Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].C[Si](C)(C)N[Si](C)(C)C.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=1.[Cl:22][C:23]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:24]=1C(OC)=O.Cl>C1COCC1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([C:30]2[CH:29]=[CH:24][C:23]([Cl:22])=[CH:32][C:31]=2[Cl:33])=[O:21])=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(Cl)cc1Cl
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Br)cc1)c1ccc(Cl)cc1Cl
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
436 ml of a 2M solution of the sodium salt of hexamethyldisilazane in THF are cooled to −60° C., under a nitrogen atmosphere, 400 ml of THF are added, followed dropwise by a solution of 75 g of 4-bromophenylacetic acid in 100 ml of THF and the medium is left for 1 hour 30 minutes with stirring at −70° C. 67.9 g of methyl 2,4-dichlorobenzoate are then added dropwise, the medium is left for 30 minutes, with stirring, and then the temperature is allowed to rise to 5° C. The reaction mixture is poured over an ice/1 liter of 2N HCl mixture, extracted with ether, the organic phase is washed with a saturated NaHCO3 solution, with water, dried over Na2SO4 and the solvent is evaporated under vacuum to a volume of 200 ml, pentane is added and the crystallized product formed is drained. 80 g of the expected compound are obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[N:12])=[N:9][CH:10]=1)(=[O:4])=[O:3].C(O)C.[ClH:16]>[Pd].O>[ClH:16].[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][NH2:12])=[N:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(C#N)nc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(CN)nc1
Yield: 82 %

Procedure:
To 5-Methanesulfonyl-pyridine-2-carbonitrile (22 kg, 1.0 mol eq, limiting reagent) was charged palladium on carbon (2.0 kg, 5% w/w), ethanol (110 L, 5 rel vol), water (14 L, 0.64 rel vol) and hydrochloric acid (25.04 kg, 32% w/w). An ethanol line rinse (16 L, 0.7 rel vol) followed. The reaction mixture was heated and subjected to an atmosphere of hydrogen until the reaction was complete as judged by HPLC analysis. Water (108 L, 4.9 rel vol) was charged, the catalyst filtered off and washed with water (36 L, 1.6 rel vol). The combined filtrates were concentrated under reduced pressure to approximately 2.5 rel vols. The reaction was then heated and ethanol (126.3 L, 5.7 rel vol) was charged. The reaction mixture was cooled, stirred and isolated by filtration. The solid was washed with ethanol (73.7 L, 3.3 rel vol) and dried to constant weight to yield the title compound (20.1 kg, 9.05 mol, 82%).
Reaction SMILES: [F:1][C@H:2]1[CH2:8][O:7][CH2:6][C:5]([NH2:9])=[N:4][C@@:3]1([C:11]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:12]=1[F:20])[CH3:10]>C(O)C.[Pd]>[NH2:17][C:15]1[CH:14]=[CH:13][C:12]([F:20])=[C:11]([C@:3]2([CH3:10])[C@@H:2]([F:1])[CH2:8][O:7][CH2:6][C:5]([NH2:9])=[N:4]2)[CH:16]=1
Reactant: C[C@]1(c2cc([N+](=O)[O-])ccc2F)N=C(N)COC[C@@H]1F
Agent: [Pd]
Solvent: CCO
Product: C[C@]1(c2cc(N)ccc2F)N=C(N)COC[C@@H]1F
Reaction time: 2 h

