Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[C@H:3]([NH:8][C:9]([N:11]([CH3:17])[CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])=[O:10])[C:4]([O:6]C)=[O:5].[Li+].[OH-]>C1COCC1>[CH3:1][CH:2]([CH3:18])[C@H:3]([NH:8][C:9]([N:11]([CH3:17])[CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])=[O:10])[C:4]([OH:6])=[O:5]
Reactant: C=CCCCN(C)C(=O)N[C@H](C(=O)OC)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCCCN(C)C(=O)N[C@H](C(=O)O)C(C)C
Reaction time: 18 h
Yield: 95 %

Procedure:
A 250 mL round bottom flask under nitrogen was charged with methyl (2S)-3-methyl-2-({[methyl(pent-4-en-1-yl)amino]carbonyl}amino)butanoate from the previous step, THF (40 mL), and aqueous LiOH (1 M, 60 mmol, 60 mL). The reaction mixture was stirred 18 hours. THF was removed by evaporation. The remaining aqueous mixture was poured into water and washed once with EtOAc. The aqueous layer was acidified with 1 M hydrochloric acid and extracted with EtOAc (3×). Combined organic extracts were dried with anhydrous NaSO4, filtered and evaporated to give the title compound as a pale oil (2.34 g, 9.66 mmol, 95%). LRMS m/e [M+H]+ 243.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:11]([O:13][C:14](=[O:26])[CH2:15][C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24])[CH3:12].CN(C)CC(O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.[Cu](I)I>[CH2:11]([O:13][C:14](=[O:26])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24])[CH3:12]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CCOC(=O)Cc1ccc(Br)cc1[N+](=O)[O-]
Agent: I[Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(Oc2cccc([N+](=O)[O-])c2)cc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 24 h
Yield: 62.6 %

Procedure:
To a sealed tube are charged with 3-nitrophenol (83 mg, 0.6 mmol), (4-bromo-2-nitro-phenyl)-acetic acid ethyl ester (180 mg, 0.63 mmol), copper iodide (12 mg, 0.06 mmol), N,N-dimethylglycine (23 mg, 0.2 mmol), Cs2CO3 (400 mg, 1.2 mmol) in 1,4-dioxane. The resulting mixture is stirred at 120° C. for 24 h. The reaction mixture is diluted with water and extracted with EtOAc. The organic phase is dried, concentrated, and purified by flash column chromatography (DCM/Hexane=9:1) to give 130 mg of the desired product (yield 62%). 1H NMR (400 MHz, CDCl3) δ 8.00-7.97 (m, 1 H), 7.82-7.81 (m, 1 H), 7.70-7.69 (m, 1 H), 7.53-7.49 (m, 1 H), 7.34-7.30 (m, 1 H), 7.22-7.19 (m, 1 H), 4.14-4.09 (m, 2 H), 3.94 (s, 2 H), 1.23-1.18 (m, 3 H). LC/MS: 347.2 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:22]=[CH:21][C:13]([O:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.O[Li].O.Cl>C1COCC1.O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:21][CH:22]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)COc1ccc(C#Cc2ccc(O)cc2)cc1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(C#Cc2ccc(O)cc2)cc1
Reaction time: 2 h

Procedure:
Ethyl 2-(4-((4-hydroxyphenyl)ethynyl)phenoxy)acetate (39.9 mg, 0.135 mmol) was dissolved in THF (1.5 mL) and LiOH.H2O (17.0 mg, 0.405 mmol) in water (1 mL) was added. The mixture was stirred for 2 h. and 14% HCl (0.2 mL) was added until pH<1. Water (10 mL) was added, and the mixture was extracted with EtOAc (3×10 mL). The combined EtOAc phases was washed with brine (10 mL), dried over MgSO4, and concentrated under reduced pressure. The product was white/yellow and solid (35.7 mg, 97%) Rf=0.01 (EtOAc:hexanes 1:1 v/v). 1H-NMR (DMSO-d6):□ 4.71 (s, 2H, OCH2); 6.78 (d, 2H, J=8.7 Hz, Ph); 6.93 (d, 2H, J=8.7 Hz, Ph); 7.33 (d, 2H, J=8.1 Hz, Ph); 7.43 (d, 2H, J=8.4 Hz, Ph); 9.87 (s, 1H, OH); 13.00 (s, 1H, COOH). 13C-NMR (DMSO-d6):□ 64.5 (OCH2); 87.2 (CC); 88.6 (CC); 112.8, 114.8, 115.4, 115.7, 132.5, 132.8, 157.6, 157.8 (Ph); 170.0 (COO). MALDI-MS: m/z calculated for C16H12O3 [M]+ 268.0730. found 268.0739.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:16][CH2:15][C:9]2([O:13][CH2:12][CH:11]([OH:14])[CH2:10]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].[CH3:19]I>C1COCC1.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][C:9]2([O:13][CH2:12][CH:11]([O:14][CH3:19])[CH2:10]2)[CH2:15][CH2:16]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC2(CC1)CC(O)CO2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1CCC2(CC1)CC(OC)CO2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 90.6 %

Procedure:
8-Ethoxycarbonyl-3-hydroxy-1-oxa-8-azaspiro[4.5]decane (1 g, 0.0044 mol) was dissolved in anhydrous THF (40 ml) under nitrogen and cooled with an ice-bath. Sodium hydride (0.22 g, 5.5 mmol as a 60% oil dispersion) was added and the reaction was stirred at 0° C. for 20 minutes. Methyl iodide (2.0 g, 0.9 ml) in THF (10 ml) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 3 hours. An additional 0.9 ml of methyl iodide was added at 0° C. and stirring was continued overnight. The cooled reaction was diluted with water (10 ml). The aqueous THF was washed with saturated brine and dried over Na2SO4. The solvents were evaporated and the residue was purified by flash chromatography on silica gel by elution with ammoniated 2% methanol/chloroform. Evaporation of the solvents gave 0.97 g of a pale orange oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[CH2:9][N:10]([CH3:25])[S:11]([C:14]2[C:15]3[CH2:22][CH2:21][CH2:20]/[C:19](=[N:23]/[OH:24])/[C:16]=3[S:17][CH:18]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>ClCCl>[CH3:36][C:35]([CH3:38])([CH3:37])[C:34]([O:24]/[N:23]=[C:19]1/[CH2:20][CH2:21][CH2:22][C:15]2[C:14]([S:11]([N:10]([CH2:9][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[OH:26])[CH3:25])(=[O:13])=[O:12])=[CH:18][S:17][C:16]/1=2)=[O:39]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1csc2c1CCC/C2=N/O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1csc2c1CCC/C2=N/OC(=O)C(C)(C)C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
To a solution of the compound (30 mg) of Example 1 and triethylamine (18 μL) in dichloromethane (10 mL) was added dropwise pivaloyl chloride (13 mg) in dichloromethane (1 mL) on an ice bath. After stirring for 30 minutes, the solvent was removed at reduced pressure, the residue was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (35 mg) was obtained as a colorless amorphous substance.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)=[S:28]
Reactant: CN1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CN1CCN(C(=S)c2cc3ccccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.3 %

Procedure:
(1H-Indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone (Example 4, 0.123 g) in THF (1 mL) was treated with Lawesson's reagent (0.243 g) and stirred at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified via preparative thin layer chromatography to afford the title compound (0.02 g). 1H NMR (400 MHz, CDCl3): δ 9.21 (br s, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.40 (d, J=8.3 Hz, 1H), 7.29 (d, J=7.3 Hz, 1H), 7.12 (m, 1H), 6.60 (s, 1H), 4.39 (br s, 4H), 3.85 (br s, 4H), 2.63 (s, 3H).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:6]=[C:5]([NH2:15])[N:4]=1)[NH2:2].[CH2:16]([CH:23]([C:27](=O)[CH3:28])[C:24](=O)[CH3:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CS(C)=O.C(Cl)Cl.C(OCC)(=O)C>[CH2:16]([C:23]1[C:24]([CH3:25])=[N:2][N:1]([C:3]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[N:6]=[C:5]([NH2:15])[N:4]=2)[C:27]=1[CH3:28])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)C(Cc1ccccc1)C(C)=O
Reactant: NNc1nc(N)nc(-c2ccccn2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nn(-c2nc(N)nc(-c3ccccn3)n2)c(C)c1Cc1ccccc1
Temperature: 75 °C

