Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[B:16]1[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]1)(C)C>>[C:1]1([N:7]2[C:11]([B:16]3[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]3)=[CH:10][CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-n2cccn2)cc1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Product: CC1(C)OB(c2ccnn2-c2ccccc2)OC1(C)C

Procedure:
The title compound, brown solid (2.0 g, 76%), MS (ISP) m/z=271.6 [(M+H)+], mp 132° C., was prepared in accordance with the general method of intermediate A from commercially available 1-phenyl-1H-pyrazol (1.40 g, 9.71 mmol) and commercially available 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([OH:10])=[O:9])[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:18](Cl)(=O)C(Cl)=O>ClCCl>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([O:10][CH3:18])=[O:9])[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Solvent: ClCCl
Product: COC(=O)c1c(C)n(C)n(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
2,3-dimethyl-5-oxo-1-phenyl-2,5-dihydro-1H-pyrazole-4-carboxylic acid (7.55 g, 33 mmol) was dissolved in dichlormethane (145 ml) and oxalyl chloride (4.1 ml, 46 mmol) was added via syringe over about 10 minutes, resulting in vigorous bubbling. After stirring at room temperature for about 30 minutes, the reaction was cautiously quenched with MeOH (100 ml). The methanol was added slowly at first as vigorous gas evolution was observed. The reaction was stirred at room temperature for 1 hour, concentrated, and then partitioned between dichlormethane (125 ml) and saturated sodium bicarbonate (125 ml). More dichlormethane and saturated sodium bicarbonate were added, and the layers of the biphasic, homogeneous solution were separated. The aqueous phase was extracted with dichlormethane (3×100 ml), and the organic phases were collected, dried over sodium sulfate, filtered, and concentrated to give desired methyl 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylate (7.82 g, 79% purity by HPLC, 25 mmol, 77% yield). MS (ESI pos. ion) m/z: 247 (MH+). Calc'd exact mass for C13H14N2O3: 246.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:11]([C:13]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1.[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][CH2:32]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][CH2:32][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)=[C:11]([C:13]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2[nH]c(-c3ccc(O)cc3)nc2C(=O)Nc2nccs2)cc1
Reactant: CN(C)CCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccc(-c2[nH]c(-c3ccc(OCCCN(C)C)cc3)nc2C(=O)Nc2nccs2)cc1

Procedure:
2-(4-Hydroxyphenyl)-5-(4-methylphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide, 3-dimethylaminopropanol, triphenyl-phosphine and diethyl azodicarboxylate are reacted and treated in the same manner as in Example 24 to give 2-(4-(3-dimethylamino-propyloxy)phenyl)-5-(4-methylphenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1.[C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)#[N:21]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:11]=[C:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:26]3[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=3)[C:20]#[N:21])[CH:10]=2)[CH2:6][C:7]21[CH2:12][C:13]1[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:19]2
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=C1c2cc(Br)ccc2CC12Cc1ccccc1C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2ccc3c(c2)C(=O)C2(Cc4ccccc4C2)C3)c1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 10.1 %

Procedure:
6-Bromo-1′,3′-dihydro-2,2′-spirobi[inden]-1(3H)-one (314 mg, 1 mmol), 3-cyanophenylboronic acid (294 g, 2 mmol) in [1,4]-dioxane (12 mL), Cs2CO3 (2 N, 3.2 mL), then Pd(PPh3)2Cl2 (5 mg, 0.01 mmol) was added under Ar2, the mixture was stirred at 100° C. for 5 minutes under microwave. The reaction mixture was concentrated in vacuo to give the residue, which was purified by TLC to give 3-(1-oxo-1,1′,3,3′-tetrahydro-2,2′-spirobi[indene]-6-yl)benzonitrile (34 mg, 10%). 1H-NMR (CDCl3): 3.00 (d, 2H), 3.33 (s, 2H), 3.62 (d, 2H), 7.31 (m, 3H), 7.67 (m, 2H), 7.78 (m, 1H), 7.96 (m, 2H), 8.02 (m, 1H), 8.11 (m, 1H).
Reaction SMILES: [N:1]1[C:11]2[C:10](=O)[CH2:9][CH2:8][C:7](=[O:13])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:14]1([NH:20][NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(=O)C.[Na+].[K+].[Br-]>C(O)(=O)C>[C:14]1([NH:20][N:21]=[C:10]2[CH2:9][CH2:8][C:7](=[O:13])[NH:6][C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:11]2=3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCC(=O)c2ncccc2N1
Reactant: NNc1ccccc1
Agent: CC(=O)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Product: O=C1CCC(=NNc2ccccc2)c2ncccc2N1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
176 mg (1.0 mmol) 5H-pyrido[3,2-b]azepine-6,9(7H,8H)-dione and 162 mg (1.5 mmol) phenylhydrazine were suspended in glacial acetic acid (11 ml) and stirred for 1 hour at 70° C. After cooling to room temperature, the mixture was poured into a 5% aqueous sodium acetate solution. The mixture was extracted with 4×20 ml ethyl acetate. The combined organic layers were dried over sodium sulfate, and evaporated to dryness. Recrystallization from ethanol afforded a white solid, yield: 82 mg (32%); m.p. 206° C.; IR (KBr): 3291 cm−1 (NH), 3060/3023 cm−1 (CH-arom.), 2953/2885 cm−1 (CH-aliphat.), 1676 cm−1 (C═O); 1H-NMR (d6-DMSO, 400 MHz): δ (ppm)=2.54-2.58 (m, 2H, part of AA′XX′-system, azepine-CH2), 3.02-3.06 (m, 2H, part of AA′XX′-system, azepine-CH2), 6.76-6.81 (m, 1H, arom. H), 7.17-7.23 (m, 4H, arom. H), 7.36 (dd, 1H, 8.0/4.4 Hz, arom. H), 7.39 (dd, 1H, 8.0/1.7 Hz, arom. H), 8.40 (dd, 1H, 4.7/1.7 Hz, arom. H), 9.32 (s, 1H, NH), 9.76 (s, 1H, NH); C15H14N4O (266.31).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]3[CH:19]=[CH:20][CH:21]=[C:11]3[CH2:10][CH2:9]2)=[O:7])=[C:4]([Cl:24])[CH:3]=1.C(N(CC)CC)C.[Cl:32][C:33]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36].[OH-].[Na+]>ClCCl>[