Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([N:13]1[C:17]2[N:18]=[CH:19][N:20]=[CH:21][C:16]=2[C:15](I)=[CH:14]1)([CH3:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:23]1([C:29](=[N:36][C:37]2[CH:38]=[N:39][CH:40]=[C:41]([CH:48]=2)[C:42](N(OC)C)=[O:43])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[Si:1]([O:8][CH2:9][C:10]([N:13]1[C:17]2[N:18]=[CH:19][N:20]=[CH:21][C:16]=2[C:15]([C:42]([C:41]2[CH:40]=[N:39][CH:38]=[C:37]([N:36]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:48]=2)=[O:43])=[CH:14]1)([CH3:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CON(C)C(=O)c1cncc(N=C(c2ccccc2)c2ccccc2)c1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(I)c2cncnc21
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N=C(c3ccccc3)c3ccccc3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Preparation 24 using 7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (see Preparation 15) and 5-[(diphenylmethylene)amino]-N-methoxy-N-methylnicotinamide (see Preparation 23) to afford the title compound as a colourless gum in 56% yield, 1.49 g.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:16][CH2:17][C@H:10]2[CH2:9]1)(OC(C)(C)C)=O>FC(F)(F)C(O)=O.O>[F:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:18][C@H:15]2[CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]3[CH2:17][CH2:16]2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@H](COc3ccc(F)cc3)CC[C@H]2C1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(OC[C@@H]2CC[C@H]3CNCCN3C2)cc1
Yield: 97.4 %

Procedure:
A solution of 44.4 g (122 mmol) of (7R,9aS)-2-BOC-7-(4-fluorophenoxy)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (Preparation 7) in 500 mL of trifluroacetic acid and 200 mL of water was stirred at room temperature for 16 h. The mixture was concentrated by evaporation, the residue dissolved in water, basified with 15% NaOH, and extracted with ethyl acetate (2×). The organic layers were dried (magnesium sulfate), filtered and evaporated to give 31.4 g (96%) of (7R,9aS)-7-(4-fluorophenoxy)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine which was suitable for use in subsequent reactions. Purification of a 0.40 g sample by flash silica gel chromatography eluting with 90:10 chloroform:methanol gave 0.38 g of colorless crystals. mp (.2 HCl) 200–201° C. 13C NMR (base, CDCl3): δ 27.2, 29.1, 36.3, 45.9, 51.9, 56.0, 59.1, 62.5, 71.7, 115.4 (d, JCF=8). 115.7 (d, JCF=23). HRMS calcd for C15H21FN2O: 264.1638, found: 264.1660.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[C:7]([NH:14][C:15]([CH3:19])([CH3:18])[CH:16]=O)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>CO.C(OCC)C.[Cl-].[NH4+]>[C:7]([NH:14][C:15]([CH3:18])([C:16]#[CH:1])[CH3:19])([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CO
Product: C#CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 5 °C
Reaction time: 6 h
Yield: 97.3 %

Procedure:
To a solution of dimethyl 1-diazo-2-oxopropyl phosphonate (see Ohira, S. Synth. Commun. 19, 561-564, (1989)) (2.97 g, 15.5 mmol) in methanol (50 ml) at 0° C. was added potassium carbonate (1.71 g, 12.4 mmol) and slowly a solution of N-Boc-2-amino-2-methyl-propionaldehyde (1.45 g, 7.74 mmol) in methanol (5 ml). The reaction mixture was stirred at 0-10° C. for additional 6 h, diluted with diethylether (˜150 ml) and with saturated aqueous ammonium chloride solution (150 ml). The organic layer was washed with saturated aqueous ammonium chloride solution (100 ml), water (100 ml), and finally with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by flash chromatography over silica gel using ethyl acetate/hexane (1/10) provided N-Boc-2-amino-2-methylbut-3-yne (1.38 g) as yellowish oil.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)=O.[C:12](#[N:15])[CH:13]=C.CN1CCOCC1>CC1C=CC(C)=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:7]([C:6]1[CH:10]=[CH:11][C:3]([CH:1]=[CH:13][C:12]#[N:15])=[CH:4][CH:5]=1)=[O:8]
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Reactant: C=CC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccc(C)cc1
Solvent: CN1CCOCC1
Product: N#CC=Cc1ccc(C=O)cc1
Yield: 8.4 %

