Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:41].C(N1C=CC(N)=N1)CC1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reactant: Cc1cccc(C)n1
Agent: Nc1ccn(CCc2ccccc2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCc3ccccc3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution containing 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 100 mg, 0.30 mmol) in methylene chloride (20 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (181 μL, 0.36 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (70 μL, 0.61 mmol) was added to the solution at 0° C. After 1 h, the crude 1-phenethyl-1H-pyrazol-3-ylamine (0.42 mmol based on theory) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-phenethyl-1H-pyrazol-3-yl)-propionamide (135 mg, 89%) as a white solid: ESI-LRMS m/e calcd for C26H30ClN3O3S [M+] 499.2, found 500.4 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.06-1.23 (m, 2H, CH2), 1.39-1.93 (m, 8H, 4×CH2), 2.09-2.33 (m, 1H, CH), 3.05 (t, J=7.2 Hz, 2H, ArCH2), 3.26 (s, 3H, SO2CH3), 3.60 (t, J=7.6 Hz, 1H, CH), 4.16 (t, J=7.2 Hz, 2H, NCH2), 6.58 (d, J=2.2 Hz, 1H, Ar), 7.00-7.05 (m, 3H, Ar), 7.16-7.29 (m, 3H, Ar), 7.47 (dd, Jo=8.1, Jm=1.6 Hz, 1H, Ar), 7.61 (d, Jm=1.6 Hz, 1H, Ar), 8.06 (d, Jo=8.1 Hz, 1H, Ar), 8.63 (s, 1H, NH).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[O:7][C:8]1[N:16]=[CH:15][C:14]([F:17])=[CH:13][C:9]=1[C:10]([OH:12])=O)[CH3:2].C(N(CC)CC)C.[NH2:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@@H:30]1[OH:35].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[NH3:16].[CH2:1]([S:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[O:7][C:8]1[N:16]=[CH:15][C:14]([F:17])=[CH:13][C:9]=1[C:10]([NH:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@@H:30]1[OH:35])=[O:12])[CH3:2]
Reactant: N[C@@H]1CCCC[C@@H]1O
Reactant: CCSc1cccc(Oc2ncc(F)cc2C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCSc1cccc(Oc2ncc(F)cc2C(=O)N[C@@H]2CCCC[C@@H]2O)c1
Product: N
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.2 %

Procedure:
2-[3-(Ethylsulfanyl)phenoxy]-5-fluoronicotinic acid (250 mg, 0.85 mmol) was dissolved in dimethylformamide (5 ml) and triethylamine (475 μl, 3.41 mmol) was added followed by (1S,2R)-2-aminocyclohexanol hydroformate (144 mg, 0.89 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (180 mg, 0.94 mmol) and 1-hydroxybenzotriazole (127 mg, 0.94 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between water (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography using dichloromethane:methanol:0.880 ammonia (98:2:0.2) as eluant to give 2-[3-(ethylsulfanyl)phenoxy]-5-fluoro-N-[(1R,2S)-2-hydroxycyclohexyl]nicotinamide (60 mg) as a colourless oil.
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O>>[CH3:21][C:22]1[CH:23]=[C:24]([CH2:25][N:4]2[CH2:5][CH2:6][CH2:7][N:1]([C:8]3[CH:9]=[CH:10][C:11]4[N:12]([C:14]([C:17]([F:18])([F:19])[F:20])=[N:15][N:16]=4)[N:13]=3)[CH2:2][CH2:3]2)[CH:27]=[CH:28][CH:29]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Reactant: Cc1cccc(C=O)c1
Product: Cc1cccc(CN2CCCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-methylbenzaldehyde was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(3-methylphenyl)methyl]-1,4-diazepan-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[C@@H:4]2[O:14][C@H:3]12.[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][NH:24][C:23](=[O:26])[C:22]=2[CH:27]=1>>[OH:14][C@H:3]1[C@H:4]([O:26][C:23]2[C:22]3[CH:27]=[C:18]([O:17][CH3:16])[CH:19]=[CH:20][C:21]=3[O:25][N:24]=2)[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=2)[O:11][C:2]1([CH3:15])[CH3:1]
Reactant: COc1ccc2o[nH]c(=O)c2c1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H]2O[C@@H]21
Product: COc1ccc2onc(O[C@@H]3c4cc(C#N)ccc4OC(C)(C)[C@H]3O)c2c1

