Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[N:10]1C=CC=CC=1.N[C:17]1[C:26]([F:27])=[C:25]([Cl:28])[CH:24]=[C:23]2[C:18]=1[N:19]=[C:20]([O:31][CH3:32])[C:21]([O:29][CH3:30])=[N:22]2.[OH-].[Na+].Cl>ClCCl.C1COCC1>[Cl:28][C:25]1[CH:24]=[C:23]2[C:18]([N:19]=[C:20]([O:31][CH3:32])[C:21]([O:29][CH3:30])=[N:22]2)=[C:17]([CH2:1][S:2]([NH2:10])(=[O:5])=[O:3])[C:26]=1[F:27]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: c1ccncc1
Reactant: COc1nc2cc(Cl)c(F)c(N)c2nc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1nc2cc(Cl)c(F)c(CS(N)(=O)=O)c2nc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
Methanesulphonic anhydride (0.55 g, 3.16 mmol) and pyridine (255 μl, 3.15 mmol) were added to a stirred suspension of 5-amino-7-chloro-6-fluoro-2,3-dimethoxyquinoxaline (see Preparation 24) (0.274 g, 1.06 mmol) in dichloromethane (15 ml) at room temperature under nitrogen. The mixture was stirred at room temperature overnight, concentrated to dryness and suspended in tetrahydrofuran (30 ml). The reaction mixture was treated with 1M sodium hydroxide (5.3 ml, 5.3 mmol) with ice-cooling, followed by stirring at 5° C. for 1.5 h. The reaction mixture was acidified to pH2 with 2M hydrochloric acid, concentrated and partitioned between water and dichloromethane. The layers were separated and the aqueous layer was extracted with dichloromethane twice. The combined organics were dried (MgSO4) and concentrated to give a pale yellow solid. Suspension in THF (30 ml) and treatment with 1M sodium hydroxide (5.3 ml, 5.3 mmol) at 5° C. was followed by stirring at room temperature for 2 h. The reaction mixture was acidified to pH2 with 2M hydrochloric acid, concentrated to a small volume, diluted with water and filtered. The filtrate was washed with water and cold diethyl ether to afford a white solid (0.32 g, 90%), m.p. 227°-228° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.CON(C)[C:13]([C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=1)=[O:14]>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:13]([C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=1)=[O:14]
Reactant: CON(C)C(=O)c1ccc(I)cc1
Reactant: Fc1ccccc1CBr
Product: O=C(Cc1ccccc1F)c1ccc(I)cc1

Procedure:
The product was prepared from 2-fluorobenzyl bromide and O,N-dimethyl-4-iodobenzenehydroxamic acid (see Preparation 30) by a similar method to Preparation 20(i) as a colourless solid, m.p. 112-114° C.
Reaction SMILES: C1[O:14][C:4]([CH3:13])([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)OC1.[Na].Cl[CH2:17][C:18]1[O:22][N:21](C2CCC=CO2)[C:20](=[O:29])[CH:19]=1.Cl>C(O)C.CC(C)=O>[CH2:5]([C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:17][C:18]2[O:22][N:21]=[C:20]([OH:29])[CH:19]=2)=[CH:10][CH:11]=1)[C:4]([CH3:13])=[O:14]
Reactant: O=c1cc(CCl)on1C1CCC=CO1
Reactant: CC1(Cc2ccc(O)cc2)OCCO1
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: CC(C)=O
Product: CC(=O)Cc1ccc(OCc2cc(O)no2)cc1
Reaction time: 4 h

