Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2[O:7][C:8]3[C:9](=[C:11]([C:23]#[N:24])[C:12]([CH3:22])=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:14]=3F)[N:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:32][N:33]([CH3:39])[C@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1>CS(C)=O>[CH2:5]1[CH2:4][CH2:3][CH:2]=[CH:1]1.[CH3:32][N:33]([CH3:39])[C@H:34]1[CH2:38][CH2:37][N:36]([C:14]2[C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:12]([CH3:22])[C:11]([C:23]#[N:24])=[C:9]3[C:8]=2[O:7][CH:6]=[N:10]3)[CH2:35]1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C3CCCC3)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C1=CCCC1
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2ocnc2c1C#N
Temperature: 95 °C
Reaction time: 4 h
Yield: 48.2 %

Procedure:
2-Cyclopentyl-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-275) (112 mg, 0.24 mmol) was dissolved in dimethyl sulfoxide (5 ml), then triethylamine (100 μl, 0.36 mmol) and (3S)-3-(dimethylamino)pyrrolidine (93 μl, 0.31 mmol) were added, followed by stirring under nitrogen atmosphere at 95° C. for 4 hours. After cooling, this was concentrated under reduced pressure, diluted, with chloroform, washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was purified by preparative TLC (chloroform:methanol=10:1, v/v) to obtain the entitled compound (48 mg, 33%) as a white crystal.
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:12]([O:16][C:17]([NH:19][CH:20]1[C:23]([CH3:25])([CH3:24])[N:22]([OH:26])[C:21]1=[O:27])=[O:18])([CH3:15])([CH3:14])[CH3:13].O>ClCCl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:21]([N+:6]([CH2:7][CH2:13][CH2:12][CH3:14])([CH2:11][CH2:10][CH2:9][CH3:8])[CH2:25][CH2:23][CH2:20][CH3:21])[CH2:20][CH2:23][CH3:24].[S:2]([O-:5])([O:26][N:22]1[C:23]([CH3:25])([CH3:24])[CH:20]([NH:19][C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[C:21]1=[O:27])(=[O:4])=[O:3]
Reactant: c1ccncc1
Reactant: O=S(=O)(O)Cl
Reactant: CC(C)(C)OC(=O)NC1C(=O)N(O)C1(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1C(=O)N(OS(=O)(=O)[O-])C1(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of chlorosulfonic acid (12.27 g, 0.105 mole) in 210 ml of dichloromethane at -40° C. under argon was treated with 20.5 g (0.26 mole) of pyridine dropwise over 10 minutes. The mixture is stirred for 10 more minutes at 0° C. and 10 minutes at 25° C. A slurry of (±)-3-[(t-butyloxycarbonyl)amino]-1-hydroxy-4,4-dimethyl-2-azetidinone in 20 ml of dichloromethane was added and the mixture stirred at 25° C. for 3.5 hours. The nearly homogenous solution was then treated with 250 ml of water and 17 g (0.05 mole) of tetrabutylammonium hydrogen sulfate. The mixture was mixed well and the organic layer separated and dried over sodium sulfate. Evaporation in vacuo gave a foam, which was purified further by dissolution in ethyl acetate, removing insolubles, and evaporation to the title compound as a foam, 30 g.
Reaction SMILES: [CH3:1][C:2]1[NH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:3]=1[CH2:4][CH2:5][NH2:6].[CH3:14][O:15][C:16](=[O:27])/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=1.[BH4-].[Na+].[ClH:30].[H][H]>CO.O>[ClH:30].[CH3:14][O:15][C:16](=[O:27])/[CH:17]=[CH:18]/[C:19]1[CH:20]=[CH:21][C:22]([CH2:25][NH:6][CH2:5][CH2:4][C:3]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:13][C:2]=2[CH3:1])=[CH:23][CH:24]=1
Reactant: COC(=O)/C=C/c1ccc(C=O)cc1
Reactant: Cc1[nH]c2ccccc2c1CCN
Reactant: [H][H]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)/C=C/c1ccc(CNCCc2c(C)[nH]c3ccccc23)cc1
Temperature: 22.5 °C
Reaction time: 1 h

Procedure:
2-Methyltryptamine (50 g, 287 mmole) and (E)-3-(4-formyl-phenyl)-acrylic acid methyl ester (54.6 g, 287 mmole) are suspended in methanol (514 g). The solution is stirred for 1 hour at 20-25° C., to allow the formation of the imine intermediate. The solution is cooled to −15° C. within ca. 20 minutes. Sodium borohydride (5.43 g, 143.5 mmole) is added in several portions during ca. 1 hour while maintaining the temperature at −15° C. to −10° C. The reaction mixture is stirred for additional 30 minutes at this temperature and the temperature is raised to 20-25° C. within ca. 25 minutes. The reaction mixture is stirred for 30 minutes at 20-25° C. and water (80 g) is slowly added while maintaining the temperature at 20-25° C. An aqueous solution of hydrochloric acid (70.5 g concentrated HCl in 50 g of water) is slowly added to the reaction mixture such that the temperature is maintained at 20-25° C. and the hydrogen gas evolution can be controlled. The addition needs ca. 1 hour in this case. A second portion of aqueous hydrochloric acid solution (70.5 g concentrated HCl in 50 g water) is added within 30 minutes and the temperature is raised to 65° C. within 30 minutes. The suspension is stirred for 30 minutes at 65° C. and the temperature is lowered to −15° C. within 45 minutes. After 10 minutes stirring at −15° C., the temperature is raised again to 65° C. and the suspension is stirred for 30 minutes at this temperature. Finally, the suspension is cooled to −15° C. within 45 minutes and stirring is continued for additional 30 minutes at this temperature. The product is isolated by filtration and the wet filter cake is washed with pre-cooled (−15° C.) methanol (2×150 g). The wet product is dried at 50° C. under reduced pressure to obtain pure (E)-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl]-phenyl)-acrylic acid methyl ester hydrochloride salt as product. The product has usually >99 area % purity according to HPLC. IR, NMR and HR-MS confirmed the proposed structure. Melting point: decomposition starting at 251-252° C.
Reaction SMILES: CO[C@H]1[C@@H]2[O:8][C:9](C)([CH3:11])[O:10][C@@H:6]2[C@@H:5]([C:13]2[O:14][C:15]([CH2:18][CH3:19])=[CH:16][N:17]=2)O1.F[C:21](F)(F)[C:22]([OH:24])=[O:23].O.[C:28]([O:31][C:32](=[O:34])[CH3:33])(=[O:30])[CH3:29]>N1C=CC=CC=1>[C:22]([O:24][C@@H:29]1[C@H:6]([O:10][C:9](=[O:8])[CH3:11])[C@@H:5]([C:13]2[O:14][C:15]([CH2:18][CH3:19])=[CH:16][N:17]=2)[O:30][C@H:28]1[O:31][C:32](=[O:34])[CH3:33])(=[O:23])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)C(F)(F)F
Reactant: CCc1cnc([C@H]2O[C@@H](OC)[C@@H]3OC(C)(C)O[C@@H]32)o1
Solvent: O
Solvent: c1ccncc1
Product: CCc1cnc([C@H]2O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)o1
Temperature: 22 °C
Reaction time: 18 h

Procedure:
To 2-[(3aR,4S,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-5-ethyl-1,3-oxazole (0.83 g) was added 9:1 trifluoroacetic acid:water (3.56 ml), and the mixture was stirred at 20° C. for 3.5 hours. The solvents were removed in vacuo to give an orange/brown oil. This material was dissolved in pyridine (7 ml), under nitrogen, acetic anhydride (2.76 ml) was added and the mixture was stirred at 22° C. for 18 h. The mixture was concentrated in vacuo, diluted with ethyl acetate (50 ml) and washed with 1M HCl (50 ml), saturated aqueous sodium bicarbonate (3×50 ml) and brine (50 ml); the organic layer was dried (MgSO4) and the solvent evaporated to dryness to furnish the title compound as a brown/orange oil (0.854 g)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1.[C:15](Cl)(Cl)=[S:16]>O1CCOCC1.O>[F:14][C:10]1[CH:9]=[C:8]([C:3]2[C:2]([N:1]=[C:15]=[S:16])=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccccc1-c1cccc(F)c1
Solvent: C1COCCO1
Solvent: O
Product: Fc1cccc(-c2ccccc2N=C=S)c1

Procedure:
Reaction of 2-amino-3'-fluorobiphenyl (10 g) and thiophosgene (9.2 g) in a mixture of dioxane (15 ml) and water (70 ml) at ambient temperature for 1.5 hours yielded 3'-fluoro-2-biphenylylisothiocyanate as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14](C(O)=O)=[CH:13][N:12]3[CH:18]=[CH:19][N:20]=[C:11]3[C:10]=2[Cl:21])=[C:4]([Cl:22])[CH:3]=1.CC[N:25]([CH2:28]C)CC.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:37])=CC=1>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]3=[C:10]([Cl:21])[C:11]4[N:12]([CH:18]=[CH:19][N:20]=4)[CH:13]=[C:14]3[NH:25][C:28]2=[O:37])=[C:4]([Cl:22])[CH:3]=1
Reactant: O=C(O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=c1[nH]c2cn3ccnc3c(Cl)c2n1-c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of 7-(4-bromo-2-chlorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxylic acid (152 mg, 0.35 mmol) (HCl salt) in 5 ml EtOAc was added NEt3 (0.14 ml, 102 mg, 1 mmol) and the mixture was stirred for 5 min upon the suspension turned into a solution. The solvents were removed in vacuo and the residue was dried in oil-pump vacuo. This residue was suspended in 4.5 ml anhydrous toluene and it was ultrasonicated for 1 min. DPPA (0.1 ml, 124 mg, 0.44 mmol) was added and the suspension was heated with stirring under argon at 125° C. oil bath temperature to reflux for 5 h. The initial suspension turns into a dark solution after about 30 min. heating, and then a precipitate is formed after about another 30 min. reaction time. After 5 h the reaction mixture was cooled to room temperature and the volatiles were removed in vacuo. To the dark residue was washed with Et2O (ultrasonication) and again dried in oil pump vacuo. The crude product was used without purification for the next step in the same reaction vessel. Rf (CHCl3/MeOH 4:1)=0.5
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[C:6]([NH:8][C:9]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:26][C:10]=1[C:11]([NH:13][C:14]1[CH:15]=[N:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:18][CH:19]=1)=[O:12])=[O:7].[SH:39][C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=1)[C:43]([OH:45])=[O:44].C(N(CC)CC)C>CN(C)C=O.O>[C:20]1([C:17]2[N:18]=[CH:19][C:14]([NH:13][C:11]([C:10]3[CH:26]=[C:27]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[CH:28]=[CH:29][C:9]=3[NH:8][C:6]([C:5]3[CH:4]=[C:3]([CH:38]=[CH:37][CH:36]=3)[CH2:2][S:39][C:40]3[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=3)[C:43]([OH:45])=[O:44])=[O:7])=[O:12])=[CH:15][N:16]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Nc1ccc(N2CCCCC2)cc1C(=O)Nc1cnc(-c2ccccc2)nc1)c1cccc(CBr)c1
Reactant: O=C(O)c1cccc(S)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cccc(SCc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3C(=O)Nc3cnc(-c4ccccc4)nc3)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.7 %

Procedure:
To a solution of 2-(3-(bromomethyl)benzamido)-N-(2-phenylpyrimidin-5-yl)-5-(piperidin-1-yl)benzamide (120 mg, 0.23 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL) was added 3-mercaptobenzoic acid (42.12 mg, 0.27 mmol, 1.20 equiv) and triethylamine (46.08 mg, 0.46 mmol, 2.00 equiv) and the resulting solution was stirred for 3 h at room temperature. The mixture was diluted with 70 mL of water, extracted with 3×50 mL of ethyl acetate and the organic layers combined, dried over sodium sulfate, and concentrated under vacuum. The crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA to afford 24.7 mg (17%) of a light yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 10.94 (m, 2H), 9.23 (d, J=9.3 Hz, 2H), 8.36 (m, 2H), 8.12 (d, J=9 Hz, 1H), 7.95 (s, 1H), 7.85 (s, 1H), 7.73 (m, 2H), 7.45 (m, 9H) 4.39 (s, 2H), 3.33 (s, 4H), 1.72 (s, 6H). MS (ES, m/z): 644 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([N:12]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[C:7]([F:25])[C:6]=1[NH:26][CH:27]1[CH2:29][CH2:28]1)C.[OH-].[Na+].CO>O1CCCC1>[C:21]([O:20][C:18]([NH:17][CH:14]1[CH2:15][CH2:16][N:12]([C:8]2[C:9]([Cl:11])=[CH:10][C:5]([C:4]([OH:30])=[O:3])=[C:6]([NH:26][CH:27]3[CH2:28][CH2:29]3)[C:7]=2[F:25])[CH2:13]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)c1cc(Cl)c(N2CCC(NC(=O)OC(C)(C)C)C2)c(F)c1NC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(c2c(Cl)cc(C(=O)O)c(NC3CC3)c2F)C1
Yield: 91.3 %

Procedure:
A solution of 4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-5-chloro-2-cyclopropylamino-3-fluorobenzoic acid ethyl ester (Example 3k, 2.00 g, 4.50 mmol) and aqueous sodium hydroxide (2.0N, 20 mL) in tetrahydrofuran (20 mL), and methanol (20 mL) is refluxed for 1 hour. The solution is partially concentrated in vacuo, acidified to pH 6, and extracted with chloroform. The combined organic extracts are dried over Na2SO4, filtered, and concentrated to give the title compound (1.70 g). 1H NMR (CDCl3): δ 7.71 (d, 1H), 4.91–4.82 (bd, 1H), 4.40–4.25 (m, 1H), 3.77–3.69 (m, 2H), 3.53–3.34 (m, 2H), 3.00–2.88 (m, 1H), 2.24–2.15 (m, 1H), 1.90–1.80 (m, 1H), 1.46 (s, 9H), 0.72–0.54 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C1CNCCN1
Product: Brc1ccc(N2CCNCC2)nc1
Temperature: 25 °C
Yield: 68.5 %

Procedure:
A mixture of 2,5-dibromopyridine (10.00 g, 42.21 mmol) and piperazine (7.98 g, 92.79 mmol) were heated as a melt at 125° for 3 h. On cooling to room temperature the mixture was triturated with 10% methanol-dichloromethane and filtered. The filtrate was evaporated and the residue subjected to column chromatography (silica, 5-8% methanol-dichloromethane) to afford the 5-bromo-2-(1-piperazinyl)pyridine (7.00 g) as a beige solid δH (CDCl3) 2.75 (1H, br s), 2.97 (4H, m), 3.47 (4H, m), 6.52 (1H, d, J 9.1 Hz), 7.52 (1H, dd, J 9.1, 2.1 Hz), and 8.18 (1H, d, J 2.1 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1.[Br:19][C:20]1[C:21]([F:31])=[CH:22][C:23]([F:30])=[C:24]([S:26](Cl)(=[O:28])=[O:27])[CH:25]=1.N12CCN(CC1)CC2>C1COCC1>[Br:19][C:20]1[C:21]([F:31])=[CH:22][C:23]([F:30])=[C:24]([S:26]([N:6]([CH2:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:3]=2[O:2][CH3:1])[C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)(=[O:28])=[O:27])[CH:25]=1
Reactant: O=S(=O)(Cl)c1cc(Br)c(F)cc1F
Reactant: COc1ccc(CNc2ccncn2)c(OC)c1
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Br)c(F)cc2F)c(OC)c1
Yield: 58.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 14b by using the N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (0.50 g, 2.06 mmol) prepared in Example 14a, 5-bromo-2,4-difluorobenzenesulfonyl chloride (0.90 g, 3.08 mmol), 1,4-diazabicyclo[2.2.2]octane (0.46 g, 4.11 mmol) and THF (10 mL), to yield the title compound (0.60 g, 58%) as a colorless amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[S:5][C:6]=1[C:7](OC)=[O:8].[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[CH3:1][C:2]1[N:3]=[C:4]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)[S:5][C:6]=1[CH2:7][OH:8]
Reactant: COC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Temperature: -78 °C
Yield: 96.4 %

Procedure:
Methyl 4-methyl-2-[4-(trifluoromethyl)phenyl]]thiazole-5-carboxylate (20.0 g, 66.4 mmol) obtained from Example 1 was dissolved in anhydrous dichloromethane (500 ml) under nitrogen atmosphere, and the reaction mixture was cooled to −78° C. Diisobutyl aluminum hydride (DIBAL-H, 166 ml, 1.0 M hexane solution, 2.5 eq.) was slowly added to the solution for 30 minutes, and the mixture was reacted for another 30 minutes at the same temperature. Subsequently, the temperature was raised to −10° C. and reacted for 30 minutes. After completion of the reaction, an excessive diisobutyl aluminum hydride was removed by ethyl acetate. The resultant residue was extracted by 10% sulfuric acid and ethyl acetate, followed by drying over magnesium sulfate. The resultant mixture was evaporated under reduced pressure to thereby yield 17.5 g of the title compound (yield: 96.4%).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[CH3:32][O:33][CH2:34][C:35](Cl)=[O:36]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][N:29]([C:35](=[O:36])[CH2:34][O:33][CH3:32])[CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCNC1
Agent: Cl
Product: COCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f15) and commercially methoxyacetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1](=[O:12])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])OC(C)(C)C.[NH2:13][C@@H:14]([CH3:17])[CH2:15][OH:16].CC(C)(N)CN>O.C(O)(C)(C)C>[C:8]([O:7][C:1]([NH:13][C@@H:14]([CH3:17])[CH2:15][OH:16])=[O:12])([CH3:9])([CH3:10])[CH3:11]
Reactant: C[C@H](N)CO
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CC(C)(N)CN
Solvent: O
Solvent: CC(C)(C)O
Product: C[C@@H](CO)NC(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
Di-t-butyl carbonate (15.7 g.) was added to a solution of (+-(S)-2-amino-1-propanol (5.0 g.) in water (13.2 ml.) and t-butanol (6.6 ml.) at ambient temperature, and the mixture was stirred for 16 hr. at ambient temperature, 1,1-Dimethylethylenediamine (2 ml.) was added and the mixture was stirred at ambient temperature for 1 hr. The solution was poured into water (200 ml.) and extracted with diethyl ether (3×100 ml.). The ethereal extract was washed successively with 1 M-hydrochloric acid (50 ml.), saturated sodium carbonate solution (50 ml.) and brine (100 ml.), and then dried (MgSO4). The solvent was evaporated to give (S)-2-t-butoxycarbonylamino-1-propanol, m.p. 42°-3°.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:6])=[CH:3]\[C:4]#[N:5].[CH3:7][O:8][CH2:9][CH2:10]N.[CH3:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH:22]=O)[CH:20]=2)[NH:15][N:14]=1>C(O)C>[CH3:7][O:8][CH2:9][CH2:10][N:1]1[C:2]([CH3:6])=[C:3]([C:4]#[N:5])[CH:22]([C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[CH3:12])[C:3]([C:4]#[N:5])=[C:2]1[CH3:6]
Reactant: C/C(N)=C/C#N
Reactant: COCCN
Reactant: Cc1n[nH]c2ccc(C=O)cc12
Solvent: CCO
Product: COCCN1C(C)=C(C#N)C(c2ccc3[nH]nc(C)c3c2)C(C#N)=C1C
Temperature: 100 °C
Reaction time: 3 h
Yield: 6.3 %

Procedure:
164.2 mg (2 mmols) 3-aminocrotononitrile and 150.2 mg (2 mmols) 2-methoxyethylamine were dissolved in 8 mL ethanol and refluxed under argon for 3 hours. The solvent was distilled off under vacuum and the residue dissolved in 10 mL acetic acid. 160.2 mg (1 mmol) 3-methyl-1H-indazole-5-carbaldehyde (from Synthetic Preparation 10) were added. The mixture was stirred for 3 hours at 100° C. and then concentrated under vacuum. Purification by column chromatography gave 1-(2-methoxy-ethyl)-2,6-dimethyl-4-(3-methyl-1H-indazol-5-yl)-1,4-dihydro-pyridine-3,5-dicarbonitrile (22 mg) (Cpd. No. 310). 1H-NMR (DMSO-d6): δ=12.68 (br s, 1H), 7.51 (s, 1H), 7.47 (d, 1H), 7.26 (d, 1H), 4.40 (s, 1H), 3.86 (t, 2H), 3.52 (t, 2H), 3.37 (s, 3H), 2.50 (s, 3H; covered by DMSO), 2.25 (s, 6H) ppm.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].C(O)[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O.[CH2:36](O)[C@H:37]1[O:42][C@H:41]([O:43][C@H:44]2[C@H:49]([OH:50])[C@@H:48]([OH:51])[C@@H:47]([O:52][C@H:53]3[C@H:58]([OH:59])[C@@H:57]([OH:60])[C@@H:56]([OH:61])[O:55][C@@H:54]3[CH2:62][OH:63])[O:46][C@@H:45]2[CH2:64][OH:65])[C@H:40]([OH:66])[C@@H:39]([OH:67])[C@@H:38]1[OH:68].C[O-].[Na+]>C(Cl)(Cl)Cl.CO.O>[C@H:11]1([O:12][CH2:36][C@H:37]2[O:42][C@H:41]([O:43][C@@H:44]3[C@@H:45]([CH2:64][OH:65])[O:46][C@H:47]([O:52][C@H:53]([C@@H:54]([CH2:62][OH:63])[OH:55])[C@H:58]([OH:59])[C@@H:57]([OH:60])[CH:56]=[O:61])[C@H:48]([OH:51])[C@H:49]3[OH:50])[C@H:40]([OH:66])[C@@H:39]([OH:67])[C@@H:38]2[OH:68])[O:4][C@H:3]([CH2:2][OH:1])[C@@H:5]([OH:6])[C@H:7]([OH:8])[C@H:9]1[OH:10]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@H]3[C@H](O)[C@@H](O)[C@@H](O)O[C@@H]3CO)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: C[O-]
Agent: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C[C@H](O)[C@@H](O)[C@H](O[C@H]1O[C@H](CO)[C@@H](O[C@H]2O[C@H](CO[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O)[C@H](O)CO
Reaction time: 24 h

Procedure:
Pullulane52 (100 g) was dissolved in water (1 l) by heating and added to a solution of acetic acid (ca 15 ml) and sodium acetate (41 g) in water (5 l). The solution was adjusted to pH 5 and pullulanase and β-amylase (200 and 200000 units respectively) were added. The reaction mixture was stirred at 37° for 24 h (TLC: SiO2, acetone:isopropanol:0.1M lactic acid; 2:2:1) and then heated at 120° for 20 min (autoclave). The solution was concentrated (final volume: 1.5 l) and treated with ion-exchange resin (Duolite C-26 (H+); 0.5 l). The resin was washed with water and the combined water solutions (ca 4 l) were ultrafiltered (Millipore PSAC 14205 NMWL 1000) which gave a colorless solution. Freeze-drying gave 91 (72 g) contaminated with glucose, maltose and maltotriose. Pure 91 was obtained by treating 92 (1.0 g) with methanolic sodium methoxide (50 ml; from ~1 mg of sodium) at room temperature while monitoring the reaction by TLC (SiO2, chloroform:methanol:water 65:35:10, lower phase). After 24 h, the reaction mixture was neutralized with dry Duolite (H+) resin, filtered, concentrated and chromatographed (Waters Preppak-500/C:water) to give 91 (337 mg, 63%, >99.5% pure by HPLC). [α]D25 +165° (c 0.8, water). Lit.25 [α]D20 +179° (c 1.14, water). 1H-NMR (D2O, TSP) δ 5.40, 5.38 (2d, each 1H, J=3.8 and 3.5 Hz, H1' and H1"), 5.26 (d, ~0.3H, J=3.7 Hz, H1), 4.99 (d, 1H, J=3.7 Hz, H1"'), 4.68 (d, ~0.7H, J=7.9 Hz, H1). 13C-NMR (D2O, TSP) δ 102.6, 102.2, 100.8 (C1', C1∆, C1"'), 98.5, 94.7 (Cl), 79.9, 79.8, 79.6, 78.9, 77.3, 76.7, 76.0, 75.97, 75.8, 74.7, 74.6, 74.4, 74.3, 74.2, 74.1, 73.9, 72.7, 72.3, 72.1, 68.6, 63.4, 63.3, 63.2. The structure of 91 was confirmed by methylation analysis26.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[I:18][CH3:19]>C(#N)C>[I-:18].[N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[CH:11][C:12]2[CH:13]=[CH:14][N+:15]([CH3:19])=[CH:16][CH:17]=2)=[CH:8][CH:9]=1)=[N+:2]=[N-:3]
Reactant: CI
Reactant: [N-]=[N+]=Nc1ccc(C=Cc2ccncc2)cc1
Solvent: CC#N
Product: C[n+]1ccc(C=Cc2ccc(N=[N+]=[N-])cc2)cc1
Product: [I-]
Temperature: 25 °C
Reaction time: 36 h
Yield: 68 %

Procedure:
In a 100 mL round bottom flask equipped with a stirbar and covered with foil, 4-[2-(4-azido-phenyl)-vinyl]-pyridine (0.57 g, 2.56 mmol) was mixed with iodomethane (0.95 g, 6.7 mmol) in acetonitrile (20 mL) and stirred at room temperature for 36 hrs. A precipitate had formed and TLC showed a single spot, so the solution was placed in the refrigerator for 30 minutes and then filtered, rinsing with diethyl ether. The product was collected as a yellow powder (0.482 g). Diethyl ether was added to the filtrates and then placed in the refrigerator for 2 hrs. Orange/brown crystals formed which were collected by suction filtration (0.15 g). The total amount of product collected was 0.63 g (68% yield). mp 166.2-168.0° C. 1H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J=6.9 Hz, 2H), 8.20 (d, J=6.9 Hz, 2H), 8.01 (d, J=16.4 Hz, 1H), 7.80 (ddd, J=1.8, 2.6, 8.5 Hz, 2H), 7.49 (d, J=16.4 Hz, 1H), 7.26 (ddd, J=1.8, 2.6, 8.5 Hz, 2H), 4.26 (s, 3H). 13C NMR (100 MHz, DMSO-d6) 152.89, 145.56, 141.80, 140.08, 132.54, 130.31, 123.90, 123.28, 120.37, 47.39. λmaxCH3CN 373 nm (ε 4.07×104). IR νmax(cm−1) 2118 (N3).