Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=3[Cl:30])=[C:19]([CH:31]=[O:32])[N:18]=[C:17]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=3[Cl:30])=[C:19]([CH2:31][OH:32])[N:18]=[C:17]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:16]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cl)c(Oc2c(C=O)nc(N3CCOCC3)nc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Cl)c(Oc2c(CO)nc(N3CCOCC3)nc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
7 g of 4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-formyl-2-(morpholin-4-yl)-pyrimidin-4-yl]-benzenesulphonamide in 300 mi of ethanol were treated with 0.9 g of sodium borohydride. The reaction mixture was stirred at 80° C. for 1 hour. Thereafter, the ethanol was distilled off and the residue was partitioned between chloroform and 1N HCI. The organic phase was washed with water and dried, the solvent was evaporated and the residue was chromatographed over silica gel with dichloromethane. After recrystallization from dichloromethane-ethanol there were obtained 4.6 g of 4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-hydroxymethyl-2-(morpholin-4-yl)-pyrimidin-4-yl]-benzenesulphonamide, m.p. 103° C., MS: M=563.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].CCOC(/N=N/C(OCC)=O)=O.O[C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.CN(C=O)C.CCOCC>[C:8]1(=[O:9])[N:4]([CH2:3][CH2:2][O:1][C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[C:5](=[O:14])[C:6]2=[CH:13][CH:12]=[CH:11][CH:10]=[C:7]12
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc(OCCN2C(=O)c3ccccc3C2=O)cc1

Procedure:
A solution of N-(2-hydroxyethyl)phthalimide (Aldrich, 19-1, 6.36 g, 33 mmol) and DEAD (5.7 mL, 36 mmol) in 25 mL THF and 10 mL DMF was added to a solution of methyl 4-hydroxybenzoate (1-2, 5.00 g, 33 mmol) and Ph3P (9.53 g, 36 mmol) in 100 mL THF during 1 h. After an additional hour the reaction was diluted with ether, washed twice with water, then 1N NaOH and brine, dried (MgSO4), filtered and concentrated. Flash chromatography (silica gel, CH2Cl2) provided 19-2 as a white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11](=[O:13])[CH3:12]>[Ni].C(OCC)(=O)C>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11](=[O:13])[CH3:12]
Reactant: CC(=O)C=Cc1ccccc1C(F)(F)F
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CC(=O)CCc1ccccc1C(F)(F)F
Reaction time: 7 h

Procedure:
200 mg of Raney nickel are added to a solution of 2.05 g of 4-(2-trifluoromethylphenyl)-3-buten-2-one in 100 ml of ethyl acetate and the mixture is stirred under a hydrogen atmosphere and at standard pressure for 7 h. The mixture is subsequently filtered and the filtrate is evaporated under reduced pressure, whereby the title compound is obtained.
Reaction SMILES: B.[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8](O)=[O:9].CO.Cl>C1COCC1>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:12])=[C:7]([CH2:8][OH:9])[CH:11]=1
Reactant: Cc1ccc(Br)cc1C(=O)O
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(Br)cc1CO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.9 %

Procedure:
Borane (10.80 mL of a 1M solution in THF, 10.80 mmol) was added to a cooled solution of 5-bromo-2-methyl-benzoic acid (116 mg, 0.54 mmol) in THF (15 mL), under nitrogen, at 0° C. (ice water bath) and the resulting mixture allowed to warm to rt overnight. The mixture was then treated with MeOH (10 mL) followed by aqueous HCl (2M, 20 mL) and the mixture stirred for about 15 minutes, concentrated under vacuum and then partitioned with EtOAc. The organic layer was washed with aqueous HCl (2M), water and brine, dried (MgSO4), filtered and reduced to give the title compound as a colourless oil (90 mg).
Reaction SMILES: C(N)C1C=CC=CC=1.[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[C:19]([NH2:28])=[N:20][C:21]([NH2:27])=[N:22]3)[CH2:11][CH2:10]1.[F:29][C:30]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32]Br>>[F:29][C:30]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[C:19]([NH2:28])=[N:20][C:21]([NH2:27])=[N:22]3)[CH2:11][CH2:10]1
Reactant: Fc1cccc(CBr)c1F
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Solvent: NCc1ccccc1
Product: Nc1nc(N)c2c(OCC3CCN(Cc4cccc(F)c4F)CC3)cccc2n1
Yield: 53 %

