Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-:1][C:2]#N.[K+].[CH3:5][O:6][C:7]1[N:12]=[CH:11][C:10]([NH:13][C:14]2([C:20]#[N:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:9][CH:8]=1.Cl.[OH2:23]>C(O)(=O)C>[CH3:5][O:6][C:7]1[N:12]=[CH:11][C:10]([N:13]2[C:14]3([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:20](=[O:23])[NH:21][C:2]2=[O:1])=[CH:9][CH:8]=1
Reactant: COc1ccc(NC2(C#N)CCCCC2)cn1
Reactant: N#C[O-]
Reactant: O
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Product: COc1ccc(N2C(=O)NC(=O)C23CCCCC3)cn1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
2.8 g (34.5 mmol, 1.6 eq.) of potassium cyanate are added at 30° C. to a solution of 5 g (21.6 mmol, 1 eq.) of 1-(6-methoxypyridin-3-ylamino)-cyclohexanecarbonitrile in 50 ml of glacial acetic acid. The reaction medium is stirred at 60° C. for 4 hours. 8 ml of hydrochloric acid and then 5 ml of water are added. The medium is heated at 90° C. for 1 hour and then at room temperature for 24 hours. It is then poured into 30 ml of water. The aqueous phase is extracted with ethyl acetate. The organic phases are combined and washed with water. They are dried over sodium sulfate. The solvents are evaporated off. The residue is chromatographed on silica gel (90/10 dichloromethane/methanol). The product is precipitated from dichloromethane and heptane and then filtered off and dried. 1-(6-Methoxypyridin-3-yl)-1,3-diaza-spiro[4.5]decane-2,4-dione is obtained in the form of a white solid.
Reaction SMILES: C([O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:25])([CH3:24])[CH2:11][C:12]#[C:13][C:14]([C:20]([F:23])([F:22])[F:21])([OH:19])[C:15]([F:18])([F:17])[F:16])(C)(C)C.[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(OC)(C)(C)C>[F:16][C:15]([F:17])([F:18])[C:14]([C:20]([F:21])([F:22])[F:23])([OH:19])/[CH:13]=[CH:12]\[CH2:11][C:10]([CH3:25])([CH3:24])[CH2:9][CH2:8][CH2:7][CH2:6][OH:5]
Reactant: CC(C)(CC#CC(O)(C(F)(F)F)C(F)(F)F)CCCCOC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: COC(C)(C)C
Product: CC(C)(C/C=C\C(O)(C(F)(F)F)C(F)(F)F)CCCCO
Yield: 94.8 %

Procedure:
A suspension of 22.13 g of 10-tert-butoxy-1,1,1 -trifluoro-6,6-dimethyl-2-trifluoromethyl-dec-3-yn-2-ol, 220 ml of tert-butylmethyl ether and 3.32 g of Lindlar catalyst was hydrogenated at 22° and 1 bar for 1.5 h after which time hydrogen up-take ceased. The suspension was filtered, the filtrate evaporated and the residue, containing pure (Z)-10-tert-butoxy-1,1,1-trifluoro-6,6-dimethyl-2-trifluoromethyl-dec-3-en-2-ol, was dissolved in 44 ml of isopropanol. The solution was treated with 22.8 g of 50% aqueous H2SO4 and the mixture was heated to 90° for 2 h after which time g.l.c. indicated completion of the reaction. The mixture was evaporated, the residue partitioned between dichloromethane and saturated NaHCO3 solution and the aqueous layer was extracted several times with dichloromethane. The combined organic layers were dried over MgSO4 and evaporated to give 17.97 g of the pure title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]([F:19])[C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[C:20]([O:23][C:24](=O)C)(=O)[CH3:21].C(OCC)(OCC)OCC>>[Br:1][C:2]1[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]([F:19])[C:3]=1[C:4]([C:6](=[CH:24][O:23][CH2:20][CH3:21])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC(=O)c1c(F)c(F)c(F)c(F)c1Br
Solvent: CCOC(OCC)OCC
Product: CCOC=C(C(=O)OCC)C(=O)c1c(F)c(F)c(F)c(F)c1Br