Procedure:
A suspension of 4-hydrazino-6-pyridin-2-yl-[1,3,5]triazin-2-ylamine (5.25 g, 25.6 mmol), 3-benzylpentane-2,4-dione (5.0 g, 28.4 mmol), and p-toluenesulfonic acid monohydrate (0.475 g, 2.50 mmol) in dimethylsulfoxide (50 mL) was heated to 75° C. for 20 hours. The reaction mixture was allowed to cool to room temperature, and the suspension was dissolved in methylene chloride (700 mL). The solution was washed three times with water, once with brine, dried (magnesium sulfate), and concentrated to afford a moist solid. The crude product was suspended in ethyl acetate (50 mL), heated to reflux, allowed to cool to room temperature, and filtered (repeated three times). The final product was obtained as a white solid containing 3% dimethylsulfoxide by weight: 8.63 g (90%). 1H NMR (CDCl3) δ 8.84-8.53 (m, 1H), 8.48 (d, J=7.9 Hz, 1H), 7.86-7.91 (m, 1H), 7.46-7.50 (m, 1H), 7.13-7.30 (m, 5H), 6.61 (br s, 1H), 6.40 (br s, 1H), 3.83 (s, 2H), 2.79 (s, 3H), 2.24 (s, 3H) ppm. MS (ESI) m/z 358 (M+H+).
Reaction SMILES: C(N(N=O)[C:9](=[O:38])[CH:10]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[N:11]1[C:15]2[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=2[N:13]=[C:12]1[C:22]1[C:23]([O:30][CH3:31])=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)C1C=CC=CC=1.O.[OH-].[Li+].OO.C(O)(=[O:48])C>O1CCCC1.O>[CH:32]1([CH:10]([N:11]2[C:15]3[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C:22]2[C:23]([O:30][CH3:31])=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[C:9]([OH:38])=[O:48])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CC(=O)O
Reactant: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(C(=O)N(Cc2ccccc2)N=O)C2CCCCC2)c(OC)n1
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(C(=O)O)C2CCCCC2)c(OC)n1
Reaction time: 1 h

Procedure:
To a suspension of 12.1 g (22.02 mmol) N-benzyl-N-nitroso-2-cyclohexyl-2-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-acetamide in 65 ml tetrahydrofuran and 15 ml water were added dropwise over 20 min. a solution of 9.24 g (220 mmol) lithium hydroxide monohydrate in 45 ml (440 mmol) hydrogen peroxide and 30 ml water. The reaction mixture turned into a turbid solution and a slight temperature raise was observed (cooled temporarily using an ice-bath). After 1 h the pH of the mixture was adjusted to pH 4 using acetic acid. The resulting light yellow solution was extracted three times with ethyl acetate. The combined organic layers were washed twice with saturated aqueous sodium bicarbonate solution, once with water and once with brine. The solution was dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in 200 ml tert-butyl methyl ether and partially evaporated until a precipitation formed. The suspension was cooled in the refrigerator for 30 min, then the solid was filtered off, washed with 50 ml ice-cold tert-butyl methyl ether and dried in high vacuum. White solid (99%). MS (Turbo Spray): m/z=432.2 [M+H].
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])=[O:8])=[N:4][CH:3]=1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C(O)C.C(OCC)(=O)C>[C:11]([NH:10][S:7]([C:5]1[S:6][C:2]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:3][N:4]=1)(=[O:9])=[O:8])([CH3:14])([CH3:13])[CH3:12]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)NS(=O)(=O)c1ncc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)NS(=O)(=O)c1ncc(-c2ccccc2)s1

Procedure:
In 10 mL of deoxygenated toluene was added 5-bromo-2-N-t-butylthiazole sulfonamide (0.30 g, 1.0 mmol), phenylboronic acid (0.12 g, 1.0 mmol) and potassium carbonate (0.28 g, 2.0 mmol) in 1.5 mL of water/ethanol (2:1). The mixture was deoxygenated for 30 min.. Tetrakis(triphenylphosphine) palladium (O) was added and reaction heated at reflux for 36 h. The reaction was diluted with ethyl acetate and washed with water (2X) followed by brine. The solvent was removed under reduced pressure and the product subjected to flash chromatography (3:1 hexane/ethyl acetate) to afford N-t-butyl-5-phenyl-2-thiazole sulfonamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: CCCCCBr
Reactant: N#CCc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCC(C#N)c1ccc(F)cc1
Reaction time: 2 h

Procedure:
To a stirred and cooled (ice-bath) solution of 27 parts of 4-fluorobenzeneacetonitrile in 180 parts of N,N-dimethylformamide are added 6.2 parts of sodium hydride dispersion 78% and the whole is stirred for 1 hour while cooling. Then there are added dropwise 31 parts of 1-bromopentane. Upon completion, stirring is continued for 2 hours at room temperature. The reaction mixture is poured onto 1000 parts of water and the product is extracted twice with 2,2'-oxybispropane. The combined extracts are washed three times with water, dried, filtered and evaporated. The residue is distilled, yielding 21 parts of 4-fluoro-α-pentylbenzeneacetonitrile; bp. 85°-93° C at 0.1 mm. pressure.
Reaction SMILES: [C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[OH-].[K+:16]>O>[C:1]([O-:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O-:12])=[O:11].[K+:16].[K+:16]
Reactant: O=C(O)CCCCCCCCC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])CCCCCCCCC(=O)[O-]

Procedure:
A mixture of 100 g of sebacic acid, 116 g of a 48% aqueous solution of caustic potash and 1171 g of water is subjected to reaction conducted in the same manner as illustrated in Example 10 to obtain an aqueous solution of potassium sebacate having a pH value of 10.1 and containing 10.1% by weight of a solid matter. To this aqueous solution is added an aqueous solution of 177 g of silver nitrate in 200 g of water to effect a double decomposition reaction in the same manner as illustrated in Example 10 whereby 195 g of silver sebacate is obtained which has a silver content of 49.8% by weight.
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[CH:7]([OH:10])([CH3:9])[CH3:8]>>[Cl:1][CH:2]([Cl:6])[C:3]([O:10][CH:7]([CH3:9])[CH3:8])=[O:4]
Reactant: CC(C)O
Reactant: O=C(Cl)C(Cl)Cl
Product: CC(C)OC(=O)C(Cl)Cl

Procedure:
9 g. (60 mMole) Dichloroacetyl chloride are added dropwise to 20 g. isopropanol cooled to 3° C. in an ice/water bath. The reaction solution is further stirred for 30 minutes at ambient temperature, whereafter excess alcohol is removed in a vacuum at ambient temperature. The residue is subsequently mixed with a mixture of ice water and dichloromethane. After separation of the phases, the organic phase is successively washed with water, aqueous sodium hydrogen carbonate solution and again with water and dried over anhydrous sodium sulphate. After removal of the solvent, there are obtained 7.5 g. (73% of theory) isopropyl dichloroacetate which, after distillation (67°-68° C., 24 hPa) is obtained as a colourless liquid.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Br:2].[CH2:6]([OH:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].B(F)(F)F.CCOCC>C(Cl)Cl>[OH:5][CH:3]([CH2:4][O:24][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:1][Br:2]
Reactant: BrCC1CO1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCO
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\CCCCCCCCOCC(O)CBr
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A 500 ml round bottom flask was charged with epibromohydrin (5.8 g, 42 mmol), linoleyl alcohol (15 g, 56 mmol), a stir bar, and then flushed with nitrogen. Anhydrous DCM (250 ml) was added via cannula, followed by BF3.Et2O (0.53 ml, 4.2 mmol), and stirred at 40° C. for 3 hours. Progress of reaction was monitored by TLC to ensure no epoxide was remaining. The reaction mixture was transferred to a 500 ml separatory funnel with DCM (2×50 ml), washed with NaHCO3 (2×200 ml), water (200 ml), brine (200 ml), dried with MgSO4, and solvent evaporated. The crude product was purified using column chromatography on silica gel (300 g) with 5-15% ether gradient in hexanes to yield 12.6 g.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:20]=[N:21][CH:22]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])=[O:4].[OH-].[Na+]>>[F:19][C:13]1[CH:14]=[C:15]([I:18])[CH:16]=[CH:17][C:12]=1[NH:11][C:10]1[N:9]2[CH:20]=[N:21][CH:22]=[C:8]2[CH:7]=[CH:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Temperature: 65 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 5-(2-fluoro-4-iodophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid methyl ester (5.6 g, 13.6 mmol) in IMS (50 mL) was added aqueous sodium hydroxide (27.2 mL, 1M, 27.2 mmol) and the reaction mixture stirred at 65° C. for 2 hours. The reaction mixture was concentrated in vacuo to remove the IMS. The resultant solution was acidified to pH 5 by addition of aqueous hydrochloric acid (1M) causing a precipitate to form. The product was collected by filtration and dried under vacuum at 45° C. to yield the title compound as a beige solid (5.4 g, 100%). LCMS (Method B): RT=2.79 min, M+H+=398.
Reaction SMILES: O.NN.[N+:4]([C:7]1[C:15]2[O:14][CH:13]=[CH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)([O-])=O>[Ni].CO>[NH2:4][C:7]1[C:15]2[O:14][CH:13]=[CH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1cccc2ccoc12
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1cccc2ccoc12
Temperature: 55 °C
Yield: 98 %