Procedure:
Following the procedure in Example 1, using (S,S)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 5-methoxy-benzo[d]isoxazol-3-one as starting materials, the title compound was prepared as a white solid.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[O:5])=[N-]>O1CCOCC1.CC(CC(C)=O)=O.CC(CC(C)=O)=O.[Cu]>[CH3:10][C:9]1([CH3:11])[CH:3]2[CH:8]1[CH2:7][O:6][C:4]2=[O:5]
Reactant: CC(C)=CCOC(=O)C=[N+]=[N-]
Agent: [Cu]
Solvent: CC(=O)CC(C)=O
Solvent: C1COCCO1
Product: CC1(C)C2COC(=O)C21
Yield: 73.9 %

Procedure:
A solution of 3-methyl-2-butenyl diazoacetate (41.3 mmole, 6.36 g) in dioxane (20 ml) was added dropwise to a refluxing solution of cupric acetylacetonate (1.03 mmole, 0.27 g) in dioxane (400 ml) over a period of 7 hours under an argon atomosphere. After completion of the addition, the reaction mixture was heated under reflux for 1 hour. The crude reaction mixture was distilled to afford (±)-6,6-dimethyl-2-oxo-3-oxabicyclo[3.1.0]hexane (3.85 g, 75% yield); bp 110°, 16 mm Hg.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([NH2:15])[CH:13]=[CH2:14]>CN(C=O)C>[CH2:12]([N:15]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])[CH:13]=[CH2:14]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: C=CCN
Solvent: CN(C)C=O
Product: C=CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.8 %

Procedure:
A 500 mL round-bottom flask was charged with phthalic anhydride (22.2 g, 150 mmol) and anhydrous DMF (150 mL) and stirred at room temperature for 5 min to dissolve the phthalic anhydride. To the solution was slowly added allylamine (11.26 mL, 150 mmol) followed by 20 g of 3A molecular sieves. The resulting mixture was stirred at room temperature 10 minutes and then heated under nitrogen at 80° C. for 16 hrs. The reaction mixture was cooled to room temperature and filtered. To the mother liquor was added 300 mL of EtOAc and 300 mL of brine solution. The organic layer was separated, washed twice with 300 mL of water, and dried over MgSO4. The drying agent was removed by filtration and the mother liquor concentrated. The resulting solid was recrystalized from CH2Cl2/hexane to yield 27.75 g (98% yield) of N-allylphthalimide (1-1).
Reaction SMILES: O.[Cl:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][CH2:11][CH:12]([F:14])[F:13])=[CH:5][CH:4]=1.[CH2:15]1[C:20](=[O:21])[O:19][CH2:18][C:16]1=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][N:10]([CH2:11][CH:12]([F:14])[F:13])[C:16]2[CH2:18][O:19][C:20](=[O:21])[CH:15]=2)=[CH:5][CH:4]=1
Reactant: O=C1COC(=O)C1
Reactant: FC(F)CNCc1ccc(Cl)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C=C(N(Cc2ccc(Cl)nc2)CC(F)F)CO1
Yield: 52 %

Procedure:
On a water separator, 21.90 g (106.0 mmol) of N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethane-1-amine (III-1), 14.85 g (148.4 mmol) of tetronic acid and 183 mg (1.1 mmol) of 4-toluenesulphonic acid in 250 ml of toluene are heated under reflux for 2 hours. The reaction mixture is concentrated under reduced pressure, the residue is then taken up in ethyl acetate and the mixture is washed successively twice with 1 N aqueous hydrochloric acid, twice with 1 N aqueous sodium hydroxide solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (silica gel 60—Merck, particle size: 0.04 to 0.063 mm) using the mobile phase ethyl acetate gives 15.9 g (52% of theory) of 4-[[(6-chloropyridin-3-yl)methyl](2,2-difluoroethyl)amino]furan-2(5H)-one.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([CH2:10]O)=[CH:8][CH:7]=[CH:6][N:5]2[CH:12]=1.S(Cl)([Cl:15])=O>ClCCl>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([CH2:10][Cl:15])=[CH:8][CH:7]=[CH:6][N:5]2[CH:12]=1
Reactant: Cc1cn2cccc(CO)c2n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cn2cccc(CCl)c2n1
Reaction time: 1 h