Procedure:
3.91 mg (1.6×10-5 mols) of palladium acetate, 6.74 g (40 millimols) of 4-formylbenzoyl chloride, 2.63 ml (40 millimols) of acrylonitrile and 4.41 ml (40 millimols) of N-methylmorpholine, in 80 ml of p-xylene, are stirred for 5 hours. Working up as described in the preceding examples affords 0.53 g (8% of theory) of 4-formylcinnamonitrile.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[OH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[Cl:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: OCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Nc1nc(OCc2ccccn2)c(Cl)c(-c2ccco2)n1

Procedure:
From 5-chloro-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, 2-(hydroxymethyl)pyridine and DBU in DME. ES-MS m/e (%): 305 (M{37Cl}+H+, 45), 303 (M{35Cl}+H+, 100).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[S:10][C:9]2[CH2:11][CH2:12][CH2:13][CH2:14][C:8]=2[C:7]=1[C:15]([NH:17][CH2:18][CH2:19][OH:20])=[O:16])=[O:4].[C:21]([C:25]1[C:29]([CH:30]=[O:31])=[CH:28][NH:27][N:26]=1)([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:21]([C:25]1[C:29]([CH:30]=[O:31])=[CH:28][N:27]([CH2:2][C:3]([NH:5][C:6]2[S:10][C:9]3[CH2:11][CH2:12][CH2:13][CH2:14][C:8]=3[C:7]=2[C:15]([NH:17][CH2:18][CH2:19][OH:20])=[O:16])=[O:4])[N:26]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1n[nH]cc1C=O
Reactant: O=C(CBr)Nc1sc2c(c1C(=O)NCCO)CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1nn(CC(=O)Nc2sc3c(c2C(=O)NCCO)CCCC3)cc1C=O
Temperature: 70 °C
Yield: 82.4 %

Procedure:
2-(2-Bromoacetamido)-N-(2-hydroxyethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (1.66 g, 4.60 mmol), 3-tert-butyl-1H-pyrazole-4-carbaldehyde (1.75 g, 11.49 mmol) and potassium carbonate (2.54 g, 18.38 mmol) were mixed with DMF (20 mL) and heated at 70° C. for 2 h. On cooling, the reaction was partitioned between EtOAc and water. The organics were washed with brine, dried over MgSO4 and concentrated directly onto silica for chromatographic purification (0-100% EtOAc/heptane). Concentration in vacuo yielded a white solid (1.64 g, 3.79 mmol, 83%).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:10]2=[CH:11][C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:21]=[C:9]2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4.C1C(=O)N([Br:30])C(=O)C1.O>C(#N)C>[Br:30][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH:11]=[C:10]3[C:2]([CH3:22])([CH3:1])[C:3]4[C:8]([C:9]3=[CH:21][C:20]2=1)=[CH:7][CH:6]=[CH:5][CH:4]=4
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccccc13
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Product: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccc(Br)cc13
Reaction time: 4 h

Procedure:
66.5 g (234.6 mmol) of 12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]-fluorene are initially introduced in 1000 ml of acetonitrile. A solution of 41.7 g (234.6 mmol) of NBS in 500 ml of CH3CN is subsequently added dropwise at −15° C. with exclusion of light, allowed to come to RT and stirred at this temperature for a further 4 h. 150 ml of water are subsequently added to the mixture, which is then extracted with CH2Cl2. The organic phase is dried over MgSO4, and the solvents are removed in vacuo. The product is washed by stirring with hot hexane and filtered off with suction. Yield: 47.5 g (131 mmol), 55.9% of theory, purity according to 1H-NMR approx. 97%.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])=[C:7]([C:12]#[N:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[OH:23].Br[CH2:25][CH2:26]Br.C(=O)([O-])[O-].[K+].[K+]>C(OCCO)C>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[NH:14][C:6]1[C:5]2[CH:4]=[C:3]3[O:23][CH2:25][CH2:26][NH:1][C:2]3=[CH:11][C:10]=2[N:9]=[CH:8][C:7]=1[C:12]#[N:13]
Reactant: BrCCBr
Reactant: N#Cc1cnc2cc(N)c(O)cc2c1Nc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCCO
Product: N#Cc1cnc2cc3c(cc2c1Nc1ccc(Cl)cc1Cl)OCCN3
Temperature: 150 °C
Yield: 14.7 %