Procedure:
A solution of (4-hydroxyphenyl)propan-2-one ethylene ketal (1.4 g) in ethanol, was treated with a solution of sodium (0.16 g) in ethanol (25 ml) and heated under reflux for 10 minutes. A solution of 5-chloromethyl-2-(1,2,3,4-tetrahydropyran-2-yl)isoxazol-3-(2H)one (1.5 g) in ethanol was added dropwise, and the reaction was heated for 18 hr. The cooled solution was evaporated in vacuo, the residue partitioned between ethylacetate and water, the organic layer separated, dried (magnesium sulphate), and the solvent removed in vacuo to give an oil which was chromatographed on silica. Elution with ether: 60:80 petrol (1:1) gave an oil which was dissolved in acetone and treated with 2M hydrochloric acid solution (5 ml) and allowed to stand at room temperature for 4 hr. The solvent was removed in vacuo, the residue dissolved in ethyl acetate, washed with 1.2M sodium bicarbonate solution (1×50 ml), dried (magnesium sulphate , filtered and evaporated to give 5-(4-acetonylphenoxymethyl)3-hydroxyisoxazole.
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:14]3[C:10](=[CH:11][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:13]=3)[CH:9]=[C:8](Br)[CH:7]=2)=[CH:4][C:3]2[CH:24]=[CH:25][CH:26]=[CH:27][C:2]1=2.C([Li])CCC.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH:39]=[O:40]>O1CCCC1>[S:1]1[C:5]([C:6]2[C:14]3[C:10](=[C:11]([CH:39]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=4)[OH:40])[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:13]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:4][C:3]2[CH:24]=[CH:25][CH:26]=[CH:27][C:2]1=2
Reactant: O=Cc1ccccn1
Reactant: C[Si](C)(C)CCOCn1cc2cc(Br)cc(-c3cc4ccccc4s3)c2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc2c(-c3cc4ccccc4s3)cccc2c1C(O)c1ccccn1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 31.4 %

Procedure:
A mixture of 7-benzo[b]thiophen-2-yl-5-bromo-2-(2-trimethylsilanyl-ethoxymethyl)-2H-indazole (Preparation #23, 0.15 g, 0.326 mmol) in tetrahydrofuran (2 mL) was cooled to about −65° C. then a solution of n-butyllithium (1.6 M, 0.36 mL, 0.36 mmol) was added dropwise. After about 30 minutes, 2-pyridinecarboxaldehyde (0.042 g, 0.39 mmol) was added. The mixture was quenched with methanol (1 mL) then warmed to room temperature. The solvent was removed in vacuo and the residue was purified by preparative reverse phase HPLC chromatography (RP-HPLC (Rainin C18, 8 mm, 300 Å, 35 cm; 5-100% acetonitrile/0.1 M ammonium acetate over 20 min, 100% acetonitrile hold 10 minutes, 21 mL/min) to give the intermediate [7-benzo[b]thiophen-2-yl-2-(2-trimethylsilanyl-ethoxymethyl)-2H-indazol-3-yl-pyridin-2-yl-methanol (50 mg) which was suspended in a mixture of 1,4-dioxane (2 mL) and manganese dioxide (90 mg, 31%). The mixture was heated to about 90° C. for 15 minutes then filtered and evaporated. The residue was purified by reverse phase HPLC (RP-HPLC (Rainin C18, 8 mm, 300 Å, 35 cm; 5-100% acetonitrile/0.1 M ammonium acetate over 20 min, 100% acetonitrile hold 10 minutes, 21 mL/min) to give (7-Benzo[b]thiophen-2-yl-1H-indazol-3-yl)-pyridin-2-yl-methanone (22 mg, 44%); (DMSO-d6, 400 MHz) δ 8.8 (bs, 1H), 8.31 (d, 1H), 8.09 (m, 4H), 7.93 (d, 1H), 7.78 (bs, 1H), 6.96 (bs, 1H), 7.51 (t, 1H), 7.43 (m, 2H); RP-HPLC (Table 1, Method e) Rt 2.60 min; m/z: (M−H)− 353.8.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>O>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CN1CCNCC1
Solvent: O
Product: CN1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 80 °C