Procedure:
A suspension of (5R,6R)-6-fluoro-5-(2-fluoro-5-nitro-phenyl)-5-methyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine (1.0 mmol) in ethanol (9 ml) and Pd/C (10%, 100 mg) was hydrogenated at 22° C. and atmospheric pressure for 2 h. The suspension was filtered and the residue evaporated to give (5R,6R)-5-(5-amino-2-fluoro-phenyl)-6-fluoro-5-methyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine as a yellow solid. MS (ISP): m/z=256.3 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:13])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].CC#N>CCOC(C)=O>[C:1]([C:5]1[C:6]([O:13][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)(C)c1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc(COc2c(C=O)cccc2C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
A suspension of 3-tert-butyl-2-hydroxybenzaldehyde (5.0 g, 28.1 mmol, 1.0 equiv), 4-methoxybenzyl chloride (4.4 g, 3.8 mL, 28.1 mmol, 1.0 equiv), powdered K2CO3 (7.8 g, 56.2 mmol, 2.0 equiv) and MeCN (100 mL) was refluxed for 6 hr. The yellow-green suspension was cooled to room temperature and allowed the stand for 48 hr. The suspension was diluted with EtOAc (50 mL) and filtered, washing the solids with EtOAc (50 mL). The filtrate was concentrated under reduced pressure to give brown oil. The oil was dissolved in EtOAc (150 mL) and the solution washed with H2O (125 mL) and brine (100 mL). The organic phase was dried over Na2SO4, filtered and the solution concentrated under reduced pressure to give a brown oil. The crude product was absorbed onto silica gel using dichloromethane and dry-loaded onto a column of silica gel (100 g) packed in heptanes. The column was eluted with heptanes (500 mL) followed by 2.5% EtOAc/heptanes (1000 mL). Product fractions were concentrated under reduced pressure to give a yellow oil. Seeding (seeds obtained by lengthy scratching with cold hexanes) of the oil induced crystallization. After crystallization was complete the yellow solid was pumped under high vacuum for 0.5 hr to give 7.5 g (89%) of 24.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][O:5][C:4](=[O:7])[CH:3]1[O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=1.[CH3:22][C@H:23]([NH2:26])[CH2:24][CH3:25]>C1COCC1>[CH:23]([NH:26][C:4](=[O:7])[CH:3]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:19])([F:18])[F:20])[CH:10]=1)[C:2]([CH3:21])([CH3:1])[CH2:6][OH:5])([CH2:24][CH3:25])[CH3:22]
Reactant: CC1(C)COC(=O)C1Oc1ccc(C#N)c(C(F)(F)F)c1
Reactant: CC[C@H](C)N
Solvent: C1CCOC1
Product: CCC(C)NC(=O)C(Oc1ccc(C#N)c(C(F)(F)F)c1)C(C)(C)CO

Procedure:
(±)-4-(4,4-Dimethyl-2-oxo-tetrahydrofuran-3-yloxy)-2-trifluoromethylbenzonitrile (66.00 g, 221 mmol) was combined with 330 mL dry THF and the (S)-(+)-2-butylamine (total of 64.5 g, 882 mmol), and the reaction mixture was heated at 40-60° C. in a sealed vessel for 124 h. The amber sol'n was concentrated under vac (35-40° C.) to an amber gum. The gum was redissolved in 500 m ethyl acetate “EtOAc” and conc'd again. The gum was redissolved in 500 mL “EtOAc” and passed through a pad of silica. The silica was washed with 500 mL EtOAc and the combined filtrate was concentrated under vac to a pale amber gum.
Reaction SMILES: [O:1]1[CH2:6][C:5](=S)[NH:4][C:3](=[O:8])[NH:2]1.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>O1CCOCC1>[N:9]1([C:5]2[CH2:6][O:1][NH:2][C:3](=[O:8])[N:4]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C1NOCC(=S)N1
Reactant: C1CCNCC1
Solvent: C1COCCO1
Product: O=C1N=C(N2CCCCC2)CON1
Temperature: 25 °C
Reaction time: 17 h
Yield: 53.5 %

Procedure:
To a solution of 0.7 g (0.005 mole) of 6H-1,2,4-oxadiazin-3(2H)-one-5(4H)-thione in 10 ml of dry freshly distilled dioxane is added 0.44 g (0.0052 mole) of piperidine. After stirring for 17 hours at room temperature, the solution is filtered, washed with chloroform and dried to give a yield of 0.49 g (54 percent) of 5-(1-piperidinyl)-6H-1,2,4-oxadiazin-3(2H)-one.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[N:8]=[C:7]2[CH:19]=O)([O-:3])=[O:2].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:28]=[C:29]([NH2:34])[C:30]([NH2:33])=[CH:31][CH:32]=2)[CH2:23][CH2:22]1.S(=O)(O)[O-].[Na+]>C1COCC1.Cl.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[N:8]=[C:7]2[C:19]1[NH:33][C:30]2[CH:31]=[CH:32][C:27]([N:24]3[CH2:23][CH2:22][O:21][CH2:26][CH2:25]3)=[CH:28][C:29]=2[N:34]=1)([O-:3])=[O:2]
Reactant: O=Cc1nn(C2CCCCO2)c2ccc([N+](=O)[O-])cc12
Reactant: Nc1ccc(N2CCOCC2)cc1N
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)c(-c1nc3cc(N4CCOCC4)ccc3[nH]1)nn2C1CCCCO1
Temperature: 25 °C
Yield: 50 %

