Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N.[Li].[CH2:3]1[CH2:16][O:15][C:10]23[O:11][CH2:12][CH2:13][O:14][C:5]2([C@:6]2([CH2:28][C:27]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=4)=[C:26]4[C@@H:17]([CH2:18][CH:19]=[C:20]5[C@@H:25]4[CH2:24][CH2:23][CH2:22][CH2:21]5)[C@@H:8]2[CH2:9]3)[CH3:7])[O:4]1.O>O1CCCC1>[CH2:13]1[CH2:12][O:11][C:10]23[O:15][CH2:16][CH2:3][O:4][C:5]2([C@:6]2([CH2:28][C@H:27]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=4)[C@H:26]4[C@@H:17]([CH2:18][CH:19]=[C:20]5[C@@H:25]4[CH2:24][CH2:23][CH2:22][CH2:21]5)[C@@H:8]2[CH2:9]3)[CH3:7])[O:14]1
Reactant: COc1ccc(C2=C3[C@H]4CCCCC4=CC[C@H]3[C@@H]3CC45OCCOC4(OCCO5)[C@@]3(C)C2)cc1
Agent: N
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc([C@H]2C[C@@]3(C)[C@@H](CC45OCCOC43OCCO5)[C@@H]3CC=C4CCCC[C@@H]4[C@H]32)cc1
Reaction time: 0.33 h

Procedure:
800 ml of ammonia are condensed at -70° C. and 1.39 g of lithium are added. After the characteristic blue colouring appears, 18.6 g (40 mmol) of 3,3;17,17-bis-(ethylenedioxy)-11-(4-methoxyphenyl)-5,9(11)-oestradiene dissolved in 400 ml of tetrahydrofuran are added dropwise. After stirring the mixture for 20 minutes, the excess lithium is decomposed by the addition of water, and the ammonia is evaporated off. The reaction mixture is poured onto saturated ammonium chloride solution and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. After chromatography of the crude product on silica gel with a mixture of ethyl acetate/hexane, 15.2 g of 3,3;17,17-bis-(ethylenedioxy)-11β-(4-methoxyphenyl)-5-oestrene and 1.4 g of 17,17-bis-(ethylenedioxy)-11-(4-hydroxyphenyl)-5, 9(11)-oestradiene, m.p. 168°-170° C. (ethyl acetate), [α]D20 =-11° (CHCl3 ; c=0.505), are isolated in the form of white foams.
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>CCOCC>[Cl:1][C:2]1[C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)c(Cl)n1
Reactant: C1COCCN1
Solvent: CCOCC
Product: Cc1cnc(Cl)c(N2CCOCC2)n1

Procedure:
16.3 g of 2,3-dichloro-5-methyl-pyrazine and 100 ml of morpholine are warmed to 100° C. for 6 hours. The reaction mixture is then diluted with 200 ml of ether and again extracted by shaking with water. The ether phase is dried over sodium sulphate and evaporated in a waterpump vacuum. The residue is distilled in a waterpump vacuum. 2-Chloro-3-morpholinyl-5-methyl-pyrazine, boiling point 166°-167° C./15 mm Hg, is thus obtained.