Procedure:
Hydrazine hydrate (0.45 ml) was added dropwise to a stirred mixture of 7-nitrobenzofuran (J. Med. Chem., 1988, 31, 1934; 0.5 g), Raney nickel (0.02 g) and methanol (9 ml) that had been warmed to 55° C. The resultant mixture was heated to reflux for 30 minutes. The catalyst was removed by filtration and the filtrate was evaporated. The residue was partitioned between methylene chloride and water. The organic phase was dried over magnesium sulphate and evaporated to give 7-aminobenzofuran (0.4 g) as an oil; NMR Spectrum: (DMSOd6) 5.25 (br s, 2H), 6.55 (d, 1H), 6.8 (m, 2H), 6.9 (t, 1H), 7.85 (d, 1H).
Reaction SMILES: O[CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:9].[F:26][CH2:27][C@@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1>>[F:26][CH2:27][C@@H:28]1[CH2:32][CH2:31][CH2:30][N:29]1[CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:9]
Reactant: O=C(c1ccc(-c2ccc(C(F)(F)F)cc2)cc1)N1CCC[C@H]1CO
Reactant: FC[C@@H]1CCCN1
Product: O=C(c1ccc(-c2ccc(C(F)(F)F)cc2)cc1)N1CCC[C@H]1CN1CCC[C@H]1CF

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure RR starting from (2-(S)-hydroxymethyl-pyrrolidin-1-yl)-(4′-trifluoromethyl-biphenyl-4-yl)-methanone and 2-(S)-Fluoromethyl-pyrrolidine (CAS 460748-85-0) MS (M+H) 435.2
Reaction SMILES: [C:1]1([C:7]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH2:19][C:20]3[N:24]([CH3:25])[C:23]4[CH:26]=[CH:27][C:28]([C@@:30]([NH:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])([C:32]([N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)=[O:33])[CH3:31])=[CH:29][C:22]=4[N:21]=3)=[CH:14][CH:13]=2)=[NH:11])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCN2CCN(C)P1N(C)[CH2:50][CH2:51]2>C(O)CCC>[C:1]1([C:7]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH2:19][C:20]3[N:24]([CH3:25])[C:23]4[CH:26]=[CH:27][C:28]([C@@:30]([NH:39][CH2:40][C:41]([O:43][CH2:44][CH2:45][CH2:50][CH3:51])=[O:42])([C:32]([N:34]5[CH2:35][CH2:36][CH2:37][CH2:38]5)=[O:33])[CH3:31])=[CH:29][C:22]=4[N:21]=3)=[CH:14][CH:13]=2)=[NH:11])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CN[C@@](C)(C(=O)N1CCCC1)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)c3ccccc3)cc1)n2C
Reactant: CN1CCN2CCN(C)P1N(C)CC2
Solvent: CCCCO
Product: CCCCOC(=O)CN[C@@](C)(C(=O)N1CCCC1)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)c3ccccc3)cc1)n2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.3 g (0.53 mmol) of (R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole in 5 ml of n-butanol is mixed with 0.1 g (0.46 mmol) of 2,8,9-trimethyl-1-phospha-2,5,8,9-tetraazabicyclo[3.3.3]undecane and stirred for 1 hour at room temperature. The reaction mixture is purified on silica gel, eluting with ethyl acetate/ethanol/conc. ammonia (50:0.95:0.05 and 20:0.95:0.05). The uniform fractions are combined and concentrated by evaporation.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][CH2:19][C@H:20]([CH:33]([CH3:35])[CH3:34])[CH2:21][C@H:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:23][OH:24])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.O>[CH2:11]([O:18][CH2:19][C@H:20]([CH:33]([CH3:35])[CH3:34])[CH2:21][C@H:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])[CH:23]=[O:24])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)[C@@H](COCc1ccccc1)C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](COCc1ccccc1)C[C@@H](C=O)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 98.9 %

Procedure:
A solution of DMSO (7.58 g, 97.2 mmol) in anhydrous CH2Cl2 (100 mL) was added dropwise to a stirred solution of oxalyl chloride (4.2 mL, 48.6 mmol) in anhydrous CH2Cl2 (150 mL) under N2 at −50° C. to −60° C. After 15 min, tert-butyl (2S,4S)-4-(benzyloxymethyl)-1-hydroxy-5-methylhexan-2-ylcarbamate (14.2 g, 40.5 mmol) in CH2Cl2 (100 mL) was added dropwise over 30 min, and stirred for about 60 min. Triethylamine (27 mL, 203 mmol) was added and the mixture was stirred overnight. Water was added, the organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with 5% aq Na2CO3 and brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography on silica gel to give tert-butyl (2S,4S)-4-(benzyloxymethyl)-5-methyl-1-oxohexan-2-ylcarbamate (14 g, 99%), which was used for next step without purification; MS: 350 (M++1).