Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[CH2:20][CH2:19][C:18]([CH2:27][C:28](O)=[O:29])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:17][C:16]2=[O:31])[CH:10]=1.C1C=CC2N(O)N=[N:38]C=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[CH2:20][CH2:19][C:18]([CH2:27][C:28]([NH2:38])=[O:29])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:17][C:16]2=[O:31])[CH:10]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)CC1(c2ccccc2)CCN(c2cccc(-c3ccc(F)cc3F)c2)C(=O)O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)CC1(c2ccccc2)CCN(c2cccc(-c3ccc(F)cc3F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.5 %

Procedure:
A solution of 2-(3-(2′,4′-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetic acid (30 mg, 0.072 mmol), HOBt (18 mg, 0.144 mmol), EDCl (30 mg, 0.144 mmol) and DIEA (0.2 ML) in anhydrous CH2Cl2 (3 mL) was stirred at 0° C. under NH3. Then the solution was stirred at rt overnight. Solvent was removed in vacuo, the residue was purified by HPLC to get 2-(3-(2′,4′-difluorobiphenyl-3-yl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetamide (1.68 mg, 6%). 1H-NMR (400 MHz, CDCl3): δ=2.58 (m, 2H), 2.80-3.00 (m, 2H), 3.27 (m, 1H), 3.50 (m, 1H), 6.00 (s, 1H), 6.36 (s, 1H), 6.78-6.90 (m, 2H), 7.05 (m, 1H), 7.23-7.55 (m, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[NH:4][CH:5]([C:9]([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=3)=[CH:21][N:22]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[CH3:54][O:55][C:56](=[O:87])[NH:57][CH:58]([C:62]([N:64]1[CH:70]([C:71]2[NH:72][C:73]([C:76]3[CH:85]=[CH:84][C:83]4[C:78](=[CH:79][CH:80]=[C:81](Br)[CH:82]=4)[CH:77]=3)=[CH:74][N:75]=2)[CH2:69][C:66]2([CH2:68][CH2:67]2)[CH2:65]1)=[O:63])[CH:59]([CH3:61])[CH3:60].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Pd](Cl)Cl>[CH3:54][O:55][C:56](=[O:87])[NH:57][CH:58]([C:62]([N:64]1[CH:70]([C:71]2[NH:72][C:73]([C:76]3[CH:85]=[CH:84][C:83]4[C:78](=[CH:79][CH:80]=[C:81]([C:26]5[CH:25]=[CH:24][C:23]([C:20]6[NH:19][C:18]([CH:17]7[CH2:16][C:13]8([CH2:14][CH2:15]8)[CH2:12][N:11]7[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:30])[CH:6]([CH3:8])[CH3:7])=[N:22][CH:21]=6)=[CH:28][CH:27]=5)[CH:82]=4)[CH:77]=3)=[CH:74][N:75]=2)[CH2:69][C:66]2([CH2:68][CH2:67]2)[CH2:65]1)=[O:63])[CH:59]([CH3:61])[CH3:60]
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: C1COCCO1
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CC7(CC7)CN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Temperature: 85 °C
Yield: 23.8 %

Procedure:
(1-{6-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.10 g, 0.24 mmol), bis(pinacolato)diboron (0.073 g, 0.29 mmol), Palladium dichloride (dppf) (0.018 g, 0.024 mmol), and potassium acetate (0.071 g, 0.72 mmol) were suspended in 1,4-dioxane (1.2 mL) and degassed with argon for 30 minutes. The suspension was heated at 85° C. for 2 hours. The mixture was cooled, (1-{6-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.182 g, 0.346 mmol) and aqueous potassium phosphate (2M, 0.84 mL, 0.84 mmol) was added. The mixture was returned to heat for 16 hours at which time, Palladium(tetrakis)triphenylphosphine (0.014 g, 0.012 mmol) was added. The reaction was heated for an additional 4 hours. Upon completion, the crude reaction mixture was concentrated in vacuo and filtered through a Pd scavenging cartridge (Polymer Labs, PL-Guanidine MP SPE). The resulting slurry was diluted in DMF and purified by reverse phase HPLC (15-40% acetonitrile: water; 0.1% formic acid modifier), and lyophilized giving [1-(6-{5-[6-(4-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.048 g, 24%) as a white solid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C[O:12][C:13](=O)[CH2:14][N:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([CH3:19])([CH3:18])[CH3:17].Cl>C1(C)C=CC=CC=1>[CH3:19][C:16]([N:15]([CH2:14][CH:13]=[O:12])[C:20](=[O:21])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])([CH3:17])[CH3:18]
Reactant: COC(=O)CN(C(=O)OC(C)(C)C)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N(CC=O)C(C)(C)C
Temperature: -78 °C
Reaction time: 3 h
Yield: 86.4 %

