Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:5]=[C:6]([CH:10]2[N:15]([CH2:16][C:17]([O:19]C)=[O:18])[C:14](=[O:21])[C:13]3([CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22]3)[N:12]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1>C1COCC1.O>[C:31]([O:30][C:28]([N:12]1[C:13]2([CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22]2)[C:14](=[O:21])[N:15]([CH2:16][C:17]([OH:19])=[O:18])[CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[CH:5]=2)[CH2:11]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: COC(=O)CN1C(=O)C2(COCCOC2)N(C(=O)OC(C)(C)C)CC1c1cccc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(c2cccc(F)c2)N(CC(=O)O)C(=O)C12COCCOC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
15 mg (0.62 mmol) lithium hydroxide were added to 0.25 g (0.55 mmol) tert-butyl 3-(3-fluorophenyl)-4-(2-methoxy-2-oxoethyl)-5-oxo-8,11-dioxa-1,4-diazaspiro[5.6]dodecane-1-carboxylate in 5 ml THF and 1 ml of water. The mixture was stirred for 2 h at RT and then the MeOH was distilled off. The residue was mixed with water and acidified with formic acid. The aqueous phase was extracted with ethyl acetate. The ethyl acetate phase was dried and evaporated down.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:32][C:33]1[C:38]([OH:39])=[CH:37][CH:36]=[C:35]([C:40]2[CH:45]=[CH:44][C:43]([C@H:46]3[CH2:51][CH2:50][C@H:49]([CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH2:48][CH2:47]3)=[CH:42][CH:41]=2)[N:34]=1.[CH2:57](O)[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64]>O1CCCC1>[F:32][C:33]1[C:38]([O:39][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])=[CH:37][CH:36]=[C:35]([C:40]2[CH:45]=[CH:44][C:43]([C@H:46]3[CH2:51][CH2:50][C@H:49]([CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH2:48][CH2:47]3)=[CH:42][CH:41]=2)[N:34]=1
Reactant: CCCCCCCCO
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(O)c(F)n3)cc2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2ccc([C@H]3CC[C@H](CCCCC)CC3)cc2)nc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.26 g (1.50 mmol) of diethyl azodicarboxylate is added dropwise at 0° C. to 0.39 g (1.50 mmol) of triphenylphosphine in 10 ml of tetrahydrofuran, and the mixture is stirred at room temperature for 30 minutes. 0.31 g (0.91 mmol) of 2-fluoro-3-hydroxy-6-[4-(trans-4-pentylcyclohexyl)phenyl]pyridine and 0.19 g (1.50 mmol) of 1-octanol are then added. After a reaction time of 2hours at room temperature, the solvent is distilled off, and the residue is purified by chromatography (silica gel, 9:1 hexane/ethyl acetate) and by recrystallization from acetonitrile, giving 0.20 g of 2-fluoro-3-octyloxy-6-[4-(trans-4-pentylcyclohexyl)phenyl]pyridine. ##STR52##
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[Cl:14])=[N+:2]=[N-:3].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][CH3:26])=[C:20]([CH2:22][C:23]#[N:24])[CH:21]=1.C[O-].[Na+]>C(O)C.C(OCC)(=O)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][CH3:26])=[C:20]([C:22]2[N:3]=[N:2][N:1]([C:4]3[CH:9]=[CH:8][C:7]([C:10]([F:12])([F:13])[F:11])=[CH:6][C:5]=3[Cl:14])[C:23]=2[NH2:24])[CH:21]=1
Reactant: [N-]=[N+]=Nc1ccc(C(F)(F)F)cc1Cl
Reactant: COc1ccc(Cl)cc1CC#N
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(Cl)cc1-c1nnn(-c2ccc(C(F)(F)F)cc2Cl)c1N
Temperature: 0 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
To an ice-cooled and stirred mixture of 1-azido-2-chloro-4-trifluoromethyl-benzene (0.500 g, 1 eq) and commercial (5-chloro-2-methoxy-phenyl)-acetonitrile (0.492 g, 1.2 eq) in ethanol (4 ml) kept under nitrogen, a solution of sodium methoxide (0.183 g, 1.5 eq) in ethanol (2 ml) is added drop-wise (15 min). After the addition, the reaction mixture is allowed to reach room temperature spontaneously and stirring is then continued overnight at room temperature. The resulting reaction mixture is diluted with ethyl acetate (25 ml), washed with water (2×25 ml), dried over MgSO4 and evaporated to dryness. The yellow solid residue (0.610 g) is purified by crystallization from a mixture of dichloromethane and hexane (1:1), to afford the title compound as white solid (0.450 g, 50% yield). M.p. 152.8-153.3° C.