Procedure:
5-Nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (214 mg, 0.777 mmol) and 4-morpholinobenzene-1,2-diamine (150 mg, 0.777 mmol) were dissolved in dry THF (10 mL), and 2N HCl (1 drop) was added. The solution was heated at a gentle reflux for 30 min and then 1N sodium bisulfite (1 mL) was added. After overnight at reflux, the solution was cooled to room temperature, and diluted with ethyl acetate (40 mL). The mixture was washed with water and brine, dried over Na2SO4, and concentrated. Purification by flash chromatography (20% ethyl acetate/hexane) afforded the title compound as a pale yellow solid in a 50% yield. 1H NMR: (400 MHz, DMSO-d6): δ 9.49 (d, 1H, J=2.0 Hz), 8.41 (dd, 1H, J=2.0 and 9.2 Hz), 8.00 (d, 1H, J=9.2 Hz), 7.71 (m, 1H), 7.12 (m, 2H), 6.05 (dd, 1H, J=2.4 and 9.2 Hz), 4.75 (dd, 1H, J=2.4 and 6.8 Hz), 4.05 (m, 1H), 3.89 (m, 4H), 3.63 (m, 1H), 3.54-3.47 (m, 1H), 3.22 (m, 4H), 2.21 (m, 2H), 1.87 (m, 1H), 1.73 (m, 1H).
Reaction SMILES: ClCCl.[CH2:4]([O:6][C:7](=[O:37])[CH:8]([NH:30][C:31]([O:33][CH2:34][CH:35]=[CH2:36])=[O:32])[CH2:9][C:10]1[O:14][N:13]=[C:12]([CH:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20](=[O:29])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[CH:11]=1)[CH3:5].[Cl:38][C:39]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[C:40]=1[C:41](Cl)=[O:42].N1C=CC=CC=1>C(OCC)(=O)C>[CH2:4]([O:6][C:7](=[O:37])[CH:8]([NH:30][C:31]([O:33][CH2:34][CH:35]=[CH2:36])=[O:32])[CH2:9][C:10]1[O:14][N:13]=[C:12]([CH:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20](=[O:29])[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([NH:28][C:41](=[O:42])[C:40]3[C:39]([Cl:38])=[CH:47][CH:46]=[CH:45][C:44]=3[Cl:48])=[CH:26][CH:27]=2)[CH:11]=1)[CH3:5]
Reactant: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)Cc2ccc(N)cc2)no1)C(=O)OCC
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)no1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.8 %

Procedure:
A dichloromethane (1 mL) solution 2-allyloxycarbonylamino-3-(3-{1-[(4-amino-phenyl)-acetyl]-pyrrolidin-2-yl}-isoxazol-5-yl)-propionic acid ethyl ester (80 mg, 0.170 mmol) was cooled to 0° C. and 2,6-dichlorobenzoylchloride (39 mg, 0.187 mmol) was added. The mixture was stirred for 15 minutes then pyridine (28 μL, 0.34 mmol)was added. The reaction was slowly warmed to room temperature and stirred overnight. The reaction was diluted with ethyl acetate and washed with water, 1 M sodium hydroxide and brine. The organic portion was dried over magnesium sulfate and concentrated to give the title compound (84 mg, 78%). MS (CI) m/z 635.3 (M+1), 632.5 (M−1)
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1)=[O:3].[F:11][C:12]([F:23])([F:22])[C:13]1[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[NH:15][N:14]=1>>[F:23][C:12]([F:11])([F:22])[C:13]1[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[N:15]([C:7]2[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=2)[N:14]=1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Reactant: CC(=O)c1ccc(I)cc1
Product: CC(=O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from 4-iodoacetophenone and 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similar procedure to that described for Example 7.
Reaction SMILES: NC1SC2CC(N)CCC=2N=1.[Br:12]Br.[C:14]([NH:17][CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1)(=[O:16])[CH3:15]>O>[Br:12][CH:22]1[CH2:23][CH:18]([NH:17][C:14](=[O:16])[CH3:15])[CH2:19][CH2:20][C:21]1=[O:24]
Reactant: CC(=O)NC1CCC(=O)CC1
Reactant: BrBr
Agent: Nc1nc2c(s1)CC(N)CC2
Solvent: O
Product: CC(=O)NC1CCC(=O)C(Br)C1