Procedure:
45 g of crude ethyl (2-bromo-3,4,5,6-tetrafluorobenzoyl)-acetate are introduced into 32.2 g (0.31 mol) of acetic anhydride and 28.4 g (0.19 mol) of triethyl orthoformate and the mixture is heated under reflux for 2 hours. Excess reagent is stripped off, first in vacuo and then under a high vacuum (bath up to 120°-130° C.), and the crude product is reacted for the next stage.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH:9]=O.[C:12](#[N:16])[CH2:13][C:14]#[N:15].N1CCCCC1>C(O)CCC>[C:1]1([CH3:11])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH:9]=[C:13]([C:12]#[N:16])[C:14]#[N:15]
Reactant: Cc1cc(C)c(C=O)c(C)c1
Reactant: N#CCC#N
Solvent: CCCCO
Solvent: C1CCNCC1
Product: Cc1cc(C)c(C=C(C#N)C#N)c(C)c1
Temperature: -20 °C
Reaction time: 5 h

Procedure:
In analogy to the methods described by M. Boehringer et al., WO 03/068748, a solution of 25 g (169 mmol) of mesitaldehyde (2,4,6-trimethylbenzaldehyde) and 13.5 g (204 mmol) of malononitrile in 70 mL of n-butanol was stirred at room temperature for 1 h and then treated dropwise with 0.4 mL of piperidine, resulting in a color change and precipitation. After 5 h, the mixture was cooled in a freezer (−20° C.) for 10 min and then filtered. The solid was washed three times with cold n-butanol and then dried to give the title compound as a white solid. LC-MS 197 (M+1). This material has been reported as being made by a similar procedure [A. M. Shestapalov et al., Chem. Heterocycl. Compd. (Engl. Transl. of Khim. Geterotsikl. Soedin.), 38, 1345 (2002)].
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]=[C:5]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17][C:4]=12)[CH3:2].[Cl:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[ClH:18].[CH2:22]([O:21][C:19]([N:15]1[CH2:16][CH2:17][C:4]2[C:5](=[N:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:3]=2[CH2:1][CH3:2])[CH2:13][CH2:14]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)Cl
Reactant: CCc1c2c(nc3ccccc13)CCNCC2
Product: CCOC(=O)N1CCc2nc3ccccc3c(CC)c2CC1
Product: Cl
Yield: 72 %

Procedure:
1,2,4,5-Tetrahydro-11-ethyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester hydrochloride was prepared from 11-ethyl-1,2,4,5-tetrahydro-3H-azepino[4,5-b]quinoline and ethyl chloroformate analogous to Example 63.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:14])[CH2:7][N:8]1[CH2:12][CH2:11][C@@H:10]([NH2:13])[CH2:9]1)[CH3:4].[Cl:15][C:16]1[S:20][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:18][CH:17]=1>C1COCC1.CCOC(C)=O>[CH2:3]([O:5][C:6](=[O:14])[CH2:7][N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][S:21]([C:19]2[S:20][C:16]([Cl:15])=[CH:17][CH:18]=2)(=[O:23])=[O:22])[CH2:9]1)[CH3:4]
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CCOC(=O)CN1CC[C@@H](N)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1CC[C@@H](NS(=O)(=O)c2ccc(Cl)s2)C1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
8.1 A suspension of 540 mg ((R)-3-amino-pyrrolidin-1-yl)-acetic acid ethyl ester dihydrochloride (example 1.2) in 5 ml THF was treated with 1.2 ml TEA and 530 mg 5-chlorothiophene-2-sulfonylchloride. The reaction mixture was stirred over night at r.t., then taken up in EtOAc and washed with water and brine. The organic layer was dried over MgSO4, filtered and concentrated to give 690 mg [(R)-3-(5-chloro-thiophene-2-sulfonylamino)-pyrrolidin-1-yl]-acetic acid ethyl ester. Oil. 353.1 ([M+H]+)
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]([C:10]([CH3:17])([OH:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:9])[CH:6]([CH3:8])[OH:7].C(N(CC)CC)C.[CH3:25][NH:26][NH2:27]>C1C=CC=CC=1.O1CCCC1>[CH2:14]([O:13][C:11](=[O:12])[C:10]([C:5](=[O:9])[CH:6]([CH3:8])[OH:7])([CH2:17][C:1](=[O:2])[N:26]([CH3:25])[NH2:27])[OH:16])[CH3:15]
Reactant: CCOC(=O)C(C)(O)C(=O)C(C)O
Reactant: CNN
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)C(O)(CC(=O)N(C)N)C(=O)C(C)O
Reaction time: 2 h