Reaction SMILES: [H-].[Na+].[N:3]1([CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]#[N:11])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21]([CH:28]([O:31][CH3:32])[O:29][CH3:30])[CH:20]=1>CCCCCC.CN(C=O)C>[CH3:30][O:29][CH:28]([O:31][CH3:32])[C:21]1[CH:20]=[C:19]([C:9]([N:3]2[CH2:4][CH2:5][O:6][CH2:7][CH2:8]2)([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10]#[N:11])[CH:24]=[CH:23][C:22]=1[N+:25]([O-:27])=[O:26]
Reactant: N#CC(c1ccccc1)N1CCOCC1
Reactant: COC(OC)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(OC)c1cc(C(C#N)(c2ccccc2)N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
NaH (0.975 mol) was washed with hexane. After the hexane was decanted off, the NaH was stirred in DMF (1950 mL) at room temperature. Morpholin-4-yl-phenyl-acetonitrile (0.70 mol) in DMF (300 mL) was added dropwise under N2 gas. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled in an ice bath and 4-chloro-2-dimethoxymethyl-1-nitrobenzene (0.86 mol) in DMF (150 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 2 hours and at room temperature overnight. The reaction mixture was poured on ice/water and extracted with diisopropyl ether. The organic layer washed with water, dried (MgSO4) and evaporated to yield the title compound as a solid.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[NH:21][CH:22]=[CH:23][N:24]=3)[CH:15]=2)[CH3:13])[C:8]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C(OCC)(=O)C>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[NH:24][CH:23]=[CH:22][N:21]=3)[CH:15]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(-c2ncc[nH]2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CCCCCCN1CC2C(C1)C2(C)c1cccc(-c2ncc[nH]2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a solution of 3-hexyl-6-[3-(1H-imidazol-2-yl)phenyl]-6-methyl-3-azabicyclo[3.1.0]hexan-2-one (Preparation 44, 190 mg, 0.56 mmol) in tetrahydrofluran (5 ml) at room temperature was added lithium aluminium hydride (1.1 ml, 1.12 nimol, 1.0 M in THF) dropwise over a few minutes. The mixture was heated under reflux for 1 hour and then cooled to 0° C. 2N sodium hydroxide (1.0 ml) was added cautiously followed by ethyl acetate (10 ml) and the mixture was stirred rapidly for 30 minutes, then filtered through celite. The filtrate was concentrated in vacuo and the residue was purified by silica column chromatography eluting with ethyl acetate:methanol:ammnonia solution (0.880) (90:10:1) to afford the title compound (140 mg, 74%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.Br[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C>[CH2:33]([N:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[C:2]1=[O:1])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCNC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCCN(Cc2ccccc2)C1=O
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 85.6 %

Procedure:
To a stirring solution of (S)-tert-butyl 2-oxoazepan-3-ylcarbamate (250 mg, 1.10 mmol) in DMF (1 mL) was added a solution of 20 weight % LiHMDS in THF (870 mg, 1.04 mmol) at −70° C. under argon. The reaction mixture was stirred at −70° C. for 10 min followed by the addition of (bromomethyl)benzene (0.137 mL, 1.15 mmol) at the same temperature. Then the reaction was allowed to stir at rt for 30 min. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with water, saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-80% EtOAc/Hex to give (S)-tert-butyl 1-benzyl-2-oxoazepan-3-ylcarbamate (300 mg, 0.942 mmol, 86% yield) as a colorless oil. Anal. Calcd. for C18H26N2O3 m/z 318.4. found: 319.3 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:22])[CH2:7][NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH3:17])=[C:12]([N+:18]([O-:20])=[O:19])[CH:11]=1)(C)(C)C>Cl.O1CCOCC1.C(Cl)Cl>[CH3:17][NH:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([NH:8][CH2:7][C:6]([OH:22])=[O:5])=[O:21])=[CH:11][C:12]=1[N+:18]([O-:20])=[O:19]
