Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:12]([NH:34][S@@](C(C)(C)C)=O)([C:20]2[CH:25]=[C:24]([O:26][C:27]([F:32])([F:31])[CH:28]([F:30])[F:29])[CH:23]=[C:22]([F:33])[CH:21]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Cl>CO.CCOCC>[F:1][C:2]1[CH:3]=[C:4]([C@:12]([C:20]2[CH:25]=[C:24]([O:26][C:27]([F:31])([F:32])[CH:28]([F:29])[F:30])[CH:23]=[C:22]([F:33])[CH:21]=2)([NH2:34])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc([C@@](Cc2ccccc2)(N[S@](=O)C(C)(C)C)c2cc(F)cc(OC(F)(F)C(F)F)c2)cc1F
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CC(C)Oc1ccc([C@](N)(Cc2ccccc2)c2cc(F)cc(OC(F)(F)C(F)F)c2)cc1F
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
To a solution of (R)—N—((R)-1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide (398 mg, 0.678 mmol) in MeOH (1.5 mL) was added HCl (1.5 mL, 4 M solution in dioxane) and the reaction mixture was stirred for 30 min. The reaction mixture was diluted with ether (50 mL) and the organic layer was washed with sat. NaHCO3 (20 mL), dried over Na2SO4, filtered and concentrated to give (R)-1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine as a colorless oil (334 mg, 100% yield). LCMS: RT=1.76 min [M-NH2] 467.24 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=3.04 min, Purity 95% (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm) NMR: 400 MHz 1H (CDCl3) 7.15 ppm, 3H, m; 6.99 ppm, 4H, m; 6.89 ppm, 1H, m; 6.84 ppm, 1H, d, J=8.79 Hz; 6.74 ppm, 2H, d, J=6.15 Hz; 5.87 ppm, 1H, m; 4.42 ppm, 1H, m; 3.47 ppm, 2H, s; 1.27 ppm, 6H, dd, J=7.91, 6.15 Hz.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH:16]([OH:18])[CH3:17].O.CCOC(C)=O>N1C=CC=CC=1>[C:1]([O:18][CH:16]([CH3:17])[CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[Br:8])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(O)Cc1ccccc1Br
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)OC(C)Cc1ccccc1Br