Procedure:
2-Methyl-8-hydroxymethylimidazo[1,2-a]pyridine 21.4 g (0.13 mol) is dissolved in 400 ml dichloromethane. To the solution at 0° C. is added dropwise with stirring 19 ml of thionyl chloride. The reaction mixture is stirred for one hour and the dichloromethane is removed under reduced pressure. The residue is dissolved in distilled water, neutralizedat 0° C. with ammonium hydroxide and extracted with dichloromethane.The extracts are combined and dried over anhydrous sodium sulfate. Following filtration, the dichloromethane is removed under reduced pressure to give 2-methyl-8-chloromethylimidazo[1,2-a]pyridine, mp. 110°-112° C.
Reaction SMILES: O=[CH:2][CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([CH2:9][CH:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:7][CH:6]=1.[NH2:19][C:20]1[C:21]([NH:30][CH3:31])=[N:22][CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1>C(O)C.C(O)(=O)C>[CH3:31][N:30]1[C:21]2=[N:22][CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=[C:20]2[N:19]=[C:2]1[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:17][CH:18]=1
Reactant: CNc1ncc(C(F)(F)F)cc1N
Reactant: O=CCOc1ccc(CC2SC(=O)NC2=O)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2cc(C(F)(F)F)cnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 7.6 %

Procedure:
4.16 g of 5-(4-(2-oxoethoxy)benzyl)thiazolidine-2,4-dione (prepared as described in Preparation 47) were added to a solution of 3.00 g of 3-amino-2-methylamino-5-trifluoromethylpyridine in a mixture of 6 ml of ethanol and 6 ml of acetic acid, and the resulting mixture was stirred at room temperature for 4 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure. 50 ml of 1,2-dimethoxyethane and 5.2 g of iodine were added to the residue, and the resulting mixture was stirred at 60° C. for one day. At the end of this time, the reaction mixture was poured into water, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent-was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent. The product was crystallized by trituration with ethyl acetate, to give 520 mg of the title compound, melting at 212°-214° C.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.CS(O[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[C:31]([CH2:38][CH2:39][NH:40][C:41](=[O:43])[CH3:42])[CH:32]=[CH:33][CH:34]=2)[CH:29]=1)(=O)=O.Cl>O.CO>[C:41]([NH:40][CH2:39][CH2:38][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:30]=1[CH:29]=[C:28]([O:27][CH2:26][CH2:25][CH2:24][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=3)=[CH:7][CH:8]=1)[CH:37]=[CH:36]2)(=[O:43])[CH3:42]
Reactant: CC(=O)NCCc1cccc2ccc(OCCCOS(C)(=O)=O)cc12
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(-c2ccc(OCCCOc3ccc4cccc(CCNC(C)=O)c4c3)cc2)cc1
Reaction time: 0.33 h

Procedure:
In a 100 ml round-bottomed flask containing 30 ml of methanol, 0.06 g of sodium is added in small portions. When the sodium has been completely used up, 0.0033 mol of methyl 4′-hydroxy[1,1′-biphenyl]-4-carboxylate is added and the mixture is stirred for 20 minutes. The methanol is removed by evaporation under reduced pressure, the residue is taken up in 15 ml of DMF, and then 0.0027 mol of the compound obtained in Step B is added. The reaction mixture is then heated at reflux for 12 hours and subsequently cooled and poured into 100 ml of water and 10 ml of 3M HCl. After extraction with ethyl acetate, the organic phase is washed with a 10% sodium hydroxide solution and then with water. After drying over MgSO4 and removal of the solvent by evaporation under reduced pressure, the title compound is purified by chromatography on silica gel.
Reaction SMILES: [CH2:1]([NH:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:21])[CH:15](O)[C:16](O)([CH3:18])C)[CH3:6])[CH:2]=[CH2:3].I(O)(=O)(=O)=O.[C:27]1(/C=C/B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CO.O.C(OCC)(=O)C>[CH2:1]([N:4]1[CH:5]([CH3:6])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14](=[O:21])[CH:15]1[CH:16]=[CH:18][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:2]=[CH2:3]
Reactant: C=CCNC(C)c1ccccc1NC(=O)C(O)C(C)(C)O
Reactant: OB(O)/C=C/c1ccccc1
Agent: [O-][I+3]([O-])([O-])O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: C=CCN1C(C=Cc2ccccc2)C(=O)Nc2ccccc2C1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
The product of Example 14 (117 mg, 0.4 mmol) was placed in a 25 mL round bottom flask and dissolved in methanol (2 mL) and water (1 mL). To this solution was added periodic acid (192 mg, 0.84 mmol), and the mixture was allowed to stir at room temperature for 2 hours. After this time, the solvent was then evaporated and the resulting residue was taken up in ethyl acetate (20 mL) and transferred to a separatory funnel. The organic layer was then washed with a saturated sodium bicarbonate solution (5×15 mL) until the aqueous layer no longer turned pink in color. The organic layer was then washed with brine (1×15 mL), dried over magnesium sulfate, filtered and evaporated. This resulting aminol was then dissolved in acetonitrile (4 mL) and to this solution was added (E)-2-Phenylvinylboronic acid (75 mg, 0.5 mmol), and the solution was brought to reflux for 4 hours. After this time, the reaction was diluted with ethyl acetate (40 mL), and transferred to a separatory funnel. The organic layer was washed with 1N NaOH (3×15 mL), brine (1×15 mL), dried over magnesium sulfate, filtered, and evaporated to yield the desired product, and an isomeric by-product in a combined yield of 81%. 1H NMR was used to estimate the ratio of product to by-product to be approximately 77:23. This mixture was taken crude to the next transformation to avoid further isomerization upon isolation. 1H NMR (250 MHz, CDCl3, major isomer) δ 7.75 (bs, 1H), 7.43-7.37 (m, 2H), 7.33-7.15 (m, 6H), 7.11-7.04 (m, 1H), 6.85-6.82 (m, 1H), 6.57 (dd, J=16.0 Hz, J=4.8 Hz, 1H), 5.92-5.69 (m, 1H), 5.18-5.03 (m, 2H), 4.44-4.39 (m, 1H), 4.29 (q, J=6.6 Hz, 1H), 3.27-3.16 (m, 1H), 2.92-2.80 (m, 1H), 1.55 (d, J=6.6 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([NH:24][C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=C=Nc1ccccc1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)Nc4ccccc4)cc3c2C1
Yield: 6.6 %

