Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@:12]1([OH:45])[CH2:20][C@H:19]([CH2:21]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:18][C@@H:17]2[C@H:13]1[CH2:14][N:15]([C:33](=[O:44])[C@H:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[O:42][CH3:43])[CH3:35])[CH2:16]2>CS(C)=O.O>[C:1]([CH2:21][C@@H:19]1[CH2:18][C@@H:17]2[C@@H:13]([CH2:14][N:15]([C:33](=[O:44])[C@H:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[O:42][CH3:43])[CH3:35])[CH2:16]2)[C@@:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH3:4])([OH:45])[CH2:20]1)#[N:2]
Reactant: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2C[C@@H](COS(=O)(=O)c3ccc(C)cc3)C[C@@](O)(c3ccccc3OC)[C@@H]2C1
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2C[C@@H](CC#N)C[C@@](O)(c3ccccc3OC)[C@@H]2C1
Temperature: 45 °C
Yield: 68.5 %

Procedure:
1.0 g of potassium cyanide is added to a solution of 5.6 g of (3aS,4S,6R,7aR)-4-(2-methoxyphenyl)-2-[(S)-2-(2-methoxyphenyl)propionyl]-6-tosyloxymethylperhydroisoindol-4-ol in 50 cm3 of dimethyl sulphoxide. After stirring at 45° C. for hours, the reaction mixture is cooled to 20° C., diluted with 300 cm3 of water and then extracted twice with 50 cm3 of ethyl acetate. The organic phase is subsequently washed with 150 cm3 of water, dried. over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.06-0.20 mm, diameter 4.4 cm, height 50 cm), eluting under a pressure of 0.2 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (40:60 by volume) and collecting fractions of 120 cm3. Evaporation to dryness of fractions 11 to 20 under reduced pressure (2.7 kPa) gives 2.9 g of (3aS,4S,6S,7aR)-6-cyanomethyl-4-(2-methoxyphenyl)-2-[(S)-2-(2-methoxyphenyl)propionyl]perhydroisoindol-4-ol in the form of a thick white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)([CH2:13][CH:14]=O)[CH2:9]1)=[O:7].[CH2:29]([O:31][CH2:32][CH2:33][N:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[N:43]1[CH2:49][CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH3:30].C([BH3-])#N.[Na+].[OH-].[Na+]>CO.CO.C(OCC)(=O)C.ClCCl>[CH3:28][O:27][C:23]1[CH:22]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:46]2[CH2:47][CH2:48][CH2:49][N:43]([C:35]3[N:34]([CH2:33][CH2:32][O:31][CH2:29][CH3:30])[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=3)[CH2:44][CH2:45]2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1cc(C(=O)N2CCC(CC=O)(c3ccccn3)C2)cc(OC)c1OC
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccn4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Reaction time: 18 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-2-yl)-3-(2-oxoethyl)pyrrolidine (0.29 g, 0.75 mmol) and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.26 g, 0.91 mmol) silica gel (about 2 g) and 3 Å molecular sieves (about 2 g) in methanol (16 mL). After 18 hours, add sodium cyanoborohydride (0.47 g, 7.5 mmol) and stir. After 7 days, add a solution of 2 M sodium hydroxide and dichloromethane. After 1 hour, filter, separate the layers in the filtrate, dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 1/1 methanol/ethyl acetate to give the title compound: mp; 40-42° C. Elemental Analysis calculated for C37H48N6O5•0.75 H2O: C, 66.30; H 7.44; N, 12.54; Found: C, 66.33; H, 7.50; N, 12.49.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1.[NH:15]1[CH:19]=[N:18][CH:17]=[N:16]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][C:5]=1/[CH:4]=[CH:3]/[CH2:2][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: c1nc[nH]n1
Reactant: ClC/C=C/c1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C(=C/c1ccc2ccccc2c1)\Cn1cncn1
Reaction time: 14 h
Yield: 10.3 %

Procedure:
A mixture of (E)-1-chloro-3-(2-naphthyl)-2-propene (0.5 g), 1H-1,2,4-triazole (0.5 g) and K2CO3(1.0 g) in DMF (20 ml) was stirred for 14 hours. The mixture was diluted with ethyl acetate and insolubles were filtered off. The filtrate was concentrated in vacuo and the residue was chromatographed on silica gel, eluting with ethyl acetate to give the titled compound (0.06 g) as colorless powder.
