7.27 (m, 4H), 6.99 (s, 1H), 3.64 (t, J=6.8 Hz, 2H), 3.14 (t, J=7.6 Hz, 2H), 2.92 (t, J=7.6 Hz, 2H), 2.76 (t, J=6.8 Hz, 2H) 2.31-2.16 (m, 2H), 1.24 (s, 1H); APCI MS m/z 383 [M+H]+.
Reaction SMILES: [C:1]([N:18]1[CH2:24][CH2:23][CH2:22][C@H:19]1[CH2:20][OH:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].[CH3:25][O:26][C:27]1[CH:48]=[CH:47][C:30]([C:31](Cl)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[CH:29][CH:28]=1.C(Cl)(Cl)Cl.CO>N1C=CC=CC=1>[C:1]([C:31]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[C:30]1[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:48][CH:47]=1)([O:3][CH2:4][CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:2].[NH:18]1[CH2:24][CH2:23][CH2:22][C@H:19]1[CH2:20][OH:21]
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC[C@H]1CO
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc(C(C(=O)OCC2c3ccccc3-c3ccccc32)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: OC[C@@H]1CCCN1
Yield: 74 %

Procedure:
The Fmoc-L-prolinol (Compound 2) (1.4 g, 4.3 mmol) was dissolved in 20 ml of pyridine and azeotroped three times. The residual substance obtained was dissolved in 20 ml of pyridine. While stirring this solution in an ice bath under argon, 4,4′-dimethoxytrityl chloride (DMTr-Cl) (1.8 g, 5.3 mmol) was added thereto. The reaction in this reaction solution was followed by TLC using chloroform/methanol, and the reaction was allowed to proceed for 4 hours until a spot of the Fmoc-L-prolinol no longer was observed. In order to quench excess DMTr-Cl, 3 ml of methanol was added to the reaction solution, and this was stirred for 10 minutes. Chloroform was further added to the reaction solution, and thereafter, an organic layer was collected. The collected organic layer was washed with saturated saline, then with a 5% aqueous solution of sodium hydrogencarbonate, and again with saturated saline. The organic layer thus washed was dried with anhydrous sodium sulfate. The organic layer then was filtered, and the filtrate obtained was vacuum concentrated. The residual substance obtained was purified by silica gel column chromatography (the eluent: chloroform, 1% pyridine). Thus, Compound 3 was obtained (2.0 g, yield: 74%). The result of NMR analysis with respect to this compound is shown below.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7]Cl.[F:9][C:10]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:11]=1[NH2:12].C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[ClH:2].[F:9][C:10]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:11]=1[N:12]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: ClCCNCCCl
Reactant: Nc1cc(F)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: Fc1ccc(F)c(N2CCNCC2)c1

Procedure:
7.0 g of bis(2-chloroethyl)amine hydrochloride was suspended in 60 ml of butanol and 5 g of 2,5-difluoroaniline was added thereto at room temperature. After heating under reflux for 72 hours, the reaction mixture was cooled and 4.1 g of sodium carbonate was added. After heating under reflux for additional 24 hours, the precipitate was taken up by filtration, dissolved in water and extracted with chloroform. Then the extract was washed successively with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was dissolved in a small amount of chloroform, converted into hydrochloride by adding a 4N hydrochloric acid/dioxane solution and filtered to thereby give 2.39 g mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:11][C@@H:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]2[F:25])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[Cl:26][C:27]1[C:28]([CH3:38])=[C:29]([S:34](Cl)(=[O:36])=[O:35])[C:30]([Cl:33])=[CH:31][CH:32]=1>>[ClH:26].[Cl:26][C:27]1[C:28]([CH3:38])=[C:29]([S:34]([NH:1][C:2]2[CH:3]=[C:4]([O:11][C@@H:12]3[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]3[F:25])[C:5]3[O:9][CH:8]=[CH:7][C:6]=3[CH:10]=2)(=[O:35])=[O:36])[C:30]([Cl:33])=[CH:31][CH:32]=1
Reactant: Cc1c(Cl)ccc(Cl)c1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2cc(N)cc3ccoc23)[C@H](F)C1
Product: Cc1c(Cl)ccc(Cl)c1S(=O)(=O)Nc1cc(O[C@@H]2CCNC[C@H]2F)c2occc2c1
Product: Cl

