Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:13])[CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:16]=[C:17]([NH:21][CH2:22][CH2:23][C:24]#[N:25])[CH:18]=[CH:19][CH:20]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:14][C:15]1[CH:16]=[C:17]([N:21]([CH2:22][CH2:23][C:24]#[N:25])[C:10](=[O:12])[CH2:9][N:8]([CH3:13])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:18]=[CH:19][CH:20]=1
Reactant: N#CCCNc1cccc(Cl)c1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN(CC(=O)N(CCC#N)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.9 %

Procedure:
To a solution of 2-(tert-butoxycarbonyl(methyl)amino)acetic acid (1.05 g, 0.0056 mol) in CH2Cl2 at 0° C. under argon atmosphere was added DMAP (0.021 g), 3-(3-chlorophenylamino)propanenitrile (1 g, 0.0056 mol) and DCC (1.27 g, 0.0061 mol). The reaction mixture was allowed to stir at room temperature for 24 h. The resulting suspension was filtered, the filtrate concentrated under reduced pressure and the crude residue was subjected to silica gel chromatography to give the tert-butyl 2-((3-chlorophenyl)(2-cyanoethyl)amino)-2-oxoethyl(methyl)carbamate (1.2 g, 80%). 1H NMR (CDCl3) δ 1.45 (s, 9H), 2.7 (m, 2H), 2.85 (m, 2H), 3.6-3.75 (m, 2H), 3.9 (m, 2H), 7.1-7.3 (m, 2H), 7.4 (m, 2H).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:20][CH2:19]3)=[C:14]([F:28])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2].[C:29]([O-])(O)=O.[Na+].ClC(OCC)=O>CC(C)=O.O>[C:1]([NH:4][CH2:5][CH:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:19][CH2:20][N:21]([C:24]([O:26][CH2:27][CH3:29])=[O:25])[CH2:22][CH2:23]3)=[C:14]([F:28])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: COC(=O)N1CCN(c2ccc(N3CC(CNC(C)=O)OC3=O)cc2F)CC1
Reactant: O=C([O-])O
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)N1CCN(c2ccc(N3CC(CNC(C)=O)OC3=O)cc2F)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
The same procedure as followed in Example 1, steps a-k, were followed. Then a solution of 100 mg (0.30 mmol) of N-((3-(4-(3-fluoro-4-(1-piperazinyl))phenyl)-2-oxo-5-oxazolidinyl)methyl)-acetamide (23) (the product from step k above) and 50 mg (0.59 mmol) of solid NaHCO3 in 2 mL acetone and 1 mL water at 0° C. was treated with 35 mg (31 μL, 0.33 mmol) of ethyl chloroformate. The solution was stirred at 0° C. for 2 hours, followed by warming to ambient temperature for 18 hours. The solution was diluted with 30 mL water and was extracted with 40 mL ethyl acetate. The organic layer was washed with 30 mL water and 30 mL saturated NaHCO3 solution. Drying (Na2SO4) and concentration in vacuo afforded a white solid. This material was subjected to radial chromatography on a 2 mm plate, eluting with 2% (v/v) methanol in chloroform. These procedures afforded 70 mg (58%) of 4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2-fluorophenyl)-1-piperazinecarboxylic acid, ethyl ester (24) as a white solid, mp=224°-226° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[CH:5][NH:4][N:3]=1.[F:8][C:9]([F:26])([F:25])[C:10](=O)[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)=O>C(O)(=O)C.O>[Br:7][C:6]1[CH:5]=[N:4][N:3]2[C:10]([C:9]([F:8])([F:26])[F:25])=[CH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=3)=[N:1][C:2]=12
Reactant: Nc1n[nH]cc1Br
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(Br)c3n2)cc1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
A stirred mixture of commercially available 3-amino-4-bromo-pyrazole (14.00 g, 86.4 mmol) and 4,4,4-trifluoro-1-(4-trifluoromethyl-phenyl)-butane-1,3-dione (Example C.1 step 1) (24.56 g, 86.4 mmol) in acetic acid (170 mL) was heated under reflux conditions for 2.5 h. The reaction mixture was cooled to room temperature, diluted with water (340 mL), the precipitate was filtered off, washed with water and dried in air at 60° C. to give the 3-bromo-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (31.77 g, 90%) as a yellow solid. MS (EI) 410.0 [(M)+], 412.0 [(M+2)+]; mp 136° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH:12][CH:13]2[CH2:18][CH2:17][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)([N:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[CH:2]1.[Cl:28][Si](C)(C)C>CC(=O)CC>[ClH:28].[ClH:28].[ClH:28].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH:12][CH:13]2[CH2:18][CH2:17][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)([N:19]([CH3:20])[CH3:21])[CH2:15][CH2:14]2)=[CH:2]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccn2)CCC(NCCc2c[nH]c3ccccc23)CC1
Solvent: CCC(C)=O
Product: Cl