Procedure:
An amount of 1100 mg (3.2 mmol) of 7-amino-4-(2,4-dichloroanilino)-6-hydroxy-3-quinolinecarbonitrile was stirred in 2-ethoxyethanol (250 mL), and to this were added 1,2-dibromoethane (6.5 g, 34 mmol), and potassium carbonate (2.7 g, 19.2 mmol). The mixture was heated at 150° C. for 0.5 hours, cooled to room temperature, and filtered through a Magnesol pad. The filtrate was evaporated to a brown oil, taken up in ethyl acetate and basified with saturated sodium bicarbonate solution. After separation of the layers, the organic layer was washed with saturated brine solution, dried over sodium sulfate, and evaporated to a brown oil. Purification was carried out by flash chromatography (ethyl acetate), to give a yellow solid (175 mg, 15% yield), mp 254-255° C.; 1H NMR (DMSO-d6) δ 9.20 (s, 1H), 8.25 (s, 1H), 7.70 (dd, 2H), 7.41 (dd, 2H), 7.14 (s, 1H), 6.92 (s, 1H), 4.23 (t, 2H), 3.43 (t, 2H); I-IRMS (EI) m/z 371.04502 (M+1). Analysis for C18H12Cl2N4O.0.1CH3CO2C2H5: Found: C, 58.03; H, 3.45; N, 14.49. Calcd: C, 58.10; H, 3.37; N, 14.74.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]([C:19]([CH:21]3[CH2:23][CH2:22]3)=[O:20])[C@@H:7]([CH3:18])[CH2:8][N:9]2[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1.O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:44]2[CH:45]=[N:46][N:47](C(OC(C)(C)C)=O)[CH:48]=2)O1>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH:21]1([C:19]([N:6]2[C:5]3[C:10](=[CH:11][C:2]([C:44]4[CH:45]=[N:46][NH:47][CH:48]=4)=[CH:3][CH:4]=3)[N:9]([C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[CH2:8][C@@H:7]2[CH3:18])=[O:20])[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)OC(=O)N1C[C@H](C)N(C(=O)C2CC2)c2ccc(Br)cc21
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)OC(=O)N1C[C@H](C)N(C(=O)C2CC2)c2ccc(-c3cn[nH]c3)cc21
Temperature: 90 °C
Reaction time: 5 h
Yield: 71.1 %

Procedure:
A 50-mL round bottomed flask fitted with a nitrogen inlet and magnetic stir bar was charged with (S)-isopropyl 7-bromo-4-(cyclopropanecarbonyl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.801 g, 2.1 mmol), dioxane (11 mL), and water (4.6 mL). Cesium carbonate (2.053 g, 6.30 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-carboxylate (0.927 g, 3.15 mmol) were then added. The reaction was purged with nitrogen and bis(triphenylphosphine)palladium (II) dichloride (0.177 g, 0.252 mmol) was added. The mixture was heated at 90° C. with vigorous stirring for 5 h and then cooled to ambient temperature. Water (25 mL) was added, and the mixture was extracted with ethyl acetate (3×25 mL). The combined organic extracts were concentrated to afford a viscous oil and purified via column chromatography (gradient elution with 75-100% ethyl acetate-hexanes). The resulting material was triturated with diethyl ether (2×10 mL) to afford (S)-isopropyl 4-(cyclopropanecarbonyl)-3-methyl-7-(1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.55 g, 71% yield) as a solid. MS (ESI, pos. ion) m/z 369 [M+1]+.
Reaction SMILES: C[C:2]1[N:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[O:5][C:6]=1[CH3:7].[CH:15]1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Cu]>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:4]2[O:5][C:6]([CH3:7])=[CH:2][N:3]=2)=[CH:13][CH:12]=1
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: Cc1nc(-c2ccc(O)cc2)oc1C
Agent: [Cu]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc(-c2ncc(C)o2)cc1
Yield: 35.5 %