Procedure:
Acetic acid anhydride (1.2 mL) was added to a solution of 1-(2-bromophenyl)-2-propanol (529 mg) in pyridine (1.0 mL) at 20° C. under stirring. The reaction mixture was stirred overnight, then poured into a mixture of water and EtOAc. The aqueous phase was extracted with more EtOAc (×2). The combined organic phases were washed with water (×3), dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a syrup.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[CH2:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([CH2:26][CH:27]([OH:42])[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:30]=3)[CH2:25][CH2:24]2)=[CH:19][CH:18]=1)[CH3:15]>CC(C)=O.O>[CH2:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([CH2:26][C:27](=[O:42])[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:30]=3)[CH2:24][CH2:25]2)=[CH:19][CH:18]=1)[CH3:15]
Reactant: CCOc1ccc(C2(CC(O)Cc3cccc(Oc4ccccc4)c3)CC2)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: CCOc1ccc(C2(CC(=O)Cc3cccc(Oc4ccccc4)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Jones reagent (2 ml, prepared by the method described in Fieser and Fieser Vol. 1, p. 142) is added dropwise to a stirring solution of 1-(4-ethoxyphenyl)-1-(3-(3-phenoxyphenyl)-2-hydroxypropyl)-cyclopropane (0.25 g) in acetone (5 ml) whilst maintaining the temperature below 5° C. After 15 min. the mixture is allowed to warm up to room temperature over 4 h, diluted with water, extracted with diethyl ether (x3), washed with water, dried and the solvent evaporated under reduced pressure. The product is purified by thin layer chromatography on silica gel diluted with 15% diethyl ether in petroleum ether (b.p. 60°-80° C.). Yield 0.03 g, nD 1.5580.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:37]=1[C:36](=[O:38])[N:35]([CH3:39])[C:34]2([CH3:41])[CH3:40]>>[F:9][C:8]([F:11])([F:10])[C:7]1[C:2]([NH:28][C:29]2[CH:30]=[CH:31][CH:32]=[C:33]3[C:37]=2[C:36](=[O:38])[N:35]([CH3:39])[C:34]3([CH3:40])[CH3:41])=[N:3][C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[N:5][CH:6]=1
Reactant: CN1C(=O)c2c(N)cccc2C1(C)C
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4c3C(=O)N(C)C4(C)C)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure from Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate and 7-Amino-2,3,3-trimethyl-2,3-dihydro-1H-isoindol-1-one (Compound 148A). 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.71 (br s, 1H), 8.94 (br s, 1H), 8.35 (s, 1H), 7.43 (dd, J=6.2, 1.9 Hz, 1H), 7.06-7.30 (m, 4H), 6.80 (br s, 2H), 3.80-3.95 (m, 4H), 3.13 (s, 3H), 3.01 (d, J=21.5 Hz, 2H), 1.27 (s, 6H), 1.14 (t, J=7.1 Hz, 6H). MS (ES+): m/z 578.16 [MH+] HPLC: tR=3.27 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl-:1].[NH4+].[N+:3]([C:6]1[CH:18]=[CH:17][C:9]([NH:10][CH2:11][CH:12]2[O:16][CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1)([O-])=O>[Zn]>[ClH:1].[ClH:1].[NH2:3][C:6]1[CH:7]=[CH:8][C:9]([NH:10][CH2:11][CH:12]2[O:16][CH2:15][CH2:14][CH2:13]2)=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(NCC2CCCO2)cc1
Reactant: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Product: Cl
Product: Nc1ccc(NCC2CCCO2)cc1

Procedure:
4.02 g of ammonium chloride and 57 g of zinc powder are added to 180 ml of an aqueous-alcoholic solution (83% of alcohol and 17% of water). This mixture is heated to the reflux temperature, whilst stirring, and 0.122 mol (27 g) of 4-nitro-N-tetrahydrofurfurylaniline is then added gradually. When the reaction medium is decolorised, it is filtered and the filtrate is collected in a flask containing 30 ml of ice-cooled hydrochloric acid (d=1.19). On cooling, the expected dihydrochloride precipitates in the form of crystals. It is filtered off and washed with absolute alcohol and then acetone. After drying in vacuo, it melts at about 190° C. with decomposition.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[C:10](OCC)(=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].CC[O-].[Na+].C(O)(=O)C>C(OCC)C.O>[CH2:14]([O:13][C:11](=[O:12])[C:10](=[O:16])/[CH:2]=[C:1](\[OH:3])/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:15]
Reactant: CC(=O)c1ccccn1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)/C=C(\O)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
A solution of 2-acetylpyridine (5.0 g, 40 mmol) and diethyl oxalate (5.9 g, 40 mmol) in diethylether (75 ml) was cooled to 0° C. and treated with sodium ethylate (16.6 ml, 21% solution in ethanol). While stirring overnight, the reaction mixture was allowed to warm-up slowly to ambient temperature. The reaction mixture was acidified with acetic acid, diluted with water and extracted with diethylether. The combined organic phases were washed with water and brine, dried and evaporated. The isolated residue was triturated with heptane (30 ml) and diethylether (5 ml) for 2 h and the resulting suspension was filtrated to collect the product. This process was repeated to obtain the product as light brown solid (3.96 g, 44%). MS: M=220.1 (M−H)−
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:13][NH:14][CH3:15].O>CN(C)C=O>[CH3:13][N:14]([CH3:15])[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CNC
Reactant: N#Cc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1ccc([N+](=O)[O-])c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
65 g of 5-chloro-2-nitrobenzonitrile was dissolved in 150 ml of dimethylformamide, and 150 ml of a 50% aqueous solution of dimethylamine was added thereto. After cooling the heat generated, the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the precipitate thus formed was collected by filtration, washed with water and then with methanol to obtain 64.5 g of 5-dimethylamino-2-nitrobenzonitrile (melting point: 174°-175° C.).
Reaction SMILES: Br[C:2]1[C:3]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl>Cl[Pd]Cl.O.O1CCOCC1>[Cl:11][C:9]1[CH:8]=[CH:7][C:4]2[S:5][CH:6]=[C:2]([C:15]3[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=3)[C:3]=2[CH:10]=1
Reactant: Clc1ccc2scc(Br)c2c1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd]Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Clc1ccc2scc(-c3ccncc3)c2c1
Yield: 127.6 %

