Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.C(OC(=O)[N:12]([C@H:14]([C:16](=[O:42])[NH:17][C@H:18]1[CH2:24][S:23][C:22]2[C:25]([NH2:29])=[CH:26][CH:27]=[CH:28][C:21]=2[N:20]([CH2:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][CH:32]=2)[C:19]1=[O:41])[CH3:15])[CH3:13])(C)(C)C.[O:44]=[C:45]([CH3:52])[CH2:46][CH2:47][CH2:48][C:49](O)=[O:50].Cl>N1C=CC=CC=1>[ClH:3].[CH3:13][NH:12][C@@H:14]([CH3:15])[C:16]([NH:17][C@H:18]1[CH2:24][S:23][C:22]2[C:25]([NH:29][C:49](=[O:50])[CH2:48][CH2:47][CH2:46][C:45](=[O:44])[CH3:52])=[CH:26][CH:27]=[CH:28][C:21]=2[N:20]([CH2:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][CH:32]=2)[C:19]1=[O:41])=[O:42]
Reactant: CC(=O)CCCC(=O)O
Reactant: O=P(Cl)(Cl)Cl
Reactant: C[C@@H](C(=O)N[C@H]1CSc2c(N)cccc2N(Cc2cccc3ccccc23)C1=O)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CN[C@@H](C)C(=O)N[C@H]1CSc2c(NC(=O)CCCC(C)=O)cccc2N(Cc2cccc3ccccc23)C1=O
Reaction time: 2 h

Procedure:
Phosphorus oxychloride (34.4 mg, 0.22 mmol) was added to a solution of [(S)-1-((R)-9-amino-5-naphthalen-1-ylmethyl-4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]thiazepin-3-ylcarbamoyl)-ethyl]-methyl-carbamic acid tert-butyl ester (80 mg, 0.15 mmol) and 5-oxo-hexanoic acid (29.2 mg, 0.22 mmol) in pyridine (1.0 mL). After 2 h, the mixture was poured into 0.5 M HCl (5 mL) and extracted with EtOAc, the combined extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to afford the title compound. HR-MS: calcd. for C30H34N4O4S (MH+) 547.2374. found 547.2374.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:25][C:26]1[CH:31]=[C:30](F)[CH:29]=[CH:28][N:27]=1>CN1C(=O)CCC1>[Cl:25][C:26]1[CH:31]=[C:30]([O:18][C:16]2[CH:15]=[CH:14][C:12]3[N:13]=[C:9]([NH:8][C@@H:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]4[OH:1])[S:10][C:11]=3[CH:17]=2)[CH:29]=[CH:28][N:27]=1
Reactant: Oc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Reactant: Fc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Oc3ccnc(Cl)c3)cc2s1
Temperature: 60 °C
Reaction time: 20 h
Yield: 90 %

Procedure:
To the mixture of 2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-ol (265 mg, 1 mmol) and cesium carbonate (651 mg, 2 mmol) in 3 ml of NMP was added 2-chloro-4-fluoropyridine (263 mg, 2 mmol). The reaction mixture was stirred at 60° C. for 20 hours. The crude reaction mixture was filtered and then purified on prep HPLC to give (1R,2R)-2-(6-(2-chloropyridin-4-yloxy)benzo[d]thiazol-2-ylamino)cyclohexanol as powder (341 mg, 0.9 mmol). ES/MS m/z 376.0 (MH+).
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH:3]([C:14]([OH:16])=[O:15])[NH:2]1.[OH-].[K+].C(O)C.[CH3:22][S:23][CH2:24]Cl.[C:26](=[S:28])=[S:27]>>[CH3:22][S:23][CH2:24][S:28][C:26]([N:2]1[CH:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1)=[S:27]
Reactant: S=C=S
Reactant: O=C(O)C1Cc2c([nH]c3ccccc23)CN1
Reactant: CSCCl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CSCSC(=S)N1Cc2[nH]c3ccccc3c2CC1C(=O)O