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.[F:18][CH:19]([C:24]([F:27])([F:26])[F:25])[C:20]([O:22][CH3:23])=[O:21].C(N(C(C)C)CC)(C)C.[CH:37](=[O:39])[CH3:38]>ClCCl>[F:18][C:19]([C:24]([F:27])([F:26])[F:25])([CH:37]([OH:39])[CH3:38])[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C(F)C(F)(F)F
Reactant: CC=O
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C(F)(C(C)O)C(F)(F)F
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
Dibutylboron triflate (5 g) was added to a stirred solution of methyl 2,3,3,3-tetrafluoropropionate (2.9 g) in dichloromethane at 0° C. under nitrogen. After 15 minutes, the solution was cooled to -10° C. and diisopropylethylamine (3.8 ml) was added in portions. After 30 minutes, freshly distilled acetaldehyde (2 ml) was added in small portions, keeping the temperature at -10° C. The reaction was stirred at -10° C. for 1 hour before quenching with a mixture of pH7 phosphate buffer (60 ml), aqueous hydrogen peroxide (100 vol; 15 ml) and crushed ice and stirring for 1.5 hours. The organic phase was separated and the aqueous layer further extracted with dichloromethane. The combined organic phases were washed with aquesous sodium metabisulphite and with brine, dried (MgSO4) and concentrated under reduced pressure to give a pink oil (2.2 g) which was distilled using a Kugelrohr apparatus. The fraction distilling at 40° C. (air bath temperature) and at 0.05 mmHg was collected; 1H NMR (270 MHz; CDCl3) (signals recorded for a 50:50 mixture of diastereomers) δ 1.34 (1.5H,d), 1.42 (1.5H,d), 2.2(1H,bs), 3.91(1.5H,bs), 3.94(1.5H,s), 4.35-4.52(1H,m) ppm.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([C:15]1[CH:19]=[CH:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][N:21]=2)[CH:16]=1)=[O:14])(C)(C)C.O>ClCCl>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([N:17]2[CH:18]=[CH:19][C:15]([C:13]([OH:14])=[O:12])=[CH:16]2)=[N:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)c1ccn(-c2ccc(Cl)cn2)c1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccn(-c2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
Trifluoroacetic acid (3 ml) was added to a solution of 1-(5-chloropyridin-2-yl)pyrrole-3-carboxylic acid tert-butyl ester (1.0 g) in dichloromethane (10 ml) and stirred at room temperature for four hours. Water was added to the reaction solution and the precipitated solid was washed with water to give the titled compound (775 mg) as a gray solid.
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](Cl)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH:28][CH2:29][CH2:30][CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33].C(N(CC)CC)C>O1CCCC1>[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:28][CH2:29][CH2:30][CH2:31][C:32](=[O:33])[N:34]([CH3:36])[CH3:35])=[O:16])=[CH:26][CH:27]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)CCCO
Reactant: O=C(Cl)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)CCCOC(=O)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F
Reaction time: 4 h
Yield: 59.2 %

Procedure:
A solution of 2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionyl chloride (3.10 g.) in tetrahydrofuran (10 ml.) is added dropwise at 0° C. to a stirred mixture of 4-hydroxy-N,N-dimethylbutyramide (885 mg.), triethylamine (773 mg.) and tetrahydrofuran (15 ml.). The mixture is kept at room temperature for 4 hours with stirring, and for 2 days without stirring, then filtered. The filtrate is evaporated, and the residue dissolved in ether. The solution is washed with water, 0.4 N-aqueous sodium hydroxide, N-hydrochloric acid and water again, dried and evaporated to a syrup (3.3 g.). The syrup is dissolved in toluene (10 ml.) and applied to a column of silica gel (90 g.). The column is washed with toluene (700 ml.), and then eluted with ether (900 ml.). The ether is evaporated, and the residue is recrystallised from ether-light petroleum (b.p. 40-60° C.) to give 3-dimethylcarbamoylpropyl 2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionate (2.1 g.), m.p. 54°-55° C.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[CH3:12][N:13]([CH3:16])[CH:14]=O.C(N(CC)CC)C.[O-][Si]([O-])=O.[Mg+2]>CO.C(Cl)(Cl)Cl.C1C=CC=CC=1>[C:1]([NH:4][CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[C:7](=[CH:12][N:13]([CH3:16])[CH3:14])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCC(=O)CC1
Reactant: CN(C)C=O
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(=O)NC1CCC(=O)C(=CN(C)C)C1
Reaction time: 1.5 h

Procedure:
A reaction mixture was prepared from 15.5 g. of 4-acetamidocyclohexanone [prepared by the procedure of Fraser and Swingle, Can. J. Chem., 48, 2065 (1970)], 80 g. of the dimethylacetal of dimethylformamide, 1.5 ml. of triethylamine and 500 ml. of benzene. The benzene was distilled therefrom over a 1.5 hour period until the volume was reduced to about 1/2 of the original volume. An additional 250 ml. of benzene were added. The reaction mixture was heated just below the boiling point of benzene for about 2 hours and was then distilled again until the volume was about one-half of that originally present (250 ml.). The above process was repeated once more except that the volume was reduced to one-third of the original volume (167 ml.). The reaction mixture was then cooled and filtered. The filter cake consisted of 4-acetamido-2-dimethylaminomethylenecyclohexanone formed in the above reaction; weight=6.45 g. Evaporation of the filtrate to dryness yielded a residue, chromatography of a chloroform solution of which over 200 g. of florisil using chloroform containing increasing amounts of methanol (0-5%) as an eluant, yielded pure 4-acetamido-2-dimethylaminomethylenecyclohexanone; m.p.=132°-133° C. (from benzene); yield=5.55 g.; total yield=12 g.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7](=[O:35])[CH:8]([O:32][CH2:33][CH3:34])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]([C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH3:26])=[CH:21][CH:20]=2)=[CH:12][CH:11]=1)C.Cl>O.O1CCCC1>[CH2:33]([O:32][CH:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]([C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH3:26])=[CH:21][CH:20]=2)=[CH:12][CH:11]=1)[C:7]([OH:35])=[O:6])[CH3:34]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(N(C)C(=O)C(C)C)cc2)cc1)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(Cc1ccc(OCCc2ccc(N(C)C(=O)C(C)C)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.2 %

Procedure:
Lithium hydroxide hydrate (62 mg; 1.48 mmole) dissolved in water (2 ml) was added to a solution of 2-ethoxy-3-(4-{2-[4-(isobutyryl-N-methylamino)phenyl]ethoxy}phenyl)propanoic acid ethyl ester (described in Example 72) (435 mg; 0.98 mmole) in tetrahydrofuran (6 ml). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was acidified with hydrochloric acid (2 M) to pH 4. Tetrahydrofuran was evaporated in vacuo, water (5 ml) was added and the mixture was extracted with ethyl acetate (10 ml). The organic phase was dried (sodium sulfate) and solvent was evaporated in vacuo to give 398 mg (yield 98%) of 2-ethoxy-3-(4-{2-[4-(isobutyryl-N-methylamino)phenyl]ethoxy}phenyl)propanoic acid.
Reaction SMILES: [Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=O)=[C:4]([F:11])[CH:3]=1.Cl.[CH3:13][C@H:14]1[CH2:19][O:18][CH2:17][CH2:16][NH:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClC(Cl)C>[Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH2:6][N:15]2[CH2:16][CH2:17][O:18][CH2:19][C@@H:14]2[CH3:13])=[C:4]([F:11])[CH:3]=1
Reactant: C[C@H]1COCCN1
Reactant: O=Cc1cc(F)c(Br)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1Cc1cc(F)c(Br)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.1 %

Procedure:
4-Bromo-2,5-difluorobenzaldehyde (331 mg, 1.5 mmol), (S)-3-methylmorpholine hydrochloride (206 mg, 1.50 mmol) and sodium triacetoxyborohydride (461 mg, 2.18 mmol) were mixed in dichloroethane (5 mL). Triethylamine (0.230 mL, 1.65 mmol) was added and the resulting mixture was stirred at RT under argon atmosphere for 24 h. NaHCO3 (25 mL) was added and the mixture was extracted with dichloromethane (3×25 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated to give (S)-4-(4-bromo-2,5-difluorobenzyl)-3-methylmorpholine (432 mg, 94%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:20])=[N:15][CH:16]=[C:17](I)[CH:18]=1)[CH3:11].[CH3:21][C:22]1[CH:26]=[CH:25][NH:24][N:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCCCCCCCCCCC.C1(N)(N)CCCCC1>CS(C)=O.[Cu](I)I>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:20])=[N:15][CH:16]=[C:17]([N:24]2[CH:25]=[CH:26][C:22]([CH3:21])=[N:23]2)[CH:18]=1)[CH3:11]
Reactant: Cc1cc[nH]n1
Reactant: CC(Oc1cc(I)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: I[Cu]I
Agent: NC1(N)CCCCC1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Solvent: CCCCCCCCCCCC
Product: Cc1ccn(-c2cnc(N)c(OC(C)c3c(Cl)ccc(F)c3Cl)c2)n1
Reaction time: 2 h
Yield: 34.2 %

Procedure:
To a stirred solution of 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-iodo-pyridin-2-ylamine (100 mg, 0.23 mmol) and 3-methyl-1H-pyrazole (59 mg, 0.70 mmol) in DMSO (1 mL was added K3PO4 (101 mg, 0.47 mmol), dodecane (0.015 mL, 0.05 mmol), cyclohexanediamine (0.009 mL, 0.07 mmol) and copper iodide (CuI) (14 mg, 0.07 mmol). The solution was bubbled with nitrogen for 5 minutes, then radiated with microwave at 150° C. for 2 hours, LCMS checked that the reaction was completed, the mixture was purified by prep-HPLC to leave 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3-methyl-pyrazol-1-yl)-pyridin-2-ylamine (30 mg), yield 34.2%
Reaction SMILES: [CH2:1]([N:8]1[CH2:31][CH:30]([CH:32]=C)[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH3:28])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:34]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl.CO>[CH2:1]([N:8]1[CH2:31][CH:30]([CH2:32][OH:34])[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:26])[CH3:27])=[C:20]([CH3:28])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC1CN(Cc2ccccc2)CC2(CCN(C(=O)c3ccc(OC(C)C)c(C)c3)CC2)O1
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(CO)O3)ccc1OC(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
To (8-benzyl-10-vinyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone (135 mg, 0.30 mmol) in DCM (4 mL) and methanol (1 mL) at −78° C. was bubbled ozone until the solution turned faint blue. NaBH4 (91 mg, 2.41 mmol) and methanol (˜2 mL) was added under an atmosphere of nitrogen and the reaction mixture was stirred at −78° C. for 30 minutes, then at 0° C. for 1 hour. The reaction mixture was concentrated in vacuo, quenched with 4N HCl/dioxane, concentrated in vacuo, then diluted with methanol-water (1:1), microfiltered and purified by prep LCMS (1-99% ACN/Water, 5 mM HCl modifier) to give [8-benzyl-10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (50 mg, 34%). ESI-MS m/z calc. 452.6. Found 453.5 (M+1)+; Retention time: 1.18 minutes (3 min run).
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][NH:6][CH2:7][CH2:8][O:9][CH3:10].[CH:11]([C:13]1[S:20][C:19]2[CH:18]=[C:17]([S:21]([NH2:24])(=[O:23])=[O:22])[S:16][C:15]=2[CH:14]=1)=O.C([BH3-])#N.[Na+].[BH4-].[Na+]>O>[CH3:2][O:3][CH2:4][CH2:5][N:6]([CH2:11][C:13]1[S:20][C:19]2[CH:18]=[C:17]([S:21]([NH2:24])(=[O:23])=[O:22])[S:16][C:15]=2[CH:14]=1)[CH2:7][CH2:8][O:9][CH3:10]
Reactant: COCCNCCOC
Reactant: NS(=O)(=O)c1cc2sc(C=O)cc2s1
Agent: Cl
Agent: [BH3-]C#N
Agent: [BH4-]
Solvent: O
Product: COCCN(CCOC)Cc1cc2sc(S(N)(=O)=O)cc2s1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Methanolic HCl (2.7 mL of a 5.10M sol., 14 mmoles) was added to a solution of N,N-bis(2-methoxyethyl)amine. The solution was stirred for 15 minutes followed by the addition of 5-formylthieno[3,2-b]thiophene-2-sulfonamide (11) (0.742 g,. 3 mmole). The mixture was stirred at room temperature for 24 hours. Sodium cyanoborohydride (0.19 g., 3 mmoles) was added and the mixture was stirred for 24 hours. The mixture was cooled in ice water bath and sodium borohydride (0.38 g., 10 mmoles) was added in divided portions followed by stirring for 2 hours. The reaction was worked up by adding water (20 mL) and evaporating the methanol in vacuo to leave 1 g of crude product. The mixture was chromatographed on a 40×150 mm silica gel column eluting with 7% methanol in chloroform to give 0.66 g of 5-[N,N-bis(2-methoxyethyl)aminomethyl]thieno[3,2-b]thiophene-2-sulfonamide.
Reaction SMILES: [C:1]([C:5]1[N:9]2[N:10]=[C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])[CH:12]=[CH:13][C:8]2=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:24]S(O)(=O)=O.[OH-].[Na+]>>[C:1]([C:5]1[N:9]2[N:10]=[C:11]([CH2:14][C:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])=[O:24])[CH:12]=[CH:13][C:8]2=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nnc2ccc(C#Cc3ccc(F)cc3F)nn12
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)c1nnc2ccc(CC(=O)c3ccc(F)cc3F)nn12
Temperature: 90 °C

Procedure:
To a round bottom flask was added 3-tert-butyl-6-((2,4-difluorophenyl)ethynyl)-[1,2,4]triazolo[4,3-b]pyridazine (0.60 g, 1.92 mmol) and 60% aqueous H2SO4 (8.53 mL, 96 mmol). The reaction mixture was heated to about 90° C. for about 2 h. The reaction mixture was diluted with ice water (10 mL) and it was basified with 50% aqueous NaOH to a pH of about 9. The product was dried over MgSO4, filtered, and concentrated in vacuo to afford 2-(3-tert-butyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1-(2,4-difluorophenyl)ethanone which was carried forward without additional purification. To a mixture of 2-(3-tert-butyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1-(2,4-difluorophenyl)ethanone in toluene (3 mL) was added 1,1-dimethoxy-N,N-dimethylethanamine (0.21 g, 1.73 mmol). The mixture was heated to about 100° C. for about 30 min. The toluene was removed in vacuo and the material was redissolved in 1,4-dioxane (3 mL). Anhydrous hydrazine (0.085 mL, 1.7 mmol) was added dropwise to the solution and it was heated to about 95° C. for about 30 min. The mixture was cooled to ambient temperature and the material was concentrated in vacuo. The material was purified by flash chromatography and eluted with DCM/MeOH (gradient, 1-4% MeOH) to afford the title compound (0.31 g, 46%): LC/MS (Table 1, Method a) Rt=1.82 min; MS m/z: 355.2 (M+H)+; 1H NMR (DMSO-d6) δ 1.17 (s, 9H), 7.19 (m, 1H), 7.32 (m, 1H), 7.56 (m, 1H), 7.63 (d, 1H), 8.28 (d, 1H), 8.66 (s (br), 1H), 13.66 (s (br), 1H).
Reaction SMILES: [O:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[P:22](OC)([O:26]C)([O:24]C)=[O:23].O.P(Cl)(Cl)(Cl)=O.N>CO.C(OCC)(=O)C>[P:22]([O:12][CH2:11][C@H:9]1[O:10][C@@H:2]([O:1][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@H:7]1[OH:8])([OH:26])([OH:24])=[O:23]
Reactant: O=[N+]([O-])c1ccccc1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: COP(=O)(OC)OC
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1O[C@@H]1O[C@H](COP(=O)(O)O)[C@H](O)[C@H](O)[C@H]1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
o-Nitrophenyl β-D-galactopyranoside 27 (903 mg, 3.0 mmol) was added to a mixture of trimethyl phosphate (7.5 mL, 64.8 mmol), water (0.05 mL, 3.0 mmol) and phosphorous oxychloride (0.84 mL, 9.0 mmol) at 0° C. The reaction mixture was stirred and after 2 h a change was observed from a white, cloudy suspension to a clear, yellow solution. After 3 h, t.1.c. (ethyl acetate:methanol, 4:1) indicated the formation of one product (Rf 0.2) and the absence of any starting material (Rf 0.3) Crushed ice (20 mL) was added and the reaction mixture neutralised with ammonia (5 mL of a 33% aqueous solution). The white crystalline solid thus formed was separated from the clear yellow solution by filtration, the filtrate concentrated in vacuo and co-evaporated with water (6×10 mL) to afford a white, crystalline solid. The residue was purified by flash column chromatography as follows; charcoal (10 g) and celite (10 g) were mixed together with hydrochloric acid (10 mL of a 1 M aqueous solution) and packed into a column. The white solid was dissolved in water (5 mL) and loaded onto the column. The column was eluted with water. Aliquots (1 mL) of each fraction were removed and tested for the presence of chloride ions by observing turbidity on addition of silver nitrate (1 mL of a 1 M aqueous solution). After elution with 1.75 L of water the presence of chloride ions were no longer detected. Further elution (water:pyridine, 2:1) yielded o-nitrophenyl β-D-galactopyranoside 6-phosphate 17 (701 mg, 62%) as a pale, yellow crystalline solid; m.p. 181.0-183.1° C. (ethanol/ether) [Lit. 180° C. (ethanol/ether)];27 [α]D25-31.1 (c, 0.2 in H2O) [Lit. [α]D20-40 (c, 2 in H2O)];27 νmax (KBr) 3400 br, OH) 1527, 1355 (sh, C—NO2), 1250 (sh, P═O)cm−1, δH (400 MHz, D2O) 1.17-1.29 (2H, m, 2 x CHNH3), 1.52-1.57 (2H, d, J=12.6 Hz, 2 x CHCHCHCNH3), 1.68-1.73 (4H, m, 4 x CHCHCNH3), 1.87 (4H, br, 4 x CHCNH3), 3.04 (2H, br, 2 x NH), 3.65-3.70 (2H, m, H-6, H-6′), 3.74-3.86 (3H, m, H-3, H-4, H-5), 3.91-3.92 (1H, m, H-1), 7.13-7.18 (1H, m, CHCHCNO2), 7.33-7.42 (1H, m, CHCHCHCHCNO2), 7.56-7.61 (H, m, CHCHCHCNO2), 7.83-7.86 (1H, m, CHCNO2).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][S:9][C:10]2[NH:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[C:3]=1[CH3:19].N12CCCN=C1CCCCC2.Cl[CH:32]([F:34])[F:33].O>CN(C)C=O>[F:33][CH:32]([F:34])[O:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][S:9][C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]=2)[C:3]=1[CH3:19]
Reactant: FC(F)Cl
Reactant: Cc1c(O)ccnc1CSc1nc2ccccc2[nH]1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: Cc1c(OC(F)F)ccnc1CSc1nc2ccccc2[nH]1

Procedure:
In N,N-dimethylforamide (DMF) (100 ml) was dissolved 2-[(4-hydroxy-3-methyl-2-pyridyl)methylthio]benzimidazole (10.5 g). To the solution was added 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) (7.1 g), to which was introduced chlorodifluoromethane for 3 hours at room temperature. The reaction mixture was poured into water (500 ml), which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), then the solvent was distilled off. The residue was subjected to a silica gel column chromatography. From the portion eluted with chloroform-methanol (100:1, v/v), 2-[(4-difluoromethoxy-3-methyl-2-pyridyl)methylthio]benzimidazole was obtained (2.5 g, 20%). Recrystallization from ethyl acetate - hexane gave colorless needles, m.p. 99°-100° C.