Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][OH:7].[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[S:26][C:25]([C:27]5[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=5)=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.Cl>>[OH:1][CH2:2][CH2:3][N:4]([CH2:31][C:30]1[CH:29]=[CH:28][C:27]([C:25]2[S:26][C:19]3[C:18]([NH:17][C:13]4[CH:12]=[C:11]5[C:16](=[CH:15][CH:14]=4)[NH:8][CH:9]=[CH:10]5)=[N:23][CH:22]=[N:21][C:20]=3[CH:24]=2)=[CH:34][CH:33]=1)[CH2:5][CH2:6][OH:7]
Reactant: OCCNCCO
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Agent: Cl
Product: OCCN(CCO)Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from 2-(2-hydroxy-ethylamino)-ethanol and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. The product was converted to the mesylate salt analogous to example 17 being converted to the HCl salt. M.P. 110-127° C.; LC-MS: 460 (MH+); HPLC RT: 3.50 minutes.
Reaction SMILES: [N:1]([C:4]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:21])[CH:5]([O:10][C:11]1[N:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[N:12]=1)[C:6]([O:8]C)=[O:7])=[N+:2]=[N-:3].[OH-].[Na+]>CO.C1COCC1>[N:1]([C:4]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([CH3:21])[CH:5]([O:10][C:11]1[N:12]=[C:13]([O:19][CH3:20])[CH:14]=[C:15]([O:17][CH3:18])[N:16]=1)[C:6]([OH:8])=[O:7])=[N+:2]=[N-:3]
Reactant: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(C)(N=[N+]=[N-])c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(OC)nc(OC(C(=O)O)C(C)(N=[N+]=[N-])c2ccccc2)n1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
4.1 g (11 mmol) of methyl 3-azido-3-phenyl-2-(4,6-dimethoxypyrimidin-2-yl)oxybutyrate (Ex. 2) are dissolved in 100 ml of methanol/THF (1:1) and treated with 13.2 g (33 mmol) of 10% strength sodium hydroxide solution. The mixture is stirred for 6 hours at 50° C. and for 12 hours at room temperature and concentrated on a rotary evaporator. The residue is taken up in 100 ml of water and acidified to pH 2 using 10% strength hydrochloric acid. The resulting precipitate is filtered off with suction, washed with diethyl ether and dried.
Reaction SMILES: [CH3:1][CH2:2][C:3](=[O:9])[CH2:4][C:5](=[O:8])[CH2:6][CH3:7].[H-].[Na+].[I-].[Na+].[CH3:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[CH2:18]Br>CC(=O)CC>[CH3:14][C:15]1[CH:22]=[C:21]([CH:20]=[C:17]([CH3:18])[CH:16]=1)[CH2:23][CH:4]([C:3](=[O:9])[CH2:2][CH3:1])[C:5](=[O:8])[CH2:6][CH3:7]
Reactant: Cc1cc(C)cc(CBr)c1
Reactant: CCC(=O)CC(=O)CC
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCC(=O)C(Cc1cc(C)cc(C)c1)C(=O)CC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.2 %

Procedure:
A solution of 3,5-heptanedione (1.24 ml, 9.13 mmol) in 2-butanone (40 ml) was treated with sodium hydride (60% dispersion in oil) (402 mg, 10.05 mmol) (added in portions) and stirred at room temperature for 10 minutes. Sodium iodide (1.5 g, 10.05 mmol) and then by 3,5-dimethylbenzyl bromide (2.0 g, 10.05 mmol) were added to the reaction mixture which was stirred at room temperature for 18 hours. The solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water (×3). The organic phase was dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with cyclohexane followed by cyclohexane:ethyl acetate (40:1, by volume) to afford the title compound as a yellow oil (995 mg).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]2[NH:8][CH:9]=[N:10][C:6]=2[C:5]=1[CH3:13].Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[NH:26][N:25]=[C:24]([CH:27]3[CH2:29][CH2:28]3)[CH:23]=2)[CH:18]=[CH:17][N:16]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:27]1([C:24]2[NH:25][N:26]=[C:22]([NH:21][C:19]3[CH:18]=[CH:17][N:16]=[C:15]([N:2]([CH3:1])[CH2:3][C:4]4[CH:12]=[CH:11][C:7]5[NH:8][CH:9]=[N:10][C:6]=5[C:5]=4[CH3:13])[N:20]=3)[CH:23]=2)[CH2:29][CH2:28]1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: CNCc1ccc2[nH]cnc2c1C
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN(C)c2nccc(Nc3cc(C4CC4)[nH]n3)n2)ccc2[nH]cnc12
Temperature: 120 °C

Procedure:
A tube was charged with 264 (40 mg, 0.23 mmol), 53 (100 mg, 0.57 mmol), and DIPEA (0.3 ml) in IPA (3 mL), degassed, sealed and heated at 120° C. overnight. After removal of the solvent in vacuo, the crude was purified by preparative HPLC to afford 25 mg (29%) of I-95 as white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][CH:8]2[CH:10]([OH:11])[CH:4]([CH2:5][N:6]([CH3:12])[CH2:7]2)[CH2:3]1.[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:12][N:6]1[CH2:5][CH:4]2[CH:10]([O:11][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]([CH2:9][N:2]([CH3:1])[CH2:3]2)[CH2:7]1
Reactant: CN1CC2CN(C)CC(C1)C2O
Reactant: ClCc1ccccc1
Product: CN1CC2CN(C)CC(C1)C2OCc1ccccc1
Yield: 32.4 %

Procedure:
18.3 g of 3,7-dimethyl-3,7-diazabicyclo[3.3.1]nonane-9-ol are reacted with 13.5 g of benzyl chloride for 4 hours at room temperature as described in Example 1. 9 g (32.3%) of 3,7-dimethyl-9-benzyloxy-3,7-diazabicyclo[3.3.1]nonane are obtained; b.p.: 137°-148° C./10 Pa. The free base rapidly crystallizes upon standing; m.p.: 70°-75° C.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)O.C(OC[CH2:13][CH2:14][NH2:15])=C.C=O>C1(C)C=CC=CC=1>[O:6]1[C:5]2[CH:4]=[CH:3][CH:1]=[CH:8][C:7]=2[CH:13]=[CH:14][NH:15]1
Reactant: C=COCCCN
Reactant: Oc1ccc(O)cc1
Agent: C=O
Solvent: Cc1ccccc1
Product: C1=Cc2ccccc2ON1

Procedure:
Hydroquinone (8.23 grams, 75 mmole), 3-amino-1-propanol vinyl ether (15.1 grams, 150 mmole), and toluene (100 mL) were placed in a 250 mL round bottom flask. Paraformaldehyde (9.0 grams, equivalent to 300 mmole of formaldehyde) was then added to the flask. The flask was then equipped with a magnetic stir bar, a Dean-Stark trap, and condenser. The mixture was stirred and heated to reflux under an argon blanket. A total of 5.2 milliliters (96% of theory) of water was collected in the trap after two hours reflux. The reaction mixture had turned black by this point. The toluene reaction solution was washed with two 50 mL aliquots of 5% aqueous sodium hydroxide, followed by one 50 mL aliquot of water. The toluene solution was passed over a bed of neutral alumina and then evaporated to yield 3.8 grams (14% of theory) of a viscous, light brown liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]([C:21]([OH:23])=[O:22])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24]OC(OC)N(C)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]([C:21]([O:23][CH3:24])=[O:22])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1Cc2ccccc2N(C(=O)OCc2ccccc2)C1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: COC(=O)C1Cc2ccccc2N(C(=O)OCc2ccccc2)C1

Procedure:
1.87 g of N-benzyloxycarbonyl-1,2,3,4-tetrahydroquinoline-3(R,S)-carboxylic acid and 5 ml of N,N-dimethylformamide dimethyl acetal are heated at 80° C. in 20 ml of toluene for 4 h. The reaction mixture is concentrated and the residue is purified by means of FC (50 g of silica gel, mobile phase D): Rf (D)=0.29; MS: (M)+ =325.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:9][N:8]([C@@H:10]2[O:22][C@H:21]([CH2:23][O:24]C(=O)C)[C@@H:16]([O:17]C(=O)C)[C@H:11]2[O:12]C(=O)C)[C:7](=[O:28])[N:6]=1)(=[O:3])[CH3:2].C[O-].[Na+].O>CO>[C:1]([NH:4][C:5]1[S:9][N:8]([C@@H:10]2[O:22][C@H:21]([CH2:23][OH:24])[C@@H:16]([OH:17])[C@H:11]2[OH:12])[C:7](=[O:28])[N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(=O)n([C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)s1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)Nc1nc(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)s1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 5-acetamido-2-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-1,2,4-thiadiazol-3-one (4, 0.5 g, 0.0011 mole) in anhydrous methanol (25 ml) was added 1N sodium methoxide in methanol, till the pH of the solution was 8.5 and the resulting solution was stirred at ambient temperature for 2.5 hr. Within 40 min the secondary O-acetyl groups were removed and by the end of 2 hr all the O-acetyl groups were removed as judged by tlc. After the O-deacetylation was complete, the sodium ions were removed by stirring the reaction mixture with Amberlite IRC-50 (H+) resin (7.0 g, dry weight) for 15 min before the neutral solution, free from resin, was evaporated to dryness. The residual gum was chromatographed on a silica gel column (3 × 27 cms) using ethyl acetate:water:n-propanol (4:2:1), v/v, upper phase). The appropriate fractions were pooled, solvent evaporated and the residue crystallized from aqueous ethanol to yield 0.23 g (67.0%), m.p. 204°-205° (dec.); [α]D25 -50.1° (c 1.0, water); 1H nmr (Me2SO-d6) δ2.28 (s, 3H, --NAc), 5.65 (d, J=5.0 Hz, C1'H); uv λmax (pH 1) 235 nm (ε 10,600), 275 (3500); λmax (pH 7) 254 nm (ε 9900), 277 sh (5400); λmax (pH 11) 254 nm (ε 12,700), 277 sh (5,900).
Reaction SMILES: [C:1]([C:9]1[CH:21]=[CH:20][C:12]([CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])=[CH:11][CH:10]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>C(O)=O.[Pd].CO>[CH2:1]([C:9]1[CH:21]=[CH:20][C:12]([CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC#Cc1ccc(CC2CCCC2=O)cc1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: CCCCCCCCc1ccc(CC2CCCC2=O)cc1
Reaction time: 48 h
Yield: 91.1 %

Procedure:
Several drops of formic acid and catalytic amount 5% Pd/C was added to a 25 mL flask charged with 10 mL methanol and 1.25 g (4.75 mmol) of 2-(4′-(oct-1-ynyl)benzyl)cyclopentanone (4). The reaction vessel was flushed with H2, three times, and then mounted with a H2 balloon. After two days under the hydrogen atmosphere, the reaction mixture was exposed to nitrogen, and then filtered through a pad of silica gel. The silica gel plug was washed with ethyl ether (2×25 mL) and the combined organic layers were concentrated to a crude product providing a light yellow oil (1.24 g, 98%).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].CN(C)C=O.[H-].[Na+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:22]([O:1][C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:8])[F:9])[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1sc(C(F)(F)F)cc1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1sc(C(F)(F)F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 64 %

Procedure:
A mixture of 5B (5.0 g) and dimethylformamide (50 ml) is treated with sodium hydride (1.06 g). Benzylbromide (3.15 ml) was slowly added to the resulting reaction mixture and stirred at room temperature for 20 hours. The reaction mixture was poured into water. The mixture was extracted with diethyl ether twice. The combined organic phases were washed with water, dried and concentrated in vacuo. The crude product was chromatographed (hexane/dichloromethane, 1/1) to give the product as a white solid (4.5 g, 64%) with a melting point of 52-53.5° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]2[O:20][N:19]=[C:18]3[C:21]4[C:26]([CH2:27][CH2:28][C:17]=23)=[CH:25][C:24]([CH:29]=C)=[CH:23][CH:22]=4)[O:9][N:8]=1.C[N+]1([O-])CC[O:35]CC1.I([O-])(=O)(=O)=O.[Na+].O>C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]2[O:20][N:19]=[C:18]3[C:21]4[C:26]([CH2:27][CH2:28][C:17]=23)=[CH:25][C:24]([CH:29]=[O:35])=[CH:23][CH:22]=4)[O:9][N:8]=1
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1onc(-c2ccccn2)c1C(F)(F)F
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccc2c(c1)CCc1c-2noc1-c1onc(-c2ccccn2)c1C(F)(F)F
Temperature: 25 °C
Yield: 97.5 %

Procedure:
To a mixture of 3-(3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazol-5-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 63F, 0.098 g, 0.239 mmol) and a 50% aqueous solution of NMO (0.050 mL, 0.239 mmol) at room temperature was added a 4% aqueous solution of osmium tetroxide (0.075 mL, 9.58 μmol). The reaction mixture was stirred at room temperature over the weekend. The intermediate diol had an HPLC ret. time=2.66 min and an LCMS M+1=443.8. Sodium periodate (0.077 g, 0.359 mmol) was added to the homogeneous mixture followed by water (0.15 mL), and the reaction was stirred for 60 min. at room temperature. Concentration under reduced pressure afforded a tan solid residue that was then diluted with ethyl acetate (40 mL), washed with the water (10 mL), and washed with brine (10 mL). The organic layer was collected, and the aqueous layer was washed with ethyl acetate (40 mL). The combined organic layers were dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 3-(3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (0.096 g, 0.233 mmol, 97% yield) as a pale yellow solid. The product had an HPLC ret. time=3.00 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=411.9.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:20][C:21]1[C:22]([O:28][C:29]2[CH:40]=[CH:39][C:32]([O:33][CH:34]([CH3:38])[C:35](Cl)=[O:36])=[CH:31][CH:30]=2)=[N:23][CH:24]=[C:25]([Cl:27])[CH:26]=1>C1(C)C=CC=CC=1>[Cl:20][C:21]1[C:22]([O:28][C:29]2[CH:40]=[CH:39][C:32]([O:33][CH:34]([CH3:38])[C:35]([O:12][CH:10]([CH3:11])[CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:36])=[CH:31][CH:30]=2)=[N:23][CH:24]=[C:25]([Cl:27])[CH:26]=1
Reactant: CC(O)COCc1ccccc1
Reactant: CC(Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(COCc1ccccc1)OC(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Temperature: 0 °C

Procedure:
16.6 g of 1-benzyloxy-2-propanol and 10.6 g of triethylamine were dissolved in 200 ml of toluene, then cooled to 0° C. To this solution was dropwise added a solution of 34.7 g of 2-[4-(3,5-dichloro-2-pyridyloxy)phenoxy]-propionyl chloride in 80 ml of toluene at 0° to 5° C. with stirring. After the dropwise addition, the mixture was gradually heated and, at 40° to 50° C., it was stirred for one hour to complete the reaction. After cooling to room temperature, it was washed successively with 1% strength by weight sodium hydroxide aqueous solution and water, followed by drying. Upon distilling off toluene under reduced pressure, there were obtained 43.3 g of pale yellow, viscous, oily 1-methyl-2-benzyloxyethyl 2-[4-(3,5-dichloro-2-pyridyloxy)phenoxy]propionate. nD20 1.5710
Reaction SMILES: I[C:2]1[C:10]2[CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][CH2:6][C:5]=2[N:4]([CH3:13])[N:3]=1.C([Mg]Cl)(C)C.[CH2:19]([Sn:23]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])Cl)[CH2:20][CH2:21][CH3:22]>C1COCC1>[CH3:13][N:4]1[C:5]2[CH2:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][C:10]=2[C:2]([Sn:23]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:19][CH2:20][CH2:21][CH3:22])=[N:3]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1nc(I)c2c1CCC(C)(C)C2
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2c1CC(C)(C)CC2
Temperature: -16 °C
Reaction time: 0.33 h

Procedure:
In a round-bottomed flask, 3-iodo-1,5,5-trimethyl-4,5,6,7-tetrahydro-1H-indazole (140 mg, 0.48 mmol) was dissolved in THF (3 ml). The colorless solution was cooled to −16° C. (NaCl/ice bath) and isopropylmagnesium chloride (2.0M in THF, 0.27 ml, 0.54 mmol) was added dropwise. The reaction mixture was stirred at −16° C. for 20 min then tributylchlorostannane (0.15 ml, 0.55 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature over 1.5 h then quenched with saturated NH4Cl, diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated to afford 1,5,5-trimethyl-3-tributylstannanyl-4,5,6,7-tetrahydro-1H-indazole as a colorless oil which was used without further purification.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([C:10]([OH:12])=[O:11])=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[CH3:14]O>>[CH:1]1([C:4]2[C:5]([C:10]([O:12][CH3:14])=[O:11])=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ncccc1C1CC1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ncccc1C1CC1

Procedure:
830 mg of a hydrochloride salt of the 3-cyclopropylpyridine-2-carboxylic acid [121-3] was dissolved in 100 mL of 10% hydrochloric acid-methanol solution, and heated overnight under reflux. The reaction solution was concentrated under reduced pressure, a saturated aqueous solution of sodium hydrogen carbonate was added to the obtained residue, and was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and 363 mg of methyl 3-cyclopropylpyridine-2-carboxylate [121-4] was obtained as a white solid.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.C([O:36][CH2:37][C:38](Cl)=[O:39])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:37](=[O:36])[CH2:38][OH:39])[CH2:31][CH2:32]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)NC1CCN(C(=O)CO)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f6) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [N+](C1C=CC(C([O:10][C@H:11]([C@H:18]2[CH2:23][O:22][CH2:21][C:20](=[O:24])[NH:19]2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)=CC=1)([O-])=O.ClCCl.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:10][C@@H:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C@@H:18]1[NH:19][C:20](=[O:24])[CH2:21][O:22][CH2:23]1
Reactant: O=C1COC[C@H]([C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc2)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: O=C1COC[C@H]([C@@H](O)c2ccccc2)N1
Reaction time: 2 h
Yield: 87.4 %

Procedure:
(S)-((3R)-5-Oxomorpholin-3-yl)(phenyl)methyl 4-nitrobenzoate (Preparation 7, 1.2 g) is treated with dichloromethane (10 mL), ethanol (30 mL) and potassium carbonate (1.0 g). After 2 h, the reaction mixture is filtered and the filtered solid is triturated with ethanol-dichloromethane (3:1 v:v, 3×30 mL). The filtrates are combined and concentrated under reduced pressure. The resulting residue is adsorbed onto silica gel and purified by flash column chromatography (methanol/CH2Cl2, 1-6%) to afford 0.61 g of the title compound. Physical characteristics. 1H NMR (400 MHz, DMSO-d6) δ 7.55, 7.4-7.2, 5.65, 4.61, 3.92, 3.9-3.8, 3.65-3.55, 3.44.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:18])[CH2:8][N:9]2[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:25]=[C:24]([C:2]2[CH:11]=[C:10]3[C:5]([NH:6][C:7](=[O:18])[CH2:8][N:9]3[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)OC(=O)N1CC(=O)Nc2ccc(Br)cc21
Reactant: OB(O)c1cccc(Cl)c1
Product: CC(C)OC(=O)N1CC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21

Procedure:
The title compound was prepared according to the procedure for Example 5 from isopropyl 7-bromo-3-oxo-3,4-dihydroquinoxaline-1(2H)-carboxylate (6.3 g, 20 mmol), and 3-chlorophenyl boronic acid (3.2 g, 20 mmol). Off-white crystals (3.7 g, 49%): m.p. 174-176° C. 1H-NMR (DMSO-d6) δ 1.27 (d, J=6.4 Hz, 6H), 4.30 (s, 2H), 4.94 (sep, J=6.2 Hz, 1H), 7.04 (d, J=8.3 Hz, 1H), 7.50 ( m, 4H ), 7.61 (t, J=1.9 Hz, 1H), 7.86 (s, 1H), 10.79 (s, 1H), MS (APCI) m/z 345/347 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH:46]1([N:52]([CH3:58])[CH2:53][CH2:54][CH2:55][CH2:56][NH2:57])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>CN(C=O)C>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:57][CH2:56][CH2:55][CH2:54][CH2:53][N:52]([CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)[CH3:58])=[O:21])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1
Reactant: O=C(O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Reactant: CN(CCCCN)C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN(CCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1)C1CCCCC1
Reaction time: 18 h

Procedure:
The compound (120 mg) obtained in Example 2-2 was dissolved in anhydrous DMF (3.0 ml) and added with WSCI hydrochloride (103.3 mg) and HOBt (72.8 mg). Then, the solution was added with a solution of the compound (76.0 mg) obtained in Example 98-2 in DMF and stirred for 18 hours. After the reaction, the solvent was distilled off and the residue was then added with a 1 mol/l sodium hydroxide aqueous solution, followed by extraction with chloroform. The extract was washed with saturated saline solution and dried with magnesium sulfate, followed by distilling the solvent off. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol) and then treated with hydrochloric acid, thereby obtaining hydrochloride (20.4 mg) of the subject compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[O:31][C:30]([CH3:32])=[N:29][C:28]=1[C:33](O)=[O:34]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:33]([C:28]3[N:29]=[C:30]([CH3:32])[O:31][C:27]=3[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][CH3:19])=[O:34])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: COc1ccccc1-c1oc(C)nc1C(=O)O
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: COc1ccccc1-c1oc(C)nc1C(=O)Nc1ccn(Cc2ccc(C(C)=O)o2)n1

Procedure:
Following general procedure B followed by either C or D, 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(2-methoxy-phenyl)-2-methyl-oxazole-4-carboxylic acid. LC-MS-conditions 01: tR=0.90 min; [M+H]+=421.09.
Reaction SMILES: [Br:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[C:10]12(CS(O)(=O)=O)C(C)(C)C(C[CH2:16]1)C[C:11]2=O.C(N(CC)CC)C>CC(C)=O>[Br:1][CH2:2][C:3]1([CH2:8][OH:9])[CH2:6][O:7][C:10]([CH3:16])([CH3:11])[O:5][CH2:4]1
Reactant: OCC(CO)(CO)CBr
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC1(C)OCC(CO)(CBr)CO1
Temperature: 25 °C
Reaction time: 48 h
Yield: 159.8 %

Procedure:
423 mg (2.13 mmol equivalents) of 2-bromomethyl-2-hydroxymethyl-1,3-propanediol was dissolved in 1.0 mL of acetone, 247 mg (1.07 mmol equivalents) of 10-camphorsulfonic acid was added thereto, and the mixture was stirred at room temperature (25° C.) for 2 days. After completion of the reaction, triethylamine was added, the solvent was removed by distillation, and the obtained crude product was then purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=3/1) to give 409 mg (1.71 mmol equivalents) of 5-bromomethyl-2,2-dimethyl-5-hydroxymethyl-1,3-dioxane.