Procedure:
In the same manner as described in Example 6, (3RS)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (3.24 g), KOH (1.75 g), 50% ethanol (70 ml), carbon disulfide (0.91 ml) and methylthiomethyl chloride (1.74 g) are reacted and treated. The product thus obtained is purified by silica gel column chromatography (solvent, chloroform:methanol:acetic acid=97:2:1) to give the title compound (2.61 g) as a pale yellow powder.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=O.P(Cl)(Cl)([Cl:11])=O.[CH2:14]([N:16](CC)[CH2:17][CH3:18])[CH3:15].N1CCCC1>ClCCl.C1(C)C=CC=CC=1>[Cl-:11].[CH3:1][NH+:2]1[CH2:6][CH2:5][N:4]([CH3:7])[CH:3]1[N:16]1[CH2:17][CH2:18][CH2:15][CH2:14]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN1CCN(C)C1=O
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Solvent: ClCCl
Product: CN1CC[NH+](C)C1N1CCCC1
Product: [Cl-]
Temperature: 65 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
In a three-necked flask equipped with a dropping funnel and a reflux condenser were placed 19.4 g (170 millimoles) of 1,3-dimethyl-2-imidazolidinone and 50 mL of toluene in an atmosphere of nitrogen. Then, 13.0 g (85 millimoles) of phosphorus oxychloride was added and stirred at 65° C. Heating was stopped after 1 hour, the flask was cooled in an ice bath, and a solution containing the chlorination product of 1,3-dimethyl-2-imidazolidinone was obtained. To this solution were added 50 mL of dichloromethane and 23.6 mL (170 millimoles) of triethylamine in succession. To the resulting solution was added dropwise a solution of 13.8 mL (170 millimoles) of pyrrolidine in 50 mL of dichloromethane over a period of approximately 30 minutes while cooling the solution in an ice bath. Upon completion of the dropwise addition, the ice bath was removed and the solution was stirred at 55° C. The reaction mixture was cooled to room temperature after 1 hour, the insoluble matters were removed by filtration, and the filtrate was distilled off under reduced pressure. The residue was purified by column chromatography to give 15.9 g of 4,5-dihydro-1,3-dimethyl-2-(1-pyrrolidinyl)-1H-imidazolium chloride as a light yellow solid; this compound is a cyclic guanidine salt comprising the cation designated by chemical formula I and Cl− and is hereinafter referred to as cyclic guanidine salt 1. The solid showed a melting point of 49° C. and was hence a cyclic guanidine salt qualified for an ionic liquid.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](=[CH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[O:22][CH3:23])[NH:7][C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]>[Pd].C(O)(=O)C>[CH2:1]([N:5]1[C:9](=[O:10])[CH:8]([CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[O:22][CH3:23])[NH:7][C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)NC(=Cc2cc(OC)c(OC)cc2OC)C1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCN1C(=O)NC(Cc2cc(OC)c(OC)cc2OC)C1=O

Procedure:
3-n-Butyl-5-(2,4,5-trimethoxybenzylidene) hydantoin (10.0 g; 0.03 mole) was mixed with glacial acetic acid (150 ml.) and hydrogenated in a Parr apparatus in the presence of 5% Pd/C (2 g). After 2 hours the catalyst was filtered off, washed with warm acetic acid and the colourless filtrate evaporated in vacuo to give a white crystalline solid. Recrystallisation from ethyl acetate gave the title compound, yield 9.2 g (91% ), m.p. 122° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Br:9][CH2:10][CH2:11][CH2:12]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:9][CH2:10][CH2:11][CH2:12][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Oc1ccccc1F
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccccc1OCCCBr
Temperature: 80 °C
Yield: 100.8 %

Procedure:
A mixture of 2-fluorophenol (2.24 g, 20.0 mmol), 1,3-dibromopropane (20.3 mL, 200 mmol), and potassium carbonate (2.76 g, 20.0 mmol) in acetonitril (30 mL) was heated at 80° C. overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 4.70 g of the title compound as a light yellow oil with a purity of ca. 80%. The product was used in the subsequent reaction step without further purification.
Reaction SMILES: [C-:1]#[N:2].[K+].[Cl-].[NH4+:5].[CH3:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12](=O)[CH2:13]2>C(O)C.O>[NH2:5][C:12]1([C:1]#[N:2])[CH2:11][CH2:10][C:9]2[C:14](=[CH:15][CH:16]=[CH:17][C:8]=2[O:7][CH3:6])[CH2:13]1
Reactant: [C-]#N
Reactant: COc1cccc2c1CCC(=O)C2
Reactant: [NH4+]
Agent: [Cl-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1cccc2c1CCC(N)(C#N)C2