Procedure:
A mixture of 5-bromo-2-nitropyridine (500 mg, 2.46 mmol) and 1-methylpiperazine (1 mL) is heated at 80° C. for 2 hour. Then water is added. The aqueous layer is extracted with EtOAc, and the organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography (SiO2, MeOH:CH2Cl2=0.7:99.3 to 6:93) to give 520 mg of the title compound as yellow solid.
Reaction SMILES: [C:1]([CH:3]([CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])[C:4]([O:6][CH3:7])=[O:5])#[N:2].Br[CH:17]([CH2:22][CH2:23][Br:24])[C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[C:10]1([CH:8]([C:3]([C:1]#[N:2])([C:4]([O:6][CH3:7])=[O:5])[CH:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:22][CH2:23][Br:24])[CH3:9])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)C(Br)CCBr
Reactant: COC(=O)C(C#N)C(C)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)C(CCBr)C(C#N)(C(=O)OC)C(C)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A mixture of methyl 2-cyano-3-phenylbutyrate (78 g, 0.37 mole), methyl 2,4-dibromobutyrate (122 g, 0.47 mole), potassium carbonate (65 g, 0.47 mole) and DMSO (50 ml) was stirred on a ball mill apparatus. The reaction was completed in four hours. Ice water was added and the mixture was neutralized by adding cold hydrochloric acid. The aqueous solution was extracted several times with ether. The combined organic solution was washed sequentially with cold aqueous sodium bicarbonate and brine, then dried over magnesium sulfate. After removal of the solvent, the residue was purified by Kugelrohr distillation (100° C., 30 microns) to remove low boiling materials. The remaining oily residue (118 g., 84%) was found to be mainly the title bromide condensation product (ν<95% GC purity). MS m/e (% relative intensity) 383(M.+, 3) 381 (3), 202 (33), 182 (7), 180 (7), 105 (100).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[CH2:16][C:17]1[C:18]([CH2:36][CH3:37])=[N:19][N:20]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH:31]([OH:34])[CH2:32][CH3:33])=[CH:26][C:25]=2[CH3:35])[C:21]=1[CH2:22][CH3:23])[CH3:4].I[CH2:39][CH3:40].C(Cl)Cl>O1CCCC1>[CH2:3]([O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[CH2:16][C:17]1[C:18]([CH2:36][CH3:37])=[N:19][N:20]([C:24]2[C:25]([CH3:35])=[CH:26][C:27]([CH:31]([O:34][CH2:39][CH3:40])[CH2:32][CH3:33])=[CH:28][C:29]=2[CH3:30])[C:21]=1[CH2:22][CH3:23])[CH3:4]
Reactant: CCI
Reactant: CCOc1ccc2ccccc2c1Cc1c(CC)nn(-c2c(C)cc(C(O)CC)cc2C)c1CC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOc1ccc2ccccc2c1Cc1c(CC)nn(-c2c(C)cc(C(CC)OCC)cc2C)c1CC
Reaction time: 0.08 h
Yield: 146.5 %