Reactant: CNc1ccc(C(=O)NCC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNc1ccc(C(=O)NCC(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
(4-Methylamino-3-nitro-benzoylamino)-acetic acid (800 mg) was prepared starting from (4-methylamino-3-nitro-benzoylamino)-acetic acid tert-butyl ester (1.2 g) in 4 M HCl-dioxane (2 mL) and DCM (2 mL). The reaction was stirred at room temperature for 8 h. The solvent was evaporated to isolate pure compound without any further purification.
Reaction SMILES: [OH-].[Na+].C([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH2:22][CH:23]([CH2:28][CH3:29])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:14][CH:15]([CH2:20][CH3:21])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:9][CH:8]=1)(=O)C.C(O)C>O>[CH2:20]([CH:15]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:14][N:13]([CH2:22][CH:23]([CH2:28][CH3:29])[CH2:24][CH2:25][CH2:26][CH3:27])[C:10]1[CH:9]=[CH:8][C:7]([NH2:6])=[CH:12][CH:11]=1)[CH3:21]
Reactant: CCCCC(CC)CN(CC(CC)CCCC)c1ccc(NC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCC(CC)CN(CC(CC)CCCC)c1ccc(N)cc1
Yield: 53.4 %

Procedure:
A mixed solution comprising 8 ml of 30% sodium hydroxide solution, 1.012 g of N-acetyl-N',N'-di(2-ethylhexyl)-p-phenylenediamine and 10 ml of ethanol was allowed to react at 75° C. for a period of 5 hr. After the completion of the reaction, the reacted solution was introduced into water and the product was extracted by ethyl acetate. After ethyl acetate was distilled away, the residue was purified by silica gel column chromatography to obtain 501 mg of oil of N,N-di(2-ethylhexyl)-p-phenylenediamine (yield 53.4%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH:16][CH2:17][C:18]1[CH:29]=[CH:28][C:21]([C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])=[CH:20][CH:19]=1>>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])=[CH:28][CH:29]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCOC(=O)c1ccc(CO)cc1
Reactant: COc1ccc(C(=O)Cl)cc1C(C)(C)C
Product: C=CCOC(=O)c1ccc(COC(=O)c2ccc(OC)c(C(C)(C)C)c2)cc1

Procedure:
In a manner similar to Example 1(d), by reaction of 2.4 g (18 mmol) of 3-tert-butyl-4-methoxybenzoyl chloride with 1.9 g (10 mmol) of allyl 4-hydroxymethylbenzoate, 2.65 g (69%) of allyl ester are obtained in the form of a slightly yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][NH:12][C:11](=[O:23])[C:10]=2[C:24]#[N:25])=[CH:5][CH:4]=1.[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:12]1[C:11](=[O:23])[C:10]([C:24]#[N:25])=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[N:13]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: ClCc1ccccc1
Reactant: COc1ccc(-c2n[nH]c(=O)c(C#N)c2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2nn(Cc3ccccc3)c(=O)c(C#N)c2-c2ccc(OC)cc2)cc1
Yield: 65.4 %

Procedure:
Using 5,6-bis(4-methoxyphenyl)-4-cyano-2H-pyridazin-3-one and benzyl chloride as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 65.4%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[CH3:23])=[C:13]([C:24]([OH:26])=O)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].[CH3:27][C:28]1([CH3:42])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:30]2([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[O:29]1>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:14]2[N:9]3[N:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:10]3[N:11]=[CH:12][C:13]=2[C:24]([N:33]2[CH2:34][CH2:35][C:30]3([C:36]4[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:28]([CH3:42])([CH3:27])[O:29]3)[CH2:31][CH2:32]2)=[O:26])=[C:17]([CH3:23])[CH:18]=1
Reactant: CCOC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)O)cnc12
Reactant: CC1(C)OC2(CCNCC2)c2ccccc21
Product: CCOC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)N3CCC4(CC3)OC(C)(C)c3ccccc34)cnc12
Yield: 78.2 %

Procedure:
In the same manner as in Example 21, step 5 and using 3-ethoxycarbonyl-7-(4-fluoro-2-methylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.14 g, 0.39 mmol) obtained in Example 139, step 2 and 3,3-dimethyl-3H-spiro[isobenzofuran-1,4′-piperidine] (WO2005/092895, 0.12 g, 0.47 mmol), the title compound (0.17 g, 77%) was obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[CH2:6][S:5][C:4]1=[N:9][OH:10])[CH3:2].[Cl:11][CH2:12][CH2:13][N:14]=[C:15]=[O:16]>C(Cl)(Cl)Cl.C(#N)C.C(N(CC)CC)C>[CH2:1]([N:3]1[C:7](=[O:8])[CH2:6][S:5][C:4]1=[N:9][O:10][C:15](=[O:16])[NH:14][CH2:13][CH2:12][Cl:11])[CH3:2]
Reactant: O=C=NCCCl
Reactant: CCN1C(=O)CSC1=NO
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1C(=O)CSC1=NOC(=O)NCCCl
Reaction time: 8 h

Procedure:
A solution of 2.0 g, 3-ethyl-2-oximino-4-thiazolidinone in 100 ml chloroform, 50 ml acetonitrile, 1.32 g., 2-chloroethylisocyanate and 2 drops of triethyl amine was placed in a pressure bottle and left standing overnight at ambient temperature. Concentration yielded 3.0 g of product. Recrystallized from isopropylether - ethyl acetate, m.p. 99°-102°C.
Reaction SMILES: [CH:1]1([C@@H:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:9][C@H:8]2[NH:23][C:24](OC2C=CC([N+]([O-])=O)=CC=2)=[O:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:36][C:37]1[C:38]([F:57])=[C:39]([C@:43]([C@@H:51]2[CH2:56][CH2:55][CH2:54][NH:53][CH2:52]2)([OH:50])[CH2:44][CH2:45][CH2:46][CH2:47][O:48][CH3:49])[CH:40]=[CH:41][CH:42]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:36][C:37]1[C:38]([F:57])=[C:39]([C@:43]([C@@H:51]2[CH2:56][CH2:55][CH2:54][N:53]([C:24]([NH:23][C@H:8]3[C@H:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[O:14])[CH2:9]3)=[O:25])[CH2:52]2)([OH:50])[CH2:44][CH2:45][CH2:46][CH2:47][O:48][CH3:49])[CH:40]=[CH:41][CH:42]=1
Reactant: COCCCC[C@@](O)(c1cccc(Cl)c1F)[C@@H]1CCCNC1
Reactant: O=C(N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1C1CCCCC1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCCC[C@@](O)(c1cccc(Cl)c1F)[C@@H]1CCCN(C(=O)N[C@@H]2CN(C(=O)OCc3ccccc3)CC[C@H]2C2CCCCC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
Half of the crude (3S,4S)-benzyl 4-cyclohexyl-3-((4-nitrophenoxy)carbonylamino)piperidine-1-carboxylate from Step 1 was added to a solution of (S)-1-(3-chloro-2-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol (29 mg, 2 equiv) and DIEA (15 μL, 3 equiv) in CH2Cl2 (2 mL). The mixture was stirred for 1 h at rt. LC-MS showed the reaction was complete. The mixture was concentrated and purified by preparative HPLC to afford (3S,4S)-benzyl 3-((R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)-4-cyclohexylpiperidine-1-carboxylate (18.4 mg, 63%). LC-MS (3 min) tR=2.40 min., m/z 672 (M+1).