Procedure:
As described for example 1, 171 mg of the polar diastereoisomer of N′-[2-(1H-indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-2-yl cyclohexane-1,4-diamine were also obtained, dissolved in 2-butanone (20 ml) and converted into the corresponding trihydrochloride with chlorotrimethyl silane (0.297 ml) (171 mg beige solid, mp 225–230° C.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=O)=[N:2]1.[F:12][CH:13]([F:29])[C:14]1[N:18]2[N:19]=[C:20]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:21]=[CH:22][C:17]2=[N:16][N:15]=1>>[F:29][CH:13]([F:12])[C:14]1[N:18]2[N:19]=[C:20]([N:23]3[CH2:24][CH2:25][N:26]([CH2:10][C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][N:2]=4)[CH2:27][CH2:28]3)[CH:21]=[CH:22][C:17]2=[N:16][N:15]=1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: FC(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)c1nnc2ccc(N3CCN(Cc4n[nH]c5ccccc45)CC3)nn12
Yield: 65 %

Procedure:
A mixture of indazole-3-carboxaldehyde and 3-(difluoromethyl)-6-(piperazin-1-yl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 5 to give 3-(difluoromethyl)-6-[4-(1H-indazol-3-ylmethyl)piperazin-1-yl][1,2,4]triazolo[4,3-b]pyridazine in 65% yield.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.[Li]CCCC.C([O:23][B:24](OC(C)C)[O:25]C(C)C)(C)C.Cl>C1COCC1.C(OCC)(=O)C>[CH2:11]([C:4]1[CH:3]=[C:2]([B:24]([OH:25])[OH:23])[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)Cc1cc(Br)c2c(c1)OCO2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Cc1cc2c(c(B(O)O)c1)OCO2
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
To a mixture of 4-bromo-6-isobutyl-benzo[1,3]dioxole (232 mg, 0.90 mmol) in THF (3 mL) cooled to −78° C. under an atmosphere of argon was added n-BuLi (0.72 mL, 2.5 M, 1.80 mmol) dropwise. The reaction mixture was stirred for 5 minutes and triisopropylborate (0.62 mL, 2.71 mmol) was added dropwise. The mixture was stirred at −50° C. for 2 hours then warmed up to room temperature and stirred overnight at room temperature. 2.0 N HCl was slowly added to the reaction mixture. After 30 minutes the mixture was diluted with ethyl acetate and the layers separated. The organic layer was further washed with water, brine, dried (MgSO4), filtered and evaporated. The residue was chromatographed on silica gel (30% ethyl acetate in hexane) to give 110 mg of 6-isobutyl-benzo[1,3]dioxole-4-boronic acid (55%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([S:10][CH3:11])[CH:3]=1.Cl.[CH3:13][O:14][NH2:15].C([O-])(=O)C.[Na+].O>CCOCC.C1COCC1>[CH3:13][O:14][N:15]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][C:4]=1[S:10][CH3:11]
Reactant: CON
Reactant: CSc1cc(F)ccc1C=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CON=Cc1ccc(F)cc1SC
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
A 250 mL round bottom flask was charged with 4-fluoro-2-methylsulfanylbenzaldehyde (5.106 g, 30 mmol), O-methylhydroxylamine hydrochloride (3.758 g, 45 mmol), sodium acetate (6.124 g, 45 mmol), water (50 mL) and THF (75 mL). The reaction mixture was stirred at room temperature for 4 h and taken up into ether (300 mL), washed with water (2×50 mL) and brine (50 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give 4-fluoro-2-methylsulfanyl-benzaldehyde-O-methyl-oxime (5.892 g, 99%) as a white solid.
Reaction SMILES: C=O.[CH2:3]([O:5][C:6](=[O:31])[C@H:7]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=1)[NH:8][S:9]([C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][NH:18][CH2:19]2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH3:4].[C:32](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:3]([O:5][C:6](=[O:31])[C@H:7]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=1)[NH:8][S:9]([C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][N:18]([CH3:32])[CH2:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:11])[CH3:4]
Reactant: CCOC(=O)[C@H](Cc1cccc(C#N)c1)NS(=O)(=O)c1ccc2c(c1)CNCC2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1cccc(C#N)c1)NS(=O)(=O)c1ccc2c(c1)CN(C)CC2
Reaction time: 1 h
Yield: 315.4 %

