Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[N:3](C)[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8](C3C=CC=CC=3)[CH2:7]2)[N:6]=1.N1(C(C2C=C(B(O)O)C=CC=2)=O)CCCC1>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:3]1[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[O:9][CH2:8][CH2:7]2)[N:6]=[CH:2]1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: O=C(c1cccc(B(O)O)c1)N1CCCC1
Solvent: C1COCCO1
Product: O=C1NC=NC12CCOc1ccccc12
Temperature: 120 °C
Yield: 20 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL of tube under Ar2 was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-(pyrrolidine-1-carbonyl)phenylboronic acid (10 mg, 0.045 mmol). The mixture was heated at 120° C. in a microwave reactor for 0.5 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 2′-amino-1′-methyl-2-phenyl-643-(pyrrolidine-1-carbonyl)phenyl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (2.10 mg, 8%). 1H-NMR (MeOD): 1.82 (m, 2H), 1.91 (m, 2H), 2.04 (m, 1H), 2.21 (m, 1H), 3.02 (s, 3H), 3.39 (t, 2H), 3.52 (t, 2H), 5.82 (d, 1H), 6.95 (d, 1H), 7.15 (m, 1H), 7.27 (m, 1H), 7.34 (m, 3H), 7.46 (m, 4H), 7.54 (m, 2H).
Reaction SMILES: C([O:4][C@H:5]1[C@@H:31]2[O:32][C@@H:30]2[C@@:29]2([CH3:33])[C:7](=[CH:8][C@@H:9]([O:35][C:36](=[O:39])[NH:37][CH3:38])[C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:34])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][O:18]2)[CH3:16])[CH2:6]1)(=O)C.C(O[C@H]1[C@@H]2O[C@@H]2[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C2OCC(C)(C)CO2)C)C1)(=O)C>>[CH3:24][C:20]1([CH3:23])[CH2:19][O:18][CH:17]([CH:15]([C@@H:14]2[C@:25]3([CH3:34])[C@H:11]([C@H:10]4[C@H:28]([CH2:27][CH2:26]3)[C@:29]3([CH3:33])[C:7]([CH2:6][C@@H:5]([OH:4])[C@@H:31]5[O:32][C@@H:30]53)=[CH:8][C@H:9]4[O:35][C:36](=[O:39])[NH:37][CH3:38])[CH2:12][CH2:13]2)[CH3:16])[O:22][CH2:21]1
Reactant: CNC(=O)O[C@@H]1C=C2C[C@@H](OC(C)=O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCC(C)(C)CO4)CC[C@H]3[C@H]12
Agent: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Product: CNC(=O)O[C@@H]1C=C2C[C@@H](O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCC(C)(C)CO4)CC[C@H]3[C@H]12
Yield: 75.4 %

Procedure:
The procedure of Example 23 was repeated except that 5.5 mg (0.01 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-(N-methylcarbamoyloxy)pregn-5-en-3β-yl acetate was used in lieu of 5 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-yl acetate to give 3.8 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-(N-methylcarbamoyloxy)pregn-5-en3β-ol (yield: 76%).
Reaction SMILES: [CH3:1]O.S(Cl)(Cl)=O.[NH2:7][C:8]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]>>[NH2:7][C:8]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([O:12][CH3:1])=[O:11]
Reactant: CO
Reactant: Nc1c(Cl)cccc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(Cl)c1N
Temperature: -5 °C
Yield: 61 %

