Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[N:8].[CH2:9]([Mg]Br)[CH3:10].O>CCOCC.O1CCCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([NH2:8])[CH2:10][CH2:9]1
Reactant: N#Cc1ccccn1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: NC1(c2ccccn2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 2-pyridinecarbonitrile (1.00 g, 9.60 mmol) in ether (30 mL) were added successively at RT titanium tetraisopropoxide (3.1 mL, 10.0 mmol) and 1.0 M of ethylmagnesium bromide in tetrahydrofuran (19 mL). After the mixture was stirred for 30 min, water (5.0 mL) was added. The mixture was extracted with diethyl ether. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to afford the crude product which was directly used in the next step without further purification.
Reaction SMILES: CS[C:3]([NH:8]CCSCC1OC(CN(C)C)=CC=1)=[CH:4][N+:5]([O-:7])=[O:6].[CH:22]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)C>[CH:22]1([NH:30][C:3]([NH2:8])=[CH:4][N+:5]([O-:7])=[O:6])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Reactant: NC1CCCCCCC1
Solvent: CCO
Product: NC(=C[N+](=O)[O-])NC1CCCCCCC1
Yield: 74.7 %

Procedure:
A solution of 1-(methylthio)-1-[2-[[[5-(dimethylamino) methyl-2-furanyl]methyl]thio]ethylamino]2-nitroethene (1.05 g, 3.2 mmol) and cyclooctyl amine (1.2 g, 9.5 mmol) in ethanol (20 ml) was stirred at 20° C. for 21 days. The solvent was then removed in vacuo and the residue was chromatographed on a column of alumina (using chloroform as eluant) to give N-[2-[[[5-dimethylamino)-methyl-2-furanyl]methyl]thio]ethyl]-N'-cyclooctyl-2-nitro-1,1-ethenediamine (0.51 g, 39%) as an oil. [NMR τ (CDCl3) -0.30 br (s, 1H), 3.46 (s, 1H), 3.85 (s, 2H), 6.20 (s, 2H), 6.56 (s, 2H), 6.30-6.90 (m, 3H), 7.15-7.30 (m, 2H), 7.75 (s, 6H), 8.00-8.70 (m, 14H)]. [Found [M+H]+ 411.2391; C20H35N4O3S requires [M+H]+ 411.2429.]
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[F:30])[NH2:26]>CCOC(C)=O>[Cl:22][C:23]1[CH:24]=[C:25]([NH:26][C:2]2[CH:3]=[C:4]([NH:8][CH:9]3[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]3)[N:5]=[CH:6][N:7]=2)[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2cc(Cl)ncn2)C1
Solvent: CCOC(C)=O
Product: Fc1ccc(Nc2cc(NC3CCCNC3)ncn2)cc1Cl
Temperature: 140 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
A mixture of tert-butyl 3-(6-chloropyrimidin-4-ylamino)piperidine-1-carboxylate (295 mg, 0.94 mmol) and 3-chloro-4-fluoroaniline (2.83 g, 19.4 mmol) was heated neat at 140° C. for 19 hours. Upon cooling, the melt was stirred in EtOAc and allowed to stand at room temperature for 1 hour. The precipitate was collected, washed with EtOAc and dried to give 256 mg (85%) of N4-(3-chloro-4-fluorophenyl)-N6-(piperidin-3-yl)pyrimidine-4,6-diamine, a grayish-violet amorphous solid. MS (APCI): (M+1)+=322.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:15]([CH3:17])[CH3:16])[C:8]([OH:14])=[C:9]([CH2:12][OH:13])[C:10]=1[CH3:11])([CH3:4])[CH3:3].[CH3:18][CH:19]1OC(C)OC(C)O1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[CH3:18][CH:19]1[O:14][C:8]2[C:7]([CH:15]([CH3:17])[CH3:16])=[CH:6][C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[C:10]([CH3:11])[C:9]=2[CH2:12][O:13]1
Reactant: Cc1c(C(C)(C)C)cc(C(C)C)c(O)c1CO
Reactant: CC1OC(C)OC(C)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(C(C)(C)C)cc(C(C)C)c2c1COC(C)O2
Temperature: 25 °C
Yield: 70.6 %

Procedure:
A mixture of 5-(1,1-dimethylethyl)-6-methyl-3-(1-methylethyl)-2-hydroxy-benzenemethanol (7.09 g, 0.03 mol), p-dioxane (150 mL), paraldehyde (13.2 g, 0.3 mol) and p-toluenesulfonic acid monohydrate (0.57 g, 0.003 mol) was heated at reflux for 1.5 hours. The mixture was cooled to 25° C., poured onto water (100 mL) and extracted with hexane (3×50 mL). The extracts were washed with saturated sodium bicarbonate solution (2×50 mL), water (4×50 mL), brine (50 mL) and dried (Na2SO4). Evaporation of solvents and distillation of the residue gave 5.56 g (71% yield, GLC purity 99%) of 2,5-dimethyl-6-(1,1-dimethylethyl)-8-(1-methylethyl)-4H-1,3-benzodioxin, bp 110°-120° C., 0.5 mm; 1H-NMR (CDCl3)δ 1.20 (6H, d, J=7 Hz), 1.40 (9H, s), 1.54 (3H, d, J=5 Hz), 2.20 (3 H, s), 2.9-3.5 (1H, m), 4.80 (2H, s), 5.07 (1H, q, J=5 Hz), 7.10 (1H, s); IR (film)νmax 2940, 1585, 1410 cm-1 ; MS m/e 262, 218, 203, 175, 161; UVλmax (ethanol) 225 (ε=6960), 281 (ε=2040).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][C@@H:14]([CH3:16])[CH2:13][C@H:12]1[C:17]1[NH:18][CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=2)[N:21]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][N:48]([C:51]2[CH:56]=[CH:55][C:54]([C:57](=[O:72])[NH:58][C:59]3[CH:64]=[C:63]([O:65][C:66]([F:69])([F:68])[F:67])[C:62](Br)=[CH:61][C:60]=3[F:71])=[CH:53][N:52]=2)[C@H:47]([CH3:73])[CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39].O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][N:48]([C:51]2[CH:56]=[CH:55][C:54]([C:57](=[O:72])[NH:58][C:59]3[C:60]([F:71])=[CH:61][C:62]([C:25]4[CH:26]=[CH:27][C:22]([C:20]5[N:21]=[C:17]([C@@H:12]6[CH2:13][C@H:14]([CH3:16])[CH2:15][N:11]6[C:9](=[O:10])[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:37])[CH:6]([CH3:8])[CH3:7])[NH:18][CH:19]=5)=[CH:23][CH:24]=4)=[C:63]([O:65][C:66]([F:69])([F:68])[F:67])[CH:64]=3)=[CH:53][N:52]=2)[C@H:47]([CH3:73])[CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(=O)Nc2cc(OC(F)(F)F)c(Br)cc2F)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc(-c2ccc(-c3cc(F)c(NC(=O)c4ccc(N5CCN(C(=O)OC(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 90 °C
Yield: 78.1 %

Procedure:
To a solution of [(S)-2-methyl-1-((2S,4S)-4-methyl-2-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (170 mg, 0.33 mmol) and (R)-4-[5-(4-bromo-2-fluoro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (192 mg, 0.33 mmol, Preparation 24) dissolved in toluene (2.1 mL) and water (0.8 mL) was added potassium carbonate (230 mg, 1.67 mmol). The reaction mixture was sparged with nitrogen, Pd(dppf)Cl2CH2Cl2 (25 mg, 0.03 mmol) was added and the reaction mixture was sparged with nitrogen and heated at 90° C. overnight. The reaction mixture was cooled to RT, filtered through a pad of Celite® and silica gel and washed with EtOAc. The filtrate was washed with water and brine to produce a brownish colored oil. The residue was purified by silica gel chromatography (24 g, 40% to 100% EtOAc/hexanes) to produce the title intermediate as a yellowish solid (227 mg, 78% yield). (m/z): [M+H]+ calcd for C44H52F4N8O7 881.39. found 881.4.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:8]=[C:7]([C:9]([O:11]C)=[O:10])[N:6]([CH3:13])[N:5]=1)[CH3:2].[OH-].[Na+]>CO>[CH2:1]([O:3][C:4]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[N:6]([CH3:13])[N:5]=1)[CH3:2]
Reactant: CCOc1cc(C(=O)OC)n(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1cc(C(=O)O)n(C)n1
Yield: 80.9 %

Procedure:
Using methyl 3-ethoxy-1-methyl-1H-pyrazole-5-carboxylate (2.59 g, 14.1 mmol), methanol (15 mL) and 8N aqueous sodium hydroxide solution (3.00 mL), and in the same manner as in Reference Example 58, the title compound (1.94 g, yield 81%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][O:7][C:8]2=[O:9])=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][O:7][CH:8]2[OH:9])=[CH:4][CH:3]=1
Reactant: O=C1OCc2ccc(Br)cc21
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: OC1OCc2ccc(Br)cc21
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 95.5 %

Procedure:
Step 1) To a solution of 6-bromophthalide (144, 550 mg, 2.58 mmol) in dichloromethane (20.0 mL) was slowly added DIBAL-H (2.7 mL, 1.0 M solution in hexane) at −78° C., and the reaction mixture was stirred for 1.5 h at −78° C. The resulting mixture was quenched with sat. Na2SO4 and allowed to warm to room temperature. To the mixture was added anhydrous Na2SO4, and the mixture was stirred for 12 h, then filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography to provide 6-bromo-1,3-dihydroisobenzofuran-1-ol (145, 530 mg, 96%) as yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19]Br)[NH:12][C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[N:10]1.Cl.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[C:33]([OH:35])=[O:34]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)[NH:12][C:13]([CH2:19][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH:28]2[C:33]([OH:35])=[O:34])=[C:14]1[C:15]([O:17][CH3:18])=[O:16]
Reactant: O=C(O)C1COCCN1
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: COC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 46.3 %

Procedure:
Methyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (4.11 g, 8.4 mmol) (The compound was synthesized according to the procedure as described in WO2010069147A) was reacted with morpholine-3-carboxylic acid hydrochloride (1.4 g, 8.4 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (2.1 g, 46%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][C:2]1([CH3:19])[C@@:6]([OH:8])([CH3:7])[CH:5]([CH2:9][OH:10])[O:4][C@H:3]1[N:11]1[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]1=[O:18].[C:20](Cl)(=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24].O>ClCCl>[C:20]([O:10][CH2:9][C@@H:5]1[C:6]([OH:8])([CH3:7])[C@:2]([F:1])([CH3:19])[CH:3]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]2=[O:18])[O:4]1)(=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CC1(F)[C@H](n2ccc(=O)[nH]c2=O)OC(CO)[C@@]1(C)O
Reactant: CCCCC(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CCCCC(=O)OC[C@H]1OC(n2ccc(=O)[nH]c2=O)[C@](C)(F)C1(C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
To a solution of 1-((2R,4R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3,4-dimethyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (about 0.30 g, 1.09 mmol) in dichloromethane (about 5 ml) was added a solution of valeroylchloride (about 0.33 ml, 2.70 mmol) in dichloromethane (about 5 ml) at about 0° C. and stirred at room temperature for overnight. Completion of the reaction monitored by thin-layer chromatography, water added to the reaction mixture and extracted with dichloromethane and the combined organic layers were washed with saturated sodium bicarbonate, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 2% methanol in dichloromethane to elude title compound (0.10 g) as a colorless solid. Yield: 27%; 1H NMR (300 MHz, CDCl3): δ 8.31 (bs, 1H), 7.39-7.35 (dd, 1H, J1=8.1 Hz, J2=8.4 Hz), 6.36 (d, 1H, J=22.5 Hz), 5.76-5.72 (dd, 1H, J1=8.1 Hz, J2=8.4 Hz), 4.58-4.52 (m, 1H), 4.40-4.36 (m, 1H), 4.26-4.20 (m, 1H), 2.64 (s, 1H), 2.40-2.35 (t, 2H), 1.65-1.59 (m, 2H), 1.44 (d, 3H, J=23.1 Hz), 1.37-1.25 (m, 5H), 0.95-0.90 (t, 3H); ES Mass: [M+Na]+: 381 (100%), [M+1]+ 359 (40%); IR cm−: 3504, 3145, 1710, 1676, 1560, 1265, 1180, 1039, 938, 824; HPLC: 99%.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH:4]([C:6]1[CH2:7][O:8][C:9]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:12][C:10]=2[CH:11]=1)=O>C(O)C.N1C=CC=CC=1>[CH:4](=[N:2][OH:3])[C:6]1[CH2:7][O:8][C:9]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:12][C:10]=2[CH:11]=1
Reactant: O=CC1=Cc2cc(Cc3cccnc3)ccc2OC1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=CC1=Cc2cc(Cc3cccnc3)ccc2OC1
Reaction time: 2.5 h
Yield: 84.1 %

Procedure:
Hydroxylamine hydrochloride was added to a mixed solution of 3.88 g (15.5 mmol) of 3-formyl-6-(3-pyridylmethyl)-2H-1-benzopyran in ethanol (35 ml) and pyridine (35 ml) at room temperature. The mixture was stirred for 2.5 hours was evaporated in vacuo and the residue was dispersed in chloroform-methanol (10:1). Then, after the organic layer was washed with water and brine, the solvent was evaporated in vacuo. The crystal precipitated during the evaporation of the solvent, was collected by filtration to obtain 3.46 g (yield=84.1%) of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:10][C:11]2[N:12]([C:14](=[O:17])[NH:15][N:16]=2)[N:13]=1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:25][C:26]([F:35])([F:36])[C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:15]2[C:14](=[O:17])[N:12]3[N:13]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[C:9]([C:18]4[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=4)=[CH:10][C:11]3=[N:16]2)=[CH:29][CH:28]=1
Reactant: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a solution of 6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (18 mg, 0.05 mmol) and 4-trifluoromethyl benzylbromide (18 mg, 0.075 mmol) in anhydrous DMF (0.5 mL)) at 70° C. was added solid K2CO3 (13.8 mg, 0.1 mmol). After addition, the reaction mixture was stirred at 70° C. for 30 min. Analysis by HPLC/MS indicated the starting material had been consumed. After cooling to room temperature, the reaction was diluted with water, and extracted with EtOAc (5 mL×3). The combined EtOAc extracts were washed with saturated aqueous NaCl, dried (Na2SO4), filtered and concentrated under reduced pressure. The obtained residue was purified using reverse phase preparative HPLC (Conditions: Phenomenex Luna 5 μ C18 21.2×100 mm; Eluted with 70% to 100% B, 8 min gradient, hold at 100% B for 6 min (A=90% H2O, 10% MeOH and B=10% H2O, 90% MeOH); Flow rate at 20 mL/min, UV detection at 220 nm) to afford 18 mg (70%) of the title compound as a yellow powder. LC/MS (method A): retention time=4.05 min, (M+H)+=515. 1H NMR (CDCl3, 400 MHz): δ 7.57-7.70 (m, 4H), 7.42-7.48 (m, 1H), 7.41 (s, 1H), 7.30-7.38 (m, 2H), 7.17-7.25 (m, 3H), 7.02 (d,J=8.0 Hz, 2H), 5.30 (s, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4]O.[BrH:10]>C(O)(=O)C>[OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][Br:10]
Reactant: OCC(CO)(CO)CO
Reactant: Br
Solvent: CC(=O)O
Product: OCC(CO)(CO)CBr
Reaction time: 3 h
Yield: 50 %

Procedure:
200 g (1.47 mol) of pentaerythritol (PE), 1.51 of glacial acetic acid and 17 ml of 48% HBr are refluxed for 1.5 h. A further 170 ml of 48% HBr are added and the reaction mixture is then boiled for another 3 h. The same procedure is repeated with the addition of 96 ml of HBr. The glacial acetic acid and water are then distilled off completely, 750 ml of 98% ethanol and 50 ml of 48% HBr are added to the viscous residue and approx. 500 ml of ethanol are removed by slow distillation. A further 750 ml of ethanol are subsequently added and then distilled off completely. After the addition of 500 ml of toluene, the solvent is distilled off and the same procedure is repeated. The viscous residue is boiled for several hours with 500 ml of dry ether, with stirring, until a white solid deposits. The solid is filtered off with suction, washed with dry ether, dried and recrystallized from chloroform/ethyl acetate=3:2. Yield: 50%. M.p.=75-76° C.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH:4]=O.[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])[CH3:8]>[O-2].[Zn+2]>[CH3:1][C:2](=[CH:3][CH:4]=[CH:8][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])[CH3:6]
Reactant: CC(=O)c1ccccc1
Reactant: CC(C)=CC=O
Agent: [O-2]
Agent: [Zn+2]
Product: CC(C)=CC=CC(=O)c1ccccc1
Yield: 87 %

Procedure:
50 Parts of 3,3-dimethylacrolein and 100 parts of acetophenone together with 10 parts of zinc oxide are kept for 3 hours at a temperature of 180° C under a pressure of 50 atmospheres. The reaction mixture is subjected to fractional distillation. 75.3 parts of 2-methyl-6-phenyl-2,4-hexadien-6-one (87% of theory based on 3,3-dimethylacrolein) is obtained at a conversion of 78% of theory. Boiling point: 107° to 110° C at 10116 4 mm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.N1C=CC=CC=1.[CH3:15][O:16][CH2:17][C:18](Cl)=[O:19].O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:18](=[O:19])[CH2:17][O:16][CH3:15])[CH:3]=1
Reactant: Nc1cc(Br)ccn1
Reactant: COCC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: COCC(=O)Nc1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.6 %

Procedure:
To a solution of 4-bromo-2-aminopyridine (173 mmol) and pyridine (347 mol) in 250 mL dichloromethane was added dropwise 2-methoxyacetyl chloride (208 mmol). The reaction mixture was stirred at room temperature for 3 h. Water was added and the reaction mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was washed with hexane to afford 35.0 g of N-(4-bromopyridin-2-yl)-2-methoxyacetamide (82% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[N:9][C:8]=1[C:18]([N:20]([CH2:42][CH:43]([CH3:45])[CH3:44])[C@H:21]1[CH2:26][C@@H:25]([C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])[CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]1)=[O:19].C(OCC)(=O)C.[ClH:52]>C(OCC)(=O)C>[ClH:52].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=[N:9][C:8]=1[C:18]([N:20]([CH2:42][CH:43]([CH3:45])[CH3:44])[C@H:21]1[CH2:26][C@@H:25]([C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])[CH2:24][NH:23][CH2:22]1)=[O:19]
Reactant: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCCc1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCOCC3)C2)nnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl (3S,5R)-3-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (235 mg) was dissolved in ethyl acetate (0.5 ml), 4N hydrogen chloride-ethyl acetate solution (0.5 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and the residue was dried under reduced pressure to give the object product (200 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3([CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[O:13][C:12]3[C:21]([CH3:28])=[C:22]([CH3:27])[C:23]([NH2:26])=[C:24]([CH3:25])[C:11]2=3)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>CO>[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:26][C:23]2[C:22]([CH3:27])=[C:21]([CH3:28])[C:12]3[O:13][C:14]4([CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]4)[CH:10]([C:7]4[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=4)[C:11]=3[C:24]=2[CH3:25])=[O:35])=[CH:32][CH:31]=1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C1(CCN(C)CC1)O2
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc(Cl)cc1)C(c1ccc(C(C)C)cc1)C1(CCN(C)CC1)O2
Yield: 58 %

Procedure:
By using 3-(4-isopropylphenyl)-1′,4,6,7-tetramethylspiro[benzofuran-2(3H),4′-piperidine]-5-amine and 4-chlorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 58%. Melting point: 293-295° C. (Methanol).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7](I)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[SH:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([NH:17][CH3:18])=[O:16]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([S:12][C:13]3[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=3[C:15]([NH:17][CH3:18])=[O:16])=[CH:8][CH:9]=2)[NH:4][N:3]=1
Reactant: CNC(=O)c1ccccc1S
Reactant: Ic1ccc2c(I)n[nH]c2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: CNC(=O)c1ccccc1Sc1ccc2c(I)n[nH]c2c1
Temperature: 70 °C
Yield: 78.1 %

Procedure:
3,6-diiodoindazole (250.00 g), 2-mercapto-N-methylbenzamide (118.48 g), Pd2(dba)3 (9.28 g), Xantphos (11.73 g), DMF (2.5 L, 10 mL/g), followed by CsOH were added sequentially to a 5 L four-neck flask equipped with a mechanical stirrer and a temperature probe. The reaction mixture was then stirred. The dark mixture was degassed three times by alternately connecting to house vacuum and then nitrogen. The mixture was heated to 70° C. over a period of 30 minutes and maintained at the same temperature for fours, at which time HPLC of the aliquot indicated that the 3,6-diiodoindazole was less than 3%. After cooling, the mixture was poured into a mixture of 7.5 L of water, 1.25 L of toluene and 1.25 L of CH2Cl2 in a 22 L extractor. The mixture was allowed to stir at ambient temperature overnight. A thick precipitate formed overnight. The mixture was filtered and the cake was sucked dry. The cake was further dried at 35° C. under house vacuum for six hours to afford 216 g of the final product. The mother liquor was then extracted with 1.5 L of EtOAc. After partitioning, the aqueous layer was discarded. The organic layer was washed twice each with 2 L of water and concentrated. The residue was treated with 250 mL of CH2Cl2 and stored overnight. A thick precipitate formed overnight. The mixture was filtered and the cake was sucked dry. The cake was dried at 35° C. under house vacuum overnight to afford 24.71 g of the final product. The combined yield was 241 g of the final product. The material showed satisfactory purity and was used in the next step without further purification.