Procedure:
According to one aspect of the present invention there is provided a method of synthesising 2,6-diamino-4,5,6,7-tetrahydro-benzothiazole, which method comprises comprising: (i) reacting bromine with a solution of 4-acetamido-cyclohexanone in water to produce 2-bromo-4-acetamido-cyclohexanone; (ii) after step (i), adding thiourea to produce 6-acetylamino-2-amino4,5,6,7-tetrahydro-benzthiazole-dihydrobromide; (iii) after step (ii), adding an aqueous solution of hydrobromic acid to produce 2,6-diamino-4,5,6,7-tetrahydro-benzthiazole; and (iv) after step (iii), isolating 2,6-diamino-4,5,6,7-tetrahydro-benzthiazole free base.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6]1[C:11]([CH2:12][NH:13][CH3:14])=[CH:10][CH:9]=[CH:8][N:7]=1.[H-].[Na+].C(Cl)(Cl)(Cl)Cl.[C:25](Cl)(Cl)=[O:26].C(Cl)(Cl)=O.CC(C)=O.N>O>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH2:12][N:13]([CH3:14])[C:25]2=[O:26])[CH:15]=[CH:16][CH:17]=1
Reactant: CNCc1cccnc1Nc1cccc(F)c1
Reactant: O=C(Cl)Cl
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CN1Cc2cccnc2N(c2cccc(F)c2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
To a solution of 2.3 g of 2-(m-fluoroanilino)-3-methylaminomethylpyridine was added 0.96 g of approximately 50% sodium hydride and the mixture was stirred at room temperature for 30 minutes. To this was added 10 g of approximately 30% carbon tetrachloride-phosgene solution, dropwise under ice-cooling, and the resulting mixture was stirred for 1 hour. After an excess of the phosgene was decomposed with 10% acetone-ammonia solution, the solvent was removed from the reaction mixture by distillation under reduced pressure. The residue thus obtained was diluted with water, extracted with ether and dehydrated. The ether solution was applied on a column of alumina and then eluted with ether. The eluate was concentrated and left to give 1.3 g of 1-(m-fluorophenyl)-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine as colorless prisms, melting at 189° - 192° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[N:14]([CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])(=O)[CH3:2].[H-].[Na+]>C(O)C>[CH3:2][C:1]1[C:4]2[C:5](=[CH:6][C:7]([C:10]([F:13])([F:11])[F:12])=[CH:8][CH:9]=2)[N:14]([CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:15](=[O:22])[C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CC(=O)N(c1cc(C(F)(F)F)ccc1C(C)=O)C1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(C)c2ccc(C(F)(F)F)cc2n(C2CCOCC2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
To a stirred solution of 550 mg (1.37 mmol) ethyl 3-((2-acetyl-5-(trifluoromethyl)phenyl)-(tetrahydro-2H-pyran-4-yl)amino)-3-oxopropanoate in ethanol (5 ml) was added 60 mg (1.51 mmol, 60% suspension in mineral oil) NaH at 0° C. The reaction mixture was stirred at RT for 30 min. Then the mixture was evaporated to dryness, the residue was diluted with water (10 ml) and acidified with 2N HCl to pH ˜3. The aq. part was extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with water (10 ml), brine (10 ml), dried over anhydrous Na2SO4 and evaporated to get the crude which was again washed with sat. Na2CO3 to yield 330 mg (0.86 mmol, 62%) ethyl 4-methyl-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-7-(trifluoromethyl)-1,2-dihydroquinoline-3-carboxylate which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH2:19][CH2:18][CH2:17][C:16](=[O:21])[C:15]=2[C:14]2[C:9]1=[CH:10][C:11]([O:22][CH3:23])=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[Br-].[Li+].C(=O)([O-])[O-].[Li+].[Li+]>[Cu](Cl)Cl.C(O)CO>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=2[C:14]2[C:9]1=[CH:10][C:11]([O:22][CH3:23])=[CH:12][CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c3c(n(Cc4ccccc4)c2c1)CCCC3=O
Agent: Cl[Cu]Cl
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: OCCO
Solvent: C1COCCO1
Product: COc1ccc2c3c(O)cccc3n(Cc3ccccc3)c2c1
Temperature: 120 °C
Yield: 61 %