Procedure:
3 ml (0.074 mol) of methanol was added to a 50 ml four-necked flask equipped with a stirrer, a reflux condenser, a thermometer, and a dropping funnel, and 1.43 g (0.012 mol) of thionyl chloride was added dropwise with stirring at −5° C. Then, a mixture of 1.71 g (0.010 mol) of 2-amino-3-chlorobenzoic acid in 2.0 ml (0.049 mol) of methanol was added dropwise with stirring at −5° C. Then, the mixture was stirred at room temperature for 15 hours and at 65° C. for 17 hours. The reaction solution was analyzed by HPLC by the absolute calibration method, and as a result, the yield was 61%.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:27]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:32])[CH2:28]C([O-])=O.[Cl-].[Mg+2].[Cl-].CC(C)([O-])C.[K+].Cl>C1COCC1.O.CCOCC>[C:34]([O:33][C:27](=[O:32])[CH2:28][C:4](=[O:6])[C@H:3]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2][CH3:1])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)CC(=O)[O-]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Flask B: To a clear solution of Boc-D-abu-oh (Bachem, 5.00 g, 24.60 mmol) in THF (40 mL) at RT under nitrogen was added 1,1′-carbonyldiimidazole (4.19 g, 25.8 mmol) in one portion. Gas evolution observed and the reaction was stirred for 2.5 h at RT. Flask A: To a mixture of mono-tert-butyl malonate (4.17 mL, 27.1 mmol) and anhydrous magnesium chloride (2.58 g, 27.1 mmol) in THF (100 mL) in a 500 mL 3-necked round-bottomed flask in an ice bath was added potassium tert-butoxide (1.0 M in THF, 27.1 mL, 27.1 mmol) slowly dropwise via addition funnel such that the temperature did not exceed 8° C. The resulting white suspension (milk-like) was stirred at RT for 2 h 30 min then the contents of flask B was added to flask A and the reaction mixture was heated at 50° C. overnight (16 h). The reaction mixture was treated with 1N HCl (15 mL) to pH=7 and then treated with Et2O (60 mL) and water (45 mL). The organic layer was separated, and washed brine (30 mL), dried over anhydrous MgSO4, filtered, and concentrated in vacuo to afford (R)-tert-butyl 4-((tert-butoxycarbonyl)amino)-3-oxohexanoate (505a) as a viscous light yellow oil. m/z (ESI, +ve) 324.2 (M+Na)+.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([NH:10][C@@H:11]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:12]([N:14]2[C@H:29]([C:30]([OH:32])=O)[CH2:28][C@@:16]3([O:20][C:19](=[O:21])[N:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17]3)[CH2:15]2)=[O:13])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:37][C@@H:38]([CH2:47][CH2:48][CH3:49])[CH:39]([OH:46])[C:40]([NH:42][CH:43]1[CH2:45][CH2:44]1)=[O:41]>>[CH:1]1([CH2:7][C:8]([NH:10][C@@H:11]([C:33]([CH3:35])([CH3:36])[CH3:34])[C:12]([N:14]2[C@H:29]([C:30]([NH:37][C@@H:38]([CH2:47][CH2:48][CH3:49])[CH:39]([OH:46])[C:40]([NH:42][CH:43]3[CH2:44][CH2:45]3)=[O:41])=[O:32])[CH2:28][C@@:16]3([O:20][C:19](=[O:21])[N:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17]3)[CH2:15]2)=[O:13])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)[C@H](NC(=O)CC1CCCCC1)C(=O)N1C[C@]2(C[C@H]1C(=O)O)CN(c1ccccc1)C(=O)O2
Reactant: CCC[C@H](N)C(O)C(=O)NC1CC1
Product: CCC[C@H](NC(=O)[C@@H]1C[C@]2(CN(c3ccccc3)C(=O)O2)CN1C(=O)[C@@H](NC(=O)CC1CCCCC1)C(C)(C)C)C(O)C(=O)NC1CC1
Yield: 30.6 %