Procedure:
Sodium hydride (60% mineral oil dispersion, 0.031 g, 0.78 mmol) was added portionwise to a solution of 1-{4-[4-(2-ethoxy-naphthalen-1-ylmethyl)-3,5-diethyl-pyrazol-1-yl]-3,5-dimethylphenyl}-propan-1-ol (0.123 g, 0.26 mmol) in 0.5 ml anhydrous tetrahydrofuran. After stirring 5 minutes, iodoethane (0.104 ml, 1.3 mmol) was added and the resulting mixture was stirred for 16 hours at ambient temperature. A second portion of sodium hydride (0.031 g of a 60% sodium hydride mineral oil dispersion; 0.78 mmol) was added, followed by a second portion of iodoethane (0.104 ml, 1.3 mmol). After stirring at ambient temperature for 4 hours, the reaction mixture was well-mixed with methylene chloride/aqueous sodium bicarbonate (10 ml of each). The aqueous phase was then twice extracted with 10 ml portions of fresh methylene chloride. The combined organic extracts were then dried over anhydrous sodium sulfate and concentrated in vacuo to afford a 190 mg residue. Flash chromatography of the entire sample (silica gel, 40 micron mesh; elution with ethyl acetate/hexanes=1:4 in volume) afforded the title compound (45 mg) as an oil.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([C:10]([OH:12])=O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C([O:20][C:21]1[C:30]([CH3:31])=[CH:29][C:24]([C:25]([NH:27][NH2:28])=O)=[CH:23][C:22]=1[CH2:32][CH3:33])C1C=CC=CC=1>>[CH2:32]([C:22]1[CH:23]=[C:24]([C:25]2[O:12][C:10]([C:8]3[S:9][C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])=[CH:6][CH:7]=3)=[N:28][N:27]=2)[CH:29]=[C:30]([CH3:31])[C:21]=1[OH:20])[CH3:33]
Reactant: CCc1cc(C(=O)NN)cc(C)c1OCc1ccccc1
Reactant: CC(C)Cc1ccc(C(=O)O)s1
Product: CCc1cc(-c2nnc(-c3ccc(CC(C)C)s3)o2)cc(C)c1O

Procedure:
2-Ethyl-4-[5-(5-isobutyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-6-methyl-phenol is prepared in analogy to Example 29 from 5-isobutyl-thiophene-2-carboxylic acid and 4-benzyloxy-3-ethyl-5-methyl-benzoic acid hydrazide; LC-MS: tR=1.03 min, [M+1]+=343.22.
Reaction SMILES: [N+](C1C=C([C:10]2[CH:11]=[C:12](CC3C=CN=CC=3)[CH:13]=[C:14]3[C:19]=2[N:18]=[CH:17][CH:16]=[CH:15]3)C=CC=1)([O-])=O.O.[NH4+].[Cl-]>CCO.[Fe]>[N:18]1[C:19]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1cccc(-c2cc(Cc3ccncc3)cc3cccnc23)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: c1ccc2ncccc2c1
Temperature: 25 °C

Procedure:
To a solution of the 8-(3-nitro-phenyl)-6-pyridin-4-ylmethyl-quinoline (1.0 eq) described in Step 1 in EtOH (0.2M) at 60° C. was added of water (final concentration 0.15M) and saturated aqueous NH4Cl (1.3 eq) followed by iron (12 eq). The final mixture was stirred at 60° C. for 2 h, cooled to room temperature, filtered on celite and concentrated to afford the title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH2:10])[CH:5]=[C:4]([NH2:11])[N:3]=1.CC([O-])=O.[K+]>O1CCCC1.CO.[Pd]>[C:8]([C:7]1[CH:2]=[N:3][C:4]([NH2:11])=[CH:5][C:6]=1[NH2:10])#[N:9]
Reactant: N#Cc1c(N)cc(N)nc1Br
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cnc(N)cc1N
Yield: 69.1 %

Procedure:
A solution of (II) (15.1 g, 0.071 mol), KOAc (7.0 g, 0.071 mol) and 5% Pd/C (4 g) in THF (tetrahydrofuran) (130 mL) and MeOH (methanol) (70 mL) was hydrogenated (55 psi/20° C.) for 7 days. The resulting solution was filtered over Celite, washing with THF/MeOH, then the solvents were removed under reduced pressure. The residue was dissolved in dilute HCl, then the solution neutralised with 40% NaOH and excess Na2CO3 to give 3-cyano-4,6-diaminopyridine (III) (6.58 g, 69%): mp (water) 197-198° C. [Metzger R., Oberdorfer J., Schwager C., Thielecke W., Boldt P., Liebigs Ann. Chem., 1980;946-953 record mp (benzene) 205° C⟧
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([OH:27])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:29]=[C:30]([NH2:38])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([C:30]1[N:38]=[C:25]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:27][N:29]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NC(Cc1ccccc1)=NO
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cc3ccccc3)no2)C1