Procedure:
112 mmol of potassium cyanide and 116 mmol of ammonium chloride ate added successively to a solution, maintained under nitrogen and with stirring, containing 110 mmol of 5-methoxy-3,4-dihydronaphthalen-2(1H)-one in 90 ml of ethanol and 50 ml of water. The whole mixture is stirred for 20 hours at 20° C. and then concentrated under vacuum. The residue is taken up in 200 ml of ethyl acetate. This phase is then washed with water and extracted with 1N hydrochloric acid. The acid phase is basified with 35% sodium hydroxide solution and extracted with methyl acetate. The combined organic phases are dried and evaporated under vacuum and lead to the expected product in the solid form.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C@@H:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[OH:8].CN(C=O)C>O>[N:1]([CH2:6][C@@H:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[OH:8])=[N+:2]=[N-:3]
Reactant: O[C@@H](CCl)c1ccc(F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H](O)c1ccc(F)cc1
Temperature: 100 °C

Procedure:
Sodium azide (41.8 g, 642 mmol) was added to a solution consisting of (1R)-2-chloro-1-(4-fluoro-phenyl)-ethanol (37.4 g, 214 mmol) and DMF (214 mL) at rt. The reaction mixture was heated to 100° C. for 3 h, diluted with water (500 mL), and extracted with EtOAc (700 mL). The organic layer was washed with brine (500 mL), and the organic layer dried (MgSO4), filtered, and concentrated, giving the title compound as a yellow liquid, which was used without further purification (39 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([NH2:17])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[C:15]#[N:16].[C:19](C1NC=CN=1)(C1NC=CN=1)=[O:20].[NH:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[NH:39][C:38]2=[O:47])[CH2:33][CH2:32]1>O1CCCC1>[CH3:1][O:2][C:3](=[O:18])[CH:4]([NH:17][C:19]([N:31]1[CH2:32][CH2:33][CH:34]([N:37]2[CH2:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[NH:39][C:38]2=[O:47])[CH2:35][CH2:36]1)=[O:20])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[C:15]#[N:16]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: COC(=O)C(N)Cc1ccc2[nH]cc(C#N)c2c1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccc2[nH]cc(C#N)c2c1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of 2-amino-3-(3-cyano-1H-indol-5-yl)-propionic acid methyl ester (25 mg, 0.11 mmol) in tetrahydrofuran (3 mL) at 0° C. was treated with carbonyl diimidazole (17.5 mg, 1.1 equiv.). The reaction was stirred for 5 min at 0° C., warmed to room temperature, stirred 10 min, and treated with 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (25 mg, 1.1 equiv.). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by column chromatography to give 40 mg (75%) as a white powder. LC/MS: tR=1.37 min, 501.33 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](O)([CH3:10])[CH3:9])[CH:5]=[N:6][CH:7]=1.F[C:13](F)(F)[C:14]([OH:16])=O.C(#[N:21])C>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:21][C:14](=[O:16])[CH3:13])([CH3:10])[CH3:9])[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC#N
Reactant: CC(C)(O)c1cncc(Br)c1
Product: CC(=O)NC(C)(C)c1cncc(Br)c1