Procedure:
Following the same procedure as Example 1 step 9 using (5R,8S)-7-((S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoyl)-2-oxo-3-phenyl-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylic acid (49 mg, 98 μmol) and (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide (31 mg, 137 μmol, 1.4 eq.) gave 20 mg (30 μmol) of (5R,8S)-7-((S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoyl)-N-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl)-2-oxo-3-phenyl-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxamide (G2). LC MS+/−: 668.56/666.64 at 3.24 min (10-90%, 3-5 min, Formic Acid).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N-]1C=CN=C1.[CH2:16]([C:20]1[C:24]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[S:38](=[O:41])(=[O:40])[NH2:39])=[CH:28][C:27]=2[F:42])=[C:23]([C:43]#[N:44])[N:22]([C:45]2[CH:50]=[C:49]([N+:51]([O-:53])=[O:52])[CH:48]=[CH:47][C:46]=2[C:54]([F:57])([F:56])[F:55])[N:21]=1)[CH2:17][CH2:18][CH3:19].C1CCN2C(=NCCC2)CC1>>[CH2:16]([C:20]1[C:24]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[S:38](=[O:40])(=[O:41])[NH:39][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])=[CH:28][C:27]=2[F:42])=[C:23]([C:43]#[N:44])[N:22]([C:45]2[CH:50]=[C:49]([N+:51]([O-:53])=[O:52])[CH:48]=[CH:47][C:46]=2[C:54]([F:56])([F:55])[F:57])[N:21]=1)[CH2:17][CH2:18][CH3:19]
Reactant: O=C(O)c1ccccc1Cl
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2C(F)(F)F)c(C#N)c1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1F
Agent: c1c[n-]cn1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2C(F)(F)F)c(C#N)c1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1F

Procedure:
By the method of Example 1, Step H, 2-chlorobenzoic acid is converted to its imidazolide and reacted with 3-n-butyl-4-[(3-fluoro-2'-sulfamoylbiphenyl-4-yl)methyl]-1-[5-nitro-2-(trifluoromethyl)phenyl]-1H-pyrazole-5-carbonitrile (from Step B) in the presence of DBU to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]2[N:6]([C@@H:9]3[O:14][C@H:13]([CH3:15])[C@@H:11]([OH:12])[C@H:10]3[F:16])[CH:7]=[N:8][C:4]=2[CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21].CO>N1C=CC=CC=1>[Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]2[N:6]([C@@H:9]3[O:14][C@H:13]([CH3:15])[C@@:11]([C:20](=[O:22])[CH3:21])([OH:12])[C@H:10]3[F:16])[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H]1O[C@@H](n2cnc3cc(Cl)c(Cl)cc32)[C@H](F)[C@@H]1O
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)[C@@]1(O)[C@@H](C)O[C@@H](n2cnc3cc(Cl)c(Cl)cc32)[C@@H]1F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5,6-Dichloro-1-(2,5-dideoxy-2-fluoro-beta-D-ribofuranosyl)-1H-benzimidazole (0.45 g, 1.5 mmoles) was dissolved in pyridine (Aldrich, Sure Seal, 20 mL) and boiled to remove water. The solution was chilled to 0° C. in an ice bath. Acetic anhydride (Aldrich, 260 μL, 2.9 mmoles, 2 eq.) was added and the reaction was allowed to warm to room temperature while stirring overnight. Methanol (3 mL) was added and the solvents removed in vacuo. Residual pyridine was removed by coevaporation with toluene (3×). The residue was partitioned between water and ethyl acetate. The ethyl acetate solution was dried with MgSO4, filtered, and the solvent removed in vacuo. The product was used without further purification. The yield was 0.45 g, 88%. MS (FAB+): m/z, 347; 1H NMR (DMSO-d6) δ8.61 (s,1H, H-2), 8.08 (s,1H, Ar—H), 8.00 (s,1H, Ar—H), 6.38 (d, 1H, H-1′, J=18 Hz), 5.70 (d, 1H, H-2′, J=53 Hz), 5.1 (m, 1H), 4.2 (m, 1H), 2.1 (s, 3H, acetyl), 1.38 (d, 3H, H-5′, J=6 Hz).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:12][CH2:11][C:10]2=[O:21].C(N(CC)CC)C>C(Cl)Cl.C(Cl)(Cl)Cl>[S:2]([N:6]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:12][CH2:11][C:10]2=[O:21])[S:2]([CH3:1])(=[O:4])=[O:3])([CH3:1])(=[O:4])=[O:3]
Reactant: CCC(=O)N1CCC(=O)c2cc(N)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCC(=O)N1CCC(=O)c2cc(N(S(C)(=O)=O)S(C)(=O)=O)ccc21
Reaction time: 1 h
Yield: 95.9 %

