Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[I:11]N1C(=O)CCC1=O>ClCCCl.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1cnc2[nH]ncc2c1
Solvent: CCOCC
Solvent: ClCCCl
Product: Clc1cnc2[nH]nc(I)c2c1
Temperature: 50 °C
Reaction time: 48 h
Yield: 96 %

Procedure:
A mixture of 5-chloro-1H-pyrazolo[3,4-b]pyridine, 30, (6.15 g, 40.10 mmol) and N-iodosuccinimide (9.46 g, 42.1 mmol) in DCE was heated to 50° C. overnight. After 16H, the reaction was cooled to room temperature and stirred overnight for 48 hr. An additional 0.20 equivalent of N-iodosuccinimide (1.80 g, 8.01 mmol) was added and the mixture was heated overnight. Then, the mixture was cooled, diluted with Et2O, washed with aq. NaHCO3, sodium thiosulfate solution, water and brine. The aqueous initial wash was back extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered through silica and concentrated in vacuo. Trituration of the resulting solid with minimal amounts of dichloromethane and Et2O provided the desired product as an off white solid. (2.02 g, 96% yield) in sufficient purity for use in the next reaction: 1H NMR (300 MHz, CDCl3) δ 11.28 (s, 1H), 8.55 (d, J=2.2 Hz, 1H) and 7.86 (d, J=2.2 Hz, 1H) ppm; LC/MS Gradient 10-90%, 0.1% formic 5 min, C18/ACN, RT=2.76 min, (M+H) 280.06.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:9]([CH:12]2[CH2:14][CH2:13]2)[CH:10]=O)=[N:4][CH:5]=[CH:6][C:7]=1[Cl:8].[C:15]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].N1CCCCC1.C(O)(=O)C>C(O)C>[CH2:20]([O:19][C:17](=[O:18])[C:16](=[CH:10][CH:9]([C:3]1[C:2]([CH3:1])=[C:7]([Cl:8])[CH:6]=[CH:5][N:4]=1)[CH:12]1[CH2:14][CH2:13]1)[C:15]([O:23][CH2:24][CH3:25])=[O:22])[CH3:21]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1c(Cl)ccnc1C(C=O)C1CC1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C(=CC(c1nccc(Cl)c1C)C1CC1)C(=O)OCC
Yield: 71.2 %

Procedure:
A mixture of (3-methyl-4-chloro-pyridin-2-yl)-cyclopropyl-acetaldehyde (4.83 g, 23.0 mmol), diethyl malonate (7.02 g, 43.8 mmol), piperidine (3.62 mL, 36.6 mmol), and acetic acid (4.19 mL, 73.2 mmol) in ethanol (100 mL) was heated to reflux overnight. The reaction mixture was concentrated to dryness. The residue was purified by flash silica column chromatography (hexane:ethyl acetate, 4:1) to afford the title compound as a yellow oil (5.76 g, 71%). ESI-MS m/z: 352 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH:15]([O:18][C:19]1[CH:20]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:22]=[CH:23][C:24]=1[OH:25])([CH3:17])[CH3:16]>>[NH2:8][C:5]1[N:6]=[N:7][C:2]([C:21]2[CH:22]=[CH:23][C:24]([OH:25])=[C:19]([O:18][CH:15]([CH3:17])[CH3:16])[CH:20]=2)=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=1
Reactant: CC(C)Oc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: CC(C)Oc1cc(-c2nnc(N)nc2-c2ccccc2)ccc1O
Yield: 18.6 %