Procedure:
The title compound was prepared according to the procedure described for Example 84 starting from tert-butyl trans-4-[(5-amino-1-benzofuran-7-yl)oxy]-3-fluoropiperidine-1-carboxylate (Intermediate 53) and 3,6-dichloro-2-methylbenzenesulfonyl chloride. Yield: 39 mg (19%), HPLC purity=98%, m/z=473 (M+H)+, 1H NMR (270 MHz, methanol-d4) δ ppm 2.11-2.34 (m, 2H) 2.47-2.54 (m, 3H) 3.14-3.56 (m, 3H) 3.63-3.79 (m, 1H) 4.76-4.97 (m, 1H) 4.97-5.22 (m, 1H) 6.77 (d, J=1.98 Hz, 1H) 6.83 (d, J=1.73 Hz, 1H) 7.06 (d, J=1.98 Hz, 1H) 7.26 (d, J=1.98 Hz, 1H) 7.50 (d, J=1.98 Hz, 1H) 7.74 (d, J=2.23 Hz, 1H).
Reaction SMILES: Br[CH:2]([CH:20]([CH3:22])[CH3:21])[C:3]([O:5]CC1C=CC=C(OC2C=CC=CC=2)C=1)=[O:4].[CH3:23][C:24]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:25]=1[NH2:26].[I-].[K+]>S(=O)(=O)(O)O>[CH3:23][C:24]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:25]=1[NH:26][C@H:2]([C:3]([OH:5])=[O:4])[CH:20]([CH3:22])[CH3:21]
Reactant: Cc1cccc(C)c1N
Reactant: CC(C)C(Br)C(=O)OCc1cccc(Oc2ccccc2)c1
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [K+]
Product: Cc1cccc(C)c1N[C@H](C(=O)O)C(C)C
Temperature: 0 °C

Procedure:
To m-phenoxybenzyl α-bromoisovalerate (2 g, 0.0055 mole), 24°, is added 2,6-dimethylaniline (3.33 g, 0.0275 mole) followed by a catalytic amount of potassium iodide (20 mg). The reaction mixture is heated at about 120° for 48 hours, and then poured into ice-water (20 ml) and 2 N sulfuric acid (10 ml) and extracted with ether (3×30 ml). The combined ether extracts are washed with water (2×20 ml) until neutral and with brine (10 ml) followed by drying over calcium sulfate. The reaction product is concentrated under vacuum and isolated by preparative TLC to give m-phenoxybenzyl ester of N-(2,6-dimethylphenyl)valine. MS m/e 403.2 (M+, 7.5).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([F:17])[CH:9]=2)=[CH:6][C:5]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:4][N:3]=1.[CH3:24][C:25]1[N:30]=[C:29]([CH2:31][NH2:32])[CH:28]=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH:32][CH2:31][C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:24])[N:30]=3)=[O:14])=[C:10]([F:17])[CH:9]=2)=[CH:6][C:5]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:4][N:3]=1
Reactant: Nc1ncc(C2CCOCC2)cc1-c1ccc(C(=O)O)c(F)c1
Reactant: Cc1cccc(CN)n1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccc(CNC(=O)c2ccc(-c3cc(C4CCOCC4)cnc3N)cc2F)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a vial were charged with 4-(2-amino-5-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)-2-fluorobenzoic acid (20 mg, 0.063 mmol), (6-methylpyridin-2-yl)methanamine (11.6 mg, 0.095 mmol), DIEA (28 μL, 0.158 mmol), PyBOP (65.8, 0.126 mmol) and DMF (0.5 mL). The mixture was stirred at room temperature for 10 min. The reaction mixture was then purified by preparative HPLC, and product fractions were combined, frozen and lyophilized to afford 4-(2-amino-5-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)-2-fluoro-N-((6-methylpyridin-2-yl)methyl)benzamide as a white powder. LCMS (m/z) 421.3 (MH+) 0.41 min. 1H NMR (DMSO-d6) δ ppm 8.99 (d, J=3.1 Hz, 1H), 7.95-7.83 (m, 3H), 7.79 (t, J=7.6 Hz, 1H), 7.53 (d, J=11.7 Hz, 2H), 7.44 (dd, J=8.0, 1.4 Hz, 1H), 7.24 (d, J=7.4 Hz, 2H), 4.60 (d, J=5.5 Hz, 2H), 4.02-3.88 (m, 2H), 3.40 (td, J=11.2, 2.7 Hz, 3H), 2.88-2.71 (m, 1H), 2.51 (br. s., 3H), 1.82-1.58 (m, 4H).