Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH:24]=[O:25])=[CH:18][CH:17]=4)[CH:13]=[N:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(CC)=C.[OH:31]P([O-])(O)=O.[Na+].Cl([O-])=O.[Na+]>CC(O)(C)C.C1COCC1>[C:1]1([C:7]2[CH:8]=[N:9][N:10]3[CH:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][C:24]([OH:31])=[O:25])=[CH:20][CH:21]=4)[CH:13]=[N:12][C:11]=23)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CCCc1ccc(-c2cnc3c(-c4ccccc4)cnn3c2)cc1
Reactant: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: C=C(C)CC
Product: O=C(O)CCc1ccc(-c2cnc3c(-c4ccccc4)cnn3c2)cc1
Reaction time: 1 h

Procedure:
A solution of 3-[4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)phenyl]propanal (2-5, 278 mg, 0.850 mmol, 1 equiv) in a 4:1 mixture of THF and t-BuOH (20 mL) was treated with 2-methyl butene (5 mL), an aqueous solution of sodium phosphate monobasic (0.14 M, 234 mg, 1.70 mmol, 2 equiv) and sodium chlorite (197 mg, 2.18 mmol, 2.57 equiv). After 1 hour at room temperature, additional solid sodium phosphate monobasic (278 mg, 1.70 mmol, 2 equiv) and sodium chlorite (197 mg, 2.18 mmol, 2.57 equiv) were added. The reaction mixture was stirred for an additional 4 hours, concentrated and the residue dissolved in EtOAc (100 mL) then washed with a 25:1 mixture of aqueous 10% sodium bisulfite solution and 10% potassium hydrogen sulfate solution (2×100 mL). The organic layer was dried over sodium sulfate and concentrated to afford 3-[4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)phenyl]propanoic acid (4-1) as a yellow solid. LRMS m/z: Calc'd for C21H18N3O2 (M+H) 344.4, found 344.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([O:11][CH2:12][CH:13]=[CH2:14])[CH:5]=1.CI.[C:18]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH3:18])[CH:7]=[C:6]([O:11][CH2:12][CH:13]=[CH2:14])[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: C=CCOc1cc(O)cc(C(=O)OC)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCOc1cc(OC)cc(C(=O)OC)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
To a solution of 3-allyloxy-5-hydroxy-benzoic acid methyl ester (1a) (10.25 g, 49.2 mmol) in DMF (20 mL) was added methyl iodide (3.67 mL, 59.1 mmol) and K2CO3 (13.6 g, 98.5 mmol). The reaction mixture was stirred at 70° C. for 2 hr, cooled to room temperature. The mixture was quenched with H2O (150 mL) and extracted with EtOAc (2×150 mL). The organic layers were washed with H2O (2×150 mL), dried over MgSO4 and concentrated to give a pale yellow oil which was purified by flash column chromatography eluting with 10% EtOAc in hexane to give a colorless oil (9.63 g, 88% yield). 1H NMR (400 MHz, CDCl3) δ 7.11-7.24 (m, 2 H) 6.68 (t, J=2.40 Hz, 1 H) 5.91-6.17 (m, 1 H) 5.38-5.51 (m, 1 H) 5.31 (dd, J=10.48, 1.39 Hz, 1 H) 4.52-4.61 (m, 2 H) 3.91 (s, 3 H) 3.83 (s, 3 H); LCMS for C12H14O4 m/z 223.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[C:12]1[N:13]=[C:14]([NH2:17])[S:15][CH:16]=1.Cl.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:11][C:4]1[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([CH3:1])[C:3]=1[C:12]1[N:13]=[C:14]([NH:17][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[S:15][CH:16]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1-c1csc(N)n1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2,6-Dimethyl-4-nitrophenyl)thiazol-2-amine (92 mg, 0.37 mmol) in DCM (2 mL) was added DMAP (90 mg, 0.74 mmol) followed by isonicotinoyl chloride hydrochloride (85 mg, 0.48 mmol). Then the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated, and the saturated aqueous sodium bicarbonate (30 mL) was added. The aqueous solution was extracted with DCM (3×10 mL). The combined organic layers were dried with anhydrous sodium sulfate. After removal of all the solvent, the residue was purified by silica gel chromatography (hexane/EtOAc=4:1) to give INH78 (82 mg, 62%) as a white solid; mp 258-260° C. 1H NMR (400 MHz, DMSO-d6) δ 8.79-8.77 (m, 2H), 8.02 (s, 2H), 8.97-8.95 (m, 2H), 7.32 (s, 1H), 2.20 (s, 6H). 13C NMR (125 MHz, DMSO-d6) δ 164.5, 150.9, 147.2, 142.9, 139.8, 139.7, 113.4, 20.7. MS (ESI) m/z 355.0 (M+H+). HRMS calculated for C17H14N4O3SH (M+H+), 355.0865. found, 355.0867.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:17][CH2:16][C@@H:15](O)[CH2:14][C@H:13]1[CH2:12][S:11][C:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:9]2.[F:27]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.C(N(CC)CC)C>C1COCC1>[F:27][C@H:15]1[CH2:16][CH2:17][C@:8]2([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[N:9]=[C:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[S:11][CH2:12][C@@H:13]2[CH2:14]1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccccc3F)CC[C@@H](O)C[C@H]2CS1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccccc3F)CC[C@H](F)C[C@H]2CS1
Reaction time: 15 h

Procedure:
tert-Butyl (±)-[(4aR*,6R*,8aS*)-8a-(2-fluorophenyl)-6-hydroxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate obtained in Preparation Example 64-(4) (500 mg) was dissolved in THF. Then, perfluorobutanesulfonyl fluoride (0.43 mL, specific gravity: 1.682 g/cm3), a triethylamine-trihydrofluoric acid complex (0.39 mL, specific gravity: 0.989 g/cm3) and triethylamine (0.99 mL, specific gravity: 0.73 g/cm3) were sequentially added at room temperature. After completion of the addition, the mixture was stirred for 15 hours. The reaction solution was concentrated under reduced pressure and then the residue was purified by silica gel column chromatography to obtain the title compound (351 mg).
Reaction SMILES: [Br:1][CH2:2][C:3]([NH:5][C:6]1[CH:10]=[CH:9][O:8][N:7]=1)=[O:4].[CH3:11][N:12]1[CH2:16][CH2:15][CH2:14][C@@H:13]1[CH2:17][OH:18]>C(#N)C>[Br-:1].[OH:18][CH2:17][C@H:13]1[CH2:14][CH2:15][CH2:16][N+:12]1([CH2:2][C:3](=[O:4])[NH:5][C:6]1[CH:10]=[CH:9][O:8][N:7]=1)[CH3:11]
Reactant: O=C(CBr)Nc1ccon1
Reactant: CN1CCC[C@@H]1CO
Solvent: CC#N
Product: C[N+]1(CC(=O)Nc2ccon2)CCC[C@@H]1CO
Product: [Br-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-bromo-N-isoxazol-3-yl-acetamide (Intermediate A) (3.9 g, 191 mmol) in acetonitrile (95 ml) is added ((R)-1-methyl-pyrrolidin-2-yl)-methanol (2.2 g, 191 mmol) in acetonitrile (5 ml). The reaction mixture is stirred at room temperature for 3 hours and then the solvent is removed in vacuo. The resulting oil is taken up in acetonitrile and ethyl acetate is then added. The resulting cloudy solution is stirred at room temperature for 30 minutes. There after, the supernatant is decanted off and the solid is dried under vacuum over two days to afford the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]3[C:13]([C:14]4[C:15]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[N:16][O:17][C:18]=4Cl)=[N:12][N:11]=[C:8]32)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[NH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1>CO>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]3[C:13]([C:14]4[C:15]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[N:16][O:17][C:18]=4[C:38]4[C:33]([CH2:32][NH2:31])=[N:34][CH:35]=[CH:36][CH:37]=4)=[N:12][N:11]=[C:8]32)=[CH:4][CH:3]=1
Reactant: Clc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(Br)cc1-2
Reactant: NCc1ccccn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: NCc1ncccc1-c1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(Br)cc1-2
Yield: 18.9 %

Procedure:
8-Bromo-3-(5-chloro-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole (50 mg, 0.12 mmol) (prepared in Example 39), sodium acetate (30 mg) and 2-(aminomethyl)pyridine (13 mg) in 5 ml methanol were heated to reflux for 18 h. The reaction was cooled, concentrated and partitioned between H2O—CH2Cl2. The organic phase and extracts were combined, dried over (MgSO4) and concentrated. The residue was purified by preparative TLC using 3% MeOH—CH2Cl2 as eluent. Trituration with 1PrOH gave the title compound as a beige solid (11 mg). 1H NMR (400 MHz, d6-DMSO) δ 8.53–8.54 (1H, m), 8.38–8.40 (1H, m), 8.1 (1H, s), 7.75–7.8 (1H, m), 7.65–7.68 (1H, m), 7.55–7.60 (2H, m), 7.38–7.5 (4H, m), 7.28–7.30 (2H, m), 4.68–4.7 (2H, m), 4.45 (2H, s). m/z (ES+) 485/487 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:37][C:38]1[CH:42]=[CH:41][O:40][N:39]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:14]4=[N:15][CH:16]=3)=[N:7][N:8]2[CH2:37][C:38]2[CH:42]=[CH:41][O:40][N:39]=2)=[CH:4][CH:3]=1
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Reactant: BrCc1ccon1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(Cc4ccon4)c4cc(Cl)ccc34)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
2-(6-Chloro-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (80 mg, 165 μmol) was dissolved in DMF (1 mL) and cooled to 0° C. Sodium hydride (10.6 mg, 264 μmol) was added and the mixture was stirred for 30 min at 0° C. 3-(Bromomethyl)isoxazole (29.4 mg, 181 μmol) was added and the mixture warmed to room temperature. After 15 h, the mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 20-50% ethyl acetate in hexanes, 15 min gradient) gave 2-(6-chloro-1-(isoxazol-3-ylmethyl)-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (91 mg, 161 μmol, 97.5%) as a yellow powder. MS (M+Na)+=588 (88% purity); 1H NMR (CDCl3) δ: 9.27 (s, 1H), 8.47 (d, J=8.7 Hz, 1H), 8.34-8.43 (m, 2H), 8.16 (d, J=8.3 Hz, 1H), 8.03 (s, 1H), 7.57 (s, 1H), 6.33 (d, J=1.5 Hz, 1H), 5.77 (s, 2H), 5.73 (s, 2H), 4.38-4.56 (m, 1H), 3.53-3.65 (m, 2H), 1.35-1.46 (m, 6H), 0.89-1.01 (m, 2H), −0.07-0.02 (m, 9H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:12][CH:13]([OH:16])[C:14]#[CH:15].CCN(CC)CC>[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:6]2[C:5]([CH:15]=[C:14]([CH:13]([OH:16])[CH3:12])[O:9][C:7]2=[O:8])=[CH:4][CH:3]=1
Reactant: C#CC(C)O
Reactant: O=C(O)c1cc(Br)ccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(O)c1cc2ccc(Br)cc2c(=O)o1
Temperature: 80 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
Part 2, Step A: A mixture of 5-bromo-2-iodobenzoic acid (12.6 g, 38.5 mmol), but-3-yn-2-ol (3.1 mL, 2.96 g, 42.4 mmol), ZnCl2 (5.2 g, 38.5 mmol), Pd(Ph3P)4 (2.23 g, 1.9 mmol), Et3N (16.0 mL, 11.7 g, 115.5 mmol) and DMF (80 mL) was stirred under argon at 80° C. for 2 hours. After removal of the volatiles under vacuum, the residue was chromatographed (silica gel, ethyl acetate in hexanes, 0-100%) to provide the intermediate 7-bromo-3-(1-hydroxyethyl)-1H-isochromen-1-one as a brown oil (7.5 g, 72%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.38-8.45 (1H, m), 7.81 (1H, dd, J=8.35, 2.05 Hz), 7.32 (1H, d, J=8.51 Hz), 6.52-6.59 (1H, m), 4.66 (1H, qd, J=6.52, 0.95 Hz), 1.54-1.60 (3H, m).
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H-].[Na+].[N+](C1C=CC([O:25][C:26](=O)[O:27][CH2:28][N:29]2[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][N:44]4[CH2:49][CH2:48][N:47]([C:50]5[C:58]6[CH:57]=[CH:56][S:55][C:54]=6[CH:53]=[CH:52][CH:51]=5)[CH2:46][CH2:45]4)[CH:37]=3)[CH:32]=[CH:31][C:30]2=[O:59])=CC=1)([O-])=O.O>C1COCC1>[CH2:1]([O:13][C:26](=[O:25])[O:27][CH2:28][N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][N:44]3[CH2:49][CH2:48][N:47]([C:50]4[C:58]5[CH:57]=[CH:56][S:55][C:54]=5[CH:53]=[CH:52][CH:51]=4)[CH2:46][CH2:45]3)[CH:37]=2)[CH:32]=[CH:31][C:30]1=[O:59])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=C(OCn1c(=O)ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOC(=O)OCn1c(=O)ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21
Reaction time: 1 h
Yield: 39.5 %

Procedure:
1-Dodecanol (0.10 g) was dissolved in anhydrous THF (5 ml) under a nitrogen atmosphere and sodium hydride (about 55% oil) (25 mg) was added under ice-cooling with stirring. The reaction mixture was stirred at room temperature for 30 min under a nitrogen atmosphere, and then the mixture was ice-cooled. To the mixture was added a solution (5 ml) of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester 4-nitrophenyl ester obtained in Example 133 (0.33 g) in anhydrous THF using a cannula. Under a nitrogen atmosphere, the reaction mixture was stirred with ice-cooling for 2 hr, and at room temperature for 1 hr. Water was added to the reaction mixture to discontinue the reaction, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated by filtration. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to give the title compound (0.14 g) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:24][OH:25]>C[O-].[Na+].CO>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:25][CH3:24])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COCCOc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Product: COCCOc1nc(N)c2nc(OC)n(Cc3ccccc3)c2n1
Reaction time: 5 h
Yield: 43 %

Procedure:
6-Amino-9-benzyl-8-bromo-2-(2-methoxyethoxy)purine (69 mg, 0.18 mmol) in methanol (50 ml) was dissolved in 28% sodium methoxide/methanol (1 ml) and the mixture was refluxed on heating under stirring for 5 hours. The reaction mixture was concentrated in vacuo to dryness, and to the residue was added water. The solution was extracted with chloroform and the organic layer was dried on sodium sulfate and concentrated in vacuo to dryness. The residue was purified with silica gel chromatography (3% methanol/chloroform) to give the subject compound (26 mg, yield 43%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH2:18]([N:25]=[C:26]=[S:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][C:26]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[S:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: S=C=NCc1ccccc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=S)NCc4ccccc4)cc23)CC1
Yield: 68.6 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 14.63 mg (0.098 mMol) benzyl isothiocyanate, 17.0 mg (86%) of the title compound were recovered.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[NH:10][N:9]=[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:5]2=[N:6][CH:7]=1.C(N(CC)CC)C>C(O)C.C1COCC1.[Pd]>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][C:8]1[C:5]2=[N:6][CH:7]=[CH:2][CH:3]=[C:4]2[NH:10][N:9]=1
Reactant: Fc1ccccc1Cc1n[nH]c2cc(Cl)cnc12
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Fc1ccccc1Cc1n[nH]c2cccnc12
Reaction time: 2 h

Procedure:
411 mg (1.57 mmol) of 6-chloro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridine from example 3A are dissolved in a mixture of 4 ml of ethanol and 4 ml of THF, and, after addition of 159 mg (1.57 mmol) of triethylamine and 140 mg of 10% palladium on carbon, the mixture is hydrogenated under a hydrogen atmosphere at atmospheric pressure for 2 h. It is then filtered to remove the catalyst, concentrated in vacuo and taken up in water. The mixture is extracted with dichloromethane, and the organic phase is dried over sodium sulfate. Concentration results in 334 mg (94% of theory) of the title compound as white crystals.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[P:6]([O:11][CH2:12][CH3:13])(=[O:10])[O:7][CH2:8][CH3:9].C([N-]C1CCCCC1)(C)C.[Li+].[CH2:25]([Sn:29](Cl)([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH3:28]>C1COCC1>[CH2:34]([Sn:29]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:30][CH2:31][CH2:32][CH3:33])[C:5]1[O:1][C:2]([P:6]([O:7][CH2:8][CH3:9])(=[O:10])[O:11][CH2:12][CH3:13])=[CH:3][CH:4]=1)[CH2:35][CH2:36][CH3:37]
Reactant: CCOP(=O)(OCC)c1ccco1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[N-]C1CCCCC1
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(P(=O)(OCC)OCC)o1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of diethyl 2-furanphosphonate (1 mmole, prepared as in Step C of Example 1) in THF was cooled at −78° C. and cannulated to a solution of lithium N-isopropyl-N-cyclohexylamide in THF at −78° C. over 15 min. The resulting mixture was stirred at −78° C. for 2 h and cannulated into a solution of tributyltin chloride (1 mmole) in THF at −78° C. over 20 min. The mixture was then stirred at −78° C. for 1 h, and at 25° C. for 12 h. Extraction and chromatography gave compound (14) as a light yellow oil.
Reaction SMILES: C(NC1CCCCC1)(C)C.C([Li])CCC.[C:16]([O:19][CH2:20][CH3:21])(=[O:18])[CH3:17].[CH2:22]([O:24][CH:25]([O:47][CH2:48][CH3:49])[CH2:26][C:27](=[O:46])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH:37][CH2:38][CH:39]=[CH:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH3:23].Cl>O1CCCC1>[CH2:48]([O:47][CH:25]([O:24][CH2:22][CH3:23])[CH2:26][C:27]([OH:46])([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH:37][CH2:38][CH:39]=[CH:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:17][C:16]([O:19][CH2:20][CH3:21])=[O:18])[CH3:49]
Reactant: CCOC(C)=O
Reactant: CCCCCC=CCC=CCCCCCCCCC(=O)CC(OCC)OCC
Agent: CC(C)NC1CCCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCC=CCC=CCCCCCCCCC(O)(CC(=O)OCC)CC(OCC)OCC
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Isopropyl cyclohexylamine (565 mg, 4 mmole) in 10 ml of anhydrous tetrahydrofuran was cooled to -78° C. in a 3 neck round bottom flask and n-butyl lithium (2 ml, 4 mmole) was added dropwise. After 10 minutes, ethyl acetate (300 mg, 4 mmole) in 5 ml of tetrahydrofuran was added dropwise over a 15 minute period and the reaction mixture was stirred for 30 minutes at -78° C. following the addition. 1,1-Diethoxy-12,15-heneicosadiene-3-one (1.5 g) in 5 ml of tetrahydrofuran was added within 1 minute and the mixture was maintained at -78° C. for another 30 minutes. 5% Aqueous hydrochloric acid (5 ml) was added and the mixture was warmed to room temperature. Solvent was removed in vacuo and 40 ml of pentane was added. The organic layer was washed until neutral and was dried, worked up to provide 1.0 g of crude reaction mixture. After purification from column chromatography, the desired product was obtained as heavy oil (1.4 g) of formula XI of Chart B.
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])=[C:16]([C:26]([F:29])([F:28])[F:27])[N:15]([CH2:30][CH2:31][OH:32])[N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:33]([O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C:17]1[C:13]([O:12][C@@H:1]2[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]2[OH:3])=[N:14][N:15]([CH2:30][CH2:31][OH:32])[C:16]=1[C:26]([F:27])([F:29])[F:28])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: OCCn1nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c(Cc2ccccc2O)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCn1nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c(Cc2ccccc2OCc2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 81.5 %

Procedure:
To a solution of 3-(β-D-glucopyranosyloxy)-4-(2-hydroxybenzyl)-1-(2-hydroxyethyl)-5-trifluoromethyl-1H-pyrazole (111 mg) in N,N-dimethylformamide (0.5 mL) were added benzyl bromide (49 mg) and potassium carbonate (43 mg), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1–5/1) to give the title compound (108 mg).
Reaction SMILES: [CH3:1][N:2]([C:4]([N:6]=[C:7]([NH2:9])[NH2:8])=[NH:5])[CH3:3].[ClH:10].[CH3:11][CH:12]1OC(C)OC(C)O1>C(O)C(C)C>[ClH:10].[NH2:8][C:7]1[NH:6][C:4]([N:2]([CH3:3])[CH3:1])=[N:5][CH:11]([CH3:12])[N:9]=1
Reactant: CN(C)C(=N)N=C(N)N
Reactant: CC1OC(C)OC(C)O1
Agent: Cl
Solvent: CC(C)CO
Product: CC1N=C(N)NC(N(C)C)=N1
Temperature: 12.5 °C
Yield: 176.6 %

Procedure:
Synthesis according to the invention: A mixture of 100.1 g of metformin hydrochloride, 36.5 g of paraldehyde and 4 g of Dowex DR-2030 in 237.8 ml of isobutanol was heated under reflux for 6 hours. The catalyst was subsequently filtered off, and some of the solvent was removed by distillation. The remainder of the solution was cooled to 10-15° C., and the white precipitate was separated off, giving 93.5 g (80.7%) of 4-amino-3,6-dihydro-2-dimethylamino-6-methyl-1,3,5-triazine hydrochloride.
Reaction SMILES: N1C[CH2:4][CH2:3][CH2:2]1.CC(C)=O.[C:10]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[OH:22])[C:16]([OH:18])=[O:17])(=[O:12])[CH3:11]>C(#N)C>[C:16]([C:15]1[CH:14]=[C:13]2[C:21](=[CH:20][CH:19]=1)[O:22][C:3]([CH3:4])([CH3:2])[CH2:11][C:10]2=[O:12])([OH:18])=[O:17]
Reactant: C1CCNC1
Reactant: CC(=O)c1cc(C(=O)O)ccc1O
Solvent: CC#N
Solvent: CC(C)=O
Product: CC1(C)CC(=O)c2cc(C(=O)O)ccc2O1
Reaction time: 48 h

Procedure:
13.8 g of pyrrolidine and 40 ml of acetone are added to a suspension of 14.7 g (0.0815 mol) of 3-acetyl-4-hydroxybenzoic acid in 200 ml of acetonitrile. The slowly discoloring solution is allowed to stand at room temperature for 2 days, the solvent is distilled off on a rotary evaporator, the residue is treated with water and adjusted to acidic pH<1 using conc. hydrochloric acid and the crystalline substance is filtered off.