Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:13]1[N:17]=[N:16][C:15]([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([OH:21])=O)=[N:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:40][O:41][C:42]1[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[C:45]([O:51][CH3:52])[C:43]=1[NH2:44].Cl>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:13]1[N:17]=[N:16][C:15]([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([NH:44][C:43]2[C:45]([O:51][CH3:52])=[CH:46][C:47]([O:49][CH3:50])=[CH:48][C:42]=2[O:41][CH3:40])=[O:21])=[N:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCn1nnc(C(C(=O)O)c2ccccc2)n1
Reactant: COc1cc(OC)c(N)c(OC)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCn1nnc(C(C(=O)Nc2c(OC)cc(OC)cc2OC)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound obtained in (d) above (6.58 g; 17.6 mmoles) was dissolved in tetrahydrofuran (50 mL), treated with carbonyldiimidazole (3.1 g; 19.1 mmoles), and stirred for 1 hour at room temperature under an atmosphere of N2. A solution of 2,4,6-trimethoxyaniline (3.2 g; 17.6 mmoles/50 mL THF) was then added in one portion and the solution was stirred at room temperature for overnight. Ethyl acetate (150 mL) was then added as well as aqueous HCl (1N). The layers were separated and the organic portion was washed with NaOH (1N), brine, and then dried over MgSO4. The drying agent was filtered and the filtrate concentrated in vacuo leaving a lavender colored solid which was purified by silica gel chromatography using chloroform (95%)/methanol (5%) as the eluent. Yield: 6.7 g (70%), mp 119°-120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C@H:9]([NH2:11])[CH3:10].C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41](O)=[O:42])=[CH:38][CH:39]=3)[C:34]([CH3:44])=[C:33]2[CH3:45])=[CH:27][CH:26]=1)=[O:18])(C)(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C@H:9]([NH:11][C:41]([C:37]1[CH:36]=[C:35]2[C:40](=[CH:39][CH:38]=1)[N:32]([CH2:31][C:28]1[CH:27]=[CH:26][C:25]([C:20]3[C:19]([C:17]([OH:18])=[O:16])=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:30][CH:29]=1)[C:33]([CH3:45])=[C:34]2[CH3:44])=[O:42])[CH3:10]
Reactant: C[C@@H](N)c1c(Cl)cccc1Cl
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)N[C@H](C)c3c(Cl)cccc3Cl)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using (R)-1-(2,6-dichlorophenyl)ethanamine and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 571 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:16])=[C:4]([NH:8][C:9](=[S:15])[NH:10][CH2:11][C:12](N)=[O:13])[CH:5]=[CH:6][CH:7]=1.[CH2:17](I)[CH3:18]>Cl>[Cl:1][C:2]1[C:3]([CH3:16])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]=[C:9]2[S:15][CH2:17][CH3:18])[CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: Cc1c(Cl)cccc1NC(=S)NCC(N)=O
Agent: Cl
Product: CCSC1=NCC(=O)N1c1cccc(Cl)c1C

Procedure:
The title compound was prepared by the procedure described in Example 6 using 12.0 g of 2-[3-(3-chloro-2-methylphenyl)-thioureido]-acetamide, and 25.0 g of ethyl iodide. The hydrochloride salt was prepared in ethereal hydrogen chloride. Crystallization from ethyl acetate afforded the title compound as a white solid, mono-hydrochloride (5.1 g), m.p. 161°-163° C. (dec.). Anal. Calcd. for. C12H13Cl N2O S . HCl: C, 47.22; H, 4.62; N, 9.18. Found: C, 47.03; H, 4.40; N, 9.09. Mass spectrum (+FAB, [M+H]+) m/z 269/271. 1H-NMR (DMSO-d6 ; 400 MHz) δ9.05-9.85 (broad s, 2 H), 7.62 (d, 1 H), 7.39 (t, 1 H), 7.33 (d, 1 H), 4.48 (q, 2 H), 3.20 (m, 2 H), 2.15 (s, 3 H), and 1.29 ppm (t, 3 H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:15][C:14]2[CH:16]=[CH:17][C:11]([Cl:10])=[CH:12][CH:13]=2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Cc1cc(Cl)nc(Cl)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2ccc(Cl)cc2)nc(Cl)n1