Procedure:
Beginning with 10.0 mg (0.0437 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 10.4 mg (0.0874 mMol) phenyl isocyanate, 1.0 mg (7%) of the title compound was recovered using the procedure described in detail in EXAMPLE B-12.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([C:14]([OH:16])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.S(Cl)(Cl)=O.[NH2:28][C:29]1[C:44]([F:45])=[CH:43][C:32]([O:33][C:34]2[CH:39]=[CH:38][N:37]=[C:36]([C:40]([NH2:42])=[O:41])[CH:35]=2)=[C:31]([F:46])[CH:30]=1>O1CCCC1>[NH2:42][C:40]([C:36]1[CH:35]=[C:34]([O:33][C:32]2[C:31]([F:46])=[CH:30][C:29]([NH:28][C:14]([C:11]3([C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])[CH2:12][CH2:13]3)=[O:16])=[C:44]([F:45])[CH:43]=2)[CH:39]=[CH:38][N:37]=1)=[O:41]
Reactant: NC(=O)c1cc(Oc2cc(F)c(N)cc2F)ccn1
Reactant: O=C(O)C1(C(=O)OCc2ccccc2)CC1
Solvent: O=S(Cl)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: NC(=O)c1cc(Oc2cc(F)c(NC(=O)C3(C(=O)OCc4ccccc4)CC3)cc2F)ccn1
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
1-[(Benzyloxy)carbonyl]cyclopropanecarboxylic acid (1.04 g) was dissolved in tetrahydrofuran (15 ml) under a nitrogen atmosphere. N-Methylmorpholine (0.520 ml) was added at 0° C., and the mixture was stirred for 15 minutes. Thionyl chloride (0.345 ml) was added to the mixture at 0° C., and the mixture was stirred at the same temperature for 30 minutes. 4-(4-Amino-2,5-difluorophenoxy)pyridine-2-carboxamide (500 mg) and N-methylmorpholine (0.520 ml) was added, and the mixture was stirred at room temperature for 2 hours and 50 minutes. The reaction mixture was partitioned after the addition of a 1N aqueous solution of sodium hydroxide (15 ml) and ethyl acetate (20 ml). The organic layer was washed with a 1N aqueous solution of sodium hydroxide (15 ml), water (15 ml) and brine (15 ml), and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:1, then 1:2). The fractions containing the target compound was concentrated under reduced pressure to give the title compound (822.7 mg, 93%) as white powder.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:13]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:12][C@H:11]2[C@H:7]([N:8]=[C:9]([CH3:19])[O:10]2)[C@H:6]1[O:20][C:21](=[O:23])[CH3:22])(=[O:3])[CH3:2].[N:24]([CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][OH:35])=[N+:25]=[N-:26].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.CCN(CC)CC>C(Cl)Cl>[C:1]([O:4][C@@H:5]1[C@H:6]([O:20][C:21](=[O:23])[CH3:22])[C@@H:7]([NH:8][C:9](=[O:10])[CH3:19])[C@H:11]([O:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][N:24]=[N+:25]=[N-:26])[O:12][C@@H:13]1[CH2:14][O:15][C:16](=[O:18])[CH3:17])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=NCCOCCOCCO
Reactant: CC(=O)OC[C@H]1O[C@@H]2OC(C)=N[C@@H]2[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@H]1[C@H](OCCOCCOCCN=[N+]=[N-])O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
This protocol was modified to synthesis 5β exclusively. Briefly, compound 2 (1.0 g, 3.03 mmol) and alcohol 4 (1.60 g, 9.11 mmol) were dissolved in anhydrous DCM (20 mL), followed by addition of dried 4 A° MS (0.4 g) and reaction mixture stirred at room temperature for 20 minutes under N2. CSA (camphor sulphonic acid, 0.615 g, 9.0 mL, 9.1 mmol) was added at room temperature and 8 hours, followed by heating to 45° C. for 24 hours. The reaction mixture was cooled to room temperature, neutralized with Et3N (0.2 mL, pH 7.5), diluted with DCM (100 mL) and extracted using saturated NaHCO3 solution. The organic layer was washed with water, brine and dried over Na2SO4. Solvents were evaporated under reduced pressure and the residue purified by silica gel column chromatography using DCM:EtOAc:MeOH (8.0:1.5:0.5) to obtain compound 5β (1.15 g, 85%). The spectral data matched with above compound 5β.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.C(N(CC)CC)C.C(#N)C.[C:27](Cl)(=[O:30])[CH:28]=[CH2:29]>O>[C:27]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:13]=[O:14])=[CH:15][CH:16]=1)(=[O:30])[CH:28]=[CH2:29]
Reactant: C=CC(=O)Cl
Reactant: O=Cc1ccc(OCCCCCCO)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CC(=O)OCCCCCCOc1ccc(C=O)cc1
Temperature: 0 °C