Procedure:
To a mixture of 9-benzyl-7-methoxy-1,2,3,9-tetrahydro-4H-carbazol-4-one (1.65 g, 5.4 mmol) in 1:1 p-dioxane:ethylene glycol (50 mL) at 80° C. is added copper (II) chloride (3.6 g, 27 mmol). The mixture is heated for 17 minutes. The mixture is partitioned between water and ethyl acetate. The layers are separated and the ethyl acetate layer washed twice with water (200 mL). The ethyl acetate is dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is dissolved in DMF (50 mL). Lithium bromide (0.94 g, 10.8 mmol) and lithium carbonate (0.8 g, 10.8 mmol) is added and the mixture heated to 120° C. for 6 hours. The mixture is partitioned between water and ethyl acetate. The layers are separated and the ethyl acetate layer washed twice with water (200 mL). The ethyl acetate is dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography, silica gel (100 mL), using CH2Cl2/CH3OH (96/4) gave 1.0 gm (61%) of the title compound; IR (drift) 1607, 1465, 1334, 1330, 1320, 1276, 1251, 1207, 1102, 809, 745, 740, 722, 711, 696 cm−1. 1H NMR (CDCl3) δ3.9, 5.4, 6.6, 6.8, 6.9, 7.2, 7.2, 8.2); Anal. Calcd for C20H17NO2: C, 79.18; H, 5.65; N, 4.62. Found: C, 78.35; H, 5.66; N, 4.55.
Reaction SMILES: [C:1]1([CH2:6][NH2:7])([CH2:4][NH2:5])[CH2:3][CH2:2]1.[C:8](=S)=[S:9]>>[CH2:3]1[C:1]2([CH2:6][NH:7][C:8](=[S:9])[NH:5][CH2:4]2)[CH2:2]1
Reactant: NCC1(CN)CC1
Reactant: S=C=S
Product: S=C1NCC2(CC2)CN1

Procedure:
By the above reaction scheme, 1,1-cyclopropanedimethanamine is reacted with carbon disulfide to yield 5,7-diazaspiro[2.5]octane-6-thione. Alkylation of this thione with methyl iodide affords 6-(methylthio)-5,7-diazaspiro[2.5]-oct-5-ene, hydriodide. Reaction of this compound with hydrazine hydrate yields 6-hydrazino-5,7-diazaspiro[2.5]oct-5-ene hydriodide. Finally, condensation of this hydrazine with 1,5-bis(α,α,α-trifluoro-p-tolyl)-1,4-pentadien-3-one yields the desired formula (1) compound: 1,5-bis(α,α,α-trifluoro-p-tolyl)-1,4-pentadien-3-one 5,7-diazaspiro[2.5]-oct-5-en-6-ylhydrazone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C@@H:17]([NH:19][C:20]([C:22]3[N:23]=[C:24]([C:35]([OH:37])=O)[N:25]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:26]=3)=[O:21])[CH3:18])[N:12]=2)[CH:5]=[C:6]([F:10])[C:7]=1[C:8]#[N:9].[CH3:38][NH:39][CH3:40]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C@@H:17]([NH:19][C:20]([C:22]3[N:23]=[C:24]([C:35]([N:39]([CH3:40])[CH3:38])=[O:37])[N:25]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:32])[CH3:33])[CH:26]=3)=[O:21])[CH3:18])[N:12]=2)[CH:5]=[C:6]([F:10])[C:7]=1[C:8]#[N:9]
Reactant: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn(COCC[Si](C)(C)C)c(C(=O)O)n1
Reactant: CNC
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn(COCC[Si](C)(C)C)c(C(=O)N(C)C)n1

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from (S)-4-((1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)carbamoyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylic acid (0.549 mmol, 300 mg) and N,N-dimethylamine (0.824 mmol, 37 mg). The product was purified by flash-chromatography. Yield 207 mg. 1H-NMR (400 MHz; CDCl3): δ −0.01 (s, 9H), 0.91 (t, 2H), 1.26 (d, 3H), 3.11 (s, 3H), 3.26 (s, 3H), 3.54 (t, 2H), 4.31-4.42 (m, 2H), 4.51-4.57 (m, 1H), 5.74 (s, 2H), 6.59 (d, 1H), 7.39 (d, 1H), 7.49 (d, 1H), 7.59 (d, 1H), 7.81 (s, 1H), 7.84 (s, 1H). LC-MS: [M+1]=574.32.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([O:10][CH2:11][CH2:12][S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[O:9])[CH:4]=[C:3]1[C:24]([O:26]C)=[O:25].[Li+].[OH-].Cl>C1COCC1.O>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([O:10][CH2:11][CH2:12][S:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)=[O:9])[CH:4]=[C:3]1[C:24]([OH:26])=[O:25]
Reactant: COC(=O)c1cc(NC(=O)OCCSc2ccc(C(F)(F)F)cc2)cn1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(NC(=O)OCCSc2ccc(C(F)(F)F)cc2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 96 h
Yield: 66.3 %