Procedure:
250 mg (0.65 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid and 107 mg (0.71 mmol) of N′-hydroxy-2-phenylethanimidamide were reacted according to the General Method 1. Yield: 44 mg (14% of theory)
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH3:15])[CH2:9]OS(C)(=O)=O)=[C:6]([Cl:16])[N:5]=[CH:4][N:3]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>C(Cl)Cl>[Cl:16][C:6]1[C:7]2[CH:8]([CH3:15])[CH2:9][N:24]([CH2:23][C:22]3[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[C:2]=2[N:3]=[CH:4][N:5]=1
Reactant: COc1ccc(CN)cc1
Reactant: CC(COS(C)(=O)=O)c1c(Cl)ncnc1Cl
Solvent: ClCCl
Product: COc1ccc(CN2CC(C)c3c(Cl)ncnc32)cc1
Yield: 100.4 %

Procedure:
To a solution of methanesulfonic acid 2-(4,6-dichloro-pyrimidin-5-yl)-propyl ester (0.54 g, 1.89 mmol) in DCM (30 mL) and TEA (4 mL) was added 4-methoxybenzyl amine (0.80 g, 5.83 mmol). The mixture was refluxed overnight. After cooling, the solvent was removed and the residue was subject to column chromatography, eluted by hexane/ethyl acetate (4:1) to give 4-Chloro-7-(4-methoxy-benzyl)-5-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (0.55 g, 99%). 1H NMR (CDCl3, 400 MHz) δ 8.24 (s, 1H), 7.17 (d, J=7.6 Hz, 2H), 6.86 (d, J=7.6 Hz, 2H), 4.55 (s, 2H), 3.80 (s, 3H), 3.66 (m, 1H), 3.37 (m, 1H), 3.07 (m, 1H), 1.31 (dd, J=7.2 Hz, J=1.2 Hz, 3H). MS (APCI+) [M+H]+291.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][C:5]=1[I:14].[C:17](=O)([O:25]C1C=CC=CC=1)[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:16][O:15][CH:3]([O:2][CH3:1])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[C:17]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:25])=[CH:6][C:5]=1[I:14]
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: COC(OC)c1nc2c(cc1I)CCCN2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(OC)c1nc2c(cc1I)CCCN2C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 7-(dimethoxymethyl)-6-iodo-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 52, 97 mg, 0.290 mmol) and diphenyl carbonate (74.6 mg, 0.348 mmol) in THF (2.5 ml) at −78° C. was treated with LHMDS (1 M in THF, 0.334 ml, 0.334 mmol) and stirred for 2 h. The reaction was then allowed to warm to room temperature over 20 min, quenched by addition of sat. aq. NH4Cl and extracted with DCM (2×). The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) to give the title compound as a white solid. (UPLC-MS 3) tR 1.19 min; ESI-MS 455.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:4]([SH:9])=[N:5][S:6][C:7]=1[SH:8])#[N:2].[Na].[Na].Cl.Cl[CH2:14][C:15]([NH2:17])=[NH:16]>C(O)C>[C:15]([CH2:14][S:9][C:4]1[C:3]([C:1]#[N:2])=[C:7]([SH:8])[S:6][N:5]=1)(=[NH:16])[NH2:17]
Reactant: N#Cc1c(S)nsc1S
Reactant: N=C(N)CCl
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: N#Cc1c(SCC(=N)N)nsc1S
Reaction time: 2 h
Yield: 54 %

