Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: IC.Br[CH2:4]C1OC(C(F)(F)F)=CC=1.[OH:14][C:15]1[C:20]([C:21]#[N:22])=[CH:19][C:18]2[C:23]3([CH2:42][O:43][C:17]=2[CH:16]=1)[C:31]1[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=1)[N:25]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[C:24]3=[O:41].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1>>[CH3:4][O:14][C:15]1[C:20]([C:21]#[N:22])=[CH:19][C:18]2[C:23]3([CH2:42][O:43][C:17]=2[CH:16]=1)[C:31]1[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=1)[N:25]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[C:24]3=[O:41]
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: COc1ccc(CN2C(=O)C3(COc4cc(O)c(C#N)cc43)c3ccccc32)cc1
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Solvent: CI
Product: COc1ccc(CN2C(=O)C3(COc4cc(OC)c(C#N)cc43)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using iodomethane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 6-hydroxy-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, 6-methoxy-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile was obtained (62%): mp 207-208° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.27-7.20 (m, 3H), 7.10-6.99 (m, 2H), 6.90-6.83 (m, 4H), 6.56 (s, 1H), 5.07-4.74 (m, 4H), 3.90 (s, 3H), 3.78 (s, 3H); MS (ES+) m/z 412.9 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([O:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:17]([OH:19])=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1.[N:27]1[C:35]2[C:30](=[N:31][CH:32]=[CH:33][CH:34]=2)[S:29][C:28]=1[NH2:36].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>CN(C=O)C>[O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([O:20][CH:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[C:17]([NH:36][C:28]3[S:29][C:30]4[C:35]([N:27]=3)=[CH:34][CH:33]=[CH:32][N:31]=4)=[O:19])=[CH:12][CH:11]=2)(=[O:8])=[O:9])[CH2:3][CH2:2]1
Reactant: Nc1nc2cccnc2s1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Nc1nc2cccnc2s1)C(OC1CCOCC1)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Yield: 21.6 %

Procedure:
The compound of example A4 was obtained by similar method described in example A2 using 2-(4-morpholinosulfonylphenyl)-2-tetrahydropyran-4-yloxy-acetic acid (Preparation 11, 0.1 g, 0.25 mmol), thiazolo[5,4-b]pyridin-2-ylamine (0.050 g, 0.31 mmol), HOBt (0.042 g, 0.31 mmol), and EDCl (0.060 g, 0.31 mmol), N-methyl morpholine (0.065 g, 0.64 mmol) in DMF (5 mL) to provide the title compound (0.028 g).
Reaction SMILES: C[C:2]([CH2:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1)([CH2:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1)[C:3]([NH:5][C@@:6]([CH3:20])([C:17]([OH:19])=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4].[OH-].[Na+]>CO.O1CCOCC1.O>[C:33]1([CH2:32][CH:2]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:3]([NH:5][C@@:6]([CH3:20])([C:17]([OH:19])=[O:18])[CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[O:4])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: CC(Cc1cccc2ccccc12)(Cc1cccc2ccccc12)C(=O)N[C@](C)(Cc1c[nH]c2ccccc12)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: C[C@](Cc1c[nH]c2ccccc12)(NC(=O)C(Cc1cccc2ccccc12)Cc1cccc2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 96 h
Yield: 57.7 %