Procedure:
2-(4-Methoxyphenyl)-5-methyloxazole was prepared in 35.5% yield by decarboxylation of the compound of part (c) with copper powder in Dowtherm at reflux temperature. The isolated product was distilled, b.p. 136°-140° C. (0.1 mm).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:37][CH:38]([CH3:40])[CH3:39])[CH:10]([OH:36])[CH2:11][NH:12][C@H:13]([C:21]([NH:23][C@H:24]([C:29]([O:31]C(C)(C)C)=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)(C)(C)C.CCOCC.[ClH:46]>C(O)(=O)C>[ClH:46].[NH2:8][C@@H:9]([CH2:37][CH:38]([CH3:40])[CH3:39])[CH:10]([OH:36])[CH2:11][NH:12][C@H:13]([C:21]([NH:23][C@H:24]([C:29]([OH:31])=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NCC(O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NCC(O)[C@@H](N)CC(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of N-[N-[(3S)-3-[[(t-butyloxy)carbonyl]amino]-2-hydroxy-5-methylhexyl]-L-phenylalanyl-L-leucine, t-butyl ester (845 mg, 1.5 mmol) in 22 ml of 1.3N hydrogen chloride in acetic acid was allowed to stir at room temperature for 2 hours. The resultant thick white slurry was evaporated to dryness in vacuo. The residue was dissolved in water and the solution was microfiltered and concentrated in vacuo to give a white gummy residue. Trituration with ether afforded 698 mg of the title compound as a fine white powder, melting point 179°-203° C. (with decomposition). The 13C-NMR spectrum was consistent with an approximately 2:1 mixture of alcohol isomers.
Reaction SMILES: [ClH:1].C([O:9][N:10]1[C:14](=[O:15])[CH2:13][C:12]2([CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[C:11]1=[O:22])C1C=CC=CC=1.[H][H]>CO.O.[Pd]>[ClH:1].[OH:9][N:10]1[C:14](=[O:15])[CH2:13][C:12]2([CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]2)[C:11]1=[O:22]
Reactant: CN1CCC2(CC1)CC(=O)N(OCc1ccccc1)C2=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: CN1CCC2(CC1)CC(=O)N(O)C2=O
Yield: 93 %

Procedure:
The compound No. 1 (2-benzyloxy-8-methyl-2,8-diazaspiro[4,5]decane-1,3-dione hydrochloride (6.4 g), listed in Table 1 in Example 4) was dissolved in 50 ml of methanol-water (1 to 1, v/v), and this was followed by catalytic hydrogen reduction for about 1 hour in the presence of palladium catalyst. The resulting solid was recrystallized from ethanol to obtain 4.3 g of a colorless crystal having a melting point of from 284° to 286° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[CH2:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[Si](C)(C)[O:23][C:24]([CH:26]=[CH2:27])=[CH2:25].Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[F:20])[CH2:27][CH2:26][C:24](=[O:23])[CH2:25][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C=CC(=C)O[Si](C)(C)C
Reactant: C=C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 130 °C
Yield: 89.3 %