Procedure:
The benzylamine was obtained by reacting 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (50 mg; 0.18 mmol) and 2,3-difluorobenzyl bromide (77 mg; 0.37 mmol) via Method BB to yield 38 mg. (53% yield). 1HNMR (400 MHz, DMSO-d6) δ 8.26 (br s, 1H), 7.8 (br s, 1H), 7.55 (t, J=8.4 Hz, 1H), 7.33 (m, 1H), 7.2 (m, 2H), 6.99 (br s, 2H), 6.9 (d, J=8 Hz, 1H), 6.81 (d, J=8.0 Hz, 2H), 4.07 (d, J=6.4 Hz, 2H), 3.59 (s, 2H), 2.85 (m, 2H), 2.04 (t, J=11.2 Hz, 2H), 1.9 (m, 1H), 1.73 (d, J=10.4 Hz, 2H), 1.33 (m, 2H). MS m/z (ESI) 400 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1([C:13](=O)[CH2:14][CH2:15][C:16]2[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>C1COCC1>[N:7]1([CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: Nc1cccc(CCC(=O)N2CCOCC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1cccc(CCCN2CCOCC2)c1
Temperature: 0 °C

Procedure:
A solution of 1M lithium aluminum hydride in THF (2.6 mL) was injected into a stirred suspension of {3-[3-(4-morpholinyl)-3-oxopropyl]phenyl}amine (120 mg, 0.51 mmol) in anhydrous THF (5 mL). The reaction was refluxed for 1 h under nitrogen. The suspension was cooled to 0° C. and quenched by careful addition of 1N NaOH. The base was added until gas evolution stopped. The reaction was concentrated to a white solid under vacuum, triturated with diethyl ether and filtered. The filtrate was concentrated under vacuum to 113 mg (89%) of the title compound, a clear oil. MS (ESI): M+H=221.17.
Reaction SMILES: [N:1]1[N:2]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[O:22])=[CH:13][CH:12]=2)[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=12.C(=O)([O-])[O-].[K+].[K+].I[CH2:30][CH3:31]>C(O)C>[CH2:30]([N:8]1[CH2:9][CH2:10][C:4]2=[CH:3][N:2]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH2:21][CH2:20][CH2:19][C:18]4=[O:22])=[CH:15][CH:16]=3)[N:1]=[C:5]2[CH2:6][CH2:7]1)[CH3:31]
Reactant: O=C1CCCN1c1ccc(-n2cc3c(n2)CCNCC3)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCN1CCc2cn(-c3ccc(N4CCCC4=O)cc3)nc2CC1

Procedure:
To a solution of 1-[4-(5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)phenyl]-2-pyrrolidinone (may be prepared as described in Description 22) (50 mg, 0.17 mmol) in ethanol (5 ml) was added potassium carbonate (70 mg, 0.51 mmol) and iodoethane (53 mg, 0.34 mmol). The resulting mixture was heated at reflux, under argon, for 18 hours. A further 3 eq. of potassium carbonate in ethanol (2 ml) was added, and stirring continued over the weekend. Reaction was removed from heat and ethanol (˜20 ml) was added. Reaction was purified by SCX, eluting with methanol and then with 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo. The resulting crude product was purified further by column chromatography on silica gel eluting with a mixture of methanol in dichloromethane (100:1-10:1) to afford the title compound (E18). MS (ES+) m/e 325 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17]([CH:21]=1)[C:18]([OH:20])=O)=[N:9][NH:8][C:7]2=[O:23].[CH2:24]([O:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH3:25].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17]([C:18]([N:30]3[CH2:31][CH2:32][CH:27]([O:26][CH2:24][CH3:25])[CH2:28][CH2:29]3)=[O:20])[CH:21]=1)=[N:9][NH:8][C:7]2=[O:23]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3cccc(Cl)c23)ccc1F
Reactant: CCOC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4cccc(Cl)c34)ccc2F)CC1
Reaction time: 1 h
Yield: 19.5 %

Procedure:
5-((8-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-fluorobenzoic acid (103) (0.2 g, 0.60 mmol), 4-ethoxypiperidine (0.078 g, 0.60 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (0.251 g, 0.78 mmol) were dissolved in DMF (10 mL), to this was added DIPEA (0.136 mL, 0.78 mmol) and the reaction was stirred for 1 hour. The solvent was evaporated to dryness and the gum was dissolved in acetonitrile (4 mL) and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound as a white foam (0.052 g, 19.49%); 1H NMR (400.132 MHz, CDCl3) δ 1.20 (3H, t), 1.59-1.48 (1H, m), 1.81-1.63 (2H, m), 1.94-1.89 (1H, m), 3.16-3.07 (1H, m), 3.57-3.45 (4H, m), 4.09-4.00 (1H, m), 4.65 (2H, s), 6.99 (1H, t), 7.17-7.13 (2H, m), 7.26 (1H, s), 7.66 (1H, t), 7.80 (1H, dd), 8.49 (1H, dd); NH missing; m/z (LC-MS, ESI+), RT=2.08 (M+H 444).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[C:14]([F:16])[CH:15]=[C:10]3[N:9]([CH3:17])[C:8]2=[O:18])[CH2:4]1.Cl[C:20]1[S:21][C:22]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:23]=2[N:24]=1.C(N(CC)C(C)C)(C)C>CS(C)=O.O>[F:16][C:14]1[CH:15]=[C:10]2[N:9]([CH3:17])[C:8](=[O:18])[N:7]([C@H:5]3[CH2:6][C@H:3]([NH:2][C:20]4[S:21][C:22]5[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:23]=5[N:24]=4)[CH2:4]3)[C:11]2=[N:12][CH:13]=1
Reactant: Cn1c(=O)n([C@H]2C[C@H](N)C2)c2ncc(F)cc21
Reactant: Fc1ccc2nc(Cl)sc2c1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cn1c(=O)n([C@H]2C[C@H](Nc3nc4ccc(F)cc4s3)C2)c2ncc(F)cc21
Temperature: 120 °C
Reaction time: 5 h

Procedure:
3-(trans-3-aminocyclobutyl)-6-fluoro-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one hydrochloride (0.100 g, 0.367 mmol), 2-chloro-6-fluorobenzothiazole (0.083 g, 0.440 mmol), and N,N-diisopropylethylamine (0.255 mL, 1.467 mmol) were mixed in DMSO (0.5 mL) in a sealed tube. The reaction mixture was stirred at 120° C. for 5 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography eluting with EtOAc in hexanes to yield the title compound (0.062 g, 0.160 mmol, 43.6% yield) as an off-white solid. M+1: 388.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.40-2.49 (m, 2 H) 3.25-3.34 (m, 2 H) 3.36 (s, 3 H) 4.50-4.59 (m, 1 H) 5.21 (quin, J=8.36 Hz, 1 H) 7.08 (td, J=9.10, 2.74 Hz, 1 H) 7.41 (dd, J=8.80, 4.89 Hz, 1 H) 7.62-7.71 (m, 2 H) 8.05 (t, J=2.25 Hz, 1 H) 8.57 (d, J=6.26 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=3)[C:21]([O:23]C)=[O:22])[CH2:14][CH2:13]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].O.[OH-].[Li+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=3)[C:21]([OH:23])=[O:22])[CH2:14][CH2:13]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)NC2CCN(c3cccc(C(=O)OC)c3)CC2)nc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCc1[nH]c(C(=O)NC2CCN(c3cccc(C(=O)O)c3)CC2)nc1Cl
Yield: 62.8 %

Procedure:
The same operation as in Example (1i) was performed using methyl 3-{4-[(4-chloro-5-ethyl-1H-imidazole-2-carbonyl)amino]piperidin-1-yl}benzoate obtained in Example (192d) (87.5 mg, 0.224 mmol) and lithium hydroxide monohydrate (47 mg, 1.12 mmol), to obtain 53 mg of the title compound as a white solid (63%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[C:20]([OH:26])[C:21]([OH:25])=[C:22]([OH:24])[CH:23]=3)=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.CC(C1C=C(C=C(C(C)(C)C)C=1O)C(NCC1C=CC([N+]([O-])=O)=CC=1)=O)(C)C>>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([C:18]3[CH:23]=[C:22]([OH:24])[C:21]([OH:25])=[C:20]([OH:26])[CH:19]=3)=[O:17])[CH2:14][CH2:15]2)=[CH:8][CH:9]=1
Reactant: O=C(c1cc(O)c(O)c(O)c1)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: CC(C)(C)c1cc(C(=O)NCc2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Product: Nc1ccc(N2CCN(C(=O)c3cc(O)c(O)c(O)c3)CC2)cc1
Yield: 61 %