Procedure:
Diisobutylaluminium hydride (1M in toluene, 3.7 mL, 3.7 mmol) was added to a stirred, cooled (−78° C.) solution of N-[(1,1-dimethylethoxy)carbonyl]-N-(1,1-dimethylethyl)glycine methyl ester (Description 158, 900 mg, 3.7 mmol) in toluene (5 mL) and the mixture was stirred at −78° C. for 3 hours. Hydrochloric acid (1M, 5 mL) was added and the mixture was allowed to warm to room temperature. The mixture was extracted with ethyl acetate (2×40 mL) and the combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless oil (688 mg, 86%). 1H NMR (400 MHz, CDCl3) δ 1.39 (9H, s), 1.45 (9H, s), 4.01 (2H, s), and 9.54 (1H, s).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:18][C@@H:17]([C:19]2([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:20]2)[C@H:16]([C:30](OCC)=[O:31])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[CH2:7]([N:14]1[CH2:18][C@@H:17]([C:19]2([NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:20][CH2:21]2)[C@H:16]([CH2:30][OH:31])[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1C1(NC(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1([C@@H]2CN(Cc3ccccc3)C[C@H]2CO)CC1
Reaction time: 4 h
Yield: 101.7 %

Procedure:
Under a nitrogen atmosphere, lithium aluminum hydride (381 mg, 9.54 mmol) was suspended in anhydrous tetrahydrofuran (30 ml) to which, while cooling in an ice bath, was subsequently added dropwise an anhydrous tetrahydrofuran (10 ml) solution of ethyl trans-1-benzyl-4-(1-tert-butoxycarbonylaminocyclopropyl)pyrrolidine-3-carboxylate (1.24 g, 3.18 mmol) over a period of 15 minutes. After 4 hours of stirring at the same temperature, ice-cooled water was gradually added to the reaction solution. The reaction suspension was subjected to celite filtration (chloroform washing) to separate the organic layer. The aqueous layer was extracted with chloroform (50 ml×2), and the organic layers were combined and dried over anhydrous sodium sulfate. By evaporating the solvent, 1.12 g (>99%) of the title compound was obtained.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:11]=[CH:12][N:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@H:24]([CH2:26][N:27]4[CH:31]=[C:30]([CH3:32])[N:29]=[N:28]4)[O:23][C:22]3=[O:33])=[CH:17][C:16]=2[F:34])[CH:14]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[F:34][C:16]1[CH:17]=[C:18]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[N:28]3)[O:23][C:22]2=[O:33])[CH:19]=[CH:20][C:15]=1[N:13]1[CH:14]=[C:10]([CH2:9][OH:8])[N:11]=[CH:12]1
Reactant: Cc1cn(C[C@H]2CN(c3ccc(-n4cnc(CO[Si](C)(C)C(C)(C)C)c4)c(F)c3)C(=O)O2)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cn(C[C@H]2CN(c3ccc(-n4cnc(CO)c4)c(F)c3)C(=O)O2)nn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.6 %

Procedure:
(5R)-3-{4-[4-(tert-Butyl(dimethyl)silyloxymethyl)-1H-imidazol-1-yl]-3-fluorophenyl}-5-[(4-methyl-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one (Intermediate 31) (1.4 g, 2.88 mmol) was dissolved in tetrahydrofuran (15 ml), and tetrabutylammonium fluoride (3.2 ml, 1.0 M solution in THF) was added. The solution was stirred for 2 hours at room temperature and water (50 ml) was added. The precipitate was collected by filtration and purified by chromatography on silica gel with 3-6% methanol in dichloromethane to give the title compound (0.36 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([S:26][CH3:27])[C:16]([N:17]([CH2:22][CH:23]4[CH2:25][CH2:24]4)[CH2:18][CH:19]4[CH2:21][CH2:20]4)=[C:12]3[CH:11]=[CH:10][CH:9]=2)=[C:4]([O:28][CH3:29])[CH:3]=1.C(OCC)(=O)C.[CH3:36][N:37](C)C=O>[C-]#N.[Zn+2].[C-]#N>[CH:19]1([CH2:18][N:17]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[C:16]2[C:15]([S:26][CH3:27])=[N:14][N:13]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([C:36]#[N:37])=[CH:3][C:4]=4[O:28][CH3:29])=[CH:9][CH:10]=[CH:11][C:12]=23)[CH2:21][CH2:20]1
Reactant: COc1cc(Br)ccc1-c1cccc2c(N(CC3CC3)CC3CC3)c(SC)nn12
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COc1cc(C#N)ccc1-c1cccc2c(N(CC3CC3)CC3CC3)c(SC)nn12
Temperature: 95 °C
Reaction time: 12 h

Procedure:
After dissolving N-[7-(4-bromo-2-methoxyphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine (60 mg) in N,N-dimethylformamide (0.26 mL), zinc cyanide (31 mg) and tetrakis (triphenylphosphine)palladium (0) complex (23 mg) were added, the mixture was heated and stirred at 95° C. for 12 hours and then cooled to room temperature, and ethyl acetate was added. After filtering out the precipitated insoluble portion, extraction was performed with ethyl acetate. The obtained organic layer was washed with water and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:8) to obtain the title compound (32 mg) as a yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].IC.[C:15](=O)=O>C1COCC1.CCCCCC.CCOCC>[CH3:15][N:7]1[C:8]2[C:4](=[CH:3][C:2]([I:1])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: Ic1ccc2[nH]ccc2c1
Reactant: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CI
Solvent: CCCCCC
Product: Cn1ccc2cc(I)ccc21

Procedure:
To a solution of 5-iodoindole (75 g, 0.31 mol) in dry THF (750 mL), at −78° C. was added sodium hydride (60% in mineral oil, 14.85 g, 0.37 mol) in one portion. The suspension was stirred at −78° C. for 1 hour after which iodomethane (28.8 mL, 0.46 mol) was added. The reaction mixture was stirred overnight with a slow elevation of temperature to room temperature (no more dry ice was added). Ether (600 mL) and hexane (1.2 L) were added and the mixture was washed with brine (1.6 L) and water (1.5 L), dried over Na2SO4 and filtered. The solution was concentrated and the residual brown solid was recrystallized from hexane to give the title compound (66 g). The impure fraction from the mother liquor was flash chromatographed (8% EtOAc in hexane) to give an additional quantity of desired product (12.5 g, combined yield of 99%). MS (DCI/NH3) m/e 258 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>C(Cl)Cl>[CH3:21][S:22]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)(=[O:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69 %

Procedure:
A solution of (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.0 g, 5.3 mmol) and triethylamine (2.77 mL, 20 mmol) in CH2Cl2 (20 mL) was cooled in an ice-water bath. To this, methanesulfonyl chloride (1.15 mL, 15 mmol) diluted in CH2Cl2 (10 mL) was added dropwise. The reaction was left stirring for 12 hours at room temperature. Water was added, and organic phases extracted in CH2Cl2 (3×50 mL), which were subsequently dried onto silica and purified by silica gel chromatography (50% EtOAc:Hexanes to 100% EtOAc gradient) to afford (S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl methanesulfonate (0.97 g, brown oil, 70% yield).
Reaction SMILES: [F:1]/[CH:2]=[CH:3]/[C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3OCCC[O:17]3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.O1CCCC1.Cl.C1(C)C=CC=CC=1>O>[F:1]/[CH:2]=[CH:3]/[C@H:4]1[CH2:5][CH2:6][C@H:7]([C:10]2[CH:11]=[CH:12][C:13]([CH:16]=[O:17])=[CH:14][CH:15]=2)[CH2:8][CH2:9]1
Reactant: F/C=C/[C@H]1CC[C@H](c2ccc(C3OCCCO3)cc2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc([C@H]2CC[C@H](/C=C/F)CC2)cc1
Reaction time: 5 h

Procedure:
Trans-1-(E-2-fluoro-1-ethenyl)-4-{4-(1,3-dioxan-2-yl)phenyl}cyclohexane (34 g, 0.12 mol), tetrahydrofurane (130 ml) and 3N-hydrochloric acid (130 ml) were heated under reflux with stirring for 5 hours, followed by cooling the reaction mixture, adding toluene (200 ml) and water (200 ml) to the mixture, washing the resulting toluene solution with water, drying over anhydrous magnesium sulfate and distilling off toluene to obtain the objective substance (25 g, 0.11 mol; E:Z=5:1).
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.C([Li])(C)(C)C.C([O:22][B:23](OCCCC)[O:24]CCCC)CCC.Cl>O1CCCC1>[NH:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([B:23]([OH:24])[OH:22])[CH:12]=2)[CH:8]=[CH:9]1
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: Brc1ccc2cc[nH]c2c1
Agent: Cl
Agent: [H-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: OB(O)c1ccc2cc[nH]c2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51.6 %

Procedure:
To a suspension of sodium hydride (130 mg, 5.41 mmol) in anhydrous tetrahydrofuran (20 mL) was added 6-bromoindole (973 mg, 4.96 mmol) (prepared according to W. A. Ayer et al., Tetrahedron 84(14):2919-2924 (1992)) at 0° C. After 15 min. of stirring at 0° C., the reaction was cooled to −78° C., and tert-butyllithium (10.2 mmol, 1.7 M in hexane) (Aldrich) was added dropwise (a white precipitate immediately formed). After 10 min. tri-n-butylborate (2.75 mL, 10.2 mmol) (Aldrich) was added dropwise. The reaction was allowed to warm to room temperature slowly, then the suspension was poured into an ice cold solution of 1N HCl. The organic phase was separated, and the aqueous phase was washed with ether. The combined organic extracts were extracted with 1N NaOH (3×25 mL), and the combined alkaline extracts were acidified to pH 1 with 1N HCl. The product was then extracted with ether, and the combined ether layers were dried over magnesium sulfate and concentrated in vacuo to yield a brownish solid. The product was recrystallized from boiling water to yield 412 mg (50%) white crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[C@@H:4]2[O:14][C@H:3]12.[NH:16]1[CH:20]=[CH:19][NH:18][C:17]1=[S:21].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:14][C@@H:3]1[C@H:4]([S:21][CH:17]2[N:18]=[CH:19][CH:20]=[N:16]2)[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=2)[O:11][C:2]1([CH3:15])[CH3:1]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H]2O[C@@H]21
Reactant: S=c1[nH]cc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](SC2N=CC=N2)[C@H]1O

Procedure:
(S,S)-2,2-Dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile (1 mmoL), 1,3-dihydro-imidazole-2-thione (1 mmoL) and anhydrous K2CO3 (1.5 mmoL) in DMF (5 mL) were heated at 100° C. for 4˜6 hrs. The solid was filtered off and the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated NH4Cl, brine, then dried over anhydrous Na2SO4, filtered and concentrated to yield a yellow oil. Silica gel chromatography separation yielded the title compound as a white solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[C:23]([N+:24]([O-])=O)=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:13][CH2:12]1>[Pd].CO>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1cccnc1NC1CCC(Nc2nc3ccccc3[nH]2)CC1
Agent: [Pd]
Solvent: CO
Product: Nc1cccnc1NC1CCC(Nc2nc3ccccc3[nH]2)CC1
Reaction time: 2 h
Yield: 87.6 %

Procedure:
A mixture of N1-(1H-benzo[d]imidazol-2-yl)-N4-(3-nitropyridin-2-yl)cyclohexane-1,4-diamine (400 mg, 1.13 mmol) and palladium on activated carbon (50% by wt, 0.20 g) in methanol (10 mL) was stirred under hydrogen at 30 psi for 2 hours. The mixture was filtered through a pad of CELITE™ and the filtrate was concentrated to give N2-[4-((1H-benzo[d]imidazol-2-yl)amino)cyclohexyl)pyridine-2,3-diamine (320 mg, 0.99 mmol, 87.4% yield) which was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]3[N:15]=[CH:16][CH:17]=[C:18]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:13]3=[N:12][C:11]=2/[CH:25]=[CH:26]/[C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)=[CH:6][CH:5]=1)([O-])=O.O.[OH-].[Na+]>C(O)(=O)C.[Fe]>[O:22]1[CH2:21][CH2:20][N:19]([C:18]2[C:13]3[N:14]([C:10]([C:7]4[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=4)=[C:11](/[CH:25]=[CH:26]/[C:27]4[CH:36]=[CH:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=4)[N:12]=3)[N:15]=[CH:16][CH:17]=2)[CH2:24][CH2:23]1
Reactant: O=[N+]([O-])c1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a suspension of compound 10a (0.85 g, 1.8 mmol) in acetic acid (20 mL) was added iron powder (0.50 g, 8.9 mmol). The reaction mixture was stirred at 80° C. for 2 h, and allowed to cool to rt. The reaction mixture was treated with water, and the pH of the solution was adjusted to ca. pH 7 using 3 N NaOH solution. The mixture was extracted with DCM (3×100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to obtain compound 10b as a dark red solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C27H24N6O: 449.2 (M+H). found: 449.1.
Reaction SMILES: [H-].[Na+].[CH:3]([OH:6])([CH3:5])[CH3:4].Br[CH2:8][CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]>C(Cl)Cl>[CH2:11]([O:10][CH:9]([O:13][CH2:14][CH3:15])[CH2:8][O:6][CH:3]([CH3:5])[CH3:4])[CH3:12]
Reactant: CC(C)O
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(COC(C)C)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH (3.35 g, 84 mmol) was added to isopropanol (5.38 mL, 69.9 mmol) at 0° C. The reaction mixture was stirred at room temperature for 30 min followed by the addition of 2-bromo-1,1-diethoxyethane (7.89 mL, 52.4 mmol). The tube was sealed, heated to 120° C. and stirred overnight. The sealed tube was cooled to room temperature and the contents were dissolved in DCM and washed with water twice. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to give 2-(2,2-diethoxy-ethoxy)-propane, which was hydrolyzed according to the method described in example 29 to give crude isopropoxy-acetaldehyde.
Reaction SMILES: [CH3:1][Mg]Cl.[Br:4][C:5]1[CH:6]=[CH:7][C:8]([C:11](=[O:13])[CH3:12])=[N:9][CH:10]=1>C1COCC1>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])([CH3:1])[CH3:12])=[N:9][CH:10]=1
Reactant: C[Mg]Cl
Reactant: CC(=O)c1ccc(Br)cn1
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
3.0 M Methylmagnesium chloride in THF (0.3 mL) was added dropwise to a mixture of 1-(5-bromopyridin-2-yl)ethanone (100 mg, 0.5 mmol) in THF (10 mL) at 0° C. After stirring for 1 h at room temperature, the reaction was quenched with 1 N NH4Cl and was extracted with EtOAc. The combined organic layer was washed with brine and dried over MgSO4, concentrated to give crude product (0.1 g, 100%). Crude was used in next step without purification. LCMS calculated for C8H11BrNO (M+H)+: m/z=215.9, 217.9. found: 215.8, 217.8.
Reaction SMILES: [OH-].[Na+].[CH3:3][NH2:4].[C:5](=[S:7])=[S:6].OO>O.CCCCCCC.C(O)(=O)C.C1COCC1>[CH3:3][NH:4][C:5](=[S:7])[S:6][S:6][C:5](=[S:7])[NH:4][CH3:3]
Reactant: CN
Reactant: S=C=S
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: O
Solvent: CC(=O)O
Product: CNC(=S)SSC(=S)NC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
In a 4-litter bottle equipped with a mechanical stirrer, sodium hydroxide (80 g, 2 mol) was dissolved in water (500 mL) and the solution was cooled to 0° C. (ice-water bath). THF (200 mL), methylamine (40% in water, 170 mL, 2 mol) and carbon disulfide (120 mL, 2 mol) were added and the mixture as stirred at 0° C. for 30 minutes. Crushed ice (1.5 kg) was added, followed by glacial acetic acid (300 mL). Hydrogen peroxide (30%, 100 mL, 1 mol) was added dropwise over 10 minutes with temperature maintained below 50° C. by adding ice with stirring. Hexanes (or heptane) (800 mL) was added and the mixture was stirred for another 30 minutes in an ice-water bath. The mixture was filtered and washed with aqueous trichloroacetic acid (2%, 5×200 mL) and hexanes (or heptane) (2×200 mL). The product was dried in air for 1 day to a constant weight to give an off-white solid (205.8, yield: 97%). M.p. 98-100° C. (dec.)
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])C)[CH2:9][C@H:8]2[NH:18][C:19](=[O:21])[CH3:20])[C:3]1=[O:22].C(N(C(C)C)CC)(C)C.Cl[C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:43]([F:46])([F:45])[F:44])[CH:41]=2)[N:36]=[CH:35][N:34]=1>CC#N>[CH:15]([NH:13][C@H:10]1[CH2:9][C@@H:8]([NH:18][C:19](=[O:21])[CH3:20])[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:33]3[C:42]4[C:37](=[CH:38][CH:39]=[C:40]([C:43]([F:45])([F:46])[F:44])[CH:41]=4)[N:36]=[CH:35][N:34]=3)[C:3]2=[O:22])[CH2:12][CH2:11]1)([CH3:16])[CH3:17]
Reactant: CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H]1C[C@H](NC(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
Example 1, Alternative Preparation, Step 8: To a mixture of acetamide 11 (28.5 g, HCl salt, 73.6% free base assay), acetonitrile (100 mL), N,N,-di-isopropyl-N-ethylamine (61 mL) at room temperature was added a solution of 13 (˜21.2 g) in MeCN (˜450 mL). The homogeneous mixture was held overnight. Upon reaction completion (HPLC), the mixture was concentrated in vacuo to approx. 125 mL. A 9.5% aqueous solution of acetic acid (240 mL) was added and the aqueous phase was extracted with methylene chloride. The aqueous phase was separated and methyl tert-butyl ether (450 mL) was added, followed by 2N aqueous lithium hydroxide solution to adjust to pH>11.5. The organic layer was separated, washed with water and filtered. Approx. half of the ether phase was diluted with methyl tert-butyl ether (˜250 mL) and concentrated in vacuo. Heptane (45 mL) was added slowly below 60° C., followed by seed crystals of Example 1 (0.4 g). Additional heptane (125 mL) was added and the mixture was slowly cooled to room temperature and the resulting slurry was held overnight. The product was isolated by filtration, the cake was washed with heptane and dried in vacuo to constant weight to give N-((1R,2S,5R)-5-(isopropylamino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)-quin-azolin-4-ylamino)pyrrolidin-1-yl)cyclohexyl)acetamide 14 (15.0 g, 85% yield).