Procedure:
Aqueous formaldehyde solution (370 w/v, 3.15 ml, 42 mmol) was added to a stirred solution of N-(1,2,3,4-tetrahydroisoquinoline-7-sulphonyl)-3-cyano-(S)-phenylalanine ethyl ester (Preparation 23; 3.5 g, 8.5 mmol) in dichloromethane (100 ml). After 1 hour, sodium triacetoxyborohydride (566 mg, 2.67 mmol) was added and stirring continued for 2 hours. The reaction mixture was then washed with saturated aqueous sodium bicarbonate solution, dried (MgSO4) and evaporated under reduced pressure to furnish the title compound (3.6 g) as a white foam. Rf 0.83 (SS 3). m/e 428 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH:20]=[CH:21][NH:22]2)=[O:17])([CH3:4])[CH3:3].[BH4-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[CH3:4][C:2]([NH:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]([C:18]1[C:19]2[CH:20]=[CH:21][NH:22][C:23]=2[CH:24]=[CH:25][CH:26]=1)[OH:17])([CH3:1])[CH3:3]
Reactant: CC(C)(C)NCCCOc1ccccc1C(=O)c1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCO
Product: CC(C)(C)NCCCOc1ccccc1C(O)c1cccc2[nH]ccc12
Yield: 94.7 %

Procedure:
A mixture of 5.25 g of the product of Step F of Example 3, 70 ml of normal butanol and 1.7 g of sodium borohydride was stirred at reflux for one hour and the mixture was cooled. 200 ml of a saturated solution of sodium carbonate were added and extraction was carried out with an ethyl acetate-tetrahydrofuran mixture. The extracts were evaporated to dryness under reduced pressure and after chromatography on silica (eluant: ethyl acetate-triethylamine (95-5)), 5.0 g of product melting at 205° C. were obtained. 4.3 g of the product were crystallized from 580 ml of acetonitrile to obtain 3.78 g of the desired product melting at 205° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:13]=[C:12]([OH:14])[N:11]([CH3:15])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH:28]([F:30])[F:29]>CCCCCC.C(OCC)(=O)C>[F:1][C:2]1[C:3]([C:9]2[CH:13]=[C:12]([O:14][CH:28]([F:30])[F:29])[N:11]([CH3:15])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cn1nc(-c2ncc(Cl)cc2F)cc1O
Reactant: FC(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1nc(-c2ncc(Cl)cc2F)cc1OC(F)F
Temperature: 85 °C