Procedure:
A solution of methanesulfonyl chloride (2.004 g) in methylene chloride (5 ml) was added dropwise to a solution of 6-amino-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (1.526 g) and triethylamine (2.121 g) in methylene chloride (15 ml) with ice cooling over a period of 15 minutes and stirred for further 1 hour. The mixture was diluted with chloroform, washed successively with 10% hydrochloric acid, water, and brine, dried over magnesium sulfate, and evaporated in vacuo. The residual solid was washed with methanol and dried to give 6-(N,N-dimesylamino)-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (2.51 g).
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:3]=1[O:4][C:5]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:18][C:8]2[NH:9][C:10]([C:12]3[CH:17]=C[CH:15]=[CH:14][N:13]=3)=[N:11][C:7]=2[CH:6]=1.[N:37]1C=CN=CC=1C(O)=O>>[F:36][C:32]1[CH:33]=[CH:34][CH:35]=[C:2]([F:1])[C:3]=1[O:4][C:5]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:18][C:8]2[NH:9][C:10]([C:12]3[CH:17]=[N:37][CH:15]=[CH:14][N:13]=3)=[N:11][C:7]=2[CH:6]=1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2c(F)cccc2F)cn1
Reactant: O=C(O)c1cnccn1
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cnccn4)nc3cc2Oc2c(F)cccc2F)cn1

Procedure:
The entitled compound was obtained as a colorless solid in the same method as in Example 197 or in accordance with the method or by combining it with an ordinary method but using 4-(2,6-difluoro-phenoxy)-5-(6-ethanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 235 and pyrazine-2-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[S:22](Cl)(=[O:24])=[O:23])=[C:16]([O:26][CH3:27])[CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]=[CH:21][S:22]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=2[S:9]([NH2:12])(=[O:10])=[O:11])(=[O:23])=[O:24])=[C:16]([O:26][CH3:27])[CH:15]=1
Reactant: Cc1ccc(N)c(S(N)(=O)=O)c1
Reactant: COc1cc(Cl)ccc1/C=C/S(=O)(=O)Cl
Product: COc1cc(Cl)ccc1C=CS(=O)(=O)Nc1ccc(C)cc1S(N)(=O)=O
Yield: 81 %

Procedure:
The title compound was synthesized as described for Example 194 a) in 81% yield, starting from 2-amino-5-methylbenzenesulfonamide and (E)-2-(4-chloro-2-methoxyphenyl)ethenesulfonyl chloride (1 equiv.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])(=O)=O>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([O:13][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C@H:10]([O:14][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]/[CH:29]=[CH:28]\[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Reactant: CCCCCCCC/C=C\CCCCCCCCCCOS(C)(=O)=O
Product: CCCCCCCC/C=C\CCCCCCCCCCO[C@@H]1CN(Cc2ccccc2)C[C@H]1OCCCCCCCCCC/C=C\CCCCCCCC

Procedure:
Compound VI-15 (251 mg, 62.7%) was obtained in the same manner as that in Reference Example 1, by using (3R,4R)-1-benzylpyrrolidine-3,4-diol (Diverchim S. A.; 103 mg, 0.534 mmol) and (Z)-icos-11-enyl methanesulfonate (Nu-Chek Prep, Inc; 500 mg, 1.34 mmol).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([CH3:22])[C:16]([CH2:23]/[CH:24]=[CH:25]/[OH:26])=[C:15]2[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1.C(N(CC)CC)C>ClCCl>[Cl:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([CH3:22])[C:16](/[CH:23]=[CH:24]/[CH:25]=[O:26])=[C:15]2[C:27]1[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=1
Reactant: Cc1nc2ccc(Cl)cc2c(-c2ccc(F)cc2)c1C/C=C/O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1nc2ccc(Cl)cc2c(-c2ccc(F)cc2)c1/C=C/C=O