Procedure:
8.9 g (0.04 mol) of 4-(6-hydroxyhexyloxy)benzaldehyde, 6.8 ml of triethylamine and 100 ml of acetonitrile were put in a three-neck flask equipped with a thermometer and a stirrer and cooled to 0° C. To this mixture was dropwise added a solution comprising 4.0 g (0.044 mol) of acryloyl chloride and 10 ml of acetonitrile with stirring at 0° C. to 5° C. After the addition, the whole mixture was stirred for one hour at 0° C. and poured into water containing ice. The crystals which precipitated out after a while were taken out by filtration, washed with water and dried by airing to obtain the intended compound. The yield of the product was 3.94 g (35.7%). The product had a melting point of 30° C. or lower.
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8](=O)[C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[CH3:19][O:20][P:21]([CH2:25][NH2:26])(=[O:24])[O:22][CH3:23].C(N(CC)CC)C.C([BH3-])#N.[Na+]>C1COCC1.CCO.C1COCC1>[CH3:19][O:20][P:21]([CH2:25][NH:26][CH:8]([CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:2][CH:3]=1)[C:9]([OH:11])=[O:10])([O:22][CH3:23])=[O:24]
Reactant: COP(=O)(CN)OC
Reactant: O=C(O)C(=O)Cc1ccc(-c2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COP(=O)(CNC(Cc1ccc(-c2ccccc2)cc1)C(=O)O)OC
Reaction time: 0.33 h

Procedure:
To a stirred suspension of 4-biphenyl-pyruvic acid in anhydrous THF-EtOH (50 mL, 9:1) is added aminomethylphosphonic acid dimethyl ester (520 mg, 3.7 mmol) in THF-EtOH (5 mL, 9:1). The pH is then adjusted with triethylamine to 6.6. After 20 minutes, sodium cyanoborohydride (100 mg, 1.6 mmol) in THF (2.5 mL) is added over 30 minutes. The solution is stirred for 18 hours and then concentrated. Ether (20 mL) is added and the mixture is cooled and treated with 1N HCl (7 mL). After stirring at room temperature for 30 minutes, the solid is filtered off and washed with ether and water to yield 2-(dimethylphosphonomethylamino)-3-(4-biphenylyl)-propionic acid as a waxy solid.