Temperature: 90 °C
Yield: 9.6 %

Procedure:
2,4-Dichloro-6-methylpyrimidine (10 g, 61.3 mmol) and 4-chloroaniline (7.83 g, 61.3 mmol) were dissolved in acetonitrile (100 mL). Diisopropylethylamine (21.37 mL, 122.7 mmol) was added and heated to 90° C. for 4 days. The reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography with ethyl acetate-hexane as eluent to give (2-chloro-6-methyl-pyrimidin-4-yl)-(4-chloro-phenyl)-amine (1.5 g, 10%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[CH:6][CH:7]=1.[CH:15]([NH:17][NH2:18])=O>C(O)CCC>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:15]=[N:17][N:18]=2)[N:4]=1
Reactant: Fc1ccccc1-c1ccc(Cl)nn1
Reactant: NNC=O
Solvent: CCCCO
Product: Fc1ccccc1-c1ccc2nncn2n1

Procedure:
A mixture of 5.0 g. of 3-chloro-6-(o-fluorophenyl)pyridazine and 2.88 g. of formylhydrazine in 75 ml. n-butanol is refluxed for 48 hrs. and worked up as in Example 35 to give 1.1 g. of product as cream colored crystals, m.p. 161°-163° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1)=[O:12]>>[Br:19][C:15]1[CH:14]=[C:13]([C:11]([C:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=2)([OH:12])[CH3:10])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: Cc1cccc([Mg]Br)c1
Product: Cc1cccc(C(C)(O)c2cccc(Br)c2)c1

Procedure:
In an analogous reaction sequence to that described for Building Block C, the reaction of 3-methyl phenylmagnesium bromide with 3-bromoacetophenone yielded the 1-(3-bromo-phenyl)-1-m-tolyl-ethanol which was used as crude material in the following elimination reaction with a catalytic amount of p-toluenesulfonic acid to yield the title compound (yield: 66% of theory) as a colourless oil. TLC: Rf: 0.83 (silica gel; heptane:ethyl acetate=4:1, UV, 254 nm).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:20])[N:4]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[NH2:8].[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=1[CH2:33][C:34](O)=O.CCN=C=NCCCN(C)C>C(O)C>[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:24][C:23]=1[CH2:33][C:34]1[NH:1][C:2]2[C:3](=[O:20])[N:4]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:5](=[O:10])[N:6]([CH3:9])[C:7]=2[N:8]=1
Reactant: COc1ccc(Cn2c(=O)c(N)c(N)n(C)c2=O)cc1
Reactant: O=C(O)Cc1cc(OC(F)(F)F)ccc1F
Agent: CCN=C=NCCCN(C)C
Solvent: CCO
Product: COc1ccc(Cn2c(=O)c3[nH]c(Cc4cc(OC(F)(F)F)ccc4F)nc3n(C)c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
To a solution of 5,6-diamino-3-(4-methoxybenzyl)-1-methylpyrimidine-2,4(1H,3H)-dione (80 mg, 0.289 mmol, intermediate 59) in ethanol (2 mL) was added 2-(2-fluoro-5-(trifluoromethoxy)phenyl)acetic acid (68.8 mg, 0.289 mmol) followed by EDCI (66.5 mg, 0.347 mmol) and the mixture was stirred at room temperature for 2 h. The reaction was partitioned between ethyl acetate and brine. The organic phase was dried and concentrated. The residue was dissolved in ethanol (3 mL) and 1 mM sodium hydroxide (1 mL) was added. The resulting mixture was stirred at reflux for 3 h. The reaction was concentrated and residue was partitioned between ethyl acetate and brine. The organic layer was dried and concentrated to give a crude solid product, which was triturated with ethanol, collected and dried to afford 8-(2-fluoro-5-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (67 mg, 48.4% yield) as a light yellow solid. LCMS retention time 1.611 min; LCMS MH+ 479.