Procedure:
In 40 ml of 50% aqueous ethanol was dissolved 2.18 g of disodium 4-cyano-3,5-dimercaptoisothiazole, to which 1.29 g of α-chloroacetamidine hydrochloride was added. The mixture was stirred for 2 hours, concentrated under reduced pressure, diluted with water and adjusted to pH 5.2. The precipitating crystals were collected by filtration and washed with water and then ethanol to give 1.23 g of 3-amidinomethylthio-4-cyano-5-mercaptoisothiazole as gray crystals (mp 198°-201° C., decomp.).
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(Cl)=C(Cl)C=1)C.C=O.[NH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[Cl:32][C:33]1[CH:34]=[C:35]([CH:49]=[CH:50][C:51]=1[Cl:52])[CH2:36][N:37]([CH3:48])[C:38]([C:40]1[CH2:41]N(C)[C:43](=[O:46])[C:44]=1[OH:45])=[O:39]>>[Cl:32][C:33]1[CH:34]=[C:35]([CH:49]=[CH:50][C:51]=1[Cl:52])[CH2:36][N:37]([CH3:48])[C:38]([C:40]1[CH2:41][N:23]([CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:43](=[O:46])[C:44]=1[OH:45])=[O:39]
Reactant: NCCN1CCCCC1
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCCCC2)C1
Yield: 38 %

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and 1-(2-aminoethyl)piperidine as described in the preparation of Compound 12. The resulting residue was purified by trituration with CH2Cl2 to yield the title compound as a white solid (81.2 mg, 38% yield). Decomposition point=178–182° C. 1H NMR (300 MHz, DMSO) δ: 10.99 (s, 1H), 7.62 (d, 1H, J=8.25), 7.52 (d, 1H, J=1.46), 7.26 (d, 1H, J=7.68), 4.60 (s, 2H), 4.13 (s, 2H), 3.81 (t, 2H, J=5.85), 3.48 (d, 2H, J=11.34), 3.27 (d, 2H. J=4.76), 3.00 (s, 2H), 2.86 (m, 3H), 1.77 (m, 6H). HRMS (M+H) calcd for C20H26N3Cl2O3: 426.1351. found: 426.1346.
Reaction SMILES: CC1C=CC(S([O:11][C@H:12]([C@@H:15]2[CH:19]=[CH:18][CH2:17][O:16]2)[CH2:13]O)(=O)=O)=CC=1.[OH-].[NH4+:21]>>[NH2:21][CH2:13][C@H:12]([C@@H:15]1[CH:19]=[CH:18][CH2:17][O:16]1)[OH:11]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H](CO)[C@@H]2C=CCO2)cc1
Reactant: [NH4+]
Agent: [OH-]
Product: NC[C@@H](O)[C@@H]1C=CCO1
Temperature: 75 °C
Reaction time: 48 h

Procedure:
(S)-1-((S)-2,5-dihydrofuran-2-yl)-2-hydroxyethyl 4-methylbenzenesulfonate (14) (1.0 g, 3.52 mmol) was suspended in ammonium hydroxide (8 mL) then stirred and heated at 75° C. in a sealed tube for 6.5 hours during which time the two liquid phases became a single phase solution. The mixture was stood at ambient temperature for 2 days then the solvents were removed in vacuo. The residue was azeotroped with diethyl ether (3×10 mL) to obtain (R)-2-amino-1-((S)-2,5-dihydrofuran-2-yl)ethanol which was used without further purification.
Reaction SMILES: CN(C)S([N:6]1[CH:10]=[C:9]([CH2:11][C:12]2([C:15]([F:18])([F:17])[F:16])[CH2:14][CH2:13]2)[N:8]=[C:7]1[C@H:19]([OH:37])[C@:20]([OH:36])([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)=[CH:27][CH:26]=1)[C:21]([F:24])([F:23])[F:22])(=O)=O.Cl>CO>[F:24][C:21]([F:22])([F:23])[C@@:20]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)=[CH:27][CH:26]=1)([OH:36])[C@@H:19]([C:7]1[NH:6][CH:10]=[C:9]([CH2:11][C:12]2([C:15]([F:17])([F:18])[F:16])[CH2:13][CH2:14]2)[N:8]=1)[OH:37]
Reactant: CN(C)S(=O)(=O)n1cc(CC2(C(F)(F)F)CC2)nc1[C@H](O)[C@](O)(c1ccc(-n2cccn2)cc1)C(F)(F)F
Agent: Cl
Solvent: CO
Product: O[C@H](c1nc(CC2(C(F)(F)F)CC2)c[nH]1)[C@@](O)(c1ccc(-n2cccn2)cc1)C(F)(F)F
Temperature: 70 °C

Procedure:
A methanol (2.0 mL) solution of N,N-dimethyl-2-{(1S,2R)-3,3,3-trifluoro-1,2-dihydroxy-2-[4-(1H-pyrazol-1-yl)phenyl]propyl}-4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1H-imidazole-1-sulfonamide (20.2 mg, 0.036 mmol) was charged with concentrated hydrochloric acid (0.5 mL, 6.0 mmol) and heated to 70° C. After the starting material has been all consumed, the reaction mixture was quenched by sodium bicarbonate and extracted with dichloromethane/ethyl acetate. The combined organic extracts were concentrated in vacuo to afford the title compound. (M+H) found 461.
Reaction SMILES: COP([CH2:7][C:8](=[O:24])[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)(OC)=O.[H-].[Na+].[N:27]1[CH:28]=[C:29]2[N:38]3[C:33](=[CH:34][CH:35]=[CH:36][C:37]=13)[S:32][C:31]([CH:39]=O)=[CH:30]2>C1(C)C=CC=CC=1.CN(C)C=O.O>[C:20]([O:19][C:17]([N:14]1[CH2:13][CH2:12][CH:11]([CH2:10][CH2:9][C:8](=[O:24])/[CH:7]=[CH:39]/[C:31]2[S:32][C:33]3[N:38]4[C:29](=[CH:28][N:27]=[C:37]4[CH:36]=[CH:35][CH:34]=3)[CH:30]=2)[CH2:16][CH2:15]1)=[O:18])([CH3:21])([CH3:22])[CH3:23]
Reactant: O=CC1=Cc2cnc3cccc(n23)S1
Reactant: COP(=O)(CC(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)/C=C/C2=Cc3cnc4cccc(n34)S2)CC1
Reaction time: 2 h

Procedure:
To a solution of 4.77 g (13.1 mM) of tert-butyl 4-[4-(dimethoxyphosphoryl)-3-oxobutyl]piperidine-1-carboxylate in 50 ml of toluene was added 0.48 g (12.0 mM) of a 60% suspension of sodium hydride in liquid paraffin at room temperature, and the mixture was stirred at the prevailing temperature for 2 hours. This reaction mixture was added to a solution of the above crude 5-thia-1,8b-diazaacenaphthylene-4-carbaldehyde in N,N-dimethylformamide (30 ml)-toluene (50 ml) with ice-cooling and the mixture was stirred at the prevailing temperature for 3 hours. This reaction mixture was poured in water and extracted with 3 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol : 9/1) to provide crude (E)-5-[1-(tert-butoxycarbonyl)piperidin-4-yl]-1-(5-thia-1,8b-diazaacenaphthylen-4-yl)-1-penten-3-one. This crude product was not purified but used as it was in the next reaction.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][Cl:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CC(C)=O>[Cl:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][Cl:8])[C:16](=[O:17])[O:18][CH2:19][CH3:20]
Reactant: CCOC(=O)Cl
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)N(CCCl)CCCl
Temperature: 25 °C
Yield: 100 %

Procedure:
bis(2-Chloroethyl)amine hydrochloride (Tokyo Chemical Industry CO., LTD., 3.0 g) was dissolved in acetone (50 ml), potassium carbonate (3.0 g) and ethyl chloroformate (2.4 ml) were added, and the mixture was heated under reflux for 4 hr. After completion of the reaction, the mixture was cooled to room temperature, and the solid was filtered off. The filtrate was evaporated under reduced pressure to give ethyl bis(2-chloroethyl)carbamate (3.7 g, yield 100%).