Procedure:
To 3-bromo-5-chloro-benzo[b]thiophene (9.80 g, 39.6 mmol) was added pyridine-4-boronic acid (4.445 g, 36.2 mmol), K3PO4 (19.5 g, 91.9 mmol), 61 mL of 1,4-dioxane and 6 mL of water. The mixture was placed under house vacuum for several minutes and flushed with nitrogen. This was repeated 5 times. Pd(dppf)Cl2.CH2Cl2 (2.71 g, 3.31 mmol), PdCl2 (0.0563 g, 0.318 mmol) and 1,1″-bis(diphenylphosphino)ferrocene (0.1747 g, 0.3151 mmol) were purged in the same way. The catalyst was added to the reaction flask which was purged with nitrogen 3 more times. The mixture was stirred (stir bar) at 80° C. for 22 hours. TLC showed little change. The mixture was mechanically stirred at 80° C. for 4 hours. The mixture was partitioned between water and ethyl acetate, filtered through Celite and the layers were separated. The organic layer was evaporated. The residue was dissolved in ethyl acetate, washed with water twice. Saturated brine was added the second time to separate the layers more quickly. The organic solution was dried over magnesium sulfate. Filtration and contration in vacuum gave 11.35 g of black oil. This was eluted from silica gel with a gradient of hexane and ethyl acetate to give 3.86 g of recovered starting material and 4.28 g of the title compound as light brown crystals, m.p. 90-91° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Product: N#Cc1ccc(N(c2ccc([N+](=O)[O-])cc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl)amino]pyrimidine and 4-fluoronitrobenzene
Reaction SMILES: N([C:28]([O:30][C:31]([CH3:34])(C)C)=[O:29])[C@H:2]([C:14]([CH2:16]OS(C1C=CC(C)=CC=1)(=O)=O)=O)[CH2:3][C:4]1C=C2C(C=CC=C2)=C[CH:5]=1.[C:35](OC(N(C1C2C(=CC=CC=2)C=CC=1)[C@H](CO)C)=O)(C)(C)C.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>N1C=CC=CC=1>[CH3:34][CH2:31][O:30][C:28]([CH3:35])=[O:29].[CH3:16][CH2:14][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: C[C@@H](CO)N(C(=O)OC(C)(C)C)c1cccc2ccccc12
Reactant: Cc1ccc(S(=O)(=O)OCC(=O)[C@H](Cc2ccc3ccccc3c2)NC(=O)OC(C)(C)C)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCCCCC
Product: CCOC(C)=O
Temperature: -30 °C
Yield: 82 %

Procedure:
Boc-Nal-CH2OTs. N-t-butyloxycarbonylnaphthylalaninol (3.71 g; 12.3 mmol) was dissolved in pyridine (15 ml) and the solution was cooled to -30° C. Tosyl chloride (2.36 g; 12.4 mmol) was added and the mixture was stirred to clearness at -30° C. and then put into the refrigerator overnight. Pyridine was removed in vacuo and the product was extracted with ether (4×30 ml). The organic layer was washed with 1N HCl (2×30 ml), H2O (1×30 ml), NaHCO3 5% (2×30 ml) and saturated NaCl (1×30 ml), then dried over Na2SO4, filtered and stripped to leave an oily residue which was crystallized from AcOEt/hexane (4.6 g; 82% yield).
Reaction SMILES: BrCC[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[O:12][C:13]1[CH:18]=C(Cl)C=C(Cl)C=1CCBr.[CH3:24][NH2:25]>>[ClH:10].[Cl:10][C:9]1[CH:4]=[C:5]([CH:6]=[C:7]([Cl:11])[CH:8]=1)[O:12][CH2:13][CH2:18][NH:25][CH3:24]
Reactant: Clc1cc(Cl)c(CCBr)c(Oc2cc(Cl)cc(Cl)c2CCBr)c1
Reactant: CN
Product: CNCCOc1cc(Cl)cc(Cl)c1
Product: Cl

