Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([OH:11])[CH2:3][CH2:2]1.[Cl:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15](Cl)[N:14]=1>O1CCOCC1.ClCCl>[Cl:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15]([O:11][CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[O:1][CH2:2][CH2:3]2)[N:14]=1
Reactant: OC1CCOc2ccccc21
Reactant: Clc1cncc(Cl)n1
Solvent: C1COCCO1
Solvent: ClCCl
Product: Clc1cncc(OC2CCOc3ccccc32)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
K-t-BuO (1.28 g, 11.42 mmol) was added to a stirred solution of 4-chromanol (1.81 g, 12.0 mmol) in dioxane (30 mL) at 0° C. (ice-bath). After being stirred for 5 min at room temperature, the mixture was chilled to 0° C. (ice-bath) and 2,6-dichloropyrazine (1.49 g, 10.0 mmol) was added. The reaction mixture was stirred at room temperature for 15 min and diluted with dichloromethane. Filtration and concentration in vacuo furnished an orange thick oil which was purified by chromatography on silica gel (15×4 cm) using n-hexane/ethyl acetate (8:2) as eluent. This furnished 1.87 g (71%) of the title compound as a colorless oil. HRMS m/z calcd for C13H11ClN2O2 (M)+ 262.0509, found 262.0520. Anal. (C13H11ClN2O2) C, H, N.
Reaction SMILES: [Li][CH3:2].[CH:3]12[O:8][CH:7]1[CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH2:4]2>CCOCC.[Cu]I>[OH:8][C@H:7]1[C@H:3]([CH3:2])[CH2:4][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:6]1
Reactant: [Li]C
Reactant: O=C(OCc1ccccc1)N1CC2OC2C1
Agent: [Cu]I
Solvent: CCOCC
Product: C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
To a stirred suspension of CuI (10.2 g, 54 mmol) in ether (120 mL) at −10° C. was added dropwise MeLi (73 mL, 109 mmol, 1.5 M in ether) ensuring that the temperature remained below −5° C. The resulting solution was stirred at −10° C. for 20 min and a solution of phenylmethyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (Example 113) (5 g, 23 mmol) in ether (50 mL) was added, maintaining the temperature below −2° C. The reaction was stirred at −10° C. for 1 hour after which time it was quenched with water and partitioned with DCM. A standard work up yielded phenylmethyl (trans)-3-hydroxy-4-methyl-1-pyrrolidinecarboxylate, which was purified and subjected to chiral chromatography, producing two enantiopure compounds of undetermined absolute stereochemistry. (Yield of E1=1.55 g, yield of E2=1.58 g).
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:30])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1.Cl>CN(C=O)C>[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][N:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21]([CH:18]3[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][O:12][C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=4[C:5]([OH:4])=[O:30])[CH2:16][CH2:17]3)=[CH:22]2)=[CH:34][CH:33]=1
Reactant: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3ccccc23)CC1
Reactant: Fc1ccc(CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1OCCN1CCC(c2cn(Cc3ccc(F)cc3)c3ccccc23)CC1
Reaction time: 18 h
Yield: 83.2 %

Procedure:
0.02 g (0.42 mmol) of a dispersion of 60% NaH in mineral oil were added to a solution of 0.06 g (0.15 mmol) of 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid methyl ester prepared in step D in 1 mL of anhydrous DMF under nitrogen atmosphere. After stirring 30 minutes at room temperature 0.026 mL (0.21 mmol) of 4-fluoro-benzyl bromide were added and the mixture was stirred for 18 hours. After addition of 0.09 g (0.12 mmol) of 3-(3-mercapto-phenyl)-propanamido-methyl-polystyrene in 1 mL of DMF the mixture was stirred overnight at room temperature. 0.1 mL of 2N HCl were added to the reaction mixture and the crude-was filtered. The solvent was removed under reduced pressure and the crude mixture was purified using a 500 mg Varian C18 chromatography column affording 0.059 g (84% yield) of 2-(2-{4-[1-(4-fluoro-benzyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid.
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>C(O)(=O)C>[CH3:3][N:4]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:5]1[CH:6]=[CH:7][C:8]([Br:1])=[CH:9][CH:10]=1
Reactant: CC(C)CCN(C)c1ccccc1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: CC(C)CCN(C)c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
A solution of 58 g of bromine in 60 ml of acetic acid was added dropwise at about 15° C. over one hour to a mixture of 64 g of the product of Step A in 300 ml of acetic acid and the mixture was stirred at 80° C. for 8 hours and was poured into iced water. The mixture was extracted with methylene chloride and the organic phase was washed with aqueous sodium bicarbonate, with water, dried and evaporated to dryness. The residue was distilled to obtain 70 g of N-methyl-N-(3-methylbutyl)-4-bromo-aniline boiling at 119° C. at 0.5 mm Hg.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3](=[O:9])[NH:4][C:5](=[NH:8])[O:6][CH3:7].[C:11]([N:15]=[C:16]=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[CH3:1][N:2]([CH3:10])[C:3]([N:4]=[C:5]([O:6][CH3:7])[NH:8][C:16]([NH:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])=[O:9]
Reactant: COC(=N)NC(=O)N(C)C
Reactant: CC(C)(C)N=C=O
Product: COC(=NC(=O)N(C)C)NC(=O)NC(C)(C)C

Procedure:
5 Parts of methyl 4,4-dimethylallophanimidate and 20 ml of t-butylisocyanate are refluxed overnight. The next day, the solution is evaporated to give an oil, which crystallizes when tirturated with petroleum-ether under cooling. In order to remove some unreacted starting material and byproducts, the solids are first triturated with water and filtered. After drying, the solids are then triturated with carbon tetrachloride and impurities removed by filtration. The carbon tetrachloride filtrate is then evaporated and the residue recrystallized from petroleum-ether to give pure methyl N-dimethylcarbamoyl-4-t-butylallophanimidate (a compound of Formula I), m.p. 96°-98° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH2:11])[O:9][CH:10]=1)=[O:5])[CH3:2].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:14])[CH3:13])[O:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1coc(N)n1
Product: CCOC(=O)c1coc(NC(C)=O)n1

Procedure:
1.0 g (6.40 mmol) 2-Amino-oxazole-4-carboxylic acid ethyl ester and 9.1 mL (96.3 mmol) acetic acid anhydride are stirred for 2 d at rt. The mixture is concentrated in vacuo to yield the desired product which is used without further purification.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9](=[O:15])OC(C)(C)C)[CH2:3]1.C([O:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:36]2[C:44]3[C:39](=[CH:40][C:41](C(O)=O)=[CH:42][CH:43]=3)[C:38]([CH3:48])=[C:37]2[CH3:49])=[CH:31][CH:30]=1)=[O:22])(C)(C)C>>[NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]([C:41]2[CH:40]=[C:39]3[C:44](=[CH:43][CH:42]=2)[N:36]([CH2:35][C:32]2[CH:31]=[CH:30][C:29]([C:24]4[C:23]([C:21]([OH:22])=[O:20])=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:34][CH:33]=2)[C:37]([CH3:49])=[C:38]3[CH3:48])=[O:15])[CH2:3]1
Reactant: CC(C)(C)OC(=O)NC1CCCC(N)C1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NC3CCCC(N)C3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using tert-butyl 3-aminocyclohexylcarbamate and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. LC-MS 496 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:22])[C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[N:7][C:6]=1[C:18]([F:21])([F:20])[F:19])C.O.[OH-].[Li+].Cl>O1CCCC1.O>[Br:11][C:9]1[C:8]([O:12][CH2:13][C:14]([F:15])([F:16])[F:17])=[N:7][C:6]([C:18]([F:21])([F:19])[F:20])=[C:5]([CH:10]=1)[C:4]([OH:22])=[O:3]
Reactant: CCOC(=O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Temperature: 25 °C

Procedure:
5-Bromo-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinic acid ethyl ester (4.0 g, 10 mmol) was dissolved in a mixture of tetrahydrofuran (70 mL) and water (25 mL). Lithiumhydroxid monohydrate (1.26 g, 30 mmol) was added and the mixture was stirred and heated at reflux-temperature for 3 h. After cooling to room temperature the mixture was acidified with hydrochloric acid (1N) to pH 4. The product precipitated and was after filtration dried and isolated as a white solid (quant.); MS (ISP) 365.8, 367.8 (M−H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:31])=[C:6]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=4[F:30])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)[CH:7]=1.[CH3:32][C:33]1([CH3:42])[CH2:38][CH:37]([NH2:39])[CH2:36][C:35]([CH3:41])([CH3:40])[NH:34]1>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:31])=[C:6]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=4[F:30])[C:10]=3[N:11]=[C:12]([NH:39][CH:37]3[CH2:38][C:33]([CH3:42])([CH3:32])[NH:34][C:35]([CH3:41])([CH3:40])[CH2:36]3)[N:13]=2)[CH:7]=1
Reactant: Cc1ccc(N)cc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CC1(C)CC(N)CC(C)(C)N1
Product: Cc1ccc(N)cc1-c1nc(NC2CC(C)(C)NC(C)(C)C2)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared as described in Example 1d from 4-(5-amino-2-methylphenyl)-8-(2,6-difluorophenyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one and 2,2,6,6-tetramethyl-4-piperidinamine: LC-MS m/z 519 (M+H)+, 1.8 min (ret time).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH2:13][CH:14]([OH:17])[CH2:15][OH:16].C(OCC)(=O)C>CS(C)=O>[OH:17][CH:14]([CH2:15][OH:16])[CH2:13][NH:12][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: NCC(O)CO
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(F)cc1NCC(O)CO
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
To a stirred solution of 2,4-difluoronitrobenzene (3.18 g., 20 mmole) in DMSO (10 ml) was added portion-wise a solution of 3-amino-1,2-propanediol (3.64 g., 40 mmole) in DMSO (5 ml) in an ice bath. The mixture was stirred at 23° C. for 30 min. and poured into crushed ice. After addition of ethyl acetate, the organic layer was separated, washed with water, dried over sodium sulfate and evaporated under reduced pressure to give the compound (18) (3.6 g., 78%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][C:17]#[N:18]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:16][C:17]#[N:18]
Reactant: N#CCCl
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CCOc1cccc(F)c1
Temperature: 50 °C
Yield: 94.2 %

Procedure:
To a solution of 3-fluorophenol (560 mg, 5.0 mmol) in DMF (10 mL) is added potassium carbonate (828 mg, 6.0 mmol) followed by chloroacetonitrile (0.315 mL, 50.0 mmol). The reaction mixture is stirred and heated at 50° C. for 14 h. The reaction mixture is cooled to RT, diluted with EtOAc, and washed with water, brine, then dried (MgSO4), and filtered. The filtrate is evaporated, and the residue purified by chromatography on silica gel; elution with dichloromethane gives 712 mg of the product 386.
Reaction SMILES: C1([CH2:7][CH:8]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][C:17]=2[N:22]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:23]2)[CH:9]([OH:13])[C:10]([OH:12])=O)C=CC=CC=1.[C:34]1([CH2:40][CH2:41][NH2:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[OH:13][CH:9]([C:10](=[O:12])[NH:42][CH2:41][CH2:40][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:8]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:23]1)[CH2:7][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccccc2)n1
Reactant: NCCc1ccccc1
Product: O=C(NC(Cc1ccccc1)C(O)C(=O)NCCc1ccccc1)c1cccnc1-n1ccc(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 4-phenyl-2-hydroxy-3-(2-(3-phenyl-1H-pyrazol-1-yl)nicotinamido)butanoic acid with 2-phenylethylamine; ESI-MS [M+H]+: 546.2
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14].[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH2:23])=[CH:18][CH:17]=1.C(N(CC)CC)C>C1COCC1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][CH2:2][C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=2[O:13][CH3:14])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: NCc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CNCc2ccc(F)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
To a solution of methyl 4-(bromomethyl)-3-methoxybenzoate (0.518 g, 2 mmol, Trans World Chemicals) in THF (10 mL) at room temperature was added (4-fluorophenyl)methanamine (1.00 g, 8.00 mmol, Aldrich) and triethylamine (0.56 mL, 4 mmol). The reaction mixture was stirred at rt for 1 h and quenched by the addition of 5 mL of saturated aq. NaHCO3 solution. The resulting mixture was extracted with DCM (3×50 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was purified by flash column chromatography (ISCO system, eluting with CH2Cl2/EtOAc) to give the desired compound (0.35 g, 57%) as a white solid. 1H NMR (CD3OD) δ 7.64 (d, 1H, J=6.0 Hz), 7.60 (s, 1H), 7.40 (d, 2H, J=7.7 Hz), 7.36 (d, 1H, J=6.0 Hz), 7.08 (t, 211, J=7.7 Hz), 3.97 (s, 3H), 3.96 (s, 3H), 3.82 (s, 2H), 3.76 (s, 2H). MS (ESI): 304.1 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:10]3[CH2:20][CH2:21][CH2:22][C:9]=3[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28](O)=[O:29].Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl>[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:10]3[CH2:20][CH2:21][CH2:22][C:9]=3[N:8]=2)[CH2:6][CH2:5]1)=[O:29]
Reactant: O=C(O)c1ccco1
Reactant: Fc1ccc(-c2nc(N3CCNCC3)nc3c2CCC3)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=C(c1ccco1)N1CCN(c2nc3c(c(-c4ccc(F)cc4)n2)CCC3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
A mixture of 2-(1-piperazinyl)-4-(4-fluorophenyl)-6,7-dihydro-5H-cyclopentapyrimidine (1.0 g), 2-furoic acid (0.38 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.79 g) and chloroform (40 ml) is stirred at room temperature for 2 hours. The reaction mixture is washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is dissolved in toluene, and the solution is subjected to silica gel column chromatography. The fractions eluted with toluene-ethyl acetate (9:1) are collected, and the product therefrom is recrystallized from ethanol to give the desired compound (0.62 g), m.p. 124°-125° C. (ethanol).
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[I-:11].[Na+]>CC(=O)CC.C(OCC)(=O)C>[I:11][CH2:2][C:3](=[O:10])[N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: [I-]
Reactant: O=C(CCl)N1CCOCC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: O=C(CI)N1CCOCC1
Yield: 86.1 %

Procedure:
Dissolve 1-chloro-2-oxo-2-(morpholin-4-yl)ethane (7.0 g, 42.8 mmol) and sodium iodide (8.0 g, 53.4 mmol) in 2-butanone (150 mL) and reflux for 3 hours under nitrogen. Dilute with ethyl acetate (200 mL), filter, concentrate under reduced pressure and chromatograph on flash silica using neat ethyl acetate to obtain 9.4 g (86%) of the title compound as a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:46])[C@H:4]([CH2:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[NH:39][CH:38]=1)[NH:5][C:6](=[O:35])[CH:7]([C:26]1[CH:31]=[CH:30][C:29]2[O:32][CH2:33][O:34][C:28]=2[CH:27]=1)[CH:8]([OH:25])[C:9]1[N:10]=[C:11]([CH2:21][CH2:22][CH2:23][CH3:24])[N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:13]=1.Cl>[OH-].[Na+].CO.C(OCC)(=O)C>[OH:25][CH:8]([C:9]1[N:10]=[C:11]([CH2:21][CH2:22][CH2:23][CH3:24])[N:12]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH:13]=1)[CH:7]([C:26]1[CH:31]=[CH:30][C:29]2[O:32][CH2:33][O:34][C:28]=2[CH:27]=1)[C:6]([NH:5][C@H:4]([C:3]([OH:46])=[O:2])[CH2:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[NH:39][CH:38]=1)=[O:35]
Reactant: CCCCc1nc(C(O)C(C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)OC)c2ccc3c(c2)OCO3)cn1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCc1nc(C(O)C(C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)c2ccc3c(c2)OCO3)cn1C(=O)OC(C)(C)C

Procedure:
A solution of N-[(2RS,3SR)-3-hydroxy-2-(3,4-methylenedioxyphenyl)-3-(2-n-butyl-1-tert-butoxycarbonyl-1H-imidazol-4-yl)propionyl]-L-tryptophan methyl ester (118 mg) in 1N aqueous sodium hydroxide solution (1.0 ml) and methanol (5.0 ml) was stirred at ambient temperature for 2 hours. The solution was acidified with 1N hydrochloric acid and the mixture was diluted with ethyl acetate followed by washing with brine. The organic layer was dried and evaporated to afford crude N-[(2RS,3SR)-3-hydroxy-2-(3,4-methylenedioxyphenyl)-3-(2-n-butyl-1-tert-butoxycarbonyl-1H-imidazol-4-yl)propionyl]-L-tryptophan.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:17]=3)[NH:12][N:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>C1COCC1>[C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)[CH:17]=3)[NH:12][N:11]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCNC1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4ccccc4)c3c2)cc1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1n[nH]c2ccc(OCCN3CCCC3)cc12
Yield: 21.8 %

Procedure:
A solution of toluene-4-sulfonic acid 2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl ester (0.347 g, 0.734 mmol) and pyrrolidine (1.0 mL, 12 mmol) in THF (8 mL) was stirred at 70° C. in a sealed tube for 6 hours. After cooling somewhat, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was then washed with water and brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 7.5% methanol in chloroform. After drying at 55° C. in vacuo, 3-benzenesulfonyl-5-(2-pyrrolidin-1-yl-ethoxy)-1H-indazole as a pale yellow solid (0.0595 g, 21.8%) was obtained. This was dissolved in methanol and chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried in vacuo at 75° C. for 16.5 hours to yield the hydrochloride as a yellow foam (0.0598 g). Mass Spectrum (+EI, [M+H]+) m/z 372.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[CH2:6][N:7]1[CH2:10][C@H:9]([NH:11][S:12]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][C:19]([O:25][CH3:26])=[CH:20][CH:21]=3)[CH:16]=2)(=[O:14])=[O:13])[C:8]1=[O:27])#[N:2].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[CH2:6][N:7]1[CH2:10][C@H:9]([N:11]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[S:12]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][C:19]([O:25][CH3:26])=[CH:20][CH:21]=3)[CH:16]=2)(=[O:14])=[O:13])[C:8]1=[O:27])#[N:2]
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CN(Cc4cccc(C#N)c4)C3=O)cc2c1
Reactant: BrCc1ccccc1
Product: COc1ccc2ccc(S(=O)(=O)N(Cc3ccccc3)[C@H]3CN(Cc4cccc(C#N)c4)C3=O)cc2c1

Procedure:
The title compound is prepared as described in EXAMPLE 25, Part A using 7-methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxoazetidin-3-(S)-yl]amide, prepared as described in Example 65, part D, and benzyl bromide. The crude product is purified by column chromatography eluting with gradient of 30% EtOAc/hexanes to 40% EtOAc/hexanes to afford the title compound as a white foam.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:12][CH2:11][CH2:10][CH2:9]1.Br[CH2:27][CH2:28][CH2:29][CH2:30][Cl:31]>>[Cl:31][CH2:30][CH2:29][CH2:28][CH2:27][N:20]1[C:19]([O:23][CH3:24])=[N:18][C:17]2[C:21]1=[N:22][C:14]([O:13][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12]1)=[N:15][C:16]=2[NH2:25]
Reactant: ClCCCCBr
Reactant: COc1nc2nc(OC3CCCC3)[nH]c(N)c-2n1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OC3CCCC3)nc2n1CCCCCl

Procedure:
Prepared similarly to Intermediate 44 from 2-(cyclopentyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 1-bromo-4-chlorobutane.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:11])=[C:6]([OH:12])[C:5]=2[CH3:13].N1C=CN=C1.[C:19]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20].Cl>CC#N>[C:19]([Si:23]([CH3:25])([CH3:24])[O:12][C:6]1[C:5]([CH3:13])=[C:4]2[C:9]([CH:10]=[C:2]([CH3:1])[CH2:3]2)=[CH:8][C:7]=1[CH3:11])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC1=Cc2cc(C)c(O)c(C)c2C1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CC#N
Product: CC1=Cc2cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Mixture of 2,5,7-trimethyl-1H-inden-6-ol (1.8 g, 10.3 mmol), imidazole (1.76 g, 25.8 mmol), and tert-butylchlorodimethylsilane (1.87 g, 12.4 mmol) in CH3CN (35 ml) was stirred for 16 h at room temperature, poured into 2% HCl (100 ml), extracted by pentane (4×20 ml). Combined organic fraction was washed by water, dried over MgSO4, and evaporated. The yield 2.8 g (94%).
Reaction SMILES: Cl.Cl.[C@H:3]12[CH2:9][C@H:6]([NH:7][CH2:8]1)[CH2:5][N:4]2[C:10]([C@@:12]1([C:26]2([OH:30])[CH2:29][CH2:28][CH2:27]2)[CH2:16][CH2:15][C@@H:14]([NH:17][C@@H:18]2[C@H:23]([O:24][CH3:25])[CH2:22][O:21][CH2:20][CH2:19]2)[CH2:13]1)=[O:11].Cl[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[N:33]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[OH:30][C:26]1([C@:12]2([C:10]([N:4]3[CH2:5][C@@H:6]4[CH2:9][C@H:3]3[CH2:8][N:7]4[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[N:33]=3)=[O:11])[CH2:16][CH2:15][C@@H:14]([NH:17][C@@H:18]3[C@H:23]([O:24][CH3:25])[CH2:22][O:21][CH2:20][CH2:19]3)[CH2:13]2)[CH2:29][CH2:28][CH2:27]1
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: CO[C@@H]1COCC[C@@H]1N[C@@H]1CC[C@@](C(=O)N2C[C@@H]3C[C@H]2CN3)(C2(O)CCC2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1CC[C@@](C(=O)N2C[C@@H]3C[C@H]2CN3c2cccc(C(F)(F)F)n2)(C2(O)CCC2)C1

Procedure:
A solution of 93 mg (0.20 mmol) of 1,5-anhydro-2,3-dideoxy-3-[{(1R,3S)-3-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-3-(1-hydroxycyclobutyl)cyclopentyl]amino}-4-O-methyl-D-erythro-pentitol dihydrochloride, 91 mg (0.49 mmol) of 2-chloro-6-trifluoromethylpyridine, and 0.14 mL (0.80 mmol) of diisopropylethylamine in 0.5 mL of DMSO was heated at 80 C for 18 h, then cooled and partitioned between ethyl acetate and water. The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The crude material was purified by preparative RP-HPLC using as the mobile phase acetonitrile-water containing 0.05% TFA. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.46-2.52 (m, 16H) 3.26-3.54 (m, 8H) 3.53-3.92 (m, 4H) 4.02 (dd, J=11.8, 4.3 Hz, 1H) 4.22 (d, J=13.0 Hz, 1H) 5.01 (d, J=14.3 Hz, 2H) 6.47 (d, J=8.5 Hz, 1H) 6.93 (d, J=7.5 Hz, 1H) 7.56 (t, J=8.0 Hz, 1H). HRMS calculated for C27H37N4O4F3: 539.2845. found: 539.2894