Procedure:
46.0 g of 3-(3-fluoro-5-chloro-2-pyridyl)-5-hydroxy-1-methyl-[1H]-pyrazole (Example P13) and 84 g of potassium carbonate are introduced into 250 ml of dry dimethylformamide and heated to 85° C. While stirring well, Freon 22 (chlorodifluoromethane) is then introduced for a period of 2 hours. TLC analysis of a worked-up sample (silica gel 60 F2s; eluant: n-hexane/ethyl acetate/glacial acetic acid 20/20/1, UV) shows that there is no starting material present. The reaction mixture is partitioned between water and diethyl ether (foaming occurs on the addition of water). After extraction by shaking, and separation of the phases, the ethereal phase is washed twice with water and once with brine. After drying the organic phase over sodium sulfate and filtration, concentration in vacuo is carried out and the residue is purified by means of flash chromatography (silica gel; eluant: n-hexane/ethyl acetate 2/1 (v/v)). 22.0 g of the desired title compound are obtained in the form of a light-yellow solid.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:9]([O:11][CH3:12])=[O:10].C(=O)([O-])O.[Na+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(OCC)(=O)C>O.C(OCC)C>[CH3:12][O:11][C:9]([CH:4]1[C:3](=[O:2])[CH2:8][CH2:7][N:6]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:5]1)=[O:10]
Reactant: CCOC(=O)CBr
Reactant: COC(=O)C1CNCCC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CN1CCC(=O)C(C(=O)OC)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
1.94 g of methyl 4-oxo-3-piperidinecarboxylate hydrochloride, 1.68 g of sodium hydrogencarbonate and 1.67 g of ethyl bromoacetate were dissolved in a mixed solvent comprising 32 ml of water and 8 ml of diethyl ether and stirred at room temperature overnight. 50 ml of ethyl acetate was added to the reaction liquid, and the organic layer was separated by liquid-liquid separation. This was dried with sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (using a gradient eluent of chloroform to chloroform/methanol=100/1) to obtain 1.5 g of ethyl 3-methoxycarbonyl-4-oxo-1-piperidineacetate as an oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10](=O)[C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=1[Cl:18]>C(O)(=O)C>[Br:17][C:15]1[CH:14]=[CH:13][C:12]([Cl:18])=[C:11]([C:10]2[NH:1][C:2]3[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=3[N:9]=2)[CH:16]=1
Reactant: Nc1ccc(F)cc1NC(=O)c1cc(Br)ccc1Cl
Solvent: CC(=O)O
Product: Fc1ccc2[nH]c(-c3cc(Br)ccc3Cl)nc2c1
Yield: 91.6 %

Procedure:
Method 3,4—Step b A solution of N-(2-Amino-5-fluoro-phenyl)-5-bromo-2-chloro-benzamide (6.90 g, 20.12 mmol) in acetic acid (40 mL) was stirred at 80° C. overnight, solvent was then removed under reduced pressure and the crude purified by precipitation from diethylether to obtain 6.00 g of the title compound (92%).
Reaction SMILES: [N+:1]([C:4]1[C:9]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:8][CH:7]=[CH:6][N:5]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.[Fe]>[F:14][C:11]([F:12])([F:13])[O:10][C:9]1[C:4]([NH2:1])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1ncccc1OC(F)(F)F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1ncccc1OC(F)(F)F
Temperature: 70 °C

Procedure:
To a stirred solution of 2-nitro-3-(trifluoromethoxy)pyridine (370 mg, 1.78 mmol) in ethanol (5 mL) were added aqueous ammonium chloride (951 mg, 17.78 mmol, in 10 mL of water) and iron powder (993 mg, 17.78 mmol). The reaction mixture was heated to 70° C. for 2 h. After cooling down the reaction mixture was filtered and the solid was washed with ethyl acetate. The mother liquid was concentrated to dryness in vacuo. The residue was diluted with water and extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The residue was used in next step directly without further purification (250 mg, 79%): 1H NMR (400 MHz, DMSO-d6) δ 7.93-7.91 (m, 1H), 7.48-7.46 (m, 1H), 6.59-6.56 (m, 1H), 6.35 (brs, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:11]([N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[C:25]2=[O:40])[CH2:12][CH2:13][CH2:14][NH:15][S:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)(=[O:18])=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].ClC(Cl)C.[O:45]1[CH:49]=[CH:48][C:47]([CH:50]=O)=[CH:46]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:11]([N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[N:34]3[CH2:39][CH2:38][N:37]([CH2:50][C:47]4[CH:48]=[CH:49][O:45][CH:46]=4)[CH2:36][CH2:35]3)[C:25]2=[O:40])[CH2:12][CH2:13][CH2:14][NH:15][S:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)(=[O:18])=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc([C@@H](CCCNS(=O)(=O)c2cccs2)N2C(=O)c3cccc(N4CCNCC4)c3C2=O)cc1OC
Reactant: O=Cc1ccoc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: CC(Cl)Cl
Product: COc1ccc([C@@H](CCCNS(=O)(=O)c2cccs2)N2C(=O)c3cccc(N4CCN(Cc5ccoc5)CC4)c3C2=O)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.4 %