Procedure:
A solution of oxalyl chloride (2.28 mL, 1.3 equivalents) in 100 mL of dichloromethane was cooled to -78° C. under a nitrogen atmosphere. A solution of dimethylsulfoxide (3.67 mL, 2.6 equivalents) in 75 mL of dichloromethane was added dropwise with stirring. Five minutes after addition was complete, a solution of (E)-3-[6-chloro-4-(4-fluorophenyl)-2-methyl-3-quinolyl]-propenol (6.59 g) in 75 mL of dichloromethane was added dropwise. This solution was stirred at -78° C. for three-quarters of an hour and then 1mL (5.0 equivalents) of triethylamine was added.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][C:17]([OH:21])=[CH:16][N:15]=1>C(Cl)Cl>[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][C:17]([O:21][S:9]([CH3:8])(=[O:11])=[O:10])=[CH:16][N:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: Oc1cnc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1cnc(Cl)c(Cl)c1
Temperature: 20 °C
Reaction time: 17 h

Procedure:
At 0° C., initially 7.9 g of triethylamine and then 8.5 g of methanesulfonyl chloride were added to 11.6 g of 2,3-dichloro-5-hydroxypyridine in 150 ml of methylene chloride. The mixture was subsequently stirred at approximately 20° C. for 17 hours and then washed with 100 ml of water. The organic phase was dried over magnesium sulfate and then concentrated. The resulting crude product was purified by silica gel chromatography (mobile phase: ethyl acetate/cyclohexane (1:1)). Yield: 9.1 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4](=[CH2:28])[CH2:5][C@H:6]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.C(O)C.[H][H]>[Pd].C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:29])[CH:4]([CH3:28])[CH2:5][CH:6]([NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1
Reactant: [H][H]
Reactant: C=C(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)OC
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)C(C)CC(Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 mg (R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid methyl ester (2-a, R1=Boc, R2=H, R3=CO2Me) is added to ethanol (5 ml) at ambient temperature. Triethylamine (176 μl) is then added to the mixture. 50 mg Palladium on carbon (10%, 50% water-wet, Degussa E101 NE/W) is then added. Hydrogen gas at ambient pressure is applied to the mixture. The mixture is then stirred overnight at ambient temperature and pressure. The mixture is then filtered and concentrated under reduced pressure to afford 2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid methyl ester (1-a, R1=Boc, R2=H, R3=CO2Me) and (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid methyl ester (1-b, R1=Boc, R2=H, R3=CO2Me). Spectroscopic data as in Example 60. Ratio of diastereomers 66:34 (1-a, R1=Boc, R2=H, R3=CO2Me: 1-b, R1=Boc, R2=H, R3=CO2Me) by integration of signals at 1.76-1.85 (1-b, R1=Boc, R2=H, R3=CO2Me) and 1.92-1.99 (1-a, R1=Boc, R2=H, R3=CO2Me).
Reaction SMILES: [H-].[Li+].[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([NH:8][CH:9]=[N:10]2)=[C:6]([O:13][CH2:14][CH2:15][O:16][CH3:17])[N:5]=1.CS(O[C@H:23]1[CH2:27][CH2:26][C@H:25]([CH2:28][O:29][Si:30]([C:43]([CH3:46])([CH3:45])[CH3:44])([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:24]1[CH2:47][O:48][Si:49]([C:62]([CH3:65])([CH3:64])[CH3:63])([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)(=O)=O.P([O-])([O-])([O-])=O>CN(C=O)C.CO>[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[C@@H:23]2[CH2:27][CH2:26][C@H:25]([CH2:28][O:29][Si:30]([C:43]([CH3:45])([CH3:44])[CH3:46])([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@H:24]2[CH2:47][O:48][Si:49]([C:62]([CH3:65])([CH3:64])[CH3:63])([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[C:6]([O:13][CH2:14][CH2:15][O:16][CH3:17])[N:5]=1
Reactant: COCCOc1nc(N)nc2nc[nH]c12
Reactant: CC(C)(C)[Si](OC[C@H]1CC[C@H](OS(C)(=O)=O)[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: CN(C)C=O
Product: COCCOc1nc(N)nc2c1ncn2[C@@H]1CC[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 1 h
Yield: 28.7 %