Procedure:
4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-(propan-2-yloxy)phenol (0.450 g, 18%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (1.9 g, 7.52 mmol) and 3-isopropoxy-4-hydroxyphenylboronic acid pinacol ester (2.5 g, 9.02 mmol) according to the general procedure of Example 1.
Reaction SMILES: CN(C)C(=CC=C(C1C=CC=CC=1)C(OCC)=O)C(OCC)=S.F[B-](F)(F)F.[CH3:29][N:30]([CH3:42])[C:31]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:32][CH:33]=[N+](C)C.CC[O-].[Na+].[CH3:47][C:48]1[CH:61]=[C:60]([CH3:62])[CH:59]=[C:58]([CH3:63])[C:49]=1[CH2:50][S:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54]>C(O)C>[CH3:29][N:30]([CH3:42])[C:31](=[CH:32][CH:33]=[C:52]([S:51][CH2:50][C:49]1[C:58]([CH3:63])=[CH:59][C:60]([CH3:62])=[CH:61][C:48]=1[CH3:47])[C:53]([O:55][CH2:56][CH3:57])=[O:54])[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Reactant: CCOC(=O)CSCc1c(C)cc(C)cc1C
Agent: CCOC(=O)C(=CC=C(C(=S)OCC)N(C)C)c1ccccc1
Agent: CC[O-]
Agent: F[B-](F)(F)F
Solvent: CCO
Product: CCOC(=O)C(=CC=C(C(=O)OCC)N(C)C)SCc1c(C)cc(C)cc1C
Yield: 45.5 %

Procedure:
The procedure is as in Example 2 for the preparation of diethyl 2-dimethylamino-5-phenylthio-2,4-hexadienedioate, starting with N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (10 g), a 2M ethanolic solution of sodium ethylate (21 cc) and ethyl (2,4,6-trimethylbenzylthio)acetate (8.8 g) in ethanol (80 cc). After purification by chromatography on a silica column with a mixture of cyclohexane and ethyl acetate (70:30 by volume) as eluent, diethyl 2-dimethylamino-5-(2,4,6-trimethylbenzylthio)-2,4-hexadienedioate (6.44 g) is obtained in the form of a yellow oil, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[C:9](Br)[CH:10]=1)=[O:4].[Li+].[Cl-].[Cl:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][C:20]=1[Cl:21].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[C:9]([C:18]2[CH:17]=[CH:16][C:15]([Cl:14])=[C:20]([Cl:21])[CH:19]=2)[CH:8]=[N:7][CH:6]=1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1cncc(Br)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cncc(-c2ccc(Cl)c(Cl)c2)c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To a solution of 5-bromopyridine-3-carboxylic acid methyl ester (2 g, 9.3 mmol) in toluene (50 ml) was added tetrakis-(triphenylphosphine)-palladium (0) (320 mg, 0.28 mmol) followed by LiCl (785 mg, 18.5 mmol) and the mixture was stirred 30 min at 20° C. Then 3,4-dichlorophenyl boronic acid (50 wt % in THF/H2O 9:1) (3.7 g, 3.3 ml, 9.7 mmol) and 2N aq. K2CO3 (11.3 ml, 2.5 eq.) were added and the stirred mixture heated under an argon atmosphere at 100° C. for 23 h. After cooling, H2O was added (25 ml) and the aqueous phase separated and extracted with AcOEt. The combined organic extracts were washed with saturated NaCl solution, dried with Na2SO4, filtered and the solvent evaporated and the product dried under high vacuum at 50° C. for 2 h to afford the title compound (2.48g, 95%) as a beige solid. MS: m/e=281.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[CH:8](C)[C:9]([OH:11])=[O:10].C(OCC)(=O)CC(OCC)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[CH2:8][C:9]([OH:11])=[O:10]
Reactant: CC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Solvent: CCOC(=O)CC(=O)OCC
Product: O=C(O)CC(=O)NCc1cc(F)cc(F)c1

Procedure:
N-(3,5-Difluoro-benzyl)-malonamic acid was prepared in analogy to N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid (example 1) from diethyl malonate.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[C:5](=[C:7]([C:16]([O:18][CH3:19])=[O:17])[S:8][C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=1.[CH2:20](I)[CH3:21].[OH-].[Na+]>CO>[CH2:20]([S:1][C:2]1[NH:3][C:4]2[C:5](=[C:7]([C:16]([O:18][CH3:19])=[O:17])[S:8][C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=1)[CH3:21]
Reactant: COC(=O)c1sc(-c2ccccc2)c2[nH]c(S)nc12
Reactant: CCI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCSc1nc2c(C(=O)OC)sc(-c3ccccc3)c2[nH]1
Yield: 68 %