Procedure:
To the mixture of 2-(5-bromo-pyridin-3-yl)-propan-2-ol (700 mg, 3.24 mmol) in acetonitrile (14 mL) is added dropwise boron trifluoride diethyl ether complex (1.1 mL, 8.7 mmol) at room temperature. Then trifluoroacetic acid (1.8 ml, 23 mmol) is added dropwise and the reaction mixture is heated to reflux for 16 hrs. All the solvent is removed in vacuo and DCM is added. 1.0 M Na2CO3 solution is used to adjust the pH of aqueous phase to 8. The aqueous layer is separated and extracted with DCM twice. All the organic layers are combined and concentrated to give the crude product. Purification by flash column chromatography affords 252 mg of N-[1(5-bromo-pyridin-3-yl)-1-methyl-ethyl]-acetamide.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:10][CH3:11])[CH2:4][NH:5][C:6](=[O:9])[CH:7]=[CH2:8].[NH:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17]>>[CH3:1][O:2][CH:3]([O:10][CH3:11])[CH2:4][NH:5][C:6](=[O:9])[CH2:7][CH2:8][N:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17]
Reactant: C=CC(=O)NCC(OC)OC
Reactant: O=C1CCCN1
Product: COC(CNC(=O)CCN1CCCC1=O)OC
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
10 g (62.8 mmol) of the acrylamido acetal from Example 2 are mixed with 6 g (70.5 mmol) of pyrrolidone and, after addition of one drop of Triton B, the mixture is warmed to 80° C. After 10 minutes, the reaction is terminated. The thin-layer chromatogram shows no UV absorbing acetal. The product is subsequently freed from traces of solvent under a high vacuum. It is a single compound according to TLC. NMR data: 2 methylene protons at each of 2.0, 2.4, 2.5, 3.3, 3.4 and 3.6 ppm(t), 6 methoxy protons at 3.35 ppm(s), 1 acetal proton at 4.4 ppm(t), 1 amide proton at 7.2 ppm. ##STR41##
Reaction SMILES: C1COC2C=CC(NC3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=CC=2O1.Cl[C:28]1[N:33]=[C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]3[O:41][CH2:42][CH2:43][O:44][C:37]=3[CH:36]=2)[C:31]([F:45])=[CH:30][N:29]=1.[CH3:46][C:47]1[O:51][N:50]=[C:49]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:48]=1[NH2:58]>>[CH2:43]1[CH2:42][O:41][C:38]2[CH:39]=[CH:40][C:35]([NH:34][C:32]3[C:31]([F:45])=[CH:30][N:29]=[C:28]([NH:58][C:48]4[C:49]([C:52]5[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=5)=[N:50][O:51][C:47]=4[CH3:46])[N:33]=3)=[CH:36][C:37]=2[O:44]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: Cc1onc(-c2ccccc2)c1N
Agent: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Product: Cc1onc(-c2ccccc2)c1Nc1ncc(F)c(Nc2ccc3c(c2)OCCO3)n1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 5-methyl-3-phenyl-4-isoxazolamine were reacted to yield N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-phenyl-5-methylisoxazol-4-yl)-2,4-pyrimidinediamine. LCMS: ret. time: 20.90 min.; purity: 96%; MS (m/e): 420 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7](C=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH3:29][O:30][CH:31](OC)[O:32][CH3:33]>CO>[CH3:29][O:30][CH:31]([O:32][CH3:33])[C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: COC(OC)OC
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COC(OC)c1ccc([N+](=O)[O-])cc1
Temperature: 50 °C

Procedure:
A flask equipped with a magnetic stir bar and vigreux column was charged with 4-nitro-benzaldehyde (5.0 g, 33.1 mmol), pyridinium p-toluenesulfonate (1.66 g, 6.62 mmol), trimethoxymethane (3.51 g, 33.1 mmol) and methanol (100 mL). The mixture was heated at 50° C. for 12 h and was concentrated in vacuo. The residue was redissolved in EtOAc and washed with aq. NaOH (1M), H2O and brine. The mixture was dried (Na2SO4), filtered and concentrated in vacuo to yield the title compound as a clear, light yellow oily product (6.36 g, 97%).
Reaction SMILES: [CH3:1][NH:2][NH2:3].F[C:5]1[CH:12]=[C:11]([N:13]2[CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[CH3:24])[C:14]2=[O:25])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8].CO>COCCO.C(Cl)(Cl)Cl>[NH2:8][C:7]1[C:6]2[C:5](=[CH:12][C:11]([N:13]3[CH2:17][CH2:16][N:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][C:23]=4[CH3:24])[C:14]3=[O:25])=[CH:10][CH:9]=2)[N:2]([CH3:1])[N:3]=1
Reactant: CNN
Reactant: Cc1ccncc1N1CCN(c2ccc(C#N)c(F)c2)C1=O
Solvent: COCCO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccncc1N1CCN(c2ccc3c(N)nn(C)c3c2)C1=O
Temperature: 170 °C
Reaction time: 12 h
Yield: 69.2 %

Procedure:
Methyl hydrazine (10 mL) was added to a stirred solution of 2-fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzonitrile (I-123a: 240 mg, 0.80998 mmol) in 2-methoxy ethanol (20 mL). The resulting mixture was stirred at 170° C. for 12 hours. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was cooled to room temperature and concentrated. Ice was added to the concentrate and the precipitate formed was collected and dried under reduced pressure to afford 180 mg of the product (69.2% yield).
Reaction SMILES: C1(C)C=CC(S([C:10]([CH3:23])([CH3:22])[CH:11]([CH:17]([O:20]C)[O:18]C)[CH2:12][C:13]([O:15]C)=O)(=O)=O)=CC=1.CCOCC.[Cl-:30].[Li+].Cl>O>[Cl:30][C:10]([C@H:11]1[C@H:17]([OH:18])[O:20][C:13](=[O:15])[CH2:12]1)([CH3:22])[CH3:23]
Reactant: [Cl-]
Reactant: COC(=O)CC(C(OC)OC)C(C)(C)S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(C)(Cl)[C@@H]1CC(=O)O[C@H]1O
Temperature: 25 °C
Reaction time: 54 h
Yield: 109.4 %

Procedure:
A mixture of 1 g of the product of Example 2, 25 ml of ether and 1 g of dry lithium chloride was stirred under a current of gaseous hydrogen chloride at -30° C. for 2 hours and then at 0° C. for 2 hours after which the current of gaseous hydrogen chloride was stopped. The mixture was stirred at room temperature for 48 hours and after 54 hours of contact, the mixture was poured into iced water. The mixture was extracted with benzene and the organic phase was dried and evaporated to dryness under reduced pressure. The 1.1 g of residue was chromatographed over silica gel and was eluted with a 1-1 benzene-ethyl acetate mixture to obtain 545 mg of dl trans 4-(2-chloro-prop-2-yl)-5-hydroxy-tetrahydrofuran-2-one in the form of crystals melting at 80° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)=[N:7][C:6]=2[CH:16]=1.C(N(CC)CC)C.[C:24](Cl)(Cl)=[S:25]>O1CCCC1>[N:1]([C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)=[N:7][C:6]=2[CH:16]=1)=[C:24]=[S:25]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc2sc(-c3cccnc3)nc2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: S=C=Nc1ccc2sc(-c3cccnc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Amino-2-(3-pyridinyl)benzothiazole, 8.0 g, 0.035 M, is dissolved in 400 cc of tetrahydrofuran and 9.8 cc, 0.070 M, of triethylamine. Thiophosgene, 2.7 cc, 0.035 M is added, and the resulting mixture stirred overnight at ambient temperature. The solids which form are filtered and washed with tetrahydrofuran. The filtrate is concentrated to dryness and chromatographed on Alumina IV; elution with benzene yields 1.0 g of white solid which is recrystallized from acetonitrile to yield the title compound, 0.52 g, m.p. 160°-162° (12% of theory).
Reaction SMILES: [Li]CCCC.[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1.[Si:14]([O:21][C@@H:22]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[C:23](OCC)=[O:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O>C1COCC1.CCOC(C)=O>[Si:14]([O:21][C@@H:22]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[C:23]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1)=[O:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16]
Reactant: Cc1ccc(N)nc1
Reactant: CCOC(=O)[C@H](CCN(C)C)O[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(NC(=O)[C@H](CCN(C)C)O[Si](C)(C)C(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.6 %

Procedure:
n-BuLi (3.40 mL, 1.6 M in hexanes, 5.44 mmol) was added slowly to a stirred solution of 2-amino-5-picoline (616 mg, 5.70 mmol) in anhydrous THF (8 mL). The reaction mixture was kept at ambient temperature for 10 minutes before a solution of ethyl (2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-(dimethylamino)butanoate (Step 2) (1.50 g, 5.18 mmol) in anhydrous THF (2 mL) was added. The reaction mixture was stirred at ambient temperature for 1 h. Water and EtOAc were added and the two phases were separated. The aqueous phase was extracted with EtOAc. The organic extracts were combined and washed with water, dried over MgSO4 and concentrated in vacuo. The residue was purified with column chromatography (silica gel, eluting with EtOAc) to give the title compound (320 mg), 1H NMR (300 MHz, CDCl3) δ 8.89 (br s, 1H), 8.12 (m, 2H), 7.51 (dd, 1H), 4.32 (t, 1H), 2.47 (m, 1H), 2.31 (m, 4H), 2.21 (s, 6H), 1.97 (m, 2H), 0.98 (s, 9H), 0.15 (d, 6H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[C:8](I)[C:9]=1[O:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:5]=[O:6].[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:16][O:15][CH2:14][CH2:13][O:12][CH2:11][O:10][C:9]1[C:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[C:2]1[CH:3]=[CH:4][CH:7]=[CH:8][CH:9]=1
Reactant: OB(O)c1ccccc1
Reactant: COCCOCOc1c(I)cc(C=O)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: COCCOC
Solvent: O
Product: COCCOCOc1c(-c2ccccc2)cc(C=O)cc1-c1ccccc1
Yield: 57 %

Procedure:
The title compound was prepared according to the procedure in Example 2, step 3 using 3,5-diiodo-4-(2-methoxyethoxymethoxy)benzaldehyde (4.029 g, 8.721 mmol), phenylboronic acid (2.339 g, 19.19 mmol), palladium(II) acetate (39.16 mg, 0.174 mmol) in DME:H2O. Purification on Biotage KP-Sil eluting with 15% EtOAc/pet. ether gave 1.803 g, (57%) of the title compound. 1H NMR (DMSO-d6) δ 2.78-2.82 (m, 2 H), 2.89-2.92 (m, 2 H), 3.01 (s, 3 H), 4,42 (s, 2 H), 7.40-7.54 (m, 6 H), 7.62-7.65 (m, 4 H), 7.91 (s, 2 H), 10.06 (s, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]([CH3:20])[CH3:19])[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[N+:26]([CH3:29])([O-:28])=[O:27]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:29]/[N+:26]([O-:28])=[O:27])[CH:14]=[CH:15][C:16]=1[O:17][CH:18]([CH3:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: CC(C)Oc1ccc(C=O)cc1OCc1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(/C=C/[N+](=O)[O-])cc1OCc1ccccc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
3-(Benzyloxy)-4-isopropoxybenzaldehyde described in Production Example 17-2 (2.59 g, 9.59 mmol) was dissolved in acetic acid (7.5 mL), then ammonium acetate (887 mg, 11.5 mmol) and nitromethane (1.25 mL, 23.1 mmol) were added under nitrogen atmosphere at room temperature, and the mixture was heated and stirred at 130° C. for 2 hours. The mixture was cooled to room temperature, and the precipitate was collected by filteration and washed with ethanol to obtain the title compound (2.20 g, 73%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31])[C:19](=O)[CH2:20][CH3:21].O1CCOCC1.C([O-])(=O)C.[Na+]>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31])=[C:19]([CH2:20][CH3:21])[NH:13]2
Reactant: CCC(=O)C(Cc1ccc(F)cc1F)C(=O)OC
Reactant: COC(=O)COc1ccc(F)c(N)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(F)cc1F
Temperature: 130 °C

Procedure:
A mixture of (3-amino-4-fluorophenoxy)acetic acid methyl ester (0.5 g), 2-(2,4-difluorobenzyl)-3-oxopentanoic acid methyl ester (0.64 g), polyphosphoric acid (2.5 mL) and dioxane (10 mL) was heated at 130° C. for 17 hours. The mixture was diluted with water and the pH adjusted to 4 by the addition of sodium acetate. The resulting precipitate was collected by filtration, washed with water and dried to give title compound as a creamy solid, 0.84 g.