Procedure:
In an atmosphere of argon gas, lithium hydride (8.4 mg, 1.06 mmoles) was added to a suspension of 2-amino-6-(2-methoxyethoxy)purine (221 mg, 1.06 mmoles) in DMF (7 ml). After stirring the mixture for one hour, (1S,2S,3S)-2,3-bis(t-butyldiphenylsilyloxymethyl)-1-cyclopentyl methanesulfonate (370 mg, 0.53 mmole) was added, and the resulting mixture was stirred at 140° C. for one hour. After cooling the mixture, 0.2M phosphate buffer (pH 7) was added, and the product formed was extracted with ethyl acetate. The extract solution was washed with water, washed with saturated aqueous solution of sodium chloride and dried on anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (methylene chloride:methanol=50:1, v/v) to obtain 2-amino-9-[(1R,2R,3S)-2,3-bis(t-butyldiphenylsilyloxymethyl)-1-cyclopentyl]-6-(2-methoxyethoxy)purine (124 mg, Yield 29%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[N:4][S:5][N:6]=1.C(N(CC)CC)C.[N:20]([C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=1)=[C:21]=[O:22]>C(Cl)Cl.CCOC(C)=O>[F:30][C:29]([F:31])([F:32])[C:27]1[CH:28]=[C:23]([NH:20][C:21]([N:10]2[CH2:9][CH2:8][N:7]([C:3]3[C:2]([Cl:1])=[N:6][S:5][N:4]=3)[CH2:12][CH2:11]2)=[O:22])[CH:24]=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:26]=1
Reactant: Clc1nsnc1N1CCNCC1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nsnc2Cl)CC1
Temperature: 25 °C
Yield: 78.7 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 4-(4-chloro-[1,2,5]thiadiazol-3-yl)-piperazine (7.8 g, 32.6 mmol, 1.0 eq.), dry CH2Cl2 (130 mL), triethyl amine (11.66 g, 16 mL, 115.2 mmol, 3.5 eq). To this mixture cooled in an ice bath was added 1-isocyanato-3,5-bis-trifluoromethyl-benzene (11.6 g, 7.9 ml, 45 mmol, 1.4 eq.) dissolved in dry CH2Cl2 (20 mL) dropwise. The resulting mixture was allowed to warm up to room temperature with stirring. After stirring for 3 hour, the reaction mixture was diluted with EtOAc. This solution was then washed with aqNaHCO3, and brine. The organic layer was dried with Na2SO4, concentrated. The residue was purified by column chromatography using acetate/hexane (1:1 to 3:1), affording 4-(4-Chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide (11.8 g, 79% yield) as a solid.
Reaction SMILES: Cl.[F:2][C:3]([F:28])([F:27])[C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[CH:6]([O:18][CH:19]1[CH2:22][NH:21][CH2:20]1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1.[C:29]([N:33]=[C:34]=[O:35])([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-]>>[F:28][C:3]([F:27])([F:2])[C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[CH:6]([O:18][CH:19]1[CH2:22][N:21]([C:34]([NH:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:20]1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1
Reactant: FC(F)(F)Oc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Reactant: CC(C)(C)N=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Product: CC(C)(C)NC(=O)N1CC(OC(c2ccc(OC(F)(F)F)cc2)c2ccccc2C(F)(F)F)C1

Procedure:
This material was prepared from 3-[2-(trifluoromethyl)-4′-(trifluoro-methoxy)benzhydryloxy]azetidine hydrochloride (141) (0.234 mmol), tert-butyl isocyanate (0.234 mmol) and MP-carbonate (2.62 mmol/g, 0.702 mmol) using the procedure described for compound (10) (78.7 mg, 69%).