Procedure:
2-[[(4-chlorophenyl)sulfonyl]methyl]-1,4-difluorobenzene (Intermediate 1) (100 g, 0.33 mol) and N,N,N′,N′-tetramethyldiaminomethane (34.2 g, 0.50 mol) were dissolved in dimethyl formamide (1000 mL) at 60° C. Acetic anhydride (68.3 g, 1.00 mol) was added slowly and the reaction mixture was aged for 5 hours. Water (1000 mL) was added dropwise and the resulting slurry was cooled to 5° C. The solids were filtered, and the cake washed sequentially with dimethyl formamide:water (40:60, 200 mL) and water (500 mL). Drying overnight in vacuo at 40° C. under a nitrogen stream furnished 2-[1-[(4-chlorophenyl)sulfonyl]ethenyl]-1,4-difluorobenzene (98 g, 95%). 1H NMR (CDCl3) 7.64-7.59 (2H, m), 7.43-7.39 (2H, m), 7.27-7.22 (1H, m), 7.08-6.88 (2H, m), 6.88 (1H, s) and 6.09 (1H, s). (ii) A solution of 2-[1-[(4-chlorophenyl)sulfonyl]ethenyl]-1,4-difluorobenzene (100 g, 0.32 mol) in xylenes (500 ml) was azeotropically distilled at 38° C., 20 mmHg, until 300 mL solvent had been removed. 2-Trimethylsilyloxybutadiene (90.4 g, 0.64 mol) was then added under a nitrogen atmosphere and the mixture heated to 130° C. After the reaction was completed, the mixture was distilled in vacuo to remove residual diene, whilst maintaining a constant volume by the addition of xylenes (400 mL). The mixture was cooled to 50° C. and THF (500 mL) and 3M HCl (424 mL, 1.27 mol) were added. After the hydrolysis was complete, the layers were separated. The organic layer was washed with water (300 mL) and then concentrated by atmospheric distillation until 350 mL of solvent had been removed. The solution was allowed to cool until crystallisation started, heptane (600 mL) was added and the resulting mixture cooled to ambient. The solids were filtered and washed sequentially with heptane:xylenes (3:1, 200 ml) and then heptane (200 ml). Drying overnight in vacuo at 40° C. furnished 4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexanone (110 g, 90% yield). 1H NMR CDCl3— as for the product obtained via Method (a).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]([F:12])([F:11])[F:10].[Br:13]Br>C(Cl)Cl.O>[Br:13][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([S:8][C:9]([F:12])([F:10])[F:11])[CH:4]=1
Reactant: BrBr
Reactant: Oc1ccccc1SC(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(Br)cc1SC(F)(F)F
Temperature: -78 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a stirred solution of 1-hydroxy-2-trifluoromethylthiobenzene (16 mmol, 1.0 eq.) in CH2Cl2 (40 mL) at −78° C. was added a solution of Br2 (0.83 mL, 16 mmol, 1.0 eq.) in CH2Cl2 (18 mL) slowly. The resulting mixture was stirred at −78° C. for 2 h and then warmed to room temperature overnight. The reaction mixture was diluted with water (300 mL) and extracted with CH2Cl2 (3×150 mL). The combined organic layer was washed with brine (400 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography using 0-10% EtOAc in hexanes as an eluent to afford 4-bromo-1-hydroxy-2-trifluoromethylthiobenzene in 93% yield as a crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.CN(C)CCO.CON(C)[C:22]([CH:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)=[O:23]>CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[O:23])[N:3]=1
Reactant: CON(C)C(=O)C1CCN(C)CC1
Reactant: Clc1ccccn1
Agent: CN(C)CCO
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CN1CCC(C(=O)c2cccc(Cl)n2)CC1
Reaction time: 1 h
Yield: 47.6 %

Procedure:
Add 2-chloropyridine (1 g, 8.8 mmole) to a mixture of n-butyl lithium (1.6 M in hexane) (22 mL, 35.2 mmole) and 2-dimethylamino-ethanol (1.56 g, 17.6 mmole) in hexane (20 mL at −78° C.) and stirred for 1 hour. Then add 1-methyl-piperidine-4-carboxylic acid methoxy-methyl-amide (3.2 g, 17.6 mmole) in hexane (5 mL) and stir the mixture for 1 hour. Quench the reaction mixture with water and extract twice with ethyl acetate, dry the organic layer with anhydrous sodium sulfate, evaporate the solvent and purify the residual product by chromatography on a silica gel column to give about 1 g of the title product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].P(OCC)(OCC)([S-])=[S:15]>C1COCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:6]([O:8][CH3:9])=[O:7])(=[S:15])[NH2:2]
Reactant: COC(=O)c1ccc(C)c(C#N)c1
Reactant: CCOP(=S)([S-])OCC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)c(C(N)=S)c1
Reaction time: 3 h
Yield: 80.9 %

Procedure:
A solution of methyl 3-cyano-4-methylbenzoate (compound 1.7, 880 mg, 5.02 mmol, 1.00 equiv) and O,O′-diethyl dithiophosphate (1.41 g, 8.29 mmol, 1.50 equiv) in THF/H2O (40 mL) was stirred at 80° C. (CAUTION: significant gas evolution occurs—this and all other reactions described herein should be carried out in well ventilated fume hoods). After 3 h, the organic solvent was removed under reduced pressure and the residual aqueous phase was extracted with 3×20 mL of ethyl acetate. The combined organic layers were concentrated under reduced pressure to yield 0.85 g (79%) of the title compound as a light yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH3:16][CH:17]1[CH2:22][NH:21][CH:20]([CH3:23])[CH2:19][N:18]1[S:24]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)(=[O:26])=[O:25]>>[CH3:16][CH:17]1[CH2:22][N:21]([C:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:8][CH2:9]2)=[O:14])[CH:20]([CH3:23])[CH2:19][N:18]1[S:24]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)(=[O:26])=[O:25]
Reactant: CC1CN(S(=O)(=O)c2ccc3ccccc3c2)C(C)CN1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Product: CC1CN(S(=O)(=O)c2ccc3ccccc3c2)C(C)CN1C(=O)C1CCN(c2ccncc2)CC1
Yield: 13 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with (2RS,5SR)-2,5-dimethyl-1-(2-naphthylsulphonyl)piperazine to give (2RS,5SR)-2,5-dimethyl-1-(2-naphthylsulphonyl)-4-[1-(4-pyridyl)-piperidin-4-ylcarbonyl]piperazine in 13% yield;
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([NH2:6])=[O:5].OC1C=CC=CN=1.[CH2:16]([O:23][C:24](=[O:56])[NH:25][C@H:26]([C@@H:47]1[CH2:51][C@@H:50]([CH:52]([CH3:54])[CH3:53])[C:49](=[O:55])[O:48]1)[CH2:27][N:28]1[CH2:33][C:32](=[O:34])[N:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[O:41][CH2:42][O:43][CH3:44])[CH2:30][C:29]1([CH3:46])[CH3:45])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(N(CC)CC)C>[CH2:16]([O:23][C:24](=[O:56])[NH:25][C@@H:26]([CH2:27][N:28]1[CH2:33][C:32](=[O:34])[N:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[O:41][CH2:42][O:43][CH3:44])[CH2:30][C:29]1([CH3:45])[CH3:46])[C@@H:47]([OH:48])[CH2:51][C@H:50]([C:49](=[O:55])[NH:1][CH2:2][C:3]([C:4](=[O:5])[NH2:6])([CH3:8])[CH3:7])[CH:52]([CH3:53])[CH3:54])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(CN)C(N)=O
Reactant: COCOc1ccccc1N1CC(C)(C)N(C[C@H](NC(=O)OCc2ccccc2)[C@@H]2C[C@@H](C(C)C)C(=O)O2)CC1=O
Agent: Oc1ccccn1
Solvent: CCN(CC)CC
Product: COCOc1ccccc1N1CC(C)(C)N(C[C@H](NC(=O)OCc2ccccc2)[C@@H](O)C[C@H](C(=O)NCC(C)(C)C(N)=O)C(C)C)CC1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 52.4 %

Procedure:
161 mg of 3-amino-2,2-di(methyl)propionamide obtained in Reference Example 2 (1.39 mmol) and 44 mg of 2-hydroxypyridine (0.46 mmol) were added to a solution of 263 mg of {(S)-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]-2-[4-(2-methoxymethoxyphenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]ethyl}carbamic acid benzyl ester obtained in the above reaction (0.46 mmol) in triethylamine (4.6 ml), and the mixture was stirred at 80° C. for two hours. The reaction mixture was cooled and then concentrated under reduced pressure and further stirred at 80° C. for 9 hours. The reaction mixture was cooled and then water was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=40/3) to obtain 166 mg of {(1S,2S,4S)-4-(2-carbamoyl-2-methylpropylcarbamoyl)-2-hydroxy-1-[4-(2-methoxymethoxyphenyl)-2,2-dimethyl-5-oxopiperazin-1-ylmethyl]-5-methylhexyl}carbamic acid benzyl ester (yield: 52%).