Procedure:
A solution of methyl 2-mercapto-4-phenylthieno[3,4-d]imidazole-6-carboxylate (1.7 g), ethyl iodide and 2N NaOH (3 ml) in methanol (30 ml) was stirred at room temperature for 6.5 hr. The reaction solution was concentrated to dryness and the residue was triturated with H2O to give a crystalline product. Recrystallization from MeOH-EtoAc to give pale yellow needles (1.3 g, 68%). m.p. 214°-215° C.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[NH:7][C:5](=[O:6])[N:4]([C@@H:10]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([N:17]=[N+:18]=[N-:19])[CH2:11]2)[CH:3]=1.[NH:20](C(OC(C)(C)C)=O)[CH2:21][C:22]([OH:24])=[O:23].C1(OC)C=CC=CC=1.[ClH:40].O1CCOCC1>C(Cl)(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C>[NH2:20][CH2:21][C:22]([OH:24])=[O:23].[CH3:1][C:2]1[C:8](=[O:9])[NH:7][C:5](=[O:6])[N:4]([C@@H:10]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([N:17]=[N+:18]=[N-:19])[CH2:11]2)[CH:3]=1.[ClH:40]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)c1ccncc1
Agent: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: NCC(=O)O
Reaction time: 8 h

Procedure:
In a mixture of chloroform-DMF (1:1) was dissolved AZT (1.0 g), and to the solution were added under ice-cooling Boc-Gly-OH (1.32 g) and DMAP (0.46 g). The mixture was stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was successively washed with 5% citric acid solution, 5% sodium hydrogencarbonate solution and saturated brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. To the residue was added n-hexane, and precipitates were filtered to give white powder. To the white powder were added anisole (0.25 ml) and 4N HCl/dioxane (5 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and to the residue was added diethylether. Precipitates were filtered to give the title compound as white powder.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[CH3:29][N:30]([CH3:45])[C:31]([CH3:44])([CH3:43])[CH2:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][C:35]=1[F:42]>>[CH3:29][N:30]([CH3:45])[C:31]([CH3:44])([CH3:43])[CH2:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[C@@H:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:36][C:35]=1[F:42]
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN(C)C(C)(C)COc1ccc(C=O)cc1F
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCC(C)(C)N(C)C)c(F)c2)c1
Yield: 24.2 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 4-(2-dimethylamino-2-methylpropoxy)-3-fluorobenzaldehyde (55 mg) according to an analogous synthetic method to Example 264 described below and purified by LC-MS, the title compound (6.6 mg) was obtained.
Reaction SMILES: [OH:1][CH:2]([CH2:21][OH:22])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[OH-].[K+].[OH:25][CH:26]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:27]([O:29]C)=O>>[OH:1][CH:2]([CH2:21][OH:22])[CH2:3][N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:27](=[O:29])[CH:26]([OH:25])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCCCCCCCCCCCCNCC(O)CO
Reactant: CCCCCCCCCCCCCCC(O)C(=O)OC
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCN(CC(O)CO)C(=O)C(O)CCCCCCCCCCCCCC

Procedure:
N-(2,3-dihydroxypropyl)-N-hexadecylamine (1.0 g, 0.0032 mole) and potassium hydroxide (0.01 g, 0.18 mmole) were heated to 85° C. under vacuum and methyl 2-hydroxyhexadecanoate (0.907 g, 0.0032 mole) was heated and added dropwise to the reaction. The reaction was heated under vacuum for 6 hours. A waxy off-white solid was obtained (crude yield=1.79 g). The waxy solid was recrystalized from hot hexane (yield=0.94 g).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C:5](Cl)=[O:6].Cl.[CH3:9][O:10][C:11](=[O:21])[C@H:12]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH2:13].C(N(CC)CC)C>ClCCl>[CH3:9][O:10][C:11](=[O:21])[CH:12]([NH:13][C:5](=[O:6])[CH2:4][CH2:3][S:2][CH3:1])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CSCCC(=O)Cl
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(Cc1ccccc1)NC(=O)CCSC
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
1.556 g (11 mmol) of 3-methylsulfanyl-propionyl chloride was added slowly to a mixture of 2.20 g (10 mmol) of phenylalanine methyl ester hydrochloride, 4.18 mL (30 mmol) of triethyl amine and 50 mL of dichloromethane and stirred at room temperature for 2 h. The reaction mixture was partitioned between DCM (50 mL) and saturated NaHCO3 solution (100 mL). The aqueous layer was separated and extracted again with dichloromethane (100 mL). The combined organic extracts were dried over sodium sulfate and evaporated. Purification by column chromatography on silica gel gave 2.574 g (92%) of 2-(3-methylsulfanyl-propionylamino)-3-phenyl-propionic acid methyl ester. LCMS: 282 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=O.ClC1[N:20]=[CH:19]C(F)=CC=1C(O)=O>>[Cl:1][C:2]1[C:3]([CH2:4][C:19]#[N:20])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1cc(F)cnc1Cl
Reactant: O=C(O)c1cccnc1Cl
Product: N#CCc1cccnc1Cl

Procedure:
(2-Chloropyridin-3-yl)acetonitrile was synthesized analogous to intermediate 13 using 2-chloronicotinic acid as a starting material in place of 2-chloro-5-fluoronicotinic acid.
Reaction SMILES: [Li]CCCC.[CH2:6]([N:13]([CH2:18][CH2:19][OH:20])[C:14]([NH:16][CH3:17])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C1COCC1>[CH2:6]([N:13]([CH2:18][CH2:19][O:20][S:28]([C:25]1[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=1)(=[O:30])=[O:29])[C:14]([NH:16][CH3:17])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CNC(=O)N(CCO)Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CNC(=O)N(CCOS(=O)(=O)c1ccc(C)cc1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
nBuLi (2.8 N, 1.01 g, 0.0157 mol) was added at −78° C. to a solution of 1-benzyl-1-(2-hydroxy-ethyl)-3-methyl-urea (3 g, 0.0143 mol, from (i) above) in 30 ml of dry TBF and stirred at same temperature for 30 min under nitrogen atmosphere. P-Toluenesulfonyl chloride (3 g, 0.0157 mol) in 20 ml of dry THF was added dropwise at −78° C. and stirred for 3 h under nitrogen atmosphere. The reaction was quenched with methanol and solvent evaporated under reduced pressure. The crude was purified by column chromatography over silica gel using 12% methanol in dichloromethane as eluent to yield 2.5 g of the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][C@@H:9]2[C:13]2[CH:14]=[C:15]([C:30]([O:32]C)=[O:31])[CH:16]=[C:17]3[C:22]=2[O:21][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:19][C:18]3=[O:29])=[CH:4][CH:3]=1.[OH-].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[CH:14]=[C:15]([C:30]([OH:32])=[O:31])[CH:16]=[C:17]3[C:22]=2[O:21][C:20]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[CH:19][C:18]3=[O:29])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc([C@H]2CCCN2c2ccc(F)cc2)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(C2CCCN2c2ccc(F)cc2)c2oc(N3CCOCC3)cc(=O)c2c1
Yield: 83.3 %

Procedure:
Methyl 8-[(2R)-(1-(4-fluorophenyl)pyrrolidin-2-yl)]-2-morpholino-4-oxo-4H-chromene-6-carboxylate (119 mg, 0.26 mmol from 2 different batches) was reacted with sodium hydroxide to give 8-(1-(4-fluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (enantiomer 2, 95 mg, 82%) as a yellow solid. Mass Spectrum: m/z [M+H]+=439.
Reaction SMILES: [NH2:1][C@@H:2]([C@@H:38]([C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[C:47]([Cl:53])[CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:3]([NH:5][C:6]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:7]=1[CH2:8][CH2:9][C@H:10]1[O:15][CH2:14][C@@H:13]([CH2:16][O:17][C:18](=[O:25])[NH:19][CH2:20][C:21]([F:24])([F:23])[F:22])[N:12]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:11]1)=[O:4].C(N(CC)CC)C.Cl[C:62]([O:64][CH3:65])=[O:63]>ClCCl>[Cl:53][C:47]1[CH:46]=[C:45]([C@@H:38]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C@H:2]([NH:1][C:62]([O:64][CH3:65])=[O:63])[C:3]([NH:5][C:6]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:7]=2[CH2:8][CH2:9][C@H:10]2[O:15][CH2:14][C@@H:13]([CH2:16][O:17][C:18](=[O:25])[NH:19][CH2:20][C:21]([F:24])([F:23])[F:22])[N:12]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:11]2)=[O:4])[CH:50]=[CH:49][C:48]=1[O:51][CH3:52]
Reactant: COC(=O)Cl
Reactant: COc1ccc([C@@H](c2ccccc2)[C@H](N)C(=O)Nc2cccc(F)c2CC[C@@H]2CN(C(=O)OC(C)(C)C)[C@H](COC(=O)NCC(F)(F)F)CO2)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)Nc1cccc(F)c1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](COC(=O)NCC(F)(F)F)CO1)[C@H](c1ccccc1)c1ccc(OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of the product from step 3 (80 mg, 0.1 mmol) in dichloromethane (2 mL) was added triethylamine (0.02 mL, 0.16 mmol) and methyl chloroformate (0.01 mL, 0.12 mmol). The mixture was stirred at ambient temperature for 6 h, then diluted with dichloromethane (10 mL) and washed with aqueous NaHCO3 and brine. The organic phase was dried (MgSO4), filtered, and the solvents were removed in vacuo. The residue was chromatographed on a 12 g SiO2 column using a gradient elution of 0-100% EtOc in hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give the title compound as a gum. (M+H)+=825.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][OH:23].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:19][C:20]2[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=2[CH2:22][OH:23])[CH:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: Nc1ccccc1CO
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1Nc1ccccc1CO
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Methyl 1-Boc-4-oxo-3-piperidinecarboxylate from Step 1 above (3.86 g, 15 mmol) was combined with 2-aminobenzyl alcohol (1.5 g, 12.2 mmol) and acetic acid (1.29 mL, 1.35 g, 22.5 mmol) in methanol (10 mL). Sodium cyanoborohydride (0.94 g, 15 mmol) was added and the mixture was stirred at ambient temperature for 3.5 h. The solvent was removed in vacuo and the residue treated with ethyl acetate (100 mL). The solution was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was chromatographed on silica gel eluted with 1:4, 1:2, and 3:5 EtOAc:hexane. The combined product fractions were evaporated to dryness in vacuo to give methyl 1-Boc-4-(2-hydroxymethylphenylamino)-3-piperidine carboxylate.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: ClCCCCCBr
Reactant: CCOC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CCCCCCl)C(C)=O
Temperature: 100 °C
Yield: 102.4 %