Procedure:
A solution of 4.24 g (7.6 mmol) of methyl bis-(1-naphthylmethyl)acetyl-(α-methyl-D-tryptophan) in 50 mL MeOH and 50 mL dioxane was treated with a solution of 1.0 g (25 mmol) of NaOH in 10 mL H2O and the solution left stirring at room temperature for 4 days. The solvent was removed under reduced pressure and the residue mixed with H2O and acidified to Congo red end point with dilute HCl. The crude product was collected and chromatographed on silica gel, eluting with CHCl3 : MeOH (95:5). There was obtained 2.37 g (57.8% yield) of the product as a solid foam. The structure was confirmed by NMR and mass spectroscopy.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([NH2:9])[N:3]=1.[CH3:10][C@H:11]1[NH:16][CH2:15][C@@H:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1.C([O-])(O)=O.[Na+].[C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=1[F:36])#[N:26]>O1CCOCC1.O.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.CCOC(C)=O>[NH2:9][C:4]1[N:5]=[C:6]([N:16]2[C@H:11]([CH3:10])[CH2:12][CH2:13][C@H:14]([C:17]([OH:19])=[O:18])[CH2:15]2)[CH:7]=[C:2]([C:30]2[CH:31]=[CH:32][C:27]([C:25]#[N:26])=[C:28]([F:36])[CH:29]=2)[N:3]=1
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 117 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
A mixture of 4,6-dichloro-2-pyrimidinamine (3 g, 18.3 mmol), (3S,6R)-6-methyl-3-piperidinecarboxylic acid (3.98 g, 20.12 mmol), and NaHCO3 (7.68 g, 91 mmol) in 1,4-dioxane (100 mL) and water (50 mL) was stirred overnight at 117° C. into a sealed tube. The reaction was allowed to cool to room temperature. LCMS showed that most of the starting material 4,6-dichloro-2-pyrimidinamine had been consumed. Then 4-cyano-3-fluorobenzeneboronic acid (3.32 g, 20.12 mmol) and Pd(Ph3P)4 (0.423 g, 0.366 mmol) were added, and the reaction mixture was stirred for 24 hours at 117° C. The mixture was poured into water (300 mL) and EtOAc (200 mL). At this moment the pH of the solution was 9. The compound stayed in the water layer. The water layer was separated from the organic layer. There was some black colored and yellow colored suspension in the water layer, which was filtered out. (They were not product). To the aqueous layer, 6N HCl was added dropwise to make the pH=4. A precipitate was formed. The precipitate was filtered, washed with water, and dried to afford the title compound (3.6 g) as a light yellow solid. LC-MS (ES) m/z=356 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=1)[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38]([C:40]1[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=1)#[N:39].Cl>CN(C)C=O>[CH2:1]([N:8]([C@@H:9]([CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=1)[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[C:44](=[O:45])[C:43]1[CH:47]=[CH:48][C:40]([C:38]#[N:39])=[CH:41][CH:42]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(OC[C@@H](CC(=O)OCc2ccccc2)NCc2ccccc2)c1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C(=O)N(Cc2ccccc2)[C@@H](COc2cccc(C#N)c2)CC(=O)OCc2ccccc2)cc1
Reaction time: 3 h

Procedure:
190 mg (0.47 mmol) of benzyl 3-(3R)-benzylamino-4-(3-cyanophenoxy)butyrate and 153 mg of triethylamine were stirred in 5 ml of dimethylformamide, and 70 mg (0.47 mmol) of 4-cyanobenzoyl chloride was added thereto under cooling with ice and stirred for 3 hours. 1 N hydrochloric acid was added thereto, followed by extraction with ethyl acetate. The extract was washed with 1 N sodium hydroxide and saturated saline and dried over magnesium sulfate anhydride, and the solvent was distilled off and the residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH:5]([O:28][CH2:29][CH3:30])[CH2:6][C:7]1[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[C:10]([O:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[O:21][C:22]=2[CH3:23])=[CH:9][CH:8]=1)C.[OH-].[Na+].CCOC(C)=O>C1COCC1.CCO>[C:24]([C:20]1[O:21][C:22]([CH3:23])=[C:18]([CH2:17][O:16][C:10]2[C:11]3[CH:15]=[CH:14][S:13][C:12]=3[C:7]([CH2:6][CH:5]([O:28][CH2:29][CH3:30])[C:4]([OH:31])=[O:3])=[CH:8][CH:9]=2)[N:19]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CCOC(=O)C(Cc1ccc(OCc2nc(C(C)(C)C)oc2C)c2ccsc12)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(Cc1ccc(OCc2nc(C(C)(C)C)oc2C)c2ccsc12)C(=O)O
Reaction time: 1 h
Yield: 94.6 %

Procedure:
0.125 g of the above prepared 3-[4-(2-tert-butyl-5-methyl-oxazol-4-ylmethoxy)-benzo[b]thiophen-7-yl]-2-ethoxy-propionic acid ethyl ester (0.281 mmol) was dissolved in 1.7 ml of THF/EtOH=1/1, treated with 0.840 ml of 1N NaOH (3 eq.), and kept at ambient temperature for 1.0 h. The reaction mixture was then poured onto crashed ice/AcOEt/HCl dil., the aqueous phase reextracted once more with AcOEt, the combined organic layers washed with water, dried over magnesium sulfate, and evaporated to dryness. Crystallization from hexane/AcOEt yielded finally 0.111 g of the title compound as white crystals of mp. 179–80°.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)=[CH:12][CH:11]=1
Reactant: OC1CCNCC1
Reactant: COc1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCC(O)CC2)cc1
Reaction time: 18 h
Yield: 80.1 %

Procedure:
0.97 g (0.00959 mol) of 4-hydroxypiperidine was dissolved in 20 ml of dimethylformamide and cooled to 0°. 1.93 g (0.0096 mol) of 4-methoxybenzyl bromide and 3.0 ml (0.0215 mol) of triethylamine were added under argon and the mixture was left to come to room temperature. It was stirred for 18 hrs., the solvent was distilled off and the residue was taken up in ethyl acetate. The organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated and the residue was chromatographed on silica gel with dicloromethane/methanol (19:1) as the eluent. 1.7 g (80%) of 1-(4-methoxy-benzyl)-piperidin-4-ol were obtained as a brown oil. MS: me/e=222 (C13H20NO2+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH2:17]([NH2:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:23][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[N:3]=1
Reactant: CCCCCCN
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: CCCCCCNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-(hexylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, n-hexylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: CNC[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:10][N:11](N=O)/[C:12](/[NH2:17])=[N:13]/[N+:14]([O-:16])=[O:15].[CH2:20](O)C>>[CH2:10]([N:11]([CH3:20])[C:12]([NH:13][N+:14]([O-:16])=[O:15])=[NH:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCO
Reactant: CN(N=O)/C(N)=N/[N+](=O)[O-]
Reactant: CNCc1ccccc1
Product: CN(Cc1ccccc1)C(=N)N[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 42 h

Procedure:
N-Methylbenzylamine (9.89 g, 0.082 mol) is added dropwise to a suspension of MNNG (10.0 g, 0.068 mol) in aqueous ethanol (1:1 ethanol:water, v/v) at 25° C. A gradual exotherm to 44° C. occurs over the next 15 minutes. After stirring for 42 hours at ambient temperature, the white slurry is filtered. The resultant white solid (7.13 g) is recrystallized from hexanes:ethanol to afford pure product (white crystals, 6.06 g, 43.0%, melting point 103° C. -107° C.).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:27])=[N:14][C:15]2[N:16]([N:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=2)[C:17]=1I)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]1[CH:30]=[C:31](B2OC(C)(C)C(C)(C)O2)[C:32]([CH3:39])=[C:33]2[C:38]=1[O:37][CH2:36][CH2:35][CH2:34]2.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.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>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:27])=[N:14][C:15]2[N:16]([N:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=2)[C:17]=1[C:31]1[C:32]([CH3:39])=[C:33]2[C:38](=[C:29]([F:28])[CH:30]=1)[O:37][CH2:36][CH2:35][CH2:34]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cc(F)c2c1CCCO2
Reactant: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(I)n2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(-c3cc(F)c4c(c3C)CCCO4)n2n1
Temperature: 100 °C
Yield: 82.4 %

Procedure:
A mixture of (S)-ethyl 6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (4.5 g, 9.20 mmol), 2-(8-fluoro-5-methylchroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.22 g, 11.04 mmol) and 2N Na2CO3 (9.20 mL, 18.39 mmol) in DMF (100 mL) was degassed and flushed with N2 for 30 min. Tetrakis(triphenylphosphine)palladium(0) (0.744 g, 0.644 mmol) was then added and the reaction was flushed with N2 for another 15 min. The mixture was then heated at 100° C. for 16 h. At this point LCMS indicated completion of reaction and appearance of desired product. After cooling to rt, water was added (50 mL) and the mixture was extracted with ether (2×200 mL). The organic phase was washed with brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was then purified by silica gel chromatography (5-60% EtOAc/hexane) to afford ethyl 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (4 g, 7.58 mmol, 82% yield) as mixture of atrope isomers (approx 10% of minor atrope isomer was present). 1H NMR (500 MHz, CDCl3) δ 7.10 (s, 1H), 6.87 (d, J=10.7 Hz, 1H), 5.00 (s, 1H), 4.41 (qd, J=7.1, 3.1 Hz, 2H), 4.35 (dd, J=5.2, 4.0 Hz, 2H), 4.14 (q, J=7.2 Hz, 2H), 2.80 (s, 3H), 2.79-2.73 (m, 2H), 2.23-2.15 (m, 2H), 1.82 (s, 3H), 1.41 (t, J=7.2 Hz, 3H), 1.22-1.19 (m, 4H), 1.18 (s, 9H). LCMS (M+H)=528.4.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([C:9]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)([CH2:13][NH:14][CH3:15])[CH2:10][CH:11]=[CH2:12])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:32](Cl)(=[O:36])[CH:33]([CH3:35])[CH3:34]>C(#N)C>[C:1]([O:5][C:6](=[O:24])[N:7]([C:9]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)([CH2:13][N:14]([C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH3:15])[CH2:10][CH:11]=[CH2:12])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C(=O)Cl
Reactant: C=CCC(CNC)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=CCC(CN(C)C(=O)C(C)C)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 64 %

Procedure:
tert-Butyl[1-(3,4-dichlorophenyl)-1-methylaminomethyl-3-butenyl]methylcarbamate (2.0 g) produced in Example 4 was dissolved in acetonitrile (40 mL). Under cooling with ice, triethylamine (1.49 mL) and isobutyryl chloride (1.12 mL) was added thereto. Under cooling with ice, the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate anhydrate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (n-hexane:ethyl acetate=3:1), to thereby give the title compound (1.53 g, 64%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[N:16]1([C:22]([C:24]2[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=2)=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:27]1[CH:26]=[CH:25][C:24]([C:22]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:23])=[CH:29][CH:28]=1)(=[O:5])=[O:4]
Reactant: O=C(c1ccc(O)cc1)N1CCOCC1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(OS(=O)(=O)C(F)(F)F)cc1)N1CCOCC1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
1.23 ml (7.24 mmol) of trifluoromethanesulphonic anhydride are slowly added dropwise to a solution, cooled to −10° C., of 1.0 g (4.83 mmol) of 4-(4-morpholinyl-carbonyl)phenol and 2.02 ml (14.48 mmol) of triethylamine in 20 ml of dichloromethane. The mixture is stirred at −10° C. for 30 min and then at 0° C. for 30 min. It is washed successively with 10% strength sodium bicarbonate solution, water and saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo, and the residue is dried under high vacuum. 1.71 g (94.6% of theory) of the title compound are obtained.
Reaction SMILES: C(C1[CH:8]=[CH:7][N:6]2[C:9]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[C:15]([N:22]5[CH2:27][CH2:26][CH:25]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24][CH2:23]5)[CH:16]=[CH:17][CH:18]=4)[N:13]=3)=[N:10][N:11]=[C:5]2[CH:4]=1)=C.C[N+]1([O-])CC[O:41]CC1.[CH3:45][C:46]([CH3:48])=[O:47]>O=[Os](=O)(=O)=O>[OH:47][CH:46]([C:48]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[C:15]([N:22]5[CH2:27][CH2:26][CH:25]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24][CH2:23]5)[CH:16]=[CH:17][CH:18]=4)[N:13]=3)=[N:10][N:11]=[C:5]2[CH:4]=1)[CH2:45][OH:41]
Reactant: CC(C)=O
Reactant: C=Cc1ccn2c(-c3ccc4cccc(N5CCC(CNC(=O)OC(C)(C)C)CC5)c4n3)nnc2c1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Product: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(-c4nnc5cc(C(O)CO)ccn45)nc23)CC1
Reaction time: 2 h

Procedure:
To tert-butyl (1-(2-(7-vinyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yl)piperidin-4-yl)methylcarbamate (68 mg, 0.14 mmol) in acetone (2 mL) was added OsO4 (178 mg, 0.014 mmol) (2% in tBuOH) and NMO (49 mg, 0.21 mmol) (50% in H2O). The reaction was then stirred for 2 hours, then concentrated and purified by flash column chromatography (20:1 Hexane/EtOAc), affording the desired product.
Reaction SMILES: [CH3:1][C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.C(O)(=O)C#CCCCCC.[CH:36]1([N:42]=[C:43]=[N:44][CH:45]2[CH2:50][CH2:49][CH2:48]CC2)CCCCC1>O1CCCC1>[CH3:1][N:42]([C:43]1[CH:48]=[CH:49][CH:50]=[CH:45][N:44]=1)[CH3:36]
Reactant: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCCCC#CC(=O)O
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Solvent: C1CCOC1
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 730 mg of radicicol, 701 mg of 2-octynoic acid, 15 ml of dry tetrahydrofuran, 1.03 g of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 611 mg of the title compound were obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:13]=3[O:12][C:11]2([CH3:21])[CH3:20])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[C:14]3[CH:15]=[C:16]([O:19][CH2:28][C:27]4[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)[CH:17]=[CH:18][C:13]=3[O:12][C:11]2([CH3:21])[CH3:20])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(C2c3cc(O)ccc3OC2(C)C)cc1
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(COc2ccc3c(c2)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Yield: 75 %

Procedure:
Using (4-isopropylphenyl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-ol and 4-methoxybenzyl chloride, the title compound was obtained in the same manner as in Example 1.
Reaction SMILES: [C:1]([Cl:4])(=O)[CH3:2].[N:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][C:21]([OH:23])=[O:22])=[N+]=[N-].O>C(O)C>[ClH:4].[NH2:5][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][C:21]([O:23][CH2:1][CH3:2])=[O:22]
Reactant: [N-]=[N+]=NCCOCCOCCOCCOCC(=O)O
Reactant: CC(=O)Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)COCCOCCOCCOCCN
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of anhydrous hydrogen chloride in ethanol was prepared by slow addition of acetyl chloride (100 mL) to anhydrous ethanol (500 mL), followed by stirring at room temperature for one hour. 3 (44 g) was added and the solution stirred for one hour. Water (1 L) was added and the solution extracted with methylene chloride (3×). The solvent was removed on a rotovap and the residue dissolved in ethanol. Activated charcoal was added and the mixture stirred for approximately half an hour after which it was filtered through celite. The solvent was then removed on a rotovap. The residue was dissolved in ethanol/water (50:50) (200 mL). Formic acid was added (16 g) followed by 10% palladium/carbon (2.7 g). The solution was warmed to 60° C. and stirred until evolution of gas had ceased. The mixture was filtered through celite. The filtrate was neutralized with aqueous sodium bicarbonate until samples diluted with water were neutral (pH˜7) by analysis with pH paper. The solvent was then removed on a rotovap. Residual water and salt were removed by filtration and azeotropic distillation with ethanol (2×), yielding crude 4 as a yellow oil (33 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH2:13][N:14]3C(=O)C4=CC=CC=C4C3=O)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.O.NN>C(O)C>[ClH:1].[NH2:14][CH2:13][C:11]1[O:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:9][N:10]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ncc(-c2ccc(Cl)cc2)o1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cl
Product: NCc1ncc(-c2ccc(Cl)cc2)o1
Yield: 154.5 %

Procedure:
A solution of 3.4 g of N-[5-(4-chlorophenyl)-2-oxazolyl]methylphthalimide and 0.55 g of 100% hydrazine hydrate in 50 ml of ethanol was heated at reflux for 1 hour. At the end of this period, the formed precipitate was filtered off, and the filtrate was evaporated to dryness in vacuo. The residue was shaken with 2N HCl - chloroform and the 2N HCl - layer was evaporated to dryness under vacuo. The residue was recrystallized from ethanol to give 1.9 g (78 percent) of 2-aminomethyl-5-(4-chlorophenyl) oxazole hydrochloride, M. P. 200° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)(=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: O=S(=O)(OCC1CCOCC1)C(F)(F)F
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: C1CCOC1
Product: COc1cn(C(CC2CCOCC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
1.65 g (4.41 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate, 1.64 g (6.61 mmol) of tetrahydro-2H-pyran-4-ylmethyl trifluoromethanesulphonate and 5.73 ml (5.73 mmol) of bis(trimethylsilyl)lithium amide (1M in THF) in 37 ml of THF were reacted according to General Method 7B. Purification by column chromatography (80 g silica cartridge, flow rate: 60 ml/min, cyclohexane/ethyl acetate gradient) gave the title compound. Yield: 1.57 g (73% of theory)