Procedure:
A 50-mL round bottom flask was charged with Compound 167 (20.0 mg, 0.032 mmol) and dichloroethane (4.0 mL). Trietheylamine (5.0 μL) was added followed by 3-furaldehyde (6.0 mg, 0.06 mmol) and tetramethylammonium triacetoxyborohydride (11.8 mg, 0.045 mmol). The mixture was stirred at room temperature for 3 h. The mixture quenched with saturated aqueous sodium bicarbonate (10 mL) and extracted with dichloromethane (50 mL). The organic layer was dried using Na2SO4, filtered through Celite®, and concentrated in vacuo. The crude oil was purified on a on a Gilson HPLC with a reversed phase Kromasil column (10u, 100 Å C18, column length 250×50 mm, gradient 90:10-0:100 H2O:MeCN) to give 13.7 mg of Compound 170 as a yellow solid. 1H NMR (300 MHz, CDCl3) 7.50-7.64 (m, 5H), 7.43 (d, J=7.2 Hz, 1H), 7.13 (d, J=8.2 Hz, 1H), 7.00-7.06 (m, 3H), 6.79 (d, J=8.0 Hz, 1H), 6.56 (s, 1H), 5.12-5.23 (m, 1H), 4.61-4.74 (m, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.63-3.75 (m, 4H), 3.41-3.51 (m, 2H), 2.94-3.35 (m, 4H), 2.53-2.65 (m, 1H), 2.18-2.30 (m, 1H), and 1.46-1.71 (m, 2H); MS (ES+) 665 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:22])[CH:5]([NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:6]([O:8]CC)=[O:7])C.[OH-].[Na+]>C(O)C>[CH2:15]([O:14][C:12]([NH:11][CH:5]([C:6]([OH:8])=[O:7])[C:4]([OH:22])=[O:3])=[O:13])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(NC(C(=O)O)C(=O)O)OCc1ccccc1
Reaction time: 19 h
Yield: 96.4 %