Procedure:
To a mixture of 50 ml of 12.5% phosgene in benzene and 50 ml of tetrahydrofuran which has been cooled to 0° to +5° is added slowly a mixture of 0.05 mole of ethyl lactyllactate and 0.05 mole of triethylamine in 50 of tetrahydrofuran. The above reaction mixture is stirred at 0° to +5° for 2 hours and is then added dropwise to a mixture of 3 gm of methylhydrazine and 0.05 moles of triethylamine in 50 ml of tetrahydrofuran which has been cooled to 0° to +5°. After stirring for 3 hours the reaction mixture is filtered to remove triethylamine hydrochloride. The filtrate is then concentrated in vacuo to give 13.6 gm of crude product. Chromatography on 700 gm of silica gel and elution with methanol/methylene chloride give 6.9 gm of 2-azaalanyllactyllactic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[N:17]([CH3:18])[N:16]=[C:15]([O:19][CH3:20])[C:14]=1[C:21]1[CH:29]=[CH:28][C:24]2[O:25][CH2:26][O:27][C:23]=2[CH:22]=1.CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[O:25]1[C:24]2[CH:28]=[CH:29][C:21]([C:14]3[C:15]([O:19][CH3:20])=[N:16][N:17]([CH3:18])[C:13]=3[NH:12][S:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])=[CH:22][C:23]=2[O:27][CH2:26]1
Reactant: COc1nn(C)c(N)c1-c1ccc2c(c1)OCO2
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: COc1nn(C)c(NS(=O)(=O)c2ccc(Br)cc2)c1-c1ccc2c(c1)OCO2
Reaction time: 8 h
Yield: 2.1 %

Procedure:
4-Bromobenzenesulfonyl chloride (210 mg) was added at room temperature under an atmosphere of nitrogen to a solution of 5-amino-4-(1,3-benzodioxol-5-yl)-3-methoxy-1-methyl-1H-pyrazole (Preparation 43) (100 mg) and dimethylaminopyridine (50 mg) in anhydrous pyridine (4 ml). The reaction was stirred overnight. The mixture was concentrated under reduced pressure, then a saturated solution of ammonium chloride (6 ml), ethyl acetate (6 ml), and brine (6 ml) were sequentially added. The aqueous phase was extracted with ethyl acetate (2*8 ml) and the combined organic fractions were washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified to yield the title compound (4 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].[CH3:13][C:14]([CH3:23])([CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:15][NH2:16].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][CH2:15][C:14]([CH3:23])([CH3:13])[CH2:17][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CC(C)(CN)CN1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NCC(C)(C)CN2CCCC2)ccc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the 4-amino-3-methoxy-benzoic acid (Aldrich; 2 g, 12 mmol) and 2,2-dimethyl-3-pyrrolidin-1-yl-propan-1-amine (WO 2004033419; 2.1 g, 13.2 mmol) were dissolved in DMF (50 mL), and to the solution was added DIPEA (3.1 g, 4.2 mL). The reaction was cooled with an ice-bath, and to it was added, portionwise, HATU (5.02 g, 13.2 mmol). The reaction mixture was stirred at ambient temperature for 18 hours. The solvent was evaporated, and the residue was partitioned between Ethyl Acetate (100 mL), and saturated aqueous sodium carbonate solution (3×40 mL), washed with brine (3×40 mL), dried over anhydrous Magnesium sulphate, filtered, and the solvent evaporated. The residue was purified by chromatography on a silica column pre-conditioned with Ethyl acetate and eluted with 10% MeOH-DCM+1% NH3. Those fractions containing the desired product were combined and the solvent was evaporated to yield the title compound as a pale brown gum, which crystallised on standing. (500 mgs; 14%).
Reaction SMILES: C[O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:10][N:9]=2)=[CH:5][CH:4]=1.C(O)(=O)C.Br>O.[OH-].[Na+]>[C:18]1([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:25][CH:24]=3)=[N:9][N:10]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1ccc(Cc2nnc(-c3ccccc3)c3ccccc23)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc(Cc2nnc(-c3ccccc3)c3ccccc23)cc1

Procedure:
To 1-(4-methoxybenzyl)-4-phenylphthalazine (0.240 g, 0.735 mmol) was added acetic acid (1.5 mL) followed by hydrobromic acid 48% (1.50 ml, 27.6 mmol). A water condenser was attached and the mixture was heated to reflux for 3 hours. The reaction was diluted with water and neutralized with 6 N NaOH until pH˜6. Filtered the resulting solid, washed with water and dried to yield 4-((4-phenylphthalazin-1-yl)methyl)phenol as an off-white solid. MS m/z=313 [M+1]+. Calc'd for C21H16N2O: 312.37.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]3[CH:15]=[C:14]([C:16]([O:18]CC)=[O:17])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].Cl>C1COCC1.O>[C:1]1([C:7]2[S:8][C:9]3[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc2nc(-c3ccccc3)sc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2nc(-c3ccccc3)sc2c1
Yield: 100.4 %

Procedure:
Ethyl 2-phenyl-benzothiazole-6-carboxylate 1y (220 mg, 0.78 mmol) was stirred with LiOH (74 mg, 3.1 mmol) in THF (4 mL) and H2O (4 mL) for 16 h. Aqueous 1N HCl solution was added to the mixture to adjust pH to 3-4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na2SO4 and concentrated to give 1z (200 mg).
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[NH2:19][C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][CH:33]=1)[C:23]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)=[O:24].C(N(CC)CC)C.C>O1CCOCC1.C(#N)C>[C:23]([C:22]1[CH:21]=[C:20]([NH:19][C:3]([C:5]2[CH:6]=[CH:7][N:8]3[C:12]=2[CH2:11][S:10][CH:9]3[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:4])[CH:33]=[CH:32][CH:31]=1)(=[O:24])[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1
Reactant: Nc1cccc(C(=O)c2ccncc2)c1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1COCCO1
Product: O=C(c1ccncc1)c1cccc(NC(=O)c2ccn3c2CSC3c2cccnc2)c1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (6 g) is added, at a temperature between 65° and 70° C., to a solution of 4-(3-aminobenzoyl)pyridine (4 g) and triethylamine (4.05 g) in dioxane (100 cc) which is heated to a temperature in the vicinity of 65° C., in the course of 15 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 6 hours and 30 minutes and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. The residue is dissolved in methylene chloride (300 cc). The solution obtained is washed with distilled water (100 cc), with an aqueous 1N sodium hydroxide solution (100 cc) and 5 times with distilled water (500 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolourizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. A crude product (6.5 g) is thereby obtained, which is dissolved in boiling acetonitrile (300 cc). Decolourizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 4° C. for 16 hours. The crystals formed are separated by filtration, washed twice with acetonitrile cooled to a temperature in the vicinity of 4° C. (20 cc in total) and twice with diethyl ether (40 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-(3-isonicotinoylphenyl)-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole7-carboxamide (5.5 g) in the form of white crystals, m.p. 186° C., is thereby obtained.
Reaction SMILES: [CH:1]1([C:6]2([CH3:19])[CH2:14][C:13]3[C:8](=[C:9]([Cl:17])[C:10]([Cl:16])=[C:11]([OH:15])[CH:12]=3)[CH:7]2[OH:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20]1(=[O:24])[O:23][CH2:22][CH2:21]1.Cl>[OH-].[Na+]>[OH:18][CH:7]1[C:8]2[C:13](=[CH:12][C:11]([O:15][CH2:22][CH2:21][C:20]([OH:24])=[O:23])=[C:10]([Cl:16])[C:9]=2[Cl:17])[CH2:14][C:6]1([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH3:19]
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1O
Reactant: O=C1CCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1(C2CCCC2)Cc2cc(OCCC(=O)O)c(Cl)c(Cl)c2C1O

Procedure:
2-Cyclopentyl-2-methyl-6,7-dichloroindan-1,5-diol (Example 5, Step C) (15.6 g., 0.05 mole) is dissolved in a 10% sodium hydroxide solution (50 ml.). The solution is heated to reflux and beta-propiolactone, (36.0 g., 0.5 mole) is added at such as to keep the reaction mixture refluxing. The reaction mixture is kept basic by the addition of 10% sodium hydroxide. The reaction mixture is cooled and acidified with dilute hydrochloric acid. The product is extracted with ether and extracted from the other solution with a 5% solution of sodium bicarbonate. Acidification affords the desired product.
Reaction SMILES: [CH2:1]([C@H:3]1[O:5][CH2:4]1)[Cl:2].[N:6]1([S:12](N)(=[O:14])=[O:13])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[CH2:16](O)C>>[Cl:2][CH2:1][C@@H:3]([OH:5])[CH2:4][N:9]1[CH2:10][CH2:11][N:6]([S:12]([CH3:16])(=[O:14])=[O:13])[CH2:7][CH2:8]1
Reactant: NS(=O)(=O)N1CCNCC1
Reactant: ClC[C@@H]1CO1
Reactant: CCO
Product: CS(=O)(=O)N1CCN(C[C@H](O)CCl)CC1
Reaction time: 18 h

Procedure:
(S)-Epichlorohydrin (48.0 mL, 0.612 mol) was added to a stirred solution of piperazine sulfonamide (87.3 g, 0.532 mol) in ethanol (1.33 L) at room temperature. The reaction mixture was stirred for 18 h and the white solid precipitate which formed was collected by filtration and washed with ethanol to afford the title intermediate (107.76 g) as a white solid which was used without further purification. (m/z): [M+H]+ calcd for C8H17ClN2O3S, 257.07; found 257.2. 1H NMR (DMSO-d6): δ (ppm) 2.37 (dd, 1H), 2.45 (dd, 1H), 2.50-2.58 (m, 4H), 2.86 (s, 3H), 3.09 (m, 4H), 3.55 (dd, 1H), 3.65 (dd, 1H), 3.84 (m, 1H), 5.09 (d, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C(N(CC)CC)C.[F:18][C:19]([F:36])([F:35])[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:27]([C:32](Cl)=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][CH:21]=1>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:32]([C:27]2[C:26]([C:23]3[CH:24]=[CH:25][C:20]([C:19]([F:18])([F:35])[F:36])=[CH:21][CH:22]=3)=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:33])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc([N+](=O)[O-])c1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.9 %

Procedure:
To a solution of 3-nitroaniline (28.8 g, 209 mmol, 1 equiv) in THF (1000 mL, 35 volumes), was added triethylamine (70 mL, 500 mmol, 2.4 equiv). 3-Nitroaniline can be obtained from Aldrich, Milwaukee, Wis. A solution of 4′-trifluoromethyl-biphenyl-2-carbonyl chloride (71.3 g, 250 mmol, 1.2 equiv) in THF (250 mL, 3.5 volumes) was added dropwise over 30 minutes. The reaction was stirred at room temperature for 48 hours. The slurry was then filtered through diatomaceous earth and the filtrate was concentrated. Water (700 mL, 24 volumes) was added and the slurry was stirred at room temperature for 12 hours. The solids were collected by filtration and dried under vacuum at 40° C. to provide 4′-trifluoromethyl-biphenyl-2-carboxylic acid (3-nitro-phenyl)-amide (80.7 g, 100%) as a pale yellow powder.
Reaction SMILES: Cl[C:2]12[O:8][CH:7]1[CH2:6][CH2:5][C:4]([Cl:10])([F:9])[CH2:3]2.ClC1(F)CCCC(Cl)([F:18])C1O.[OH-].[Na+]>O>[Cl:10][C:4]1([F:9])[CH2:5][CH2:6][CH:7]2[C:2]([F:18])([O:8]2)[CH2:3]1
Reactant: FC1(Cl)CCC2OC2(Cl)C1
Reactant: OC1C(F)(Cl)CCCC1(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: FC1(Cl)CCC2OC2(F)C1
Reaction time: 0.25 h

Procedure:
The same procedure was employed as for the preparation of 2e in Example 17: it was performed with 0.18 g (0.88 mmol) of pure alcohol 1g, 3 cm of distilled water and 0.12 g (3 mmol) of sodium hydroxide, reaction time was 1 h 15 min; ether extraction (3×12 cm). After treatment, 0.13 g of epoxide 2f were obtained (macrobore GC purity>98%). The yield of epoxide 2f was 81%.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:9]=[C:10]([OH:26])[C:11]3[N:12]=[CH:13][N:14]([C:24]=3[N:25]=2)[C@@H:15]2[O:23][C@H:20]([CH2:21][OH:22])[C@@H:18]([OH:19])[C@H:16]2[OH:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[C:31](=[O:33])[CH3:32])(=O)C>>[CH:1]1([NH:7][C:8]2[N:9]=[C:10]([OH:26])[C:11]3[N:12]=[CH:13][N:14]([C:24]=3[N:25]=2)[C@@H:15]2[O:23][C@H:20]([CH2:21][O:22][C:31](=[O:33])[CH3:32])[C@@H:18]([O:19][C:18](=[O:19])[CH3:20])[C@H:16]2[O:17][C:16](=[O:17])[CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)nc(NC4CCCCC4)nc32)[C@H](O)[C@@H]1O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(O)nc(NC4CCCCC4)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
By a procedure similar to that of Example 4(a), 1 part by weight of 2-cyclohexylaminoinosine is reacted with 5 parts by volume of acetic anhydride to obtain 1.1 parts by weight of 2-cyclohexylamino-2',3',5'-tri-O-acetylinosine as a colorless resinous product.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:21]([CH:31]2[CH2:33][CH2:32]2)[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([Cl:20])[CH:15]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[S:34]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1.CN1C(=O)CCC1>CO>[Cl:20][C:16]1[CH:15]=[C:14]([NH:13][C:11]([C:8]2[N:6]3[N:7]=[C:2]([NH:40][CH:37]4[CH2:38][CH2:39][S:34][CH2:35][CH2:36]4)[CH:3]=[C:4]([N:21]([CH:31]4[CH2:32][CH2:33]4)[CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:5]3=[N:10][CH:9]=2)=[O:12])[CH:19]=[CH:18][N:17]=1
Reactant: NC1CCSCC1
Reactant: COc1ccc(CN(c2cc(Cl)nn3c(C(=O)Nc4ccnc(Cl)c4)cnc23)C2CC2)cc1
Solvent: CO
Solvent: CN1CCCC1=O
Product: COc1ccc(CN(c2cc(NC3CCSCC3)nn3c(C(=O)Nc4ccnc(Cl)c4)cnc23)C2CC2)cc1
Yield: 23.1 %

Procedure:
A microwave tube was charged with 6-chloro-N-(2-chloropyridin-4-yl)-8-(cyclopropyl(4-methoxybenzyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (100 mg, 0.207 mmol), tetrahydro-2H-thiopyran-4-amine (121 mg, 1.034 mmol), and NMP (2 mL). The reaction mixture was irradiated at 120° C. (300 W) for 20 minutes. The crude reaction product was dissolved in a small amount of MeOH and purified by reversed phase HPLC (YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min, 60 min gradient, monitored at 254 nm). The product (retention time=68.837 minutes) was isolated and lyophilized to dryness to afford N-(2-chloropyridin-4-yl)-8-(cyclopropyl(4-methoxybenzyl)amino)-6-(tetrahydro-2H-thiopyran-4-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide (27 mg, 17.32%). HPLC Rt=4.816 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). [M+H+]=563.9.
Reaction SMILES: C[O:2][C:3](=[O:28])[C@H:4]([CH3:27])[N:5]([C:21](=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1.CCCCC(Cl)=O.[N:36]#[N:37].C([N:40](CC)CC)C>>[C:3]([C@@H:4]([N:5]([C:21](=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[NH:20][N:40]=[N:37][N:36]=2)=[CH:9][CH:8]=1)[CH3:27])([OH:2])=[O:28]
Reactant: CCN(CC)CC
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)[C@@H](C)C(=O)OC
Reactant: N#N
Agent: CCCCC(=O)Cl
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@@H](C)C(=O)O

Procedure:
N-valeryl-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-alanine methyl ester starting from 1.65 g of N-[(2'-cyanobiphenyl)-methyl]-(L)-alanine methyl ester, 2.7 ml of triethylamine and 2.35 ml of n-valeryl chloride and subsequent flash chromatography (N2). (TLC: system N2) Rf : 0.62.