Reaction SMILES: N[C@H:2]([C:8](O)=[O:9])CCCCN.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:20][C:21]([C@H:23]([N:31]([CH3:56])[C:32]([C@H:34]([NH:46][C:47](=[O:55])/[CH:48]=[CH:49]/[CH2:50][C:51]([NH2:54])([CH3:53])[CH3:52])[CH2:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=1)=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C:17](=[O:19])[NH2:18]>>[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:20][C:21]([C@H:23]([N:31]([CH3:56])[C:32]([C@H:34]([NH:46][C:47](=[O:55])/[CH:48]=[CH:49]/[CH2:50][C:51]([NH2:54])([CH3:53])[CH3:52])[CH2:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=1)=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C:17](=[O:19])[NH2:18])(=[O:9])[CH3:2]
Reactant: CN(C(=O)[C@@H](Cc1ccc2ccccc2c1)NC(=O)/C=C/CC(C)(C)N)[C@H](Cc1ccccc1)C(=O)N[C@@H](CCCCN)C(N)=O
Reactant: NCCCC[C@H](N)C(=O)O
Product: CC(=O)NCCCC[C@H](NC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)NC(=O)/C=C/CC(C)(C)N)C(N)=O

Procedure:
This compound was prepared by acetylation of the epsilon amino group in the lysine fragment using the general method described above and using the compound prepared in example 19 as starting material.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[CH2:6][C:7]([NH:30][C:31](=[O:43])[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]([C:39]([F:42])([F:41])[F:40])[CH:33]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]([F:18])([F:17])[F:16])[CH:9]=1.[N+](=[CH:46][Si](C)(C)C)=[N-]>C1COCC1.CO>[F:38][C:35]1[CH:36]=[CH:37][C:32]([C:31]([NH:30][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]([F:16])([F:17])[F:18])[CH:9]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:27])([F:28])[F:29])[CH:20]=2)[CH2:6][C:5]2[N:4]=[N:3][N:2]([CH3:46])[N:1]=2)=[O:43])=[CH:33][C:34]=1[C:39]([F:40])([F:41])[F:42]
Reactant: O=C(NC(Cc1nn[nH]n1)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nnc(CC(NC(=O)c2ccc(F)c(C(F)(F)F)c2)(c2cccc(OC(F)(F)F)c2)c2cccc(OC(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
To a solution of N-(2-(2H-tetrazol-5-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-4-fluoro-3-(trifluoromethyl)benzamide (18 mg, 0.029 mmol) in THF (0.4 mL) and MeOH (0.1 mL) at rt was added (diazomethyl)trimethylsilane (0.02 mL, 2.0 M solution). The resulting solution was stirred at rt for 20 min. The solvents were evaporated and resulting residue was purified by ISCO flash chromatography (silica gel, hexane/EtOAc) to give 4-fluoro-N-(2-(2-methyl-2H-tetrazol-5-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-3-(trifluoromethyl)benzamide (Example 281, 11 mg, yield: 60%). LCMS: RT=4.06 mm [M+H] 638.23, [M+Na] 661.26 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:11])[C:7]=1[CH:8]([OH:10])[CH3:9].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH2:14]([O:10][CH:8]([C:7]1[C:2]([Br:1])=[CH:3][N:4]=[CH:5][C:6]=1[Br:11])[CH3:9])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: CC(O)c1c(Br)cncc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(OCc1ccccc1)c1c(Br)cncc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
To a cooled (0° C.) solution of 1-(3,5-dibromo-pyridin-4-yl)-ethanol (600 mg, 1.4 mmol) in DMF (12 mL) is added sodium hydride (60% dispersion in mineral oil, 60 mg, 1.5 mmol). After stirring at 0° C. for 30 min, benzyl bromide (281 mg, 1.6 mmol) is added. The reaction is warmed and stirred at room temperature for 16 h. The reaction is quenched with the addition of saturated aqueous NH4Cl and H2O and is extracted with EtOAc. The combined organic layers are dried and concentrated. The crude product is purified by flash column chromatography to provide 306 mg of 4-(1-benzyloxy-ethyl)-3,5-dibromo-pyridine.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[CH:15]([NH2:17])=O.Cl[CH2:19][C:20]([C:22]1[N:23]=[CH:24][N:25]2[CH:29]=[CH:28][S:27][C:26]=12)=O.C(=O)([O-])O.[Na+]>ClCCl.O>[S:2]1[CH:19]=[C:20]([C:22]2[N:23]=[CH:24][N:25]3[CH:29]=[CH:28][S:27][C:26]=23)[N:17]=[CH:15]1
Reactant: NC=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C(CCl)c1ncn2ccsc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: c1nc(-c2ncn3ccsc23)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diphosphorus pentasulfide (846 mg) was added to 8.4 ml of formamide. The mixture was stirred at room temperature overnight. 7-Chloroacetylimidazo[5,1-b]thiazole (2.32 g) was added to the reaction solution. The mixture was stirred at room temperature for 15 hr. Water (20 ml) and 10 ml of dichloromethane were added thereto. The mixture was adjusted to pH 8.8 by gradually adding a sodium hydrogencarbonate powder. Extraction was carried out six times with 50 ml of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2) to give 1.72 g of 7-(thiazol-4-yl)imidazo[5,1-b]thiazole.