Procedure:
The experimental protocol used is the same as that described for intermediate 2.2, with 5-{[4-(4-nitrophenyl)-1-piperazinyl]carbonyl}-benzene-1,2,3-triol replacing the 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide. A beige powder is obtained with a yield of 61%. This is used directly in the following stage without additional purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH2:14]([S:26][CH2:27][CH2:28]O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:13][O:12][C:10](=[O:11])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:28][CH2:27][S:26][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:7][CH:6]=1
Reactant: CCCCCCCCCCCCSCCO
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCSCCOc1ccc(CCC(=O)OC)cc1
Reaction time: 3 h
Yield: 84.6 %

Procedure:
A solution of methyl 3-[4-hydroxyphenyl)propionate (2.46 g, 13.6 mmol), 2-(dodecylthio)ethanol (3.40 g, 13.7 mmol) and triphenylphosphine (3.60 g, 13.8 mmol) in dry benzene (50 ml) was treated at 22° C. with diethyl azodicarboxylate (2.43 g, 13.9 mmol) added dropwise over 10 min. After 3 h at 22° C., the reaction mixture was diluted with ethyl acetate, washed with water, brine and dried (magnesium sulfate). Evaporation under reduced pressure gave an oil which was triturated with hexane to precipitate the triphenylphosphine oxide and the hydrazine side products. The filtrate was chromatographed on silica gel using a gradient of ethyl acetate (0-5%) in hexane as eluent to give 4.70 g(84%) of 3-[4-[2-(dodecylthio)ethoxy]phenyl]propanoic acid methyl ester as a white solid. Recrystallization from methanol gives white leaflets: m.p. 48° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[NH2:31][CH:32]([CH2:35][OH:36])[CH2:33][OH:34]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12]([NH:31][CH:32]([CH2:35][OH:36])[CH2:33][OH:34])[N:13]=2)=[C:4]([CH3:30])[CH:3]=1
Reactant: NC(CO)CO
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1F
Product: Cc1cc(F)ccc1-c1nc(NC(CO)CO)nc2c1ccc(=O)n2-c1ccccc1F

Procedure:
The product of Example 59, and serinol were reacted by the procedure of Example 60 to afford the title compound 4-(4-fluoro-2-methyl-phenyl)-8-(2-fluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR: δ 2.24 (s, 3H), 2.68 (br s, 2H), 3.42 (m, 1H), 3.61 (m, 4H), 6.30 (br s, 1H), 6.38 (d, 1H, J=9.7 Hz), 7.02 (m, 21H), 7.27 (m, 5H), 7.46 (m, 1H). LC MS (m/e)=439 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19](O)=[O:20])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2].Cl.[NH2:27][CH2:28][C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][C:38]=1[F:39])[C:32]([O:34]C)=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Li+].[OH-]>>[CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19]([NH:27][CH2:28][C:29]3[CH:30]=[C:31]([CH:36]=[CH:37][C:38]=3[F:39])[C:32]([OH:34])=[O:33])=[O:20])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2]
Reactant: COC(=O)c1ccc(F)c(CN)c1
Reactant: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)O)cn2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)NCc3cc(C(=O)O)ccc3F)cn2)C1

Procedure:
(R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-4-fluorobenzoic acid was prepared from (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid and methyl 3-(aminomethyl)-4-fluorobenzoate hydrochloride using Amidation Method 1 (HATU) and Ester Hydrolysis Method 1 (LiOH). 1H NMR (300 MHz, DMSO-d6) δ 8.92 (m, 1H), 8.78 (s, 2H), 7.91 (d, 1H), 7.85 (m, 1H), 7.19 (dd, 1H), 7.05 (d, 1H), 6.90 (m, 3H), 4.51 (d, 2H), 4.32 (m, 1H), 4.20 (d, 1H), 3.90 (m, 5H), 2.05 (m, 1H), 1.83 (m, 2H), 1.52 (m, 1H), 1.21 (t, 3H). MS (ES+) 495.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]2[C:13]([CH3:20])=[C:14]([NH2:19])[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]=2[O:3]1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:19][C:14]2[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]3[O:3][C:2]([CH3:21])([CH3:1])[CH:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:5]=3[C:13]=2[CH3:20])=[O:29])=[CH:26][CH:25]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccccc1)C(C)(C)O2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccccc2)C(C)(C)O3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
To a solution of 2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine (1.60 g, 5.69 mmol) and 4-methoxybenzoyl chloride (1.16 g, 6.82 mmol) in chloroform (20 ml) was added triethylamine (0.87 ml, 6.26 mmol) and the mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure. Water (30 ml) was added into the residue and the product was extracted twice with ethyl acetate. The combined organic layers were washed with 1N hydrochloric acid and an aqueous, saturated solution of sodium hydrogen carbonate, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was crystallized from methanol to obtain 1.70 g (72% yield) of the title compound. Melting point: 190-192° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@H:19]1[CH2:24][C@@H:23]([C:25]2[NH:29][N:28]=[N:27][N:26]=2)[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]1)=[O:17].C(OCC)(=O)C.[ClH:47]>>[ClH:47].[ClH:47].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@H:19]1[CH2:24][C@@H:23]([C:25]2[NH:29][N:28]=[N:27][N:26]=2)[CH2:22][NH:21][CH2:20]1)=[O:17]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](c3nnn[nH]3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](c3nnn[nH]3)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl (3S,5R)-3-{{{1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}-5-(1H-tetrazol-5-yl)piperidine-1-carboxylate (304 mg) was dissolved in 2M hydrogen chloride-ethyl acetate (2 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and ethyl acetate-diisopropyl ether was added. The precipitate was collected by filtration, and washed with ethyl acetate-diisopropyl ether to give the object product (219 mg).
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(OC=3C3C=CC=CC=3)=C3C(=CC=4)NN=C3)=CC=2)CCC1.C(OC(=O)[NH:38][C:39]1([C:43]2[CH:48]=[CH:47][C:46]([C:49]3[C:54](=[O:55])[C:53]4[CH:56]=[CH:57][C:58]5[N:59]=[C:60]([CH3:63])[NH:61][C:62]=5[C:52]=4[O:51][C:50]=3[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:45][CH:44]=2)[CH2:42][CH2:41][CH2:40]1)(C)(C)C>>[NH2:38][C:39]1([C:43]2[CH:44]=[CH:45][C:46]([C:49]3[C:54](=[O:55])[C:53]4[CH:56]=[CH:57][C:58]5[N:59]=[C:60]([CH3:63])[NH:61][C:62]=5[C:52]=4[O:51][C:50]=3[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:47][CH:48]=2)[CH2:40][CH2:41][CH2:42]1
Reactant: Cc1nc2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c2[nH]1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5[nH]ncc54)c3=O)cc2)CCC1
Product: Cc1nc2ccc3c(=O)c(-c4ccc(C5(N)CCC5)cc4)c(-c4ccccc4)oc3c2[nH]1
Yield: 71 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-2-phenyl-7H-pyrano[2,3-e]indazol-4-one, {1-[4-(2-methyl-6-oxo-8-phenyl-1,6-dihydro-chromeno[7,8-d]imidazol-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a beige solid (20 mg, 71%). 1H NMR (400 MHz, DMSO-d6): δ 7.85 (d, J=8.9 Hz, 1H), 7.57 (d, J=8.9 Hz, 1H), 7.50-7.45 (m, 2H), 7.44-7.34 (m, 5H), 7.17-7.13 (m, 2H), 2.59 (s, 3H), 2.40-2.32 (m, 2H), 2.11-2.02 (m, 2H), 2.02-1.93 (m, 1H), 1.70-1.60 (m, 1H). LCMS (Method E): RT=2.62 min, [M+H]+=422.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13](=[O:15])[CH3:14].[Br-:16].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C(OCC)C.C(=O)([O-])O.[Na+]>[Br:16][CH2:14][C:13]([C:4]1[CH:5]=[C:6]([C:9]([F:11])([F:10])[F:12])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[O:15]
Reactant: [Br-]
Reactant: COc1ccc(C(F)(F)F)cc1C(C)=O
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: COc1ccc(C(F)(F)F)cc1C(=O)CBr
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To a solution of 1-[2-methoxy-5-(trifluoromethyl)phenyl]ethanone (1.00 g, 4.60 mmol) in diethyl ether (15 mL) was added phenyltrimethylammonium tribromide (1.78 g, 4.60 mmol), and the mixture was stirred overnight. The reaction mixture was diluted with diluted aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (1.35 g, 98%) as a colorless solid.