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:34]([O:41][C:42]([NH:44][C@@H:45]([CH2:50][CH2:51][CH2:52][CH2:53][NH:54][C:55]([O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:56])[CH2:46][C:47]([OH:49])=O)=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[C:65]([O:69][C:70](=[O:77])[NH:71][CH2:72][CH:73]([OH:76])[CH2:74][NH2:75])([CH3:68])([CH3:67])[CH3:66]>CN(C=O)C>[CH2:34]([O:41][C:42](=[O:43])[NH:44][C@H:45]([CH2:46][C:47]([NH:75][CH2:74][CH:73]([OH:76])[CH2:72][NH:71][C:70]([O:69][C:65]([CH3:67])([CH3:66])[CH3:68])=[O:77])=[O:49])[CH2:50][CH2:51][CH2:52][CH2:53][NH:54][C:55]([O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:56])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)NCC(O)CN
Reactant: O=C(O)C[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(O)CNC(=O)C[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
418.2 mg (1.1 mmol) of HATU and 258.7 mg (2 mmol) of N,N-diisopropylethylamine are added to a solution of 428.5 mg (1 mmol) of (3S)-3,7-bis{[(benzyloxy)carbonyl]amino}heptanoic acid in 30 ml of anhydrous DMF. After stirring at RT for 15 min, 209.2 mg (1.1 mmol) of tert-butyl(3-amino-2-hydroxypropyl)carbamate are added. The reaction mixture is stirred at RT for 15 h. The solvent is then evaporated and the residue is taken up in dichloromethane. The organic phase is washed with water, dried over magnesium sulfate and concentrated. The crude product is purified by preparative HPLC.
Reaction SMILES: [F:1][C:2]([F:19])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[CH:16][NH:15][C:14]2=[O:18])=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].[H-].[Na+].[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29](=[O:40])[C@@H:30](OS(C(F)(F)F)(=O)=O)[CH3:31]>CN1CCCC1=O.O1CCCC1.C(O)(=O)C.C(OCC)(=O)C.C(OC(C)C)(C)C>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29](=[O:40])[C@H:30]([N:15]1[CH:16]=[CH:17][N:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][C:2]([F:1])([F:19])[CH:3]([F:4])[F:5])=[CH:8][CH:9]=2)[C:14]1=[O:18])[CH3:31]
Reactant: C[C@H](OS(=O)(=O)C(F)(F)F)C(=O)c1ccccc1F
Reactant: O=c1[nH]ccn1-c1ccc(OC(F)(F)C(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C[C@H](C(=O)c1ccccc1F)n1ccn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O
Temperature: 25 °C
Yield: 34.1 %

Procedure:
1-[4-(1,1,2,2-Tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone (9.7 g) was dissolved in 60 ml of 1-methyl-2-pyrrolidone, to which 1.08 g of 72% sodium hydride in oil was added. The mixture was stirred at room temperature for an hour. The reaction solution was ice-cooled and added dropwise under nitrogen atmosphere over the period of 25 minutes to a solution of 11.6 g of (2S)-2'-fluoro-2-trifluoromethanesulfonyloxypropiophenone in 100 ml of tetrahydrofuran which was cooled to -40° C. After the reaction temperature was raised to -35° C. over the period of 10 minutes, the reaction solution was stirred for 20 minutes. The reaction solution was diluted with 3 ml of acetic acid, 450 ml of ethyl acetate and 200 ml of diisopropyl ether, washed with water (250 ml×2), 0.5N-hydrochloric acid (150 ml×2) and 300 ml of a saturated aqueous solution of sodium chloride successively, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (eluent; hexane:ethyl acetate:acetic acid=2:1:0.04) and crystallized from diisopropyl ether to give 5.1 g of 1-[(1R)-2-(2-fluorophenyl)-2-oxo-1-methylethyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone (yield: 34%) as colorless prisms.