Reaction SMILES: I[CH2:2][CH3:3].[C:4]([O:8][C:9](=[O:23])[NH:10][C@@H:11]1[C:17](=[O:18])[NH:16][C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[O:13][CH2:12]1)([CH3:7])([CH3:6])[CH3:5]>>[C:4]([O:8][C:9](=[O:23])[NH:10][C@@H:11]1[C:17](=[O:18])[N:16]([CH2:2][CH3:3])[C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[O:13][CH2:12]1)([CH3:7])([CH3:5])[CH3:6]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N[C@H]1COc2ccccc2NC1=O
Product: CCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)COc2ccccc21

Procedure:
In an analogous manner to that described in example 5d), the alkylation by iodoethane of (S)-(8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid tert-butyl ester [Chem.Pharm.Bull. 1986, 34(3), 1128–47] yielded (87% of theory) the title compound as a white solid, m.p.: 112° C., MS m/e (%): 307.1 (M+H+, 93).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:29]([CH:31]2[CH2:36][CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]2)=[O:30])=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:29]([CH:31]2[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]2)=[O:30])=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)N2CCCCC2C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCCN1C(=O)C1CCCNC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.2 %

Procedure:
1-(1-tert-butoxycarbonylpiperidine-3-carbonyl)-piperidine-2-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (81) (1.35 g; 2.29 mmol) is dissolved in methylene chloride (40 mL) at ambient temperature. Trifluoroacetic acid (20 mL) is added in a slow stream, and the solution is stirred for 4 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken the layers separated. The water layer is extracted with methylene chloride (3×50 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (1.09 g) as an oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][CH:17]([OH:28])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[C:21]=1[NH2:27])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[C:38](Cl)(Cl)=[S:39].O>C(Cl)Cl.N1C=CC=CC=1>[OH:28][CH:17]([CH2:16][N:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:18][O:19][C:20]1[C:21]2[NH:27][C:38](=[S:39])[NH:26][C:22]=2[CH:23]=[CH:24][CH:25]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1cccc(OCC(O)CN(Cc2ccccc2)Cc2ccccc2)c1N
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: OC(COc1cccc2[nH]c(=S)[nH]c12)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
[3-(N,N-Dibenzylamino)-2hydroxypropoxy]-2,3-diamino benzene (400 mg, 1.1 mmol) was dissolved in a mixture of methylene chloride (70 mL) and pyridine (35 mL) and cooled to 0° C. Dimethylamino pyridine (DMAP; 311 mg, 2.5 mmol) was added and thiophosgene (179 mg, 0.119 mL, 1.6 mmol) was introduced in a dropwise fashion. After 30 minutes, another equivalent of thiophosgene was added and the mixture was stirred for 5 hours. Water was carefully added and the resulting biphasic mixture extracted with methylene chloride. The organic solution was dried over MgSO4 and, filtered and evaporated to leave a brown oil (445 mg, ca. 100%). MS, NMR.