Procedure:
A mixture of ethyl acetoacetate [VI-1] (260.6 g, 2.0 mol), toluene (300 g) and 1-bromo-5-chloropentane [V-1] (311.0 g, 1.68 mol) is heated to 80°-90° C. Thereto is added anhydrous potassium carbonate (300 g), and the temperature thereof is raised to 100° C. The mixture is reacted at the same temperature for 18 hours. After completion of the reaction, the mixture is filtered, and the toluene layer is washed with water, and concentrated under reduced pressure to give crude ethyl 7-chloro-2-(1-oxoethyl)-heptanoate [II-1] (403.8 g, content; 68.8%, yield; 69.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][N:15]([CH2:28][CH2:29][OH:30])[C:14]3=[O:31])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[O-:34][C:35]#[N:36].[Na+].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:35](=[O:34])([O:30][CH2:29][CH2:28][N:15]1[CH2:16][CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:33][CH:32]=3)=[CH:12][CH:11]=2)[C:14]1=[O:31])[NH2:36]
Reactant: N#C[O-]
Reactant: O=C1N(CCO)CC(c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)OCCN1CC(c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(4-(4-chlorophenoxy)phenyl)-1-(2-hydroxyethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one (10.0 mg, 0.021 mmol) in DCM (0.3 mL) are added sodium cyanate (5.5 mg, 0.084 mmol) and TFA (6.46 μL, 0.084 mmol). The mixture is stirred at room temperature overnight before removal of the solvent. The residue is purified by preparatory TLC to provide the title compound; HPLC-MS calculated for C25H21ClF3N3O4 (M+H+) 520.1, found 520.1.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=O)(C)(C)C.[H-].[Na+].[CH3:16][O:17][CH2:18][CH2:19]Br.[ClH:21].O1CCOCC1>CN(C=O)C.CCOC(C)=O.O>[ClH:21].[ClH:21].[CH3:16][O:17][CH2:18][CH2:19][N:11]1[CH2:12][CH2:13][CH:9]([NH2:8])[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: COCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COCCN1CCC(N)C1
Reaction time: 1 h
Yield: 100 %

Procedure:
3-(t-Butoxycarbonylamino)pyrrolidine (1 g, 1 eq) is dissolved in DMF (15 mL) and NaH 60% in oil (258 mg, 1.2 eq) is added followed by 2-bromoethyl methyl ether (656 μL, 1.3 eq). Water (150 mL) and EtOAc (150 mL) are added and the two layers are separated. The aqueous layer is extracted with EtOAc (2×150 mL). The combined organic layers are washed with brine, dried over MgSO4 filtered and concentrated under reduced pressure. The residue is purified by flash chromatography (100% EtOAc). The isolated compound (300 mg, 23%) is dissolved in dioxane (2 mL) and HCl 4 M solution in dioxane (5 mL, 20 eq) is added. The solution is stirred for 1 h and the reaction mixture is then concentrated and co-evaporated with toluene to afford 1-(2-methoxy-ethyl)-pyrrolidin-3-ylamine 2HCl (266 mg, 100%).
Reaction SMILES: C[O:2][C:3]1[C:11]2[O:10][C:9]([CH3:12])=[N:8][C:7]=2[CH:6]=[C:5]([C:13]([O:15]C)=[O:14])[CH:4]=1.[OH-].[Li+]>C(O)C>[OH:2][C:3]1[C:11]2[O:10][C:9]([CH3:12])=[N:8][C:7]=2[CH:6]=[C:5]([C:13]([OH:15])=[O:14])[CH:4]=1
Reactant: COC(=O)c1cc(OC)c2oc(C)nc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2cc(C(=O)O)cc(O)c2o1
Temperature: 60 °C
Yield: 69.3 %

Procedure:
Methyl 7-methoxy-2-methyl-1,3-benzoxazole-5-carboxylate (365 mg) was dissolved in 16 mL ethanol and 3.3 mL of 1 M lithium hydroxide was added. Reaction was heated at 60° C. overnight. Volatiles were removed under vacuum and the residue dissolved in water and acidified with 1 M HCl to pH3. Collected the tan solid by filtration and washed with water. Air dried to yield 221 mg (65%) of 7-hydroxy-2-methyl-1,3-benzoxazole-5-carboxylic acid LC/MS=208 (M+H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:8]1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:8]1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@H]1CCCN1C1CC[C@H](c2ccc(N)cc2)C1
Product: C[C@H]1CCCN1C1CC[C@H](c2ccc(NC(=O)c3ccccc3)cc2)C1

Procedure:
The title compound was synthesized essentially in the same manner as Example 28 by employing 4-[(S)-3-((S)-2-methyl-pyrrolidin-1-yl)-cyclopentyl]-phenylamine (Intermediate 14) and benzoyl chloride.