Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:42]=[CH:41][C:6]2[NH:7][C:8]([C:10]([C:22]3[C:30]([O:31][CH3:32])=[CH:29][C:28]([CH3:33])=[C:27]4[C:23]=3[CH:24]=[CH:25][N:26]4C(OC(C)(C)C)=O)([NH:15][CH2:16][C:17]([O:19]CC)=[O:18])[C:11]([F:14])([F:13])[F:12])=[N:9][C:5]=2[CH:4]=1)#[N:2].C([O-])([O-])=O.[Cs+].[Cs+]>CCO>[C:1]([C:3]1[CH:42]=[CH:41][C:6]2[NH:7][C:8]([C:10]([NH:15][CH2:16][C:17]([OH:19])=[O:18])([C:22]3[C:30]([O:31][CH3:32])=[CH:29][C:28]([CH3:33])=[C:27]4[C:23]=3[CH:24]=[CH:25][NH:26]4)[C:11]([F:12])([F:13])[F:14])=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: CCOC(=O)CNC(c1nc2cc(C#N)ccc2[nH]1)(c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: COc1cc(C)c2[nH]ccc2c1C(NCC(=O)O)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F
Temperature: 60 °C

Procedure:
To a solution of (±)-tert-butyl 4-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-1-((2-ethoxy-2-oxoethyl)amino)-2,2,2-trifluoroethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (75 mg, 0.128 mmol) in EtOH (1.28 mL) at room temperature under nitrogen, Cs2CO3 (209 mg, 0.640 mmol) was added and the reaction was stirred at 60° C. After 95 minutes additional Cs2CO3 (209 mg, 0.640 mmol) was added. After 1 more hour the reaction was cooled, quenched with NH4Cl, extracted with EtOAc (×5), dried with MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-30% MeOH in DCM, MeOH contains 10% ammonium hydroxide) to provide the title compound as the ammonium salt. 1H NMR (ammonium salt, 400 MHz, DMSO-d6 with about 5 μL TFA) δ ppm 11.05 (br. s., 1H) 8.12 (br. s., 1H) 7.65 (d, J=8.08 Hz, 1H) 7.58 (dd, J=8.34, 1.52 Hz, 1H) 7.20 (br. s., 1H) 6.81 (s, 1H) 6.15 (br. s., 1H) 3.40 (br. s., 3H) 3.27 (d, J=17.43 Hz, 1H) 2.87 (d, J=17.31 Hz, 1H) 2.44-2.48 (m, 3H). HRMS calcd. for C22H18F3N5O3 (M+H)+ 458.1440. found 458.1418.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)[C:4]([NH:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH:26](=O)[CH2:27][CH:28]([CH3:30])[CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].Cl>C(Cl)Cl.C(OCC)C.CCOC(C)=O>[ClH:1].[CH2:19]([O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][C@H:3]([NH:2][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C:4]([NH:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:5])=[CH:17][CH:16]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)CCN[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
(S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide monohydrochloride (5.0 g, 14 mmol, Example 2, Step A) and isovaleraldehyde (1.5 mL, 14 mmol, Aldrich, Milwaukee, Wis.) were mixed in CH2Cl2 (70 mL). After stirring at ambient temperature under a nitrogen atmosphere for 30 minutes, the solution was cooled to 0° C. in an ice-water bath. To this solution was added sodium triacetoxyborohydride (4.4 g, 21 mmol). The resulting reaction mixture was stirred for 30 minutes at 0° C., followed by an additional 12 hours at ambient temperature. Saturated aqueous NaHCO3 solution (100 mL) was added to the reaction mixture, and the resulting mixture was stirred for 5 minutes. The two layers were separated and the aqueous layer was extracted with CH2Cl2 (2×70 mL). The combined organic solution was dried over Na2SO4. TLC (70% EtOAc in Hexanes as the eluant) showed two spots with Rf values of 0.84 and 0.51. The solution was concentrated in vacuo affording a viscous oil. The lower spot on the TLC (Rf=0.51) was isolated by flash chromatography (50% EtOAc in hexanes). The free amine was dissolved in 20 mL of ethyl ether and treated with ethereal HCl to afford 3.67 g (62%) of the pure titled compound as a white solid; mp 182-184° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[C:29](O)(=[O:33])[C@H:30]([CH3:32])[OH:31].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[OH:31][C@@H:30]([CH3:32])[C:29]([O:19][C@H:18]1[CH2:20][CH2:21][C@@:22]2([CH3:23])[C:16](=[CH:15][CH2:14][C@@H:13]3[C@@H:24]2[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:17]1)=[O:33]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: C[C@H](O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)[C@H](C)O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 4 h

Procedure:
A solution of 3.86 g of cholesterol and 0.85 ml of L-(+)-lactic acid (90% in water) in 80 ml of toluene is boiled for 1 hour. The water is separated, the cooled reaction mixture is treated with 0.3 g of p-toluene-sulphonic acid and boiled for a further 4 hours. The reaction mixture is treated with 30 ml of water and extracted with ether. The organic phase is dried over sodium sulphate and concentrated. The residue is purified on silica gel, with petroleum ether/ether 4:1 used as the elution agent. There are obtained 1.5 g of cholest-5-en-3β-yl (S)-2-hydroxypropionate, m.p. 120°-122° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[CH:22]=[CH:21][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH:8]=1.C(N(CC)CC)C.[CH:39]1([C:45](Cl)=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[CH:22]=[CH:21][C:4]=1[CH2:5][N:6]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH:8]=1)[C:45]([CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)=[O:46]
Reactant: COc1cc(OC2CCCCO2)ccc1CNc1ccc(OCCN2CCCC2)cc1
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC2CCCCO2)ccc1CN(C(=O)C1CCCCC1)c1ccc(OCCN2CCCC2)cc1
Reaction time: 1 h

Procedure:
To a solution of [2-methoxy-4-(tetrahydro-pyran-2-yloxy)-benzyl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (0.100 g, 0.23 mmol) and triethylamine (0.10 mL, 0.70 mmol) in 2 mL methylene chloride was added cyclohexanecarbonyl chloride (0.078 mL, 0.58 mmol), dropwise. The reaction mixture was stirred for 1 hr. at room temperature. Saturated aqueous sodium bicarbonate was added and the layers were separated. The aqueous layer was washed with an additional 2 mL of methylene chloride. The combined organic layers were concentrated in vacuo to give the title compound of Step A. MS 537.2 (M+1)+
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[CH:8]=[CH:9][C:10]=1[CH3:11].C1C(=O)N([Br:28])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:28][CH2:11][C:10]1[CH:9]=[CH:8][C:7]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:6][C:5]=1[O:4][CH2:3][O:2][CH3:1]
Reactant: COCOc1cc(-c2nc3ccccc3o2)ccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COCOc1cc(-c2nc3ccccc3o2)ccc1CBr
Temperature: 25 °C

Procedure:
A solution of 2-[3-(methoxymethoxy)-4-methylphenyl]-1,3-benzoxazole (200 mg, 0.74 mmol, 84%), NBS (179 mg, 0.81 mmol), and benzoyl peroxide (50 mg) in CCl4 (10 mL), was refluxed for 12 h. After cooling to rt, CCl4 was removed in vacuo and residue was purified by flash column (silica gel, hexanes:EtOAc 5:1) to afford 2-[4-(bromomethyl)-3-(methoxymethoxy)phenyl]-1,3-benzoxazole. MS (ESI) 349 (M+H)+.
Reaction SMILES: [C:1]([NH:8][C:9]1[C:10]([N+:19]([O-:21])=O)=[C:11]([C:17]#[N:18])[C:12](=[CH:15][CH:16]=1)[C:13]#[N:14])([C:3](OCC)=[O:4])=[O:2].CN(C)C=O.N>O1CCCC1.[Pt]>[C:13]([C:12]1[C:11]([C:17]#[N:18])=[C:10]2[C:9]([NH:8][C:1](=[O:2])[C:3](=[O:4])[N:19]2[OH:21])=[CH:16][CH:15]=1)#[N:14]
Reactant: CCOC(=O)C(=O)Nc1ccc(C#N)c(C#N)c1[N+](=O)[O-]
Agent: [Pt]
Agent: N
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#Cc1ccc2[nH]c(=O)c(=O)n(O)c2c1C#N
Yield: 58.4 %

Procedure:
2 g (0.9 mmol) 4-ethoxalylamino-3-nitrophthalonitrile in 15 ml tetrahydrofuran:dimethylformamide: 25% aqueous ammonia (30:10:0.7) was hydrogenated at atm. pressure by using 25 mg 5% Pt-C as a catalyst. The precipitate was filtered off and washed with tetrahydrofuran. The filter cake was washed several times with 1N aqueous potassium hydroxide. The filtrate was acidified with concentrated hydrochloric acid. The precipitate was filtered off and washed with water, ethanol and ether to give 0.120 g (76%) of 7,8-dicyano-1-hydroxyquinoxaline-2,3(1H,4H)-dione. M.p. decomp. 1H-NMR (DMSO-d6): 7.7 (2H, dd). IR (KBr): 2240 (m). MS (m/e): 228 (M+, 3%), 184 (100%).
Reaction SMILES: [CH3:1][C:2]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)([CH3:7])[C:3](OC)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:7][C:2]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)([CH3:1])[CH2:3][OH:4]
Reactant: COC(=O)C(C)(C)OC1CCCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CO)OC1CCCCO1
Reaction time: 2 h
Yield: 108.4 %

Procedure:
To a solution of methyl 2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propanoate (1.25 g, 6.16 mmol) in THF (20 ml) under nitrogen was added portionwise lithium aluminium hydride (0.246 g, 6.16 mmol) at 0° C. and the reaction mixture was stirred 2 h, followed by slow addition of Na2SO4.10H2O (1.98 g, 6.16 mmol). After 30 minutes of stirring at 0° C. to room temperature, the insoluble materials were filtered off. The filtrate was concentrated in vacuo to give 2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propan-1-ol (1.16 g, 6.68 mmol, quant.) as a colorless oil which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11 (s, 6H) 1.29-1.62 (m, 5H) 1.67-1.80 (m, 1H) 3.19-3.31 (m, 2H) 3.34-3.43 (m, 1H) 3.77-3.88 (m, 1H) 4.40 (t, J=5.94 Hz, 1H) 4.75-4.81 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>O>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Reactant: C1CCNCC1
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1N1CCCCC1

Procedure:
2-Bromo-5-nitroanisole (5.0 g, 21.5 mmol) and piperidine (8.5 ml) is stirred for 5 h at 105° C. under N2-atmosphere. Water (80 ml) is added and the mixture is extracted twice with CH2Cl2 (2×80 ml). The organic phases are washed with water and brine, dried (Na2SO4) and concentrated. The crude product is dissolved in AcOEt, SiO2 is then added and the solvent evaporate off In vacuo. The resulting powder is put on top of a chromatography column (SiO2; AcOEt/hexane 9:1) and the title compound eluted with hexane/AcOEt 9:1→4:1: MS: [M+1]+=237; Rf=0.2 (AcOEt/hexane 9:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]([CH3:18])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:18][C:10]1[C:11]2[C:16](=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[N:9]=1
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2cc(F)ccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1nc(CBr)c2ccc(F)cc21
Yield: 60.9 %

Procedure:
12.68 g (50.7 mmol) 6-Fluoro-3-methyl-indazole-1-carboxylic acid tert-butyl ester, prepared as in Part C, is combined with 9.92 g (55.7 mmol, 1.1 equiv) N-Bromosuccinimide and 1.23 g (5.1 mmol, 0.1 equiv) Benzoyl peroxide in 600 mL CCl4 and refluxed 10 h. The reaction mixture is filtered and the filtrate concentrated in vacuo and purified by flash chromatography on 300 g silica gel eluted successively with DCM/Hexanes (1:2, 3 L), (1:1, 3 L). Appropriate fractions were combined and concentrated in vacuo to give 10.18 g (30.9 mmol) of 3-Bromomethyl-6-fluoro-1-tert-butoxycarbonyl-1H-indazole as an amber oil: 1H NMR (CDCl3, 300 MHz) δ7.82 (m, 2H), 7.13 (m, 1H), 4.76 (s, 2H), 1.72 (s, 9H); TLC Rf =0.17 (EtOAc/Hexanes, 1:19).
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14](Cl)[N:13]=[C:12]([CH3:20])[CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][NH:28][CH3:29]>O1CCOCC1>[NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([N:28]([CH3:29])[CH3:27])[N:13]=[C:12]([CH3:20])[CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2c(c(Cl)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Reactant: CNC
Solvent: C1COCCO1
Product: Cc1cc2c(c(N(C)C)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 80 °C
Yield: 90.8 %

Procedure:
A mixture of 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (80 mg, 0.22 mmol) and dimethylamine (3M in THF, 0.73 mL, 2.20 mmol) in dioxane (3 mL) was heated to 80° C. for 24 h. The reaction mixture was cooled, concentrated in vacuo, diluted with water and the resulting mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo to give 2-anilino-5-(dimethylamino)-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (74 mg, 91%): LCMS RT: 1.86 min, MH+: 371.3
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][C:13]2([C:17]3[CH:18]=[C:19](OS(C(F)(F)F)(=O)=O)[CH:20]=[CH:21][CH:22]=3)[CH2:16][CH:9]1[CH2:10][CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=[NH:44])(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Cl>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([N:8]1[CH2:15][CH2:14][C:13]2([C:17]3[CH:18]=[C:19]([NH2:44])[CH:20]=[CH:21][CH:22]=3)[CH2:16][CH:9]1[CH2:10][CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(Oc1cccc(C23CCCC(C2)N(Cc2ccccc2)CC3)c1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Product: Nc1cccc(C23CCCC(C2)N(Cc2ccccc2)CC3)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 62.3 %

Procedure:
Trifluoro-methanesulfonic acid 3-(2-benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl ester (13.33 g, 30.33 mmol) was azeotroped with THF (2×50 mL) then dissolved in anhydrous THF (150 mL) with benzophenone imine (6.3 mL, 17.61 mmol), cesium carbonate (14.23 g, 43.67 mmol) and BINAP (racemic, 1.89 g, 3.03 mmol). The reaction vessel was degassed (evac./N2 purge 3×) before charging with palladium (II) acetate (410 mg, 1.82 mmol). The reaction was warmed to 80° C. for 18 h, at which point it was judged incomplete by APCI MS. After cooling additional BINAP (racemic, 1.89 g, 3.03 mmol) and palladium (II) acetate (410 mg, 1.82 mmol) were introduced and the reaction was warmed to 80° C. for 60 h, at which point it was judged complete by APCI MS. The reaction was cooled and filtered through Celite, rinsed with THF and concentrated. The resulting oil was dissolved in CH2Cl2 (200 mL), washed with water (100 mL) and saturated aqueous NaCl solution (100 mL), dried through a cotton plug and concentrated to give the crude product. To this was added fresh THF (150 mL) followed by 2N HCl (150 mL) and this stirred solution was warmed to 65° C. for 60 min then at room temperature for 18 h. The reaction mixture was treated with hexanes (150 mL). The resulting orange solid is filtered. (On occasion an orange gum separates and is separated by decantation or filtration.) The biphasic filtrate was separated and the hexane layer discarded. The aqueous layer was extracted with Et2O (150 mL) and the Et2O layer discarded. The aqueous layer was then neutralized with 25% aqueous NaOH solution to achieve pH 9 and the product was extracted with CH2Cl2 (5×40 mL), washed with saturated aqueous NaCl solution (1×30 mL), dried over Na2SO4 and concentrated to give the crude product. Flash chromatography provided the title compound as a thick yellow oil (3.36 g, 36%). (TLC 50% EtOAc/hexanes Rf 0.30); 1H NMR (400 MHz, CDCl3) δ 7.24 (m, 2H), 7.36 (m, 2H), 7.26 (m, 2H), 7.07 (t, J=7.9 Hz, 1H), 6.71 (dd, J=7.9, 1.6 Hz, 1H), 6.64 (m, 1H), 6.50 (dd, J=7.9, 2.0 Hz, 1H), 3.80 (m, 2H), 3.61 (m, 1H), 3.15 (m, 2H), 2.80 (m, 1H), 2.17 (br d, J=14.2 Hz, 2H), 2.00 (m, 3H), 1.79 (br d, J=12.5 Hz, 1H), 1.72 (m, 1H), 1.64 (m, 1H), 1.38 (m, 1H); APCI MS m/z 307.1 (M+1)+.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12](Cl)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:16][N:17]([CH2:19][CH:20]([OH:30])[CH2:21][O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)[CH3:18]>C(O)CCC.CO>[NH:1]([C:8]1[N:13]=[C:12]([NH:27][C:26]2[CH:28]=[CH:29][C:23]([O:22][CH2:21][CH:20]([OH:30])[CH2:19][N:17]([CH3:16])[CH3:18])=[CH:24][CH:25]=2)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CC(O)COc1ccc(N)cc1
Reactant: Clc1ccnc(Nc2ccccc2)n1
Agent: Cl
Solvent: CCCCO
Solvent: CO
Product: CN(C)CC(O)COc1ccc(Nc2ccnc(Nc3ccccc3)n2)cc1
Temperature: 80 °C
Yield: 65.7 %

Procedure:
2-Anilino-4-chloropyrimidine (145 mg, 0.71 mmol) was dissolved in n-butanol (20 ml). To this solution was added a hot solution of 4-[3-(N,N-dimethyl)amino-2-hydroxy-propoxy]aniline hydrochloride (Reference Example D-1; 178 mg, 0.63 mmol) in methanol (2 ml). The reaction mixture was heated at 80° C. for 18 hours, allowed to cool to ambient temperature and then evaporated onto silica (3 ml). The residue was purified by column chromatography eluting with 0–8% 2.0M methanolic ammonia solution in DCM to give the title product as a colourless solid (157 mg, 65%). NMR (300 MHz): 2.18 (s, 6H), 2.33 (m, 2H), 3.83 (m, 3H), 4.77 (d, 1H), 6.11 (d, 1H), 6.86 (m, 3H), 7.19 (m, 2H), 7.51 (d, 2H), 7.69 (d, 2H), 7.96 (d, 1H), 9.01 (s, 1H), 9.08 (s, 1H); m/z: (ES+) 380.4 (MH+).
Reaction SMILES: C(O[C:4](=[O:8])[O:5][CH2:6][CH3:7])C.[H-].[Na+].[Si:11]([O:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH2:31][CH2:32][CH2:33][C:34]2=[O:39])([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[Si:11]([O:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH2:31][CH2:32][CH:33]([C:4]([O:5][CH2:6][CH3:7])=[O:8])[C:34]2=[O:39])([C:24]([CH3:26])([CH3:27])[CH3:25])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)OCC
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCCC2=O)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCc2c(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cccc2C1=O
Reaction time: 4 h

Procedure:
To a solution of diethylcarbonate (10.3 ml) and sodium hydride (4.2 g, 60% in oil) in toluene (300 ml) was added 5-t-butyldiphenylsilyloxy-1-oxo-1,2,3,4-tetrahydronaphthalene (17 g) at 100° C. The mixture was stirred for 4 hours at the same temperature and then the cooled solution was washed with sat. NaHCO3 and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give 5-t-butyldiphenylsilyloxy-2-ethoxycarbonyl-1-oxo-1,2,3,4-tetrahydronaphthalene (20 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:16])=[N:4][S:5][C:6]=1[NH:7][C@H:8]([C:13]([OH:15])=O)[CH2:9][CH:10]([CH3:12])[CH3:11].C1CN([P+](O[N:34]2N=[N:41][C:36]3C=CC=C[C:35]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.NCC#N.C(N(CC)CC)C>CN(C=O)C.CCOCC>[Br:1][C:2]1[C:3]([CH3:16])=[N:4][S:5][C:6]=1[NH:7][C@H:8]([C:13]([NH:41][CH2:36][C:35]#[N:34])=[O:15])[CH2:9][CH:10]([CH3:11])[CH3:12]
Reactant: Cc1nsc(N[C@@H](CC(C)C)C(=O)O)c1Br
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1nsc(N[C@@H](CC(C)C)C(=O)NCC#N)c1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To an ice cold solution of N-(4-bromo-3-methylisothiazol-5-yl)-L-leucine (9.83 g, 32 mmol), PyBOP (18.6 g, 35.7 mmol) and 2-aminoacetonitrile hydrochloride (6.5 g, 70.3 mmol) in DMF (250 mL) was slowly added over 5 min triethylamine (15.6 mL, 112 mmol). The resulting suspension was stirred at room temperature for 18 h. The reaction mixture was partitioned between EtOAc and half-saturated NaHCO3. The organic layer was washed once with water, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc in hexane to give a colorless syrup. This syrup was disolved in Et2O, washed once with 3% HCl and once with diluted NaHCO3, dried over Na2SO4 and concentrated in vacuo to give N2-(4-bromo-3-methylisothiazol-5-yl)-N1-(cyanomethyl)-L-leucinamide as a white foam.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([NH:7][C@H:8]([C:12]([NH:14][C@H:15]([C:31]([NH2:33])=[O:32])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:6])[CH3:4].FC(C(O)=O)(F)F.[NH:41]([C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80])[C@H:42]([C:58]([NH:60][C@H:61]([C:67]([NH:69][C@H:70]([C:75](NN)=[O:76])[CH2:71][CH2:72][CH2:73][CH3:74])=[O:68])[CH2:62][CH2:63][C:64](=[O:66])[NH2:65])=[O:59])[CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49]>CN(C=O)C.O1CCOCC1.N(OC(C)(C)C)=O.C(N(CC)CC)C>[NH:41]([C:79]([O:81][C:82]([CH3:83])([CH3:85])[CH3:84])=[O:80])[C@H:42]([C:58]([NH:60][C@H:61]([C:67]([NH:69][C@H:70]([C:75]([NH:2][C@H:3]([C:5]([NH:7][C@H:8]([C:12]([NH:14][C@H:15]([C:31]([NH2:33])=[O:32])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:6])[CH3:4])=[O:76])[CH2:71][CH2:72][CH2:73][CH3:74])=[O:68])[CH2:62][CH2:63][C:64](=[O:66])[NH2:65])=[O:59])[CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49]
Reactant: CCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NN
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(N)=O
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(N)=O)C(C)C
Temperature: -30 °C
Reaction time: 0.58 h

Procedure:
0.58 g, 0.9 mmol) was dissolved in anhydrous DMF (18 ml) and cooled to -30° C. 4.56M HCl in dioxane (0.90 ml) was added followed by t-butyl nitrite (0.12 ml). The reaction was left for 30 to 40 min at -30° C. then cooled to -60° C. Triethylamine (0.60 ml) was added followed by the deprotected amide (X) (0.384 g, 0.68 mmol) and a further addition of triethylamine (0.1 ml). The mixture (M) was left to stand, reaching ambient temperature over 2 days. A further amount of (XIV) (0.29 g, 0.45 mmol) in DMF (10 ml) was treated at -30° C. with 4.5M HCl in dioxane (0.45 ml), t-butyl nitrite (0.06 ml) and triethylamine (0.3 ml) as described above and added to the reaction mixture (M) at -30° C. The whole was left to stand, reaching ambient temperature over a further 4 days.