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:7](=[C:19]([C:22]4[O:26][N:25]=[C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:23]=4[C:33]([F:36])([F:35])[F:34])[O:20][N:21]=3)[CH2:8][N:9](C(OC(C)(C)C)=O)[C:10]=2[CH:11]=1.Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:7](=[C:19]([C:22]4[O:26][N:25]=[C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:23]=4[C:33]([F:36])([F:34])[F:35])[O:20][N:21]=3)[CH2:8][NH:9][C:10]=2[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1Cc2c(noc2-c2onc(-c3ccccc3)c2C(F)(F)F)-c2ccc(Br)cc21
Agent: Cl
Solvent: C1CCOC1
Product: FC(F)(F)c1c(-c2ccccc2)noc1-c1onc2c1CNc1cc(Br)ccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.9 %

Procedure:
A mixture of tert-butyl 7-bromo-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)isoxazolo[4,3-c]quinoline-5(4H)-carboxylate (Preparation 77C, 0.030 g, 0.053 mmol) and 6 N aqueous hydrochloric acid (0.107 mL, 0.640 mmol) in THF (5.0 mL) was stirred at room temperature overnight. The reaction mixture was concentrated, dissolved in dichloromethane (3 mL) and treated with TFA (0.5 mL) for 2 h. The reaction mixture was concentrated under vacuum, dissolved in 5 ml dichloromethane and carefully neutralized with 1N NaOH to approx. pH=7, filtered and the filtrate concentrated to give 7-bromo-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydroisoxazolo[4,3-c]quinoline (0.025 g, 0.054 mmol, 100%) as a yellowish solid. The product had an HPLC ret. time=4.43 min. (condition B). LC/MS M+1=463.4 and 465.2.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH2:7][PH:8](=[O:14])[O:9][CH2:10][CH2:11][O:12][CH3:13])=[CH:4][C:3]=1[O:17][CH3:18].Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])[C:23]([C:37]([F:40])([F:39])[F:38])=[CH:22][N:21]=1>>[CH3:18][O:17][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:2]=1[NH:1][C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=2[C:29](=[O:30])[NH:31][CH3:32])[C:23]([C:37]([F:40])([F:38])[F:39])=[CH:22][N:21]=1)[CH2:6][CH2:7][PH:8](=[O:14])[O:9][CH2:10][CH2:11][O:12][CH3:13]
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Reactant: COCCO[PH](=O)CCc1ccc(N)c(OC)c1
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc(CC[PH](=O)OCCOC)cc2OC)ncc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedure for Example 102 using 2-methoxyethyl (4-amino-3-methoxybenzyl)methylphosphinate and 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (Compound 104A). 1H NMR (DMSO-d6, 400 MHz): δ=1.33 (d, J=14.15 Hz, 3 H), 2.76 (d, J=4.55 Hz, 3 H), 3.21 (d, J=17.94 Hz, 2 H), 3.26 (s, 3 H), 3.48-3.52 (m, 2 H), 3.77 (s, 3 H), 4.03 (ddt, J=6.19, 4.48, 3.13, 3.13 Hz, 2 H), 6.81-6.87 (m, 1 H), 7.02 (s, 1 H), 7.07 (t, J=7.45 Hz, 1 H), 7.38 (t, J=8.08 Hz, 1 H), 7.51 (d, J=7.33 Hz, 1 H), 7.64-7.70 (m, 1 H), 8.37 (s, 1 H), 8.72 (d, J=4.29 Hz, 1 H), 8.79 (br. s., 1 H), 11.43 (s, 1 H). MS (ES+): m/z 568.15 [MH+] (TOF, polar).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:13])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[S:5][C:4](=[O:14])[CH:3]=1.S(OC)(O[CH3:19])(=O)=O>>[CH3:19][O:1][C:2]1[C:6]([CH3:13])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[S:5][C:4](=[O:14])[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: CCCCCCC1(C)SC(=O)C=C1O
Product: CCCCCCC1(C)SC(=O)C=C1OC
Yield: 57.6 %

Procedure:
From 33 (40.3 mg, 0.19 mmol) and dimethyl sulfate (35 μL, 0.37 mmol) following general procedure H was obtained 36 (25 mg, 58%) after flash chromatography (15% EtOAc/Hexanes). 1H NMR (300 MHz, CDCl3) δ 0.86 (t, J=6.7 Hz, 3H), 1.08-1.13 (m, 1H), 1.24 (s, 6H), 1.35-1.39 (m, 1H), 1.61 (s, 3H), 1.75-1.82 (m, 2H), 3.81 (s, 3H), 5.30 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 14.0, 22.5, 25.1, 26.4, 29.2, 31.5, 38.9, 59.4, 59.4, 101.3, 187.3, 193.8.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][C:32]=2[Si:38]([CH3:41])([CH3:40])[CH3:39])[CH2:26][CH2:25]1>>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([NH:35][C:34]2[CH:36]=[CH:37][C:31]([CH2:30][N:27]3[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]3)=[C:32]([Si:38]([CH3:39])([CH3:41])[CH3:40])[CH:33]=2)=[O:18])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C#Cc2cc(C(=O)O)ccc2C)cn1
Reactant: CN1CCN(Cc2ccc(N)cc2[Si](C)(C)C)CC1
Product: CC(=O)Nc1ccc(C#Cc2cc(C(=O)Nc3ccc(CN4CCN(C)CC4)c([Si](C)(C)C)c3)ccc2C)cn1

Procedure:
This compound can be made in a similar way described in alternative synthesis of example 1 using 3-{[6-(acetylamino)pyridin-3-yl]ethynyl}-4-methylbenzoic acid and 4-[(4-methylpiperazin-1-yl)methyl]-3-(trimethylsilyl)aniline.
Reaction SMILES: [N:1]([CH2:4][C:5]1[O:6][CH:7]=[C:8]([C:10]2([CH3:15])[O:14][CH2:13][CH2:12][O:11]2)[N:9]=1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[CH3:15][C:10]1([C:8]2[N:9]=[C:5]([CH2:4][NH2:1])[O:6][CH:7]=2)[O:14][CH2:13][CH2:12][O:11]1
Reactant: CC1(c2coc(CN=[N+]=[N-])n2)OCCO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC1(c2coc(CN)n2)OCCO1
Temperature: 55 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (4-(2-methyl-[1,3]dioxolan-2-yl)-oxazol-2-yl)-methanol (230 mg, 1.24 mmol) in dry CH2Cl2 (10 mL) was treated at 0° C. with Et3N (0.23 mL, 1.64 mmol) followed by DMAP (15 mg, 0.12 mmol) and Ms-Cl (0.13 mL, 1.61 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (4-(2-methyl-[1,3]dioxolan-2-yl)oxazol-2-yl)methyl methanesulfonate as a colorless oil. The crude material was dissolved in dry DMF (6 mL) and treated with NaN3 (93 mg, 1.41 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 2-(azidomethyl)-4-(2-methyl-[1,3]dioxolan-2-yl)oxazole as a colorless oil. To a solution of the crude azide in THF (9 mL) were added polymer-supported Ph3P (1.4 eq.) and water (3 mL). The reaction mixture was stirred at 55° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. sat. NaHCO3 and the layers separated. The aq. layer was concentrated under reduced pressure, the residue triturated in EtOH and the solid filtered off. The filtrate was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as an orange oil. LC-MS-conditions 01: tR=0.22 min; [M+H]+=185.00.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH:10]([OH:21])[CH:9]1[CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][Si:14]([C:17]([CH3:18])([CH3:20])[CH3:19])([CH3:16])[CH3:15])[CH:10]([O:21][S:45]([CH3:44])(=[O:47])=[O:46])[CH:9]1[CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)C(O)C1CCNC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)C(OS(C)(=O)=O)C1CCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution containing crude 8 (500 mg, 1.01 mmol) in DCM (15 mL) was cooled to 0° C. DIPEA (261 mg, 2.02 mmol) was added followed by the addition of MsCl (117 mg, 1.02 mmol) and DMAP (13 mg, 0.1 mmol). After 2 h, the reaction mixture was warmed to ambient temperature, diluted with DCM, washed successively with 1M HCl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 578 mg (quant.) of crude 9 as a tan-colored foam which was used without further purification. 1H NMR (CDCl3, 300 MHz), mixture of rotomers: δ7.35 (m, 5H), 5.90 (m, 1H), 5.10 (m, 2H), 4.67 (m, 1H), 4.40 (m, 1H), 4.11 (m, 2H), 3.94 (m, 0.5H), 3.80 (m, 0.5H), 3.74 (app dd, J=12.2, 5.0 Hz, 1H), 3.51 (m, 0.5H), 3.31 (m, 0.5H), 3.02 (s, 3H), 1.96 (m, 0.5H), 1.85 (m, 0.5H), 1.46 (s, 9H), 0.88 (s, 9H), 0.05 (s, 6H) ppm. Mass spectrum, m/z [595.2] (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][N:8]([C:10](OC(C)(C)C)=[O:11])[CH2:7][N:6]1[C:17](=[O:27])[CH:18]([NH:22][C:23]([O:25][CH3:26])=[O:24])[CH:19]([CH3:21])[CH3:20])=[O:4].Cl.[CH:29](N(C(C)C)CC)(C)C.C(OC(=O)C)(=O)C>ClCCl>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][N:8]([C:10](=[O:11])[CH3:29])[CH2:7][N:6]1[C:17](=[O:27])[CH:18]([NH:22][C:23]([O:25][CH3:26])=[O:24])[CH:19]([CH3:21])[CH3:20])=[O:4]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)NC(C(=O)N1CN(C(=O)OC(C)(C)C)CC1C(=O)OC)C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: COC(=O)NC(C(=O)N1CN(C(C)=O)CC1C(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
3-(2-Methoxycarbonylamino-3-methyl-butyryl)-imidazolidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (465 mg, 1.2 mmol) was dissolved in dichloromethane (1 mL) and HCl (4M dioxane, 3 mL) was added. The resultant suspension was stirred at room temperature for 30 minutes, after which all volatiles were removed in vacuo. The crude material was dissolved in THF and diisopropyl ethylamine (154 mg, 1.2 mmol) was added, followed by acetic anhydride (122 mg, 1.2 mmol). The reaction was stirred at room temperature. After 30 minutes, all volatiles were removed in vacuo. The crude material was purified by silica gel chromatography (eluent: DCM/MeOH) to yield the product 1-Acetyl-3-(2-methoxycarbonylamino-3-methyl-butyryl)-imidazolidine-4-carboxylic acid methyl ester (273 mg, 0.829 mmol): LCMS-ESI+: calc'd for C14H23N3O6: 329.4 (M+); Found: 330.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@@H:15]([C:19](O)=[O:20])[CH2:14]2)=[CH:9][CH:8]=1.CN.[CH3:27][N:28](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:27][NH:28][C:19]([C@@H:15]1[CH2:16][C:17](=[O:18])[N:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]3[CH:22]=[CH:23][CH:24]=[C:2]([Cl:1])[CH:3]=3)=[CH:8][CH:9]=2)[CH2:14]1)=[O:20]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(Cl)c3)cc2)C1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Product: CNC(=O)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(Cl)c3)cc2)C1

Procedure:
In an analogous manner to that described in Example 24f), the condensation of the (R)-1-[4-(3-chloro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid with methylamine using HBTU as the condensation agent yields the (R)-1-[4-(3-chloro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methylamide as a white solid. MS: m/e=359 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][CH:11]=2)[N:3]=1.[ClH:21]>>[ClH:21].[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:19][CH:20]=2)[N:3]=1
Reactant: CCOC(=O)c1ccc(CCc2cccc(N)n2)cc1
Agent: Cl
Product: Nc1cccc(CCc2ccc(C(=O)O)cc2)n1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A suspension of ester 8-5 (625 mg, 2.31 mmol) in 6N HCl (12 ml) was heated to 60° C. After ˜20 h, the reaction was concentrated to give acid 8-6 as a tan solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[CH:20]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[OH:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:30]I.O>C1COCC1>[CH:22]1([CH:20]([O:21][CH3:30])[C:11]2[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:10]=2[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CI
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(C(F)(F)F)ccc1C(O)C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(c1ccc(C(F)(F)F)cc1CO[Si](C)(C)C(C)(C)C)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of (2-((tert-butyldimethylsilyloxy)methyl)-4-(trifluoromethyl)-phenyl)-(cyclohexyl)-methanol (1.25 g, 3.11 mmol) in THF (5 mL) at 0° C. was added sodium hydride (385 mg, 9.6 mmol). The mixture was stirred at room temperature for 1 hour, cooled to 0° C. and methyl iodide (1.0 mL, 16 mmol) was added. The mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography over 25+S Biotage silica column (eluted with 0-5% ethyl acetate in heptane) to afford the title compound as a colorless oil (1.14 g, 88%). 1H NMR (400 MHz, CDCl3) δ ppm 0.12 (s, 6H) 0.94-0.96 (m, 9H) 0.98-1.29 (m, 6H) 1.54-1.59 (m, 1H) 1.61-1.67 (m, 2H) 1.71-1.79 (m, 1H) 2.00 (d, J=12.03 Hz, 1H) 3.13 (s, 3H) 4.08 (d, J=7.47 Hz, 1H) 4.71 (d, J=13.69 Hz, 1H) 4.85 (d, J=13.69 Hz, 1H) 7.44 (d, J=8.30 Hz, 1H) 7.52 (d, J=7.88 Hz, 1H) 7.76 (s, 1H).
Reaction SMILES: C(OC(=O)[N:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30](=[O:34])[NH:31][CH2:32]C)=[CH:26][N:25]=2)=[CH:19][CH:18]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:32][NH:31][C:30](=[O:34])[C:27]1[CH:28]=[CH:29][C:24]([O:23][C:20]2[CH:21]=[CH:22][C:17]([CH2:16][NH:7][CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:18][CH:19]=2)=[N:25][CH:26]=1
Reactant: CCNC(=O)c1ccc(Oc2ccc(CN(CCc3ccccc3)C(=O)OC(C)(C)C)cc2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1ccc(Oc2ccc(CNCCc3ccccc3)cc2)nc1
Reaction time: 24 h
Yield: 95 %

Procedure:
Combine [4-(5-Ethylcarbamoyl-pyridin-2-yloxy)-benzyl]-phenethyl-carbamic acid tert-butyl ester (55.4 mg, 0.12 mmol), CH2Cl2 (4 mL), and TFA 99% (0.8 mL) in a 7 mL reaction vial. After reaction shakes on shaker at room temperature for 24 hours, concentrate under reduced pressure. Add the reaction mixture to a 2 g SCX column, wash with MeOH, and elute with 1N NH3 MeOH. Concentrate sample to afford 41.2 mg (95% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 1.5 (1H, br m), 2.7-3.0 (7H, m), 3.7 (2H, s), 6.2 (1H, br s), 6.9 (1H, d), 7.0-7.4 (9H, m), 8.0 (1H, d), 8.4 (1H, s); MS m/z 363 (M+1).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1>CN(C=O)C.CCOC(C)=O>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:3]2[C:2]([NH2:1])=[N:6][N:5]=[N:4]2)=[CH:17][CH:16]=1
Reactant: Nc1nnn[nH]1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nnnc2N)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 17.3 %

Procedure:
To a suspension of 5-amino-1H-tetrazole (1.50 g, 17.6 mmol) in DMF (30 mL) were added Cs2CO3 (8.62 g, 26.4 mmol) and PMBCl (2.90 g, 18.5 mmol). After stirred at 60° C. for 3 hours, the reaction mixture was cooled to room temperature and diluted with EtOAc. The mixture was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was diluted with DCM and the resulted precipitate was collected by filtration to give 1-(4-methoxy-benzyl)-1H-tetrazol-5-ylamine (0.625 g). 1H NMR (400 MHz, DMSO-d6) δ 3.73 (s, 3H), 5.27 (s, 2H), 6.78 (s, 2H), 6.92 (d, 2H, J=8.8 Hz), 7.21 (d, 2H, J=8.8 Hz).