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[CH:7]=[C:6]([C:14]([O:16][CH2:17][CH2:18][OH:19])=[O:15])[C:5]2=[O:20].[CH2:21]([NH:23][C:24](=[O:44])[NH:25][C:26]1[N:31]=[CH:30][C:29](B(O)O)=[C:28]([C:35]2[S:36][CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[N:39]=2)[CH:27]=1)[CH3:22].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.[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>[CH2:12]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([C:29]3[CH:30]=[N:31][C:26]([NH:25][C:24](=[O:44])[NH:23][CH2:21][CH3:22])=[CH:27][C:28]=3[C:35]3[S:36][CH:37]=[C:38]([C:40]([F:43])([F:41])[F:42])[N:39]=3)=[CH:11][N:10]=2)[C:5](=[O:20])[C:6]([C:14]([O:16][CH2:17][CH2:18][OH:19])=[O:15])=[CH:7]1)[CH3:13]
Reactant: CCn1cc(C(=O)OCCO)c(=O)c2cc(Br)cnc21
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B(O)O)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)OCCO)cn3CC)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58.3 %

Procedure:
2-Hydroxyethyl 6-bromo-1-ethyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Intermediate 23, 170 mg, 0.50 mmol) was dissolved in dimethylformamide (25 mL), purged with argon, tetrakis (triphenylphosphine) palladium (57 mg, 0.049 mmol) followed by 6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-ylboronic acid (Intermediate 9, 264 mg, 0.598 mmol) was added and stirred for 20 min at room temperature, sodium carbonate solution (231 mg, 2 mmol) (dissolved in minimum amount of water) was added to reaction mixture and the mixture was heated to 90° C. for 3 h. The reaction mixture was passed through a celite bed and the celite was washed with dimethylformamide. The dimethylformamide layer was poured into water (100 mL) and a solid precipitate formed. The solid was filtered and dried then purified by flash column chromatography over silica gel (100-200 mesh) using MeOH (0-6%) in CHCl3 as an eluent to afford 168 mg (60%) 2-hydroxyethyl 1-ethyl-6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate as white solid.
Reaction SMILES: N[C:2]1[N:3]=[C:4](SC)[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].N([O-])=O.[Na+].[BrH:18]>Cl.[Zn].[Cu]Br>[Br:18][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: Br
Reactant: CCOC(=O)c1sc(SC)nc1N
Agent: [Cu]Br
Agent: Cl
Agent: O=N[O-]
Product: CCOC(=O)c1scnc1Br

Procedure:
Ethyl 2-mercaptoacetate is reacted with dimethyl N-cyanodithioimino-carbonate under the action of N-ethyldiisopropylamine in dimethylformamide to give ethyl 4-amino-2-methylthiothiazole-5-carboxylate, according to the method of Gompper, et al., Tet. Letters, 1885 (1966). Selective desulfurization is accomplished by the procedure of Baldwin and Ponticello, J. Med. Chem., 23(1), 65 (1980) by stirring at ambient temperature with zinc dust in 3N hydrochloric acid. The resultant ethyl 4-aminothiazole-5-carboxylate is nitrosated by the slow addition of sodium nitrite to a solution in 48% hydrobromic acid containing copper (I) bromide to give ethyl 4-bromothiazole-5-carboxylate. Heating an ethanolic solution of the bromide with the compound resulting from Example 21A and N-ethyldiisopropylamine in a sealed tube by the procedure described in Example 11B gives the fully protected product. This compound is deprotected by the procedure described in Example 11C and hydrolyzed by the procedure described in Example 12 to give the title compound.