Procedure:
Methyl 1-methyl-4-[2-(4-trifluoromethyl-phenylsulfanyl)-ethoxycarbonylamino]-1H-pyrrole-2-carboxylate (5.0 g, 12.43 mmol) prepared in the capping step was dissolved in THF/H2O (200 ml/100 ml), 1N LiOH (30 ml) was added thereto, and the mixture was stirred for 4 days at room temperature. The reaction solution was acidified to pH 2.0 by 1N HCl and then extracted with EA and water. The organic layer was washed with aqueous NaCl solution and dried over anhydrous MgSO4. The solvent contained therein was removed to give a white solid, which was then recrystallized from EA and n-hexane to give 1-methyl-4-[2-(4-trifluoromethyl-phenylsulfanyl)-ethoxy carbonylamino]-1H-pyrrole-2-carboxylic acid (3.20 g, 66.29%) of a pale yellow solid.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][C:14]([F:20])([F:19])[CH2:15][CH:16]1[CH2:18][CH2:17]1)[C:10]([OH:12])=[O:11])=O)(C)(C)C.[ClH:21]>>[ClH:21].[NH2:8][C@@H:9]([CH2:13][C:14]([F:19])([F:20])[CH2:15][CH:16]1[CH2:18][CH2:17]1)[C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(F)(F)CC1CC1)C(=O)O
Agent: Cl
Product: N[C@@H](CC(F)(F)CC1CC1)C(=O)O

Procedure:
A preferred aspect of the invention is a process for the preparation of (S)-methyl 2-amino-5-cyclopropyl-4,4-difluoropentanoate hydrochloride, which process comprises: (a) reacting (R,S)-ethyl 2-(tert-butoxycarbonylamino)-5-cyclopropyl-4,4-difluoropentanoate with Alcalase to give a mixture of (R)-ethyl 2-(tert-butoxycarbonylamino)-5-cyclopropyl-4,4-difluoropentanoate and (S)-2-(tert-butoxycarbonylamino)-5-cyclopropyl-4,4-difluoropentanoic acid; (b) isolating the (S)-2-(tert-butoxycarbonylamino)-5-cyclopropyl-4,4-difluoropentanoic acid; (c) deprotecting the (S)-2-(tert-butoxycarbonylamino)-5-cyclopropyl-4,4-difluoropentanoic acid with hydrochloric acid to give (S)-2-amino-5-cyclopropyl-4,4-difluoropentanoic acid hydrochloride; and (d) treating the (S)-2-amino-5-cyclopropyl-4,4-difluoropentanoic acid hydrochloride with methanol.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24](=[NH:27])[NH:25][OH:26])=[CH:20][CH:19]=2)=[O:17])[CH2:12][CH2:11]1.[C:28](Cl)(=O)[CH2:29][CH3:30].B(F)(F)F.CCOCC>O1CCOCC1.C(Cl)Cl.C([O-])(O)=O.[Na+]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([C:18]2[CH:19]=[CH:20][C:21]([C:24]3[N:27]=[C:28]([CH2:29][CH3:30])[O:26][N:25]=3)=[CH:22][CH:23]=2)=[O:17])[CH2:12][CH2:11]1
Reactant: N=C(NO)c1ccc(C(=O)N2CCC(c3nc4ccccc4[nH]3)CC2)cc1
Reactant: CCC(=O)Cl
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: ClCCl
Product: CCc1nc(-c2ccc(C(=O)N3CCC(c4nc5ccccc5[nH]4)CC3)cc2)no1
Temperature: 40 °C
Reaction time: 4 h
Yield: 3.2 %

Procedure:
To a stirred solution of 4-{[4-(1H-benzimidazol-2-yl)piperidin-1-yl]carbonyl}-N-hydroxybenzene carboximidamide (0.15 g, 0.41 mmol) in anhydrous 1,4-dioxane (5 mL) is added dropwise propionyl chloride (34 μL, 0.39 mmol). The reaction is heated to 40° C. for 1 h before adding boron trifluoride etherate (10.5 μL, 0.083 mmol). Heating is continued at 80° C. for 4 h. The mixture is diluted with DCM and saturated aqueous NaHCO3 giving a suspension which is filtered. The organic layer is separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give 5 mg of [4-(1H-benzimidazol-2-yl)piperidin-1-yl][4-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl]methanone.