Procedure:
A solution of 31.56 g (0.118 mole) 2-bromoethyl-3,5-dichlorophenyl ether in excess methylamine was agitated overnight in a bomb at room temperature. The methylamine was evaporated under nitrogen and the residue partitioned between water and methylene chloride. The methylene chloride was evaporated to give an oil, the free base of the title compound. A portion of the oil was reacted with ethereal hydrogen chloride to give the hydrochloride salt which was recrystallized from methanol-diethyl ether to give a white crystalline product in 35.7% overall yield, m.p. 173°-175° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].Cl.[CH2:8]([S:10][C:11](=[NH:13])[NH2:12])[CH3:9].O.[OH-].[Na+]>C(Cl)Cl.C(#N)C>[CH2:5]([O:4][C:2]([NH:12][C:11]([NH2:13])=[SH:10][CH2:8][CH3:9])=[O:3])[CH3:6]
Reactant: CCSC(=N)N
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CCOC(=O)NC(N)=[SH]CC
Reaction time: 1.33 h

Procedure:
302 g. (2.78 moles) of ethyl chloroformate was added to 2 moles of S-ethylisothiourea hydrochloride in 800 ml. of water and 200 ml. of acetonitrile. A 25% solution of sodium hydroxide was added dropwise so rapidly that, with external cooling, a temperature of +25° C. was not exceeded. The solution of sodium hydroxide was added for as long as the pH value did not rise above 8. Stirring was effected for a further 80 minutes during which control of the pH value was continued. If necessary, a little more solution of sodium hydroxide was added. A two phase system, aqueous and organic, resulted. The product was isolated from the organic phase by extraction with methylene chloride and concentration in vacuo to a light yellow oil.
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H][H]>[Pd].C(O)C>[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][C:2]([CH3:1])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(N)cc1

Procedure:
A mixture of 50.6 g. (0.2 mol) ethyl 2-methyl-2-(4-nitrophenoxy)-propionate, 500 ml. ethanol and about 20 g. 5% palladium charcoal is hydrogenated in a shaker at ambient temperature and atmospheric pressure until the necessary amount of hydrogen has been taken up. The reaction mixture is subsequently filtered with suction and the liquid phase is evaporated to give a quantitative yield of crude ethyl 2-(4-aminophenoxy)-2-methylpropionate in the form of a distillable oil (b.p. 134°-135° C./0.05 mm.Hg.); nD20 =1.5035; m.p. of the hydrochloride 153°-154° C.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH3:7])[N:5]=[N:4][N:3]=1.[N:8]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[S:10][C:9]=1[NH2:17].Cl[C:19]1[C:20]2[N:28]=[C:27](Cl)[CH:26]=[CH:25][C:21]=2[N:22]=[CH:23][N:24]=1>>[CH3:7][N:6]1[C:2]([S:1][C:27]2[CH:26]=[CH:25][C:21]3[N:22]=[CH:23][N:24]=[C:19]([NH:17][C:9]4[S:10][C:11]5[C:16]([N:8]=4)=[CH:15][CH:14]=[CH:13][N:12]=5)[C:20]=3[N:28]=2)=[N:3][N:4]=[N:5]1
Reactant: Nc1nc2cccnc2s1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Reactant: Cn1nnnc1S
Product: Cn1nnnc1Sc1ccc2ncnc(Nc3nc4cccnc4s3)c2n1

Procedure:
The compound of Example 53 was manufactured by the same method as in Example 31, by a similar method thereto or by a combination of such a method with a conventional method using 5-mercapto-1-methyl-1H-tetrazole, thiazolo[5,4-b]pyridin-2-yl-amine and 4,6-dichloro-pyrido[3,2-d]pyrimidine.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N+:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][C:18]([CH3:21])=[CH:19][N:20]=2)=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[CH2:3]([N:10]1[CH2:11][CH:12]=[C:13]([C:16]2[O:17][C:18]([CH3:21])=[CH:19][N:20]=2)[CH2:14][CH2:15]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cnc(-c2cc[n+](Cc3ccccc3)cc2)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cnc(C2=CCN(Cc3ccccc3)CC2)o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
21.6 g sodium borohydride was added to 130 g 1-benzyl-4-(5-methyl-oxazol-2-yl)-pyridinium in 1.5 L ethanol at 0° C. under nitrogen. The reaction was stirred 30 min at 0° C. and 2 h at RT. The mixture was concentrated and treated with water and ethyl acetate. The organic layer was separated and washed with brine and evaporated. The residue was purified by chromatographie on silica to give 81.2 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:9][CH3:10])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].O>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:18](=[O:19])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[CH2:9][CH3:10])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCc1cc(Br)ccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cc(Br)ccc1NC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
4-Bromo-2-ethylaniline (500 mg, 2.50 mmol) was dissolved in toluene (25 mL), sodium carbonate (397 mg, 3.75 mmol) and benzyl chloroformate (0.428 mL, 3.00 mmol) were added and the mixture stirred under nitrogen at room temperature. After 20 hours water (25 mL) was added, the aqueous phase separated and washed with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated. Chromatography (40 g silica cartridge, 0-100% ethyl acetate/petroleum benzine 40-60° C.) gave the title compound (I38) (708 mg, 85%) as a pink solid; 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.44-7.28 (m, 7H), 6.43 (s, 1H), 5.20 (s, 2H), 2.54 (q, J=7.6 Hz, 2H), 1.21 (t, J=7.6 Hz, 3H). LCMS Method C: rt 6.46 min; m/z 258.0 [M-PhCH2O+CH3OH]+.
Reaction SMILES: [C:1]([C@@H:3]([NH:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]1[NH:18][C:19]([C:21]1[N:22]([CH3:30])[C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=[O:11])[CH2:4][CH2:5][C:6]([OH:8])=O)#[N:2].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[C:1]([C@@H:3]([NH:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]1[NH:18][C:19]([C:21]1[N:22]([CH3:30])[C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=[O:11])[CH2:4][CH2:5][C:6]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:8])#[N:2]
Reactant: Cn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)N[C@H](C#N)CCC(=O)O)cc2ccccc21
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)N[C@H](C#N)CCC(=O)N2CCOCC2)cc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.9 %

