Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[C:8]2[C:21](=[CH:22][CH:23]=1)[CH2:20][C@:10]1([C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]1=[O:19])[CH2:9]2.[NH4+].[OH-:25]>O.OS(O)(=O)=O>[OH:25][C:6]1[CH:7]=[C:8]2[C:21](=[CH:22][CH:23]=1)[CH2:20][C@:10]1([C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]1=[O:19])[CH2:9]2
Reactant: [OH-]
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: O
Product: O=C1Nc2ncccc2[C@]12Cc1ccc(O)cc1C2
Temperature: 25 °C

Procedure:
A solution of sodium nitrite (275 mg, 3.98 mmol) in water (1.6 mL) was slowly added to a cooled mixture of (2R)-5-Amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (1.00 g, 3.98 mmol, Intermediate 1) in 10% H2SO4 (0.8 mL conc H2SO4+7.2 mL water) at 0° C. The ice bath was removed and the stirred reaction was allowed to warm to ambient temperature. The reaction was then placed into a 70° C. oil bath and heated to 100° C. Bubbling was observed and heating was continued until LCMS analysis showed a completed reaction. The reaction was slowly quenched/neutralized with concentrated aqueous NH4OH (about 2 mL) such that the pH was about 8 at the end of multiple sonication/heating cycles in order to produce a stable pH and a solid suitable for filtration. The solid was collected by filtration and washed with water. The solid was then air dried and chromatographed by first mixing with about twice the amount of silica and then dry loading on a silica gel column. The product was eluted with 10% MeOH/DCM. Pooling and concentration of the product containing fractions provided the title compound. MS: m/z=253 (M+1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[N:11][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([CH:34]=3)[CH2:19][CH2:20][C:21]3[CH:29]=[C:25]([NH:26][C:27]=1[N:28]=2)[CH:24]=[C:23]([C:30]([O:32]C)=[O:31])[CH:22]=3.O>C(#N)C.[OH-].[Na+]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[N:11][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([CH:34]=3)[CH2:19][CH2:20][C:21]3[CH:29]=[C:25]([NH:26][C:27]=1[N:28]=2)[CH:24]=[C:23]([C:30]([OH:32])=[O:31])[CH:22]=3
Reactant: COC(=O)c1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)c1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Yield: 36.6 %

Procedure:
A solution of methyl 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene-11-carboxylate trifluoroacetate (45 mg, 90.9 μmol) in acetonitrile (5 mL) and 2.0 M of sodium hydroxide in water (227 μL, 0.455 mmol) were stirred at 25° C. overnight. Purification by preparative LCMS gave the desired product as a white solid (16 mg, 48%). LCMS for C19H16ClN4O2 (M+H)+: m/z=367.1. 1H NMR (400 MHz, DMSO-d6): δ 9.33 (s, 1H), 9.28 (s, 1H), 8.12 (s, 1H), 8.01 (m, 1H), 7.86 (m, 1H), 7.71 (m, 1H), 7.58 (m, 1H), 7.11 (t, 1H), 6.91 (m, 1H), 6.82 (m, 1H), 2.93 (m, 2H), 2.87 (m, 2H).
Reaction SMILES: [C:1]([Si:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)Cl)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Br:24][CH2:25][C@H:26]([CH3:29])[CH2:27][OH:28].O>C1COCC1>[Br:24][CH2:25][C@H:26]([CH3:29])[CH2:27][O:28][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: C[C@H](CO)CBr
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](CBr)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyldiphenylchlorosilane (83 mL) and imidazole (30 g) were added to a solution of (R)-3-bromo-2-methyl-1-propanol (45 g) in THF (150 mL) under ice-cooling, and the reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 117 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([CH3:8])[CH2:5][CH2:4][C:3]1([CH2:11][OH:12])[CH:9]=[CH2:10].C(N(CC)CC)C.[CH3:20][C:21](OC(C)=O)=[O:22]>CN(C1C=CN=CC=1)C.CCOCC>[C:21]([O:12][CH2:11][C:3]1([CH:9]=[CH2:10])[CH2:4][CH2:5][C:6]([CH3:8])=[CH:7][CH:2]1[CH3:1])(=[O:22])[CH3:20]
Reactant: C=CC1(CO)CCC(C)=CC1C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CC1(COC(C)=O)CCC(C)=CC1C
Reaction time: 5 h
Yield: 86.7 %

Procedure:
To a solution of (2,4-dimethyl-1-vinylcyclohex-3-enyl)methanol (3.50 g, 21.1 mmol), triethylamine (3.83 g, 38 mmol) and a catalytic amount of DMAP in Et2O (30 ml) was added Ac2O (3.22 g, 31.6 mmol). The mixture was stirred for 5 h, poured on water and extracted with Et2O. The combined organic layers were washed with water and brine, dried and evaporated in vacuo. The residue was distilled bulb-to-bulb to yield (2,4-dimethyl-1-vinylcyclohex-3-enyl)methyl acetate (3.81 g, 86%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:25])[CH:3]=1.[CH3:26][O:27][C:28]1[C:33](B(O)O)=[CH:32][C:31]([CH3:37])=[CH:30][N:29]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:33]5[C:28]([O:27][CH3:26])=[N:29][CH:30]=[C:31]([CH3:37])[CH:32]=5)[CH:3]=[C:4]([CH3:25])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: COc1ncc(C)cc1B(O)O
Reactant: Cc1cc(Cl)nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)c1
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: COCCOC
Product: COc1ncc(C)cc1-c1cc(C)cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)n1
Temperature: 120 °C
Yield: 99.2 %

Procedure:
To a mixture of N-(6-chloro-4-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (60 mg, 0.16 mmol) and 2-methoxy-5-methylpyridin-3-ylboronic acid (41 mg, 0.25 mmol) in DME (2 mL) and Na2CO3 (2M, 0.165 mL, 0.32 mmol) was added Pd(PPh3)4 (9.5 mg, 0.008 mmol). The mixture was heated in microwave oven at 120° C. for 30 min. The reaction was re-partitioned between EtOAc and H2O and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were washed with brine and dried over MgSO4. After the removal of solvent, the residue was purified by column chromatography (0-20% EtOAc-Hexane) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-4,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (72 mg, 97%). 1H NMR (400 MHz, CDCl3) 7.98 (s, 1H), 7.96 (dd, J=0.7, 2.4 Hz, 1H), 7.77 (d, J=2.3 Hz, 1H), 7.68 (s, 1H), 7.48 (d, J=9.0 Hz, 1H), 7.23 (dd, J=1.7, 9.4 Hz, 2H), 7.10 (d, J=8.2 Hz, 1H), 3.96 (s, 3H), 2.40 (s, 3H), 2.26 (s, 3H), 1.77-1.70 (m, 2H), 1.19-1.11 (m, 2H). Retention time: 2.01 min; ESI-MS m/z calc. 453.4. found 454.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH2:7][C:8]([CH3:24])([CH3:23])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=3)[NH:10][C:11]=2[CH:12]=[C:13]([F:15])[CH:14]=1)=[O:4].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH2:7][C:8]([CH3:24])([CH3:23])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:17]=3)[NH:10][C:11]=2[CH:12]=[C:13]([F:15])[CH:14]=1)=[O:4]
Reactant: COC(=O)c1cc(F)cc2c1CC(C)(C)C(c1cccc(Br)c1)N2
Reactant: C1COCCN1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: COC(=O)c1cc(F)cc2c1CC(C)(C)C(c1cccc(N3CCOCC3)c1)N2
Temperature: 120 °C
Reaction time: 16 h
Yield: 78.7 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-7-fluoro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (6.0 g, 15.3 mmol), morpholine (13.3 mL, 153 mmol), copper(I) iodide (874 mg, 4.6 mmol), N,N-dimethylglycine hydrochloride (1.3 g, 9.2 mmol) and potassium carbonate (8.5 g, 61.2 mmol) in dimethyl sulfoxide (15 mL) was stirred at 120° C. for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 7-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (4.8 g, 80%) as a white solid which was used for next step without further purification: LC/MS m/e calcd for C23H27FN2O3 (M+H)+: 399.48, observed: 399.1.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:20][O:21][CH3:22])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[O:31])=[CH:26][CH:25]=1>>[CH:1]1([CH:7]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:31])=[CH:28][CH:29]=2)[C:9]2[C:10]([CH2:20][O:21][CH3:22])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: COCc1nn(-c2ccccc2)cc1C(O)C1CCCCC1
Product: COCc1nn(-c2ccccc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 39.3 %

Procedure:
Using cyclohexyl[3-(methoxymethyl)-1-phenyl-1H-pyrazol-4-yl]methanol (0.50 g) synthesized in Example 37(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.42 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.33 g, 39%) was obtained as a white solid.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[Cl:13][C:14]([Cl:19])(Cl)[C:15](Cl)=[O:16].COCCOC>C(OCC)C.[Zn]>[Cl:13][C:14]1([Cl:19])[C:15](=[O:16])[CH2:1][C:2]21[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]2
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C=C1CN(C(=O)OC(C)(C)C)C1
Agent: [Zn]
Solvent: CCOCC
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC2(CC(=O)C2(Cl)Cl)C1
Temperature: 10 °C
Reaction time: 14 h

Procedure:
Under an inert atmosphere, 7.728 g (118.19 mmoles) of zinc in nanopowder form are suspended in 100 ml of diethyl ether. 5.00 g (29.55 mmoles) of tert-butyl 3-methylene-azetidine-1-carboxylate (WO 2008124085) are added, then the medium is cooled to 10° C. A solution of 6.60 ml (59.09 mmoles) of trichloroacetyl chloride in ml of 1,2-dimethoxyethane is added drop by drop while maintaining the temperature of the reaction medium between 26 and 30° C. After stirring for 14 hrs at ambient temperature, the medium is filtered over celite, the celite is copiously rinsed with diethyl ether and the filtrate is partially concentrated under reduced pressure. The crude reaction product thus obtained is used as such in the following stage.
Reaction SMILES: C(O[CH:4](OCC)[N:5]([CH3:7])[CH3:6])C.[Cl-:11].[CH3:12][N:13]([CH3:39])[C:14]1[CH:38]=[CH:37][C:17]([CH:18]=[N:19][N+:20]2[CH:24]=[CH:23][N:22]([N:25]=[CH:26][C:27]3[CH:32]=[CH:31][C:30]([N:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=3)[C:21]=2[CH3:36])=[CH:16][CH:15]=1.CCOCC>CN(C)C=O>[Cl-:11].[CH3:35][N:33]([CH3:34])[C:30]1[CH:31]=[CH:32][C:27]([CH:26]=[N:25][N+:22]2[CH:23]=[CH:24][N:20]([N:19]=[CH:18][C:17]3[CH:16]=[CH:15][C:14]([N:13]([CH3:12])[CH3:39])=[CH:38][CH:37]=3)[C:21]=2[CH:36]=[CH:4][N:5]([CH3:7])[CH3:6])=[CH:28][CH:29]=1
Reactant: Cc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Reactant: CCOC(OCC)N(C)C
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(C)C=Cc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Reaction time: 96 h

Procedure:
73.5 g of N,N-dimethylformamide diethyl acetal are added to 20.5 g of 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-methylimidazolium chloride in 400 ml of dry dimethylformamide. After stirring at 50° for 4 days, the mixture is left to cool. Then, 250 ml of ether are added thereto and the product is removed by filtration and is recrystallized from dry ethanol. There is obtained 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-[2-(dimethylamino)vinyl]imidazolium chloride of melting point 265° (decomposition).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]([CH3:24])([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH:16]2[CH2:20][NH:19][C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][C:8]=1[CH3:23])[CH3:5].[C:26]1([C:32]2[CH:39]=[CH:38][C:35]([CH2:36]Cl)=[CH:34][CH:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:32]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:39]=[CH:38][C:35]([CH2:36][N:19]2[CH2:20][CH:16]([CH2:15][CH2:14][CH2:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][C:4]([CH3:24])([CH3:5])[C:3]([OH:25])=[O:2])=[C:8]([CH3:23])[CH:9]=3)[N:17]([CH3:22])[C:18]2=[O:21])=[CH:34][CH:33]=1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)C(C)(C)Oc1ccc(CCCC2CNC(=O)N2C)cc1C
Product: Cc1cc(CCCC2CN(Cc3ccc(-c4ccccc4)cc3)C(=O)N2C)ccc1OC(C)(C)C(=O)O

Procedure:
The titled compound was prepared using 2-Methyl-2-{2-methyl-4-[3-(3-methyl-2-oxo-imidazolidin-4-yl)-propyl]-phenoxy}-propionic acid methyl Ester (0.112 g, 0.322 mmole) and 4-phenyl benzyl chloride (0.078 g, 0.186 mmole) to produce an oil (0.054 g, 34%). Mass [EI+] 501 (M+H)+, [EI−] 499 (M−H)−.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[S:6].Cl.I[CH3:18].[OH-].[Na+]>O.C(O)C>[NH2:1][CH2:2][CH2:3][NH:4][C:5](=[N:7][C:8]1[C:9]([Cl:15])=[CH:10][CH:11]=[CH:12][C:13]=1[Cl:14])[S:6][CH3:18]
Reactant: CI
Reactant: NCCNC(=S)Nc1c(Cl)cccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSC(=Nc1c(Cl)cccc1Cl)NCCN

Procedure:
A solution of 12.68 g. of 1-(2-aminoethyl)-3-(2,6-dichlorophenyl)thiourea in 80 ml. of ethanol, 4.0 ml. of concentrated hydrochloric acid and 12 ml. of iodomethane was refluxed for 2 hours. On cooling, the mixture was poured onto 200 ml. of water and sufficient 4N sodium hydroxide was added to bring the pH to 11. The aqueous solution was extracted 3 × 150 ml. of methylene chloride, and the combined organic layers were washed 1 × 100 ml. of water, dried over potassium carbonate and concentrated. The resulting gum gave a solid on standing, i.e., 1-(2-aminoethyl)-3-(2,6-dichlorophenyl)-2-methylthiopseudourea, m.p. 74°-79°, whose spectral data were consistent with the assigned structure. The material was too labile for purification and was acidified with hydrochloric acid and crystallized from ethanol-ether to give 14.10 g. (84%) of 1-(2-aminoethyl)-3-(2,6-dichlorophenyl)-2-methylthiopseudourea dihydrochloride, m.p. 179°-184°. Two crystallizations from ethanol-ether gave an analytical sample, m.p. 179°-182°.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13](Br)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][O:19][CH3:20])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)=[O:23].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCO.O.C(OCC)(=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]12([C:11]3[CH:12]=[C:13]([C:27]4[CH:28]=[CH:29][C:24]([CH:22]=[O:23])=[CH:25][CH:26]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][O:19][CH3:20])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COCOc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Reactant: O=Cc1ccc(B(O)O)cc1
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: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COCOc1ccc(-c2ccc(C=O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Yield: 77.1 %

Procedure:
A mixture of 3-(1-adamantyl)-4-methoxymethoxy-bromobenzene (8.48 g, 24.16 mmol), 4-formylphenylboronic acid (3.99 g, 26.57 mmol) and potassium carbonate (10.02 g, 72.47 mmol) in 300 mL of toluene:EtOH (4:1) and water (15 mL) was degassed with argon for 30 minutes. Tetrakis(triphenylphosphine)palladium(0) (2.79 g, 2.41 mmol) was added and the mixture heated at reflux for 14 hours. The solution was cooled to room temperature, diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified on silica gel (eluent: hexane:ether, 95:5) to give 7.01 g of 4-[3-(1-adamantyl)-4-methoxymethoxyphenyl]benzaldehyde (78%) as a solid. 1H NMR (300 MHz; CDCl3): δ 1.80 (s, 6H), 2.10–2.17 (m, 9H), 3.55 (s, 3H), 5.29 (s, 2H), 7.20 (d, J=8.4 Hz, 1H), 7.44 (dd, J1=8.7 Hz, J2=2.4 Hz, 1H), 7.52 (d, J=2.4 Hz, 2H), 7.72 (d, J=8.4 Hz, 2H), 7.92 (d, J=7.8 Hz, 2H), 10.03 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2.[C:14](Cl)(=[O:18])[CH:15]([CH3:17])[CH3:16]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[CH2:9][CH2:8]2
Reactant: COc1cccc2c1CC(N)CC2
Reactant: CC(C)C(=O)Cl
Product: COc1cccc2c1CC(NC(=O)C(C)C)CC2
Yield: 71 %

Procedure:
Using a procedure similar to that described in Example 1, 0.22 g of 8-methoxy-2-amino-tetralin yielded 0.18 g (71%) of 8-methoxy-2-iso-butyramido-tetralin following treatment with iso-butyryl chloride.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[C:6]([O:9][C@@H:10]1[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:14]([O:20][C:21](=[O:23])[CH3:22])[C@@H:13]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[O:12][C@@H:11]1Br)(=[O:8])[CH3:7].O.C(OC(=O)C)(=O)C>CCOCC.N1C=CC=CC=1.C(O)(=O)C>[C:6]([O:9][C@@H:10]1[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:14]([O:20][C:21](=[O:23])[CH3:22])[C@@H:13]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[O:12][C@H:11]1[CH2:3][CH:2]=[CH2:1])(=[O:8])[CH3:7]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C=CC[Mg]Br
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: C=CC[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of allyl magnesium bromide (100 mL, 100 mmol, 1.0 M in ether,) at 0° C. was added dropwise 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (4.45 g, 10.82 mmol) in ether (60 mL) over a period of 1 hr. After completion of the addition, the mixture was allowed to warm up and stirred at rt overnight. To the resulting mixture was carefully added water (200 mL) and followed by the addition of acetic acid to dissolve magnesium salts. Th organic layer was separated and concentrated. The residue was treated with acetic anhydride (70 mL, 740 mmol) and pyridine (100 mL). After stirring at rt overnight, the mixture was concentrated and the residue taken up in EtOAc (200 mL) and washed with sat'd NaHCO3 (5×300 mL), dried over MgSO4, filtered and evaporated. The residue was purified by flash chromatography on silica gel (120 g, eluting with 0-100% EtOAc in hexanes) to give the title compound. 1H NMR (CDCl3) δ 2.00 (s, 3H), 2.03 (s, 3H), 2.04 (s, 3H), 2.09 (s, 3H), 2.26-2.37 (m, 2H), 3.51 (m, 1H), 3.65 (m, 1H), 4.10 (dd, J=12.2, 2.2, 1H), 4.24 (dd, J=12.2, 5.0, 1H), 4.93 (t, J=9.4, 1H), 5.07 (m, 2H), 5.09 (s, 1H), 5.17 (t, J=9.4, 1H), 5.83 (m, 1H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11](Cl)=[C:12]([F:14])[CH:13]=1)(=[O:3])[CH3:2].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11]([C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)=[C:12]([F:14])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cnc(Cl)c(F)c1
Reactant: OB(O)c1cccnc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cnc(-c2cccnc2)c(F)c1

Procedure:
By carrying out the operation analogously to example 213, starting from 6-chloro-5-fluoro-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation XI, and 3-pyridineboronic acid, the desired product is obtained and is used directly in the deacetylation stage.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].[C:13](=S)=[S:14].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]2[O:5][C:13]([SH:14])=[N:2][CH:3]=2)=[CH:7][CH:8]=1
Reactant: NCC(=O)c1ccc(Cl)cc1
Reactant: S=C=S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Sc1ncc(-c2ccc(Cl)cc2)o1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 172.9 %

Procedure:
2-amino-1-(4-chlorophenyl)ethanone hydrochloride (0.80 g, 3.88 mmol) and carbon disulfide (0.47 mL, 0.59 g, 7.76 mmol) was suspended in ethanol (10 mL). To this was slowly added a solution of sodium carbonate (0.44 g, 4.08 mmol) in water (4 mL) at ambient temperature. After heating to 80° C. ext. temp. for 18 h the cold mixture was filtered. The filtrate was diluted with acetic acid (40 mL) and stirred for 15 min. at room temperature. Evaporation of the solvents in vacuo gave 1.42 g of a crude 5-(4-chlorophenyl)oxazole-2-thiol which was of ca. 61% purity (HPLC-MS) and used as is in the next step. The crude oxazole-2-thiol compound (1.42 g, max. 3.88 mmol) was suspended in phosphorous oxychloride (5 mL). To this was added dropwise triethyl amine (1.15 mL, 0.84 mg, 8.27 mmol) and the mixture heated to 105° C. ext. temperature for 4 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with aq. sat. bicarbonate (100 mL) and water (50 mL). Drying (sodium sulfate) and concentration in vacuo yielded crude product (615 mg), which was purified by column chromatography (SiO2, 5-40% ethyl acetate in heptanes) to give pure 2-chloro-5-(4-chlorophenyl)oxazole (105 mg, 0.49 mmol, 13%, purity 96% HPLC-MS).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:17][NH:18][C:19]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=3)=[O:20])[CH3:16])[C:10]=2[OH:31])[CH:5]=[CH:6][C:7]=1[CH3:8].CO.[OH-].[Na+].Cl>O>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:17][NH:18][C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=3)=[O:20])[CH3:16])[C:10]=2[OH:31])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C)c(C)c3)c2O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=NNC(=O)c1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc(C)c(C)c2)c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.4 %

Procedure:
To methyl 4-[(2-{1-[5-(3,4-dimethylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethylidene}hydrazino)carbonyl]benzoate (0.051 mmol, 21.6 mg), methanol (2.0 mL) was added, and 1 M aqueous sodium hydroxide (5 eq., 0.257 mL) was added at room temperature. After 30 minutes of stirring at room temperature and 1.5 hours of stirring at 60° C., the reactor was cooled to room temperature, and 1 M hydrochloric acid (5 eq., 0.257 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump to give the desired product as a yellow solid (17.5 mg, yield 84%).