Reaction SMILES: [C:1]1([CH:7]2[CH2:13][C:12](=[O:14])[O:11][C:9](=[O:10])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH2:23]([N:25](CC)CC)C>C(Cl)Cl>[C:17]1([CH2:23][NH:25][C:12](=[O:14])[CH2:13][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C:9]([OH:11])=[O:10])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CNc1ccccc1
Reactant: O=C1CC(c2ccccc2)CC(=O)O1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)CC(CC(=O)NCc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
3-Phenylglutaric anhydride (8.0 g) in CH2Cl2 (100 mL) at 0° C. was treated sequentially with N-methylaniline (5.63 g), triethylamine (5.32 g) and N,N-dimethylaminopyridine (1.0 g). The mixture was stirred at 0° C. for two hours then allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was washed with 1N HCl (2×50 mL) and water (100 mL). The organic layers were dried over MgSO4, filtered and concentrated to afford the title compound (11.5 g).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][C:11](=O)[NH2:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[C:11]([CH2:10][CH:9]([NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:14]([OH:16])=[O:15])#[N:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC(CC#N)C(=O)O
Temperature: 23 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
20.0 g (86 mmol, 1 equiv.) of Boc-L-asparagine was dissolved in 120 mL of dry pyridine and 20.0 g (97 mmole, 1.3 equiv.) of dicyclohexylcarbodiimide dissolved in 60 mL of dry pyridine was added dropwwise over a period of 30 minutes. The reaction was stirred for 3 hours at 23° C. and filtered through a 2 μm nylon filter. The filtrate was concentrated in vacuo on a rotary evaporator and 100 mL of water was added. The pH was adjusted to 10 with 40% NaOH (aq.) and the solution filtered through a 2 μm nylon filter once again. The filtrate was passed through a 120 mL bed of Dowex 50X8-400 ion exchange resin and the resin washed with four column volumes of 1:1 methanol:water. The filtrate was concentrated in vacuo to yield 17.5 g (95% yield) of the title compound as a white solid. 1H-NMR (CD3OD): 4.40 p.p.m (m, 1H); 2.95 p.p.m. (m, 2H); 1.40 p.p.m. (s, 9H).
Reaction SMILES: CN(C(ON1[N:17]=[N:16][C:11]2[CH:12]=[CH:13]C=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:34][CH2:35][C:36]1[C:37]([CH3:51])=[CH:38][C:39]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[N:40][C:41]=1[CH3:42].CN([CH:55]=[O:56])C>C(OCC)(=O)C.O>[NH:17]1[CH:13]=[C:12]([C:55]([NH:34][CH2:35][C:36]2[C:37]([CH3:51])=[CH:38][C:39]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[N:40][C:41]=2[CH3:42])=[O:56])[CH:11]=[N:16]1
Reactant: CN(C)C=O
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CN
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cn[nH]c1
Temperature: 23 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl pyrazole-4-carboxylate (1 g, 7.14 mmol) in EtOH/THF/water 2/1/1 (8 ml) was added LiOH monohydrate (329 mg, 7.84 mmol). Reaction mixture was stirred for 1 day at 80° C. 4M HCl in dioxane (1.962 ml, 7.85 mmol) was added to reaction mixture which was evaporated to dryness to afford the free carboxylic acid. This material (1.218 g, 7.14 mmol) was dissolved in DMF (30 ml), to which were added HBTU (4.06 g, 10.71 mmol), DIPEA (3.74 ml, 21.43 mmol) then tert-butyl (5-(aminomethyl)-4,6-dimethylpyridin-2-yl)carbamate (2.69 g, 10.71 mmol). Reaction mixture was stirred overnight at 23° C. Reaction mixture was diluted with ethyl acetate and water. Phases were separated and organic layer was washed with NaHCO3 sat. solution and brine. Organic layer was dried over sodium sulfate, filtered and evaporated to afford the crude material, which was purified by normal phase chromatography (silica gel, 100% ethyl acetate) followed by reverse phase chromatography (C18, acetonitrile/water) to afford the title compound. HPLC (Method G) Rt=1.245 min, MS (Method V) [M+H]+=346.2.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:13]2[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:11][CH:10]=[CH:9][C:8]=2[C@H:7]2[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][C@H:6]2[NH:5]1.I[CH2:29][CH3:30]>C1COCC1>[CH2:29]([N:5]1[C@@H:6]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][C@@H:7]2[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([C:14]([F:16])([F:17])[F:15])[C:13]=2[C:4]1=[O:3])[CH3:30]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2c3cccc(C(F)(F)F)c3C(=O)N[C@@H]2C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1C(=O)c2c(cccc2C(F)(F)F)[C@H]2CN(C(=O)OC(C)(C)C)C[C@H]21
Reaction time: 0.33 h
Yield: 71 %

Procedure:
To a suspension of NaH (11 mg of 60% in mineral oil, hexane-washed, 0.28 mmol) in 2 mL of THF at ambient temperature was added (±)-cis-tert-butyl 5-oxo-6-(trifluoromethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate from Example 1, Part H (40 mg, 0.11 mmol) as a solution in 2 mL of THF. The reaction was stirred for 20 min, at which time gas evolution had ceased and the reaction mixture was homogeneous. Then there was added iodoethane (0.039 mL, 0.63 mmol) and the reaction was allowed to stir at 45° C. in a sealed vial for 18 h. The reaction was quenched with water, diluted with EtOAc and washed with 1N HCl, sat'd aq NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (230-400 mesh silica gel, elution with 2:1 hexane/EtOAc) to afford 30 mg (71%) of the title compound. LRMS (ESI): 407.22 (M+H+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([NH:23][C@H:24]([C:30](O)=[O:31])[CH2:25][C:26]([F:29])([CH3:28])[CH3:27])[C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1.[NH2:33][C@H:34]([C:45]#[N:46])[CH2:35][C:36]1[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][C:37]=1[F:44]>>[C:45]([CH:34]([NH:33][C:30](=[O:31])[C@@H:24]([NH:23][C@@H:18]([C:15]1[CH:16]=[CH:17][C:12]([C:3]2[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=2[Cl:1])=[CH:13][CH:14]=1)[C:19]([F:22])([F:21])[F:20])[CH2:25][C:26]([F:29])([CH3:27])[CH3:28])[CH2:35][C:36]1[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][C:37]=1[F:44])#[N:46]
Reactant: N#Cc1ccc(C[C@H](N)C#N)c(F)c1
Reactant: CC(C)(F)C[C@H](N[C@@H](c1ccc(-c2ccc(S(C)(=O)=O)cc2Cl)cc1)C(F)(F)F)C(=O)O
Product: CC(C)(F)C[C@H](N[C@@H](c1ccc(-c2ccc(S(C)(=O)=O)cc2Cl)cc1)C(F)(F)F)C(=O)NC(C#N)Cc1ccc(C#N)cc1F

Procedure:
(S)-2-[(S)-1-(2′-Chloro-4′-methanesulfonyl-biphenyl-4-yl)-2,2,2-trifluoro-ethylamino]-4-fluoro-4-methyl-pentanoic acid [1-cyano-2-(4-cyano-2-fluoro-phenyl)-ethyl]-amide was prepared from N-{(1S)-1-[2′-chloro-4′-(methylsulfonyl)biphenyl-4-yl]-2,2,2-trifluoroethyl}-4-fluoro-L-leucine and 4-[(2S)-(2-amino-2-cyanoethyl)]-3-fluorobenzonitrile using procedure described in Example 6.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.[CH2:12]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]O)=[CH:25][CH:24]=1)/[CH:13]=[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])\[CH3:15]>ClCCl.[Cl-].[Na+].O>[CH2:12]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][Cl:1])=[CH:25][CH:24]=1)/[CH:13]=[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])\[CH3:15]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(CO)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CSC
Product: CC(C)=CCC/C(C)=C/COc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of N-chorosuccinimide (1.15 g) in dichloromethane (40 ml) was added dimethylsulfide (0.72 g) while being cooled with ice. Then, a solution of 4-geranyloxybenzyl alcohol (1.50 g) in dichloromethane (10 ml) was added thereto and the resulting mixture was stirred for 3 hours at room temperature. The reaction solution, with brine added thereto, was extracted with ethyl acetate. The extract was concentrated under a vacuum to yield a raw product of 4-geranyloxybenzyl chloride.
Reaction SMILES: [C:1]1([C:7]([CH2:23][CH3:24])=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][N:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[CH2:31]O>>[CH3:25][N:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[CH2:31][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:23][CH3:24])=[CH:21][CH:20]=1
Reactant: CN1CCCC1CO
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(O)cc1)c1ccccc1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCC2CCCN2C)cc1)c1ccccc1
Yield: 33.2 %

Procedure:
Following same procedure of Mitsunobu reaction as described in example 16, step D, 4,4′-(2-phenylbut-1-ene-1,1-diyl)diphenol (220 mg, 0.473 mmol) was reacted with (1-methylpyrrolidin-2-yl)methanol (82 mg, 0.712 mmol, made from DL-proline Following Arch. Pharm. Phamz. Med. Chem. 1996, 329, 95-104.) to give 65 mg desired product (33% yield). m/z=414[M+1]+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[ClH:12].Cl.[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[C:30]2[O:29][C:28]([C:31]([NH:33][C@H:34]3[CH:39]4[CH2:40][CH2:41][N:36]([CH2:37][CH2:38]4)[CH2:35]3)=[O:32])=[CH:27][C:26]=2[CH:25]=[CH:24][CH:23]=1.C1COCC1>CN(C=O)C>[ClH:12].[N:36]12[CH2:37][CH2:38][CH:39]([CH2:40][CH2:41]1)[C@H:34]([NH:33][C:31]([C:28]1[O:29][C:30]3[C:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[CH2:15][NH:14][C:10]([NH:9][CH3:8])=[O:11])=[CH:23][CH:24]=[CH:25][C:26]=3[CH:27]=1)=[O:32])[CH2:35]2
Reactant: CN=C=O
Reactant: NCc1ccccc1-c1cccc2cc(C(=O)N[C@@H]3CN4CCC3CC4)oc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)NCc1ccccc1-c1cccc2cc(C(=O)N[C@@H]3CN4CCC3CC4)oc12
Reaction time: 18 h

Procedure:
36 μl (0.26 mmol) of triethylamine and 29.5 μl (0.52 mmol) of methyl isocyanate are added to a solution of 57.9 mg (0.13 mmol) of 7-[2-(aminomethyl)phenyl]-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide dihydrochloride (Example 174) in 0.7 ml of a 5:1 mixture of THF and DMF. After 18 h at room temperature, the reaction mixture is concentrated and purified by preparative HPLC. The product fractions are concentrated and, after addition of a 3:1 mixture of methanol and 1N hydrochloric acid, again concentrated and dried under high vacuum. 49.2 mg (81.2% of theory) of the title compound are obtained.
Reaction SMILES: [N:1]([C@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:5]1)=[N+]=[N-].[ClH:20]>[Pd].C(O)C>[Cl-:20].[NH3+:1][C@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[C@H:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:5]1
Reactant: COC(=O)[C@@H]1C[C@@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Reactant: Cl
Agent: [Pd]
Solvent: CCO
Product: COC(=O)[C@@H]1C[C@@H]([NH3+])CN1C(=O)OC(C)(C)C
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Palladium on carbon (10%, 0.5 g) was added to a solution of 1-(tert-butyl)-2-methyl(2S,4R)-4-azidotetrahydro-1H-1,2-pyrroledicarboxylate (5) (0.81 g, 3.0 mmol) in 2% v/v hydrochloric acid in ethanol (8 mL). The reaction mixture was evacuated and purged with nitrogen (three times), then placed under an atmosphere of hydrogen and vigorously stirred at room temperature overnight. The mixture was filtered through a pad of Celite and evaporated under reduced pressure to give the crude product. This was triturated with diethyl ether at 0° C. and the resulting slurry was filtered, washed with ice-cold diethyl ether and dried under vacuum. The title salt (6) was obtained in quantitative yield: