Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3](O)([CH2:6][CH2:7][O:8][CH:9]([CH2:11][CH3:12])[CH3:10])[CH:4]=[CH2:5])[CH3:2].Br.BrCC=C(CC)CCOC(CC)C.[CH:28]1[CH:33]=[C:32]([CH:34]=[O:35])[C:31]([OH:36])=[CH:30][CH:29]=1.[OH-].[K+]>COCCOC>[CH2:1]([C:3]([CH2:6][CH2:7][O:8][CH:9]([CH2:11][CH3:12])[CH3:10])=[CH:4][CH2:5][O:36][C:31]1[CH:30]=[CH:29][CH:28]=[CH:33][C:32]=1[CH:34]=[O:35])[CH3:2]
Reactant: C=CC(O)(CC)CCOC(C)CC
Reactant: O=Cc1ccccc1O
Agent: Br
Agent: CCC(=CCBr)CCOC(C)CC
Agent: [K+]
Solvent: COCCOC
Product: CCC(=CCOc1ccccc1C=O)CCOC(C)CC

Procedure:
9.3 g (0.05 mol) of 3-ethyl-5-sec.butoxy-1-penten-3-ol are added dropwise at 5° in the course of 15 minutes and while stirring to 20 cc of 48% hydrobromic acid. After stirring the mixture vigorously at 5° to 10° for half an hour it is extracted with ether, the ether extract is extracted with 10% soda solution and subsequently with saturated solution of sodium chloride, is dried with potassium carbonate and concentrated by evaporation. The resulting 1-bromo-3-ethyl-5-sec.butoxy-2-pentene is added without purification to 6.1 g (0.05 mol) of salicylic aldehyde and 2.8 g (0.05 mol) of potassium hydroxide in 80 cc of 1,2-dimethoxy ethane. The mixture is stirred at 20°-25° for 24 hours, is subsequently filtered and concentrated by evaporation at reduced pressure. The residue is taken up in ether, extracted with icy cold 10% sodium hydroxide solution and subsequently with saturated salt solution, is dried with sodium sulphate and evaporated.
Reaction SMILES: [CH3:1][C@@:2]1(/[CH:28]=[C:29]2/[C:30](=[O:39])[N:31]([CH2:34][C:35]([F:38])([F:37])[F:36])[CH2:32][CH2:33]/2)[S:8](=[O:10])(=[O:9])[C@H:7]2[N:4]([C:5](=[O:11])[CH2:6]2)[C@H:3]1[C:12]([O:14]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13].[K+].[Br-]>>[CH3:1][C@@:2]1(/[CH:28]=[C:29]2/[C:30](=[O:39])[N:31]([CH2:34][C:35]([F:38])([F:37])[F:36])[CH2:32][CH2:33]/2)[S:8](=[O:10])(=[O:9])[C@H:7]2[N:4]([C:5](=[O:11])[CH2:6]2)[C@H:3]1[C:12]([OH:14])=[O:13]
Reactant: C[C@]1(/C=C2\CCN(CC(F)(F)F)C2=O)[C@H](C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C[C@H]2S1(=O)=O
Agent: [Br-]
Agent: [K+]
Product: C[C@]1(/C=C2\CCN(CC(F)(F)F)C2=O)[C@H](C(=O)O)N2C(=O)C[C@H]2S1(=O)=O

Procedure:
192 mg (0.34 mmol) of benzhydryl (E)-(2S,3S,5R)-3-methyl-3-[2-oxo-1-(2,2,2-trifluoro-ethyl)-pyrrolidin-3-ylidenemethyl]-4,4,7-trioxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylate were deprotected analogously to Example 11. Yield: 78 mg (59%) of colorless crystal powder MS: (M+NH4)+ 414.4 IR (KBr): 2800(br), 1790, 1729, 1674, 1646, 1321, 1166 cm-1
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:29]=[CH:28][C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[N:13][N:12]=2)=[CH:8][C:7]=1[O:30]C>ClCCl>[Cl:5][C:6]1[CH:29]=[CH:28][C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[N:13][N:12]=2)=[CH:8][C:7]=1[OH:30]
Reactant: COc1cc(Nc2nnc(Cc3ccncc3)c3ccccc23)ccc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cc(Nc2nnc(Cc3ccncc3)c3ccccc23)ccc1Cl
Reaction time: 18 h

Procedure:
A solution of 2 ml boron tribromide (≈1M in CH2Cl2) is mixed with a suspension of 0.19 g (0.50 mmol) 1-(4-chloro-3-methoxyanilino)-4-(4-pyridylmethyl)phthalazine (Example 68B) in 4 ml dichloromethane at 0° C. under a nitrogen atmosphere. The resinous mixture is left to stand for 18 h at RT, the dichloromethane phase is then decanted, and the glutinous residue stirred with 10 ml THF and 5 ml sat. NaHCO3 solution. The resulting suspension is filtered, the filter residue washed with THF and discarded. The THF phase is separated and dried (Na2SO4), concentrated by evaporation, chromatographed (SiO2; acetate/CH3OH, 40:1→19:1) and title compound crystallized from acetonitrile/methanol: m.p.: 245-246° C.; HPLC: tRet(Grad5-40)=8.8; FAB MS (M+H)+=363.
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[N:16](S(C2C=CC=CC=2)(=O)=O)[C:8]2=[N:9][CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=[C:7]2[CH:6]=1)#[CH:4].O.C(OCC)(=O)C>C1COCC1>[C:3]([C:5]1[NH:16][C:8]2=[N:9][CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=[C:7]2[CH:6]=1)#[CH:4]
Reactant: C#Cc1cc2cc([N+](=O)[O-])cnc2n1S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#Cc1cc2cc([N+](=O)[O-])cnc2[nH]1
Temperature: 60 °C
Yield: 106.9 %

Procedure:
Sodium hydroxide (0.39 mL, 0.39 mmol, 1M in water) was added to a solution of 2-ethynyl-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.032 g, 0.10 mmol) in THF (0.5 mL). The reaction mixture was heated at 60° C. for 90 minutes. The reaction mixture was then cooled down and treated with water and ethyl acetate. The layers were then separated. The aqueous layer was extracted once with ethyl acetate. The organic layers were dried over sodium sulfate, filtered, and evaporated to afford 2-ethynyl-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.02 g, quantitative yield).
Reaction SMILES: O[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][N:4]1[CH2:6][CH2:5]1.N1CC1.C1OC1C1C=CC=CC=1>>[CH2:3]=[CH:2][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH:4]1[CH2:6][CH2:5]1
Reactant: OC(CN1CC1)c1ccccc1
Agent: C1CN1
Agent: c1ccc(C2CO2)cc1
Product: C=Cc1ccccc1

Procedure:
The simplest compound according to formula I, 1-(2'-hydroxy-2'-phenylethyl)aziridine is known and may be made according to A. Funke and G. Benoit, Bulletin de la Societe Chimique de France, 1953, 1021. These authors, using ethylenimine and styrene oxide in equimolar ratios obtained yield of no more than 48%. We have repeated these experiments and have found that the material so produced is far from pure and, unless subjected to a separate purification process, is unsuitable as a starting material for Reaction 1. Impurities, particularly gums, are formed in Funke's process, presumably oligomers or polymers of either styrene or ethylenimine or of both which are difficult to remove and which contaminate the ultimate reaction products when Funke's compound is used in further reactions and render the isolation of the ultimate products difficult or inefficient. The conditions under which undesired side reactions of the two reactants, epoxides and aziridines, particularly polymerisation, can be prevented, unfortunately are in conflict; strongly alkaline conditions favour stability of the aziridines, but lead to spontaneous polymerisation of epoxides and acids polymerise or ring-open the aziridines. In addition we consider that under Funke's conditions the undesired isomer ##STR18## is formed which is particularly difficult to separate and to analyse. The presence of these impurities leads to further undesired by-products in subsequent reactions which cannot be readily removed or analysed and which prevent the crystallisation of the desired products. This is a serious difficulty. As far as we are aware, the synthesis of compounds of the formula V from basic chemicals currently made on technical scale has hitherto been suggested as a multistep process only. Even according to the simpler process of the present invention a 3 to 4 step synthesis is required; if in the first reaction of our combination process, the reaction between an epoxide and an aziridine, gums and impurities are formed, the crude reaction product cannot be used efficiently. It, and subsequent intermediates, must either be purified or, alternatively, yields in subsequent steps fall off rapidly. Thus, in a combination process involving 3 to 4 steps and starting from an impure first reaction product, the ultimate yield is drastically diminished, either because a sequence of purification processes involves losses, or because of low yields and difficulties with isolation.
Reaction SMILES: [Br:1][C:2]1[C:6]([Br:7])=[C:5](Br)[N:4]([CH2:9][C:10](OCC)=[O:11])[N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>CCOCC.O>[Br:1][C:2]1[C:6]([Br:7])=[CH:5][N:4]([CH2:9][CH2:10][OH:11])[N:3]=1
Reactant: CCOC(=O)Cn1nc(Br)c(Br)c1Br
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: OCCn1cc(Br)c(Br)n1
Yield: 75 %

Procedure:
A solution of 9.7 g. (0.025 mole) ethyl 3,4,5-tribromopyrazole-1-acetate in 125 ml. dry ether was mixed with a suspension of 1.9 g. (0.05 mole) lithium aluminum hydride in 50 ml. dry ether. The reaction mixture was heated at the reflux temperature for two hrs. and then cooled. Ethyl acetate (5 ml.) and then water (30 ml.) were added and after settling the ether portion was decanted. The ether solution was washed with two 40-ml. portions of water and dried over anhydrous sodium sulfate. After removing the ether by evaporation, the oily residue was treated with decolorizing charcoal and crystallized from a mixture of ethyl ether and petroleum ether (boiling at the temperature range 30° C. to 60° C.). There was thus obtained 6.5 gms. (75% yield) of 3,4-dibromopyrazole-1-ethanol having a melting point of 64° to 66° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19]Cl)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][O:31][C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: CCN1c2ncc(CCl)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: COc1cccc(O)c1
Product: CCN1c2ncc(COc3cccc(OC)c3)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 54 %

Procedure:
Using a procedure analogous to that described in Example 98, the title compound, m.p. 95°-97° C., was prepared from 2-chloro-8-chloromethyl-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and 3-methoxyphenol. The yield was 54% of theory.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)=[CH2:2].N(C(C)(CC)C#N)=NC(C)(CC)C#N>CO>[CH:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1
Reactant: C=Cc1ccc(O)cc1
Agent: CCC(C)(C#N)N=NC(C)(C#N)CC
Solvent: CO
Product: C#Cc1ccc(O)cc1
Reaction time: 3 h
Yield: 19.5 %

Procedure:
To 506.5 g of the same p-vinylphenol fraction as used in Example 5, obtained by vacuum flash distillation were added 150.3 g of methanol as a solvent and 4.4 g of 2,2′-azobis(2-methylbutyronitrile) as an initiator. A polymerization reaction was conducted at 80° C. for 3 hours to obtain 97.2 g of a poly(p-vinylphenol). The polymer had a Mw of 11,000, a Mn of 6,300, a light transmittance at 248 nm, of 75.2% and a light transmittance at 450 nm, of 95.7%.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH:5]([CH2:8][NH:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][CH3:13])[CH2:6][CH3:7].[Cl:18][CH:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21]>>[Cl:18][CH:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20]([N:9]([CH2:8][CH:5]([CH2:6][CH3:7])[CH2:4][CH2:3][CH2:2][CH3:1])[CH2:10][CH:11]([CH2:12][CH3:13])[CH2:14][CH2:15][CH2:16][CH3:17])=[O:21]
Reactant: CCCCC(CC)CNCC(CC)CCCC
Reactant: O=C(Cl)C(Cl)c1ccccc1
Product: CCCCC(CC)CN(CC(CC)CCCC)C(=O)C(Cl)c1ccccc1
Yield: 96 %

Procedure:
Step A is conducted starting from 2,2′-diethylhexylamine and α-chlorophenylacetyl chloride and leads to 2-chloro-N,N-bis(2-ethylhexyl)-2-phenyl-acetamide (Yield: 96%) for which the characterisations by 1H and 13C NMR are given below:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[N:9]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1.Br[CH2:28][CH2:29][O:30][CH3:31].OS([O-])(=O)=O.[K+]>C1COCC1>[CH2:18]([O:17][C:15]([C:12]1([CH2:28][CH2:29][O:30][CH3:31])[CH2:11][CH2:10][N:9]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:14][CH2:13]1)=[O:16])[CH3:19]
Reactant: COCCBr
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCOC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -5 °C
Reaction time: 3 h

Procedure:
To a solution of 38 mL (76 mmol) LDA in THF (2N) was added 9.8 g (38 mmol) 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (commercially available) in 10 mL THF at −5° C. and stirred at −5° C. for 3 h. 10.58 g (76 mmol) 1-bromo-2-methoxyethane in 10 mL THF was added drop-wise, stirred for 1 h at −5° C. and stirred at room temperature over night. KHSO4 aq. (1M) was added and the mixture was extracted with ethyl acetate. The combined organic layers were dried with MgSO4 and evaporated to dryness. The residue was purified by column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane to yield after evaporation of the product containing fractions 8.19 g (68%) of the title compound as yellow oil. MS m/e: 315.2 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.[Cl:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[CH:12][N:11]=1.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:9][C:10]1[N:15]=[C:14]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH:13]=[CH:12][N:11]=1
Reactant: OB(O)c1ccsc1
Reactant: Clc1ccnc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Clc1nccc(-c2ccsc2)n1
Temperature: 90 °C
Yield: 88.5 %

Procedure:
To a solution of 3-thiopheneboronic acid (500 mg, 3.91 mmol) and 2,4-dichloropyrimidine (1.16 g, 7.81 mmol) in acetonitrile (20 mL) was added a 0.4 M solution of Na2CO3 (20 mL) followed by Pd(PPh3)4 (450 mg, 0.39 mmol). The suspension was degassed and heated at 90° C. for 16 h under nitrogen, cooled down, concentrated and extracted with EtOAc. Organic layer was successively washed with saturated solution of NH4Cl, brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc/CH2Cl2: 2/98) to afford the title compound 14 (680 mg, 3.46 mmol, 88% yield). 1H NMR: (400 MHz, CDCl3) δ (ppm): 8.56 (d, J=5.2 Hz, 1H), 8.19 (dd, J=3.2, 1.2 Hz, 1H), 7.66 (dd, J=5.2, 1.2 Hz, 1H), 7.46 (d, J=5.2 Hz, 1H), 7.43 (dd, J=5.2, 2.8 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([C:9]#[N:10])[C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14]([O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[C:26]([F:29])([F:28])[F:27])[CH3:15].C(=O)([O-])[O-].[K+].[K+].C1COCC1>C(OCC)C>[NH2:1][C:2]1[CH:7]=[C:6]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH2:14][CH3:15])=[C:18]([C:26]([F:27])([F:29])[F:28])[CH:19]=2)[N:5]=[C:4]([C:9]#[N:10])[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CCOc1ccc(B(O)O)cc1C(F)(F)F
Reactant: N#Cc1nc(Cl)cc(N)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOc1ccc(-c2cc(N)c([N+](=O)[O-])c(C#N)n2)cc1C(F)(F)F
Temperature: 150 °C
Yield: 50.7 %

Procedure:
A stirred mixture 4-amino-6-chloro-3-nitro-pyridine-2-carbonitrile (1 g, 5.04 mmol), 4-ethoxy-3-trifluoromethylphenylboronic acid (1.33 g, 6.04 mmol), tetrakis-(triphenylphosphine)palladium(0) (˜500 mg,10 mol %), potassium carbonate (2.09 g, 15.12 mmol) and THF (10 ml) was degassed under a stream of nitrogen before heating in the “Smith” microwave at 150° C. for 10 minutes. The crude mixture was concentrated under reduced pressure to remove THF before partitioning between ethyl acetate and water. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give a dark brown oil. Trituration with diethylether gave a light brown solid which was filtered and dried under a stream of air to afford 4-amino-6-(4-ethoxy-3-trifluoromethyl-phenyl)-3-nitro-pyridine-2-carbonitrile (900 mg). 1H NMR (DMSO): δ 8.25-8.1 (m, 3H), 7.63 (s, 1H), 7.44 (d, 2H), 4.27 (q, 2H), 1.38 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][S:14][CH2:15][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28](O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][S:14][CH2:15][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:17]([O:19][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CSCCNC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CSCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Yield: 74.1 %

Procedure:
A solution of 2.30 g (5.77 mmol) of (R)-3-(2-benzyloxycarbonylaminoethylsulfanyl)-2-tert-butoxycarbonylaminopropionic acid, 0.60 ml (0.62 g, 5.77 mmol) of benzyl alcohol, 0.07 g (0.58 mmol) of 4-dimethylaminopyridine and 1.33 g (6.93 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride in 30 ml of dichloromethane was stirred at RT overnight. The reaction mixture was washed successively with 1N hydrochloric acid, 1N sodium bicarbonate solution and with water. After drying over sodium sulfate, filtering and concentrating, the residue was chromatographed on silica gel. 2.09 g of the title compound were obtained as a colorless oil. LC/MS (method C): Rt=3.63 min, m/z: 389.17 [M−Boc+H+].
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]2[S:10]N=N[C:7]=2[CH:11]=1.[C:14]1([N:20]=[C:21]=[S:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:21](=[N:20][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:22][C:7]=2[CH:11]=1
Reactant: FC(F)(F)c1ccc2snnc2c1
Reactant: S=C=Nc1ccccc1
Product: FC(F)(F)c1ccc2sc(=Nc3ccccc3)sc2c1

Procedure:
A solution of 5-(trifluoromethyl)-1,2,3-benzothiadiazole (5 g) in 50 ml of phenylisothiocyanate is heated at reflux under an inert atmosphere until the evolution of nitrogen ceases (approximately 3 hours). The excess phenyl isothiocyanate is removed by distillation. The residue is chromatographed on 1000 ml of silica gel eluting with pentane/dichloromethane (4:1). Fractions containing the desired product are combined and concentrated in vacuo. The resultant solid is recrystallized from hexane to yield 4 g of the title compound, melting point 122°-123° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][O:13][C:14]([C:22]([F:25])([F:24])[F:23])([C:18]([F:21])([F:20])[F:19])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N+](=[CH2:30])=[N-]>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][O:13][C:14]([C:18]([F:19])([F:20])[F:21])([C:22]([F:23])([F:24])[F:25])[C:15]([O:17][CH3:30])=[O:16])=[CH:26][CH:27]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F

Procedure:
A solution of 2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionic acid (1.2 g.) in ether (20 ml.) is treated at 0° C. with an excess of an ethereal solution of diazomethane. The solution is evaporated, and the residue is recrystallised from light petroleum (b.p. 40°-60° C.) to give methyl 2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionate (1.1 g.), m.p. 61.5°-62.5° C.
Reaction SMILES: N[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:18][C:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[S:22][CH:23]=2)[N:3]=1.N([O-])=O.[Na+].[ClH:35]>>[Cl:35][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:18][C:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[S:22][CH:23]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cncs1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cncs1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 0° C., 50 mg (0.107 mmol) of 2-amino-6-([2-(4-chlorophenyl)-1,3-thiazol-4-yl]methylsulfanyl)-4-(1,3-thiazol-5-yl)pyridine-3,5-dicarbonitrile were dissolved in 1.5 ml of concentrated hydrochloric acid, and 22 mg (0.321 mmol) of sodium nitrite were added. The mixture was stirred initially at 0° C. for one hour and then at room temperature overnight. Purification of the reaction mixture was by preparative HPLC (acetonitrile/water: 10:90→95:5, 0.1% TFA added). This gave 9 mg (17% of theory) of the target compound.
Reaction SMILES: [OH:1][C:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([O:5][CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:4].[O:25]1[CH2:29][CH2:28][O:27][CH:26]1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[OH:1][C:2]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:3]([O:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:40][C:39]2[CH:38]=[CH:37][C:36]([O:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH:26]3[O:25][CH2:29][CH2:28][O:27]3)=[CH:43][CH:42]=2)[CH2:9][CH2:8]1)=[O:4]
Reactant: O=C(OCC1CCNCC1)C(O)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(OCCCCCC2OCCO2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCC1CCN(Cc2ccc(OCCCCCC3OCCO3)cc2)CC1)C(O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.9 %

Procedure:
To a stirred solution of piperidin-4-ylmethyl 2-hydroxy-2,2-diphenylacetate (0.4 g, 1.23 mmol) and 4-((5-(1,3-dioxolan-2-yl)pentyl)oxy)benzaldehyde (0.38 g, 1.44 mmol) in DCM (5 mL) was added sodium triacetoxyborohydride (0.388 g, 1.83 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between EtOAc and saturated sodium hydrogen carbonate. The organic phase was dried (sodium sulfate), filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 1 to 10% methanol in ethyl acetate to afford the title compound as a colourless oil (0.50 g, 26%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH2:10]Cl)=[CH2:9])[N:3]=1.[I-:12].[K+].CC(C)=O.CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH2:10][I:12])=[CH2:9])[N:3]=1
Reactant: [I-]
Reactant: C=C(CCl)c1cccc(Cl)n1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: C=C(CI)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.6 %

Procedure:
A mixture of 0.50 g of 2-chloro-6-(1-chloromethylvinyl) pyridine, 0.88 g of potassium iodide, 5 ml of acetone and 0.5 ml of N,N-dimethylformamide was stirred at 50° to 60° C. for 5 hours. After the reaction mixture was cooled to room temperature, water was added thereto to extract the mixture with ethyl acetate. The extract was subsequently washed with an aqueous solution of 10% sodium thiosulfate, water, saturated saline solution in that order, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluted with dichloromethane) to obtain 0.45 g of the objective compound.