Procedure:
The (S)-4-cyano-4-({(1R,2S)-2-[(1-methyl-1H-indole-2-carbonyl)-amino]-cyclohexanecarbonyl}-amino)-butyric acid (140 mg, 0.341 mmol), morpholine (50 μL, 0.57 mmol), EDCI hydrochloride (102 mg, 0.532 mmol), HOBT (50 mg, 0.37 mmol) and N-methyl morpholine (0.10 mL, 0.91 mmol) were dissolved in 5.0 mL of DMF and stirred at room temp for 4 hours. The reaction mixture was partitioned between 50 mL of water and 50 mL of ethyl acetate. The organic layer was washed with water (2×50 mL), dried with sodium sulfate, filtered and concentrated to give 98 mg (60%) of 1-Methyl-1H-indole-2-carboxylic acid [(1S,2R)-2-((S)-1-cyano-4-morpholin-4-yl-4-oxo-butylcarbamoyl)-cyclohexyl]-amide as a white amorphous solid. MS: 480 (M+H+).
Reaction SMILES: C([O:3][P:4]([C:9]([C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([C:22]#[N:23])=[N:19]2)=[CH:14][C:13]=1[Br:24])([F:11])[F:10])(=[O:8])[O:5]CC)C.Br[Si](C)(C)C.[NH3:30].CO>ClCCl>[Br:24][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:12]=1[C:9]([P:4](=[O:3])([O-:5])[O-:8])([F:11])[F:10])[N:19]=[C:18]([C:22]#[N:23])[CH:17]=[CH:16]2.[NH4+:30].[NH4+:19]
Reactant: N
Reactant: CCOP(=O)(OCC)C(F)(F)c1cc2nc(C#N)ccc2cc1Br
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: ClCCl
Product: N#Cc1ccc2cc(Br)c(C(F)(F)P(=O)([O-])[O-])cc2n1
Product: [NH4+]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of diethyl[(6-bromo-2-cyanoquinolin-7-yl)(difluoro)methyl]phosphonate (370 mg, 0.883 mmol) in dichloromethane (9) at 0° C. was added dropwise bromotrimethylsilane (1.15 mL, 8.83 mmol). The reaction mixture was stirred at room temperature overnight. It was concentrated to dryness, and co-evaporated with dichloromethane (2×). Ethanol (5 mL) was added to the residue, which was stirred for 20 minutes. It was concentrated to dryness and co-evaporated with ethanol (2×). The residue was dissolved in methanol (8 mL) and 2.0 M ammonia in methanol (4.4 mL, 8.80 mmol) was added dropwise. It was stirred for 20 minutes, concentrated to dryness and suspended in diethyl ether. The precipitate was filtered to afford diammonium[(6-bromo-2-cyanoquinolin-7-yl)(difluoro)methyl]phosphonate.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:16])[C:12]([OH:15])([CH3:14])[CH3:13])=[CH:7][CH:6]=1.[P:17]([O:22]C)([O:20][CH3:21])[O:18][CH3:19]>>[CH3:19][O:18][P:17]([CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:16])[C:12]([OH:15])([CH3:14])[CH3:13])=[CH:7][CH:6]=1)(=[O:22])[O:20][CH3:21]
Reactant: CC(C)(O)C(=O)c1ccc(OCCBr)cc1
Reactant: COP(OC)OC
Product: COP(=O)(CCOc1ccc(C(=O)C(C)(C)O)cc1)OC
Temperature: 130 °C
Yield: 54.8 %

Procedure:
A mixture of 5.80 grams (0.0202 mol) of 1-[4-(2-bromoethoxy)phenyl]-2-hydroxy-2-methylpropan-1-one and 6.27 g (0.0505 mol) of trimethyl phosphite is heated to 130° C. for 16 hours. The crude product is passed through a short column of silica gel which is eluted with a mixture of 1:1 heptane:ethyl acetate followed by methanol. Evaporation of solvent gives 3.5 g (55% yield) of the title compound as a yellow oil.
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:5][CH2:6][CH3:7])[CH3:4].Cl[NH:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]C.[C:23]([OH:27])(C)(C)C>O.CC(C)=O>[CH2:3]([N:5]([CH2:6][CH3:7])[C:23]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:27])[CH3:4]
Reactant: CCNCC
Reactant: CC(C)(C)O
Reactant: CCCCCCCCCCCC(=O)NCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCCCCNC(=O)N(CC)CC
Temperature: 40 °C
Yield: 90 %

Procedure:
4 g. (0.1 mol) of sodium hydroxide, dissolved in 10 ml of water, and 7.3 g. (0.1 mol) of diethylamine were simultaneously added to a solution containing 23.35 g. (0.1 mol) of lauric N-chloramide in 200 ml of tertiary butanol. The resulting mixture was heated to 40° C., and then allowed to react for 30 minutes at this temperature. Any precipitated sodium chloride was removed by filteration and the filtrate was concentrated producing a residue. The residue was taken up in 100 ml of acetone and filtered to yield 24.3 g. (90% yield) of N,N-diethyl-N'-n- undecyl urea of the formula ##STR4## having a melting point of 33°-35° C. and the following analysis: