Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([CH3:12])[C:10]#[N:11].[CH2:13](N)[CH2:14][NH2:15]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([C:10]1[NH:15][CH2:14][CH2:13][N:11]=1)[CH3:12]
Reactant: NCCN
Reactant: CC(C#N)c1c(F)cccc1F
Product: CC(C1=NCCN1)c1c(F)cccc1F

Procedure:
rac-2-[1-(2,6-Difluoro-phenyl)-ethyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(2,6-difluoro-phenyl)-propionitrile and ethylene diamine in analogy to Example 19 b): white solid; MS (ISP): 211.1 ((M+H)+.).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][C:12]([F:15])([F:14])[F:13].[O:16](C(OC(C)(C)C)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=O.CCN(CC)CC>CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:17]([NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][C:12]([F:15])([F:13])[F:14])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:16]
Reactant: NCc1ccccc1SCC(F)(F)F
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1ccccc1SCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-aminomethyl-(2,2,2-trifluoroethylthio)benzene hydrochloride (500 mg, 1.94 mmol) in CH2C2 (20 mL) were added successively (BOC)2O (465 mg, 2.13 mmol), DMAP (23.7 mg, 0.194 mmol) and Et3N (0.27 mL, 1.94 mmol). The reaction mixture was stirred overnight at room temperature and was then diluted with EtOAc and washed successively with 10% aqueous citric acid, brine, and water. The organic layer was dried over MgSO4 and concentrated at reduced pressure. Silica gel chromatography (isocratic elution with 20% EtOAc-hexanes) afforded the title compound as a colorless oil:
Reaction SMILES: [NH2:1][C@@H:2]([C@H:5]([CH2:11][CH3:12])[CH2:6][C:7]([F:10])([F:9])[F:8])[CH2:3][OH:4].C(N(CC)CC)C.[Cl:20][C:21]1[S:25][C:24]([S:26](Cl)(=[O:28])=[O:27])=[CH:23][CH:22]=1>C(Cl)Cl>[Cl:20][C:21]1[S:25][C:24]([S:26]([NH:1][C@H:2]([CH2:3][OH:4])[C@H:5]([CH2:11][CH3:12])[CH2:6][C:7]([F:8])([F:9])[F:10])(=[O:28])=[O:27])=[CH:23][CH:22]=1
Reactant: CC[C@H](CC(F)(F)F)[C@H](N)CO
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](CC(F)(F)F)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)s1
Reaction time: 0.25 h

Procedure:
To a stirred solution of (2S,3R)-2-amino-3-ethyl-5,5,5-trifluoropentan-1-ol (120 mg, 0.701 mmol), triethylamine (0.1 mL, 1.4 mmol) and methylene chloride (50 mL) cooled to 0° C., was added 5-chlorothiophene-2-sulfonyl chloride (220 mg, 0.841 mmol) as a solution in methylene chloride (5 mL), dropwise. After 15 min, the ice bath was removed and the reaction was allowed to attain 25° C. overnight. Additional methylene chloride (15 mL) was added and the reaction mixture was poured into saturated sodium bicarbonate solution (25 mL). The organic phase was separated and washed sequentially with 1N HCl solution, H2O, brine and dried over MgSO4. The organic phase was filtered and evaporated to produce a crude oil (0.36 g) that was purified by flash chromatography using ethyl acetate-hexane, 1-4 as eluent. This provided the title compound 5-chloro-N-[(1S,2R)-2-ethyl-4,4,4-trifluoro-1-(hydroxymethyl)butyl]thiophenfe-2-sulfonamide as an oil (125 mg, 53%). The oil (125 mg) was further purified by prep-chiral HPLC [SFC; AD, 25×0.46 cm; mobile phase, 8:2 hexane-ipa (1 mL/min)] to obtain 5-chloro-N-[(1 S, 2R)-2-ethyl-4,4,4-trifluoro-1-(hydroxymethyl)butyl]thiophene-2-sulfonamide as a white crystalline solid (0.15 mg, 6.4%, chiral purity 100%, analytical purity 100%). Mass Spectrum (−ESI): 364 (M−H)−.
Reaction SMILES: CC1C=CC(S(N(Cl)[Cl:12])(=O)=O)=CC=1.Cl.[CH3:15][CH:16]([CH2:28][CH3:29])[CH2:17][O:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>C(O)(=O)C>[CH3:15][CH:16]([CH2:28][CH3:29])[CH2:17][O:18][C:19](=[O:27])[C:20]1[CH:21]=[CH:22][C:23]([OH:26])=[C:24]([Cl:12])[CH:25]=1
Reactant: CCC(C)COC(=O)c1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)N(Cl)Cl)cc1
Agent: Cl
Solvent: CC(=O)O
Product: CCC(C)COC(=O)c1ccc(O)c(Cl)c1
Reaction time: 8 h
Yield: 144.2 %

Procedure:
On the other hand, dichloramine T (28.0 g, 0.12 mol) was dissolved in acetic acid (450 ml), and hydrochloric acid (1.5 ml) was added. The resulting solution was dropwise added to a solution of the above p-hydroxybenzoic acid 2-methyl-butyl ester (50 g, 0.24 mol) dissolved in acetic acid (450 ml), followed by refluxing the mixture, allowing to stand overnight, distilling off acetic acid and filtering off deposited crystals to obtain 3-chloro-4-hydroxy-benzoic acid 2-methyl-butyl ester (42 g) (b.p. 135°~138° C./4 mmHg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14]([C:16](OCC)=[O:17])[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14]([CH2:16][OH:17])[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH2:5][CH2:6]1
Reactant: CCOC(=O)c1cn2ccnc(N3CCOCC3)c2n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cn2ccnc(N3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
To a solution of compound 1c (8.40 g, 30.4 mmol) in THF (100 mL) was added LiAlH4 (2.55 g, 60.8 mmol) in portions at 0° C. The reaction mixture was stirred at rt for 2 h. The reaction was slowly quenched with H2O (10 mL). The resulting mixture was extracted with DCM (2×100 mL), and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain compound 1d as a yellow solid (3.80 g, 53% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C11H14N4O2: 235.1 (M+H). found: 235.2.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]=[N:14][O:15][CH2:16][CH2:17][OH:18])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:20]1[CH:52]=[CH:51][C:23]([CH2:24][CH:25]2[S:29][C:28](=[O:30])[N:27]([C:31]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]2=[O:50])=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]=[N:14][O:15][CH2:16][CH2:17][O:18][C:20]3[CH:52]=[CH:51][C:23]([CH2:24][CH:25]4[S:29][C:28](=[O:30])[N:27]([C:31]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:26]4=[O:50])=[CH:22][CH:21]=3)=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCON=Cc1ccc(-c2ccccc2)nc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1SC(Cc2ccc(OCCON=Cc3ccc(-c4ccccc4)nc3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 78.6 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 390 mg of 2-(2-phenyl-5-pyridylmethyleneaminooxy)ethanol (prepared as described in Preparation 10), 576 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 422 mg of triphenylphosphine and 280 mg of diethyl azodicarboxylate, 671 mg of the title compound were obtained as a crystalline powder, melting at 146-148° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[C:14]([NH2:16])=[O:15].[C:17]([O:21][C:22]([N:24]1[CH2:27][CH:26]([N:28]2[CH2:33][CH2:32][CH2:31][CH:30]([C:34](OC)=O)[CH2:29]2)[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(O)C>[CH3:13][C:4]1[C:3]2[C:14](=[O:15])[NH:16][C:34]([CH:30]3[CH2:31][CH2:32][CH2:33][N:28]([CH:26]4[CH2:25][N:24]([C:22]([O:21][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:23])[CH2:27]4)[CH2:29]3)=[N:1][C:2]=2[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=1
Reactant: COC(=O)C1CCCN(C2CN(C(=O)OC(C)(C)C)C2)C1
Reactant: Cc1nn(-c2ccccc2)c(N)c1C(N)=O
Solvent: CCO
Product: Cc1nn(-c2ccccc2)c2nc(C3CCCN(C4CN(C(=O)OC(C)(C)C)C4)C3)[nH]c(=O)c12

Procedure:
Into a 100-mL 3-necked round-bottom flask, was placed a solution of Na (128 mg, 5.57 mmol, 6.00 equiv) in ethanol (10 mL) at room temperature. To the resulting mixture was then added a solution of 5-amino-3-methyl-1-phenyl-1H-pyrazole-4-carboxamide (200 mg, 0.93 mmol, 1.00 equiv) in C4H10O (10 mL), in portions at room temperature, followed by a solution of methyl 1-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidine-3-carboxylate (1.66 g, 5.57 mmol, 6.00 equiv) in C4H10O (20 mL), in portions at room temperature. The resulting solution was heated to reflux overnight. The reaction was then quenched by the addition of water (20 mL). The resulting solution was extracted with DCM (3×30 mL) and the organic layers combined. The resulting mixture was washed with sodium chloride (2×30 mL). The mixture was dried over anhydrous sodium sulfate, the solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (50:1) to yield tert-butyl 3-(3-(3-methyl-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperidin-1-yl)azetidine-1-carboxylate as a yellow solid.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2O)[CH:3]=[CH:2]1.O=P(Cl)(Cl)[Cl:13].[NH4+].[OH-]>O>[Cl:13][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:3]=[CH:2][S:1][C:9]=12
Reactant: Oc1ccnc2ccsc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Clc1ccnc2ccsc12
Temperature: 105 °C

Procedure:
A suspension of thieno[3,2-b]pyridin-7-ol (4.6 g, 30.4 mmol) in POCl3 (15 mL, 30.4 mmol) was refluxed at 105° C. for 4 hr. The solvent was evaporated to afford a dark brown oil that was cooled in an ice bath and diluted with cold water. The aqueous layer was adjusted to a basic pH (˜8) by adding an NH4OH solution. The aqueous mixture was extracted with EtOAc and DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to afford an oil. Purification of the crude material by silica gel chromatography using a BIOTAGE® machine (hexanes:ethyl acetate 75:25) afforded the title compound as a pale buff solid (4.7 g, 91%). ESI MS (M+H)+=170.0.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+].CCOCC.CCCCCC>FC(F)(F)C(O)=O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:5]([C:11](=[O:13])[CH2:10][CH2:9][S:8]2)=[CH:6][CH:7]=1
Reactant: Cc1cccc(SCCC(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Product: Cc1ccc2c(c1)SCCC2=O
Temperature: 25 °C
Reaction time: 1.9 h
Yield: 32 %

Procedure:
3-(3-Methylphenylthio)propanoic acid from Step 1 (10.12 g, 52 mmol) was dissolved in trifluoroacetic acid (20 mL), treated with trifluoroacetic anhydride (10 mL) and stirred at room temperature for 1.9 hours. The reaction was poured into 10% Na2CO3 (100 mL), extracted with ether, washed with brine, dried over MgSO4, and concentrated in vacuo to give an orange oil which was passed through a column of silica gel eluting with 8% ether/hexane to give 7-methylthiochroman-4-one (2.97 g, 32%) as a yellow oil: 1H NMR (CDCl3) 300 MHz 7.97 (d, J=8.1 Hz, 1H) 7.06 (s, 1H) 6.97 (d, J=7.7 Hz, 1H) 3.17 (m, 2H) 2.95 (m, 2H) 2.31 (s, 3H). Mass spectrum: M+H=179.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[C:19]([S:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:18]=1>C(O)C>[Cl:16][C:17]1[CH:22]=[C:21]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[N:20]=[C:19]([S:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:18]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)CSc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSc1nc(Cl)cc(NCc2ccc(F)cc2)n1

Procedure:
A stirred mixture of 3.75 g of p-fluorobenzylamine, 3.18 g of anhydrous sodium carbonate and 8.01 g of (4,6-dichloro-2-pyrimidinylthio)acetic acid, ethyl ester in 150 ml of ethanol was heated under reflux for 5 hr. The reaction mixture was filtered and water was added to the filtrate until a precipitate was formed. The solid was collected and recrystallized from benzene-petroleum ether giving 3.6 g of product, mp. 70°-75°C.
Reaction SMILES: O=[C:2]1[N:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]2[N:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4](=[O:18])[NH:3]1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[CH2:27][CH2:28]C(=N)N.FC(F)(F)C1C=CC(C2C=CC(CN)=CC=2)=CC=1.CC(N1CCC(=O)CC1)(C)C(OC)=O>>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[CH2:27][CH2:28][C:2]1[N:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]2[N:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4](=[O:18])[N:3]=1
Reactant: N=C(N)CCc1ccc(F)cc1F
Reactant: CCOC(=O)Cn1c(=O)[nH]c(=O)c2cccnc21
Agent: COC(=O)C(C)(C)N1CCC(=O)CC1
Agent: NCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Product: CCOC(=O)Cn1c(CCc2ccc(F)cc2F)nc(=O)c2cccnc21
Temperature: 25 °C

Procedure:
A mixture of ethyl (2,4-dioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)acetate (WO 02/30911, Intermediate B52) (40.8 g, 1.2 equiv) and 3-(2,4-difluorophenyl)propanimidamide (made by methods analogous to those described for the 2,3-difluoro isomer, Intermediates A1 to A3 of WO 02/30911) (30.0 g, 1 equiv) was fused in a 150° C. oil bath for 25 min, then cooled quickly to room temperature in a water bath. Chromatography (silica, crude product loaded in DCM and eluted with 50-100% ethyl acetate in hexane) gave the desired product (43.56 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[NH2:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:18]([O:20][CH3:21])=[O:19]>CCOC(C)=O.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[C:18]([O:20][CH3:21])=[O:19])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: COC(=O)c1sccc1N
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1sccc1Nc1ccc(Cl)cc1[N+](=O)[O-]

Procedure:
5-Chloro-2-fluoro-nitrobenzene and methyl 3-amino-thiophene-2-carboxylate, m.p. 207°-208° C. (EtOAc/Hexane).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C@@H:8]([NH:11]S(C(C)(C)C)=O)[CH2:9][CH3:10])[CH:3]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[BH4-].[Li+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C@@H:8]([NH2:11])[CH2:9][CH3:10])[CH:3]=1
Reactant: CC[C@H](NS(=O)C(C)(C)C)c1cc(Br)ccn1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@H](N)c1cc(Br)ccn1
Reaction time: 3 h

Procedure:
To a chilled (−78° C.) solution of 2-methyl-propane-2-sulfinic acid [(S)-1-(4-bromo-pyridin-2-yl)-propyl]-amide (985 mg, 3.10 mmol) in THF (25 mL) was added a 1 M solution of L-Selectride (3.2 mL, 3.2 mmol) in THF. The reaction was monitored by TLC (ethyl acetate-ether 3:7) indicating a single diastereomer when compared to a mixture of diastereomers prepared by reduction of 2-methyl-propane-2-sulfinic acid [(S)-1-(4-bromo-pyridin-2-yl)-propyl]-amide with lithium borohydride in THF. After 3 hours, the mixture was quenched with saturated aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine (3×30 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in dichloromethane. The material from the column was crystallized from hexanes to afford (S)-1-(4-bromo-pyridin-2-yl)-propylamine.
Reaction SMILES: [N+]([O-])(O)=O.[CH3:5][N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8][C:7]1=[O:16].[ClH:17]>C(O)(=O)C>[Cl:17][C:12]1[NH:11][C:10]2[C:9](=[O:15])[NH:8][C:7](=[O:16])[N:6]([CH3:5])[C:14]=2[N:13]=1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: Cl
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Cn1c(=O)[nH]c(=O)c2[nH]c(Cl)nc21
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
Nitric acid (9 ml) was slowly added dropwise to a suspension of 3-methylxanthine (10 g) in acetic acid (180 ml) at 100° C., and the resulting white suspension was stirred at 100° C. for 30 minutes followed by 140° C. for 20 minutes. After cooling the reaction solution to room temperature, the solvent was removed by distillation at reduced pressure at 60° C. to give a yellow solid. The resulting yellow solid was washed with water, and recrystallization from 0.5 M hydrochloric acid gave a pale yellow solid. A suspension of the solid in concentrated hydrochloric acid (500 ml) was stirred at 110° C. for 15 minutes, then the reaction solution was cooled to room temperature, and the solvent was removed by distillation at reduced pressure to give a yellow-white solid. Recrystallization of the resulting solid from water gave 6.75 g of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([S:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH2:2]1.O=[C:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.C([BH3-])#N.[Na+].O>C(O)C.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][CH:17]([N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([S:7]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)(=[O:8])=[O:9])[CH2:2]2)[CH2:18][CH2:19]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=S(=O)(C1CCCNC1)N1CCOCC1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(N2CCCC(S(=O)(=O)N3CCOCC3)C2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.1 %

Procedure:
A mixture of the 4-(piperidine-3-sulfonyl)-morpholine (710 mg, 3.03 mmol), tert-butyl 4-oxo-1-piperidinecarboxylate (1 eq, 605 mg) and Ti(OiPr)4 (1.25 eq, 1.12 mL) was stirred under nitrogen at ambient temperature for 1 hr. A solution of sodium cyanoborohydride (0.7 eq, 133 mg) in anhydrous ethanol (3 mL) was added and the clear solution was stirred overnight. Water (0.6 mL) was added followed by sufficient ethanol to permit stirring. The thick suspension was filtered through Celite® rising through with ethanol and the filtrate was evaporated to a cloudy oil which was redissolved in dichloromethane/ethanol, a few drops of water added and the mixture was filtered through Celite®. The filtrate was diluted with toluene, evaporated under vacuum and the residue purified by chromatography on silica gel eluting with 2.5% methanol-dichloromethane. The desired fractions were combined, evaporated under vacuum and the residue chromatographed on silica gel eluting with 2.5% methanol-dichloromethane to give 3-(morpholine-4-sulfonyl)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester (520 mg, 41%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]2[N:13]=[C:14]([S:17][CH:18]([CH2:24][CH3:25])[C:19]([O:21]CC)=[O:20])[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]2[N:13]=[C:14]([S:17][CH:18]([CH2:24][CH3:25])[C:19]([OH:21])=[O:20])[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1
Reactant: CCOC(=O)C(CC)Sc1ccc2nnc(-c3ccccc3F)n2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCC(Sc1ccc2nnc(-c3ccccc3F)n2n1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-((3-(2-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thio)butanoate (1 mmol) in dioxane (3 mL) was added 0.5 ml of sodium hydroxide (2N), and the reaction mixture was stirred at room temperature. After 2 hours, the mixture was evaporated to dryness, and the obtained residue dissolved in water (2 mL) and then acidified with an hydrochloric acid solution. The resulting precipitate was filtered, washed with water, and dried to give 2-((3-(2-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thio)butanoic acid.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:14]2[CH2:15][O:16][C@H:12]([O:13]2)[C@H:11]([O:17][CH3:18])[C@@H:10]1[OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH3:22]I.O>CS(C)=O>[CH2:1]([O:8][C@@H:9]1[C@H:14]2[CH2:15][O:16][C@H:12]([O:13]2)[C@H:11]([O:17][CH3:18])[C@@H:10]1[O:19][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@H]1[C@@H]2OC[C@@H](O2)[C@@H](OCc2ccccc2)[C@H]1O
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CO[C@H]1[C@@H](OC)[C@@H]2OC[C@@H](O2)[C@H]1OCc1ccccc1
Reaction time: 8 h
Yield: 51.4 %

Procedure:
1,6-Anhydro-4-O-benzyl-2-O-methyl-β-D-allopyranose (0.135 g) (see Example 29) was dissolved in dimethylsulphoxide (0.5 ml) and stirred with powdered potassium hydroxide (0.118 g). Methyl iodide (0.568 g) was added in two portions, and the reaction mixture was left overnight at room temperature. Water (10 ml) was added and the mixture was extracted with chloroform (3×10 ml). The combined extracts were washed with brine, filtered through Whatman 1PS paper, and evaporated to a red oil. This was subjected to preparative t.l.c. on silica gel eluted with ethyl acetate/hexane, 1:1, to yield the title compound as a colourless syrup (0.073 g); 1H-nmr data: 7.2-7.5 (m, Ph), 5.6 (d, H-1), 4.8 (m, PhCH2O), 4.55 (m, H-5), 3.3-3.7 (m, H-2,3,4,6,6'), and 3.40 and 3.57 (s, OMe).
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(OCC)(=O)C>CN1C(=O)CCC1.O>[CH2:29]([N:7]1[C:2](=[O:1])[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:11][CH:10]=2)=[CH:6]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(=O)NC(C)CCc1ccc(Oc2ccc(O)nc2)cc1
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(=O)NC(C)CCc1ccc(Oc2ccc(=O)n(Cc3ccccc3)c2)cc1

Procedure:
N-{3-[4-(6-Hydroxypyridin-3-yloxy)phenyl]-1-methylpropyl}acetamide (150 mg, 0.5 mmol) was stirred with potassium tert-butoxide (168 mg, 1.5 mmol) and benzylbromide (342 mg, 2 mmol) in 3 ml of NMP at room temperature for 10 h. The batch was admixed with ethyl acetate and water, and the organic phase was separated off, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 22 mg (11%), M+H+: 391.15. N-{3-[4-(1-Benzyl-6-oxo-1,6-dihydropyridin-3-yloxy)phenyl]-1-methylpropyl}acetamide was obtained as by-product.
Reaction SMILES: [N:1]([CH:4]([C:8]1[N:9]=[C:10]2[CH:16]=[CH:15][N:14]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:11]2=[N:12][CH:13]=1)[CH2:5][CH:6]=[CH2:7])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[ClH:46].CCOCC>C1COCC1.O.CCOC(C)=O>[ClH:46].[S:17]([N:14]1[C:11]2=[N:12][CH:13]=[C:8]([CH:4]([NH2:1])[CH2:5][CH:6]=[CH2:7])[N:9]=[C:10]2[CH:16]=[CH:15]1)([C:20]1[CH:21]=[CH:22][C:23]([CH3:24])=[CH:25][CH:26]=1)(=[O:18])=[O:19]
Reactant: C=CCC(N=[N+]=[N-])c1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCC(N)c1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Temperature: 50 °C
Reaction time: 15 h
Yield: 62 %

Procedure:
To a solution of 2-(1-azidobut-3-enyl)-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (3.90 g, 10.6 mmol) in THF (60 mL) and water (30 mL) was added triphenylphosphine (3.33 g, 12.7 mmol). The reaction mixture was heated to about 50° C. for about 15 h. The reaction mixture was cooled to ambient temperature and concd in vacuo. The residue was dissolved in EtOAc (30 mL) and HCl (gas) was added until a pH of about 1 was maintained followed by the addition of Et2O to induce precipitate formation. After stirring for about 15 h, the precipitate was collected by filtration to provide 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)but-3-en-1-amine hydrochloride (2.5 g, 62%) as a tan solid: LC/MS (Table 1, Method a) Rt=1.80 min; MS m/z: 343 (M+H)+.