Procedure:
Compound 2 (3.49 mmol, 1.08 g) was dissolved in 3 mL 95% ethanol and treated with 3.49 mL 2N NaOH. The clear, colorless solution was left at room temperature for 19 h until no starting material could be detected by tlc on silica gel (benzene:ethyl acetate, 4:1). Ethanol was evaporated under reduced pressure at room temperature. The aqueous solution was washed once with ether and then acidified with concentrated HCl to pH 2.5. The milky solution was extracted with ethyl acetate (3x). The pooled extract was washed with brine, drived over anhydrous Na2SO4 and evaporated to dryness. The product was crystallized from ether to yield 0.852 g of compound 3; mp 144°-145° C.; homogenious by tlc on silica gel (CHCl3 :methanol:acetic acid, 5:13:0.1); 250 MHz nmr (acetone-d6, ppm) 5.00 (1H, d, J=8 Hz, α-H), 5.10 (2H, s, ArCH2 --), 6.84 (1H, d, J=8 Hz, amide H), 7.36 (5H, m, ArH5). In a 60 MHz spectrum run in low water content acetone, a 9.7 ppm (2H, broad s, exchangeable with D2O) was also observed.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1([C:11]([OH:13])=O)[CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:2].Cl.[NH2:16][C@@H:17]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:31][CH:30]=1)[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].CCN=C=NCCCN(C)C.Cl.ON1C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:32]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:33]=[CH:34][C:29]([CH2:28][C@H:17]([NH:16][C:11]([C:6]2([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10]2)=[O:13])[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[CH:30][CH:31]=1
Reactant: N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1
Reactant: CCOC(=O)CC1(C(=O)O)CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CC1(C(=O)N[C@@H](Cc2ccc(-c3ccccc3)cc2)C(=O)OCc2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
A solution of 1-(2-ethoxy-2-oxoethyl)cyclopentanecarboxylic acid (672 mg, 3.36 mmol), (S)-benzyl 2-amino-3-(biphenyl-4-yl)propanoate hydrochloride (957 mg, 2.60 mmol), WSC.HCl (833 mg, 4.34 mmol), 1-hydroxy-7-azabenzotriazole (591 mg, 4.34 mmol) and DIPEA (0.759 ml, 4.34 mmol) in DMF (15 ml) was allowed to stir at room temperature for 2 hours. The reaction was quenched with H2O (10 ml) and 35% NH4OH aqueous (2 ml). The mixture was stirred for 30 minutes. The product was extracted with EtOAc, washed twice with 1 M HCl aqueous, once with H2O, and then once with brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel (heptane/EtOAc=100:0 to 60:40) to give (S)-benzyl 3-(biphenyl-4-yl)-2-(1-(2-ethoxy-2-oxoethyl)cyclopentanecarboxamido)propanoate (1.143 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([C:14]1([CH2:29][CH2:30][CH2:31][OH:32])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][CH2:17][C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]1=2)[CH2:12][CH3:13].C(N(CC)CC)C>ClCCl>[CH2:11]([C:14]1([CH2:29][CH2:30][CH:31]=[O:32])[C:15]2[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=2[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]1=2)[CH2:12][CH3:13]
Reactant: CCCC1(CCCO)c2ccccc2CCc2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCCC1(CCC=O)c2ccccc2CCc2ccccc21
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 87.8 %

Procedure:
Dissolved oxalyl chloride (1.6 mL, 2.38 g, 0.0187 mol) in 40 mL of dry dichloromethane, and cooled to -78° C. under a nitrogen atmosphere. Added dimethylsulfoxide (2.7 mL, 2.93 g, 0.0374 mol) dissolved in 10 mL of dry dichloromethane dropwise via addition funnel. Stirred for 15 mins at -78° C., and then added 3-[10,11-dihydro-5-propyl-5H-dibenzo[a,d]cyclohepten-5-yl]-propanol (4.41 g, 0.0150 mol) dissolved in 25 mL of dry dichloromethane dropwise via addition funnel. Stirred for 20 mins at -78° C., and then added triethylamine (6.3 mL, 4.55 g, 0.0449 mol). Warmed slowly to room temperature. Added water, and extracted with dichloromethane. Washed combined organic extracts with 0.5N HCl and saturated NaCl, dried with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 3% ethyl acetate-hexane, 6% ethyl acetate-hexane, and then 10% ethyl acetate-hexane. Combined appropriate fractions, and evaporated to give 3.85 g (88% yield) of 3-[10,11-dihydro-5-propyl-5H-dibenzo[a,d]cyclohepten-5-yl]-propanal as a colorless oil.
Reaction SMILES: NC(N)=S.[CH2:5]([O:7][C:8]1[CH:9]=[C:10]([C:14](=[O:16])[CH3:15])[CH:11]=[CH:12][CH:13]=1)[CH3:6].[Br:17]Br>>[Br:17][CH2:15][C:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:7][CH2:5][CH3:6])[CH:9]=1)=[O:16]
Reactant: CCOc1cccc(C(C)=O)c1
Reactant: BrBr
Agent: NC(N)=S
Product: CCOc1cccc(C(=O)CBr)c1

Procedure:
This compound was prepared from resin-bound thiourea of Example 24 and 2-bromo-(3-ethoxyphehyl)-ethanone by the procedure used in Example 36. MS (ES) MH+=453. The 2-bromo-(3-ethoxyphenyl)-ethanone was prepared by treating 1-(3-ethoxy-phenyl)-ethanone (prepared in accordance with the procedure in J. Chem. Soc. Perkin Trans. 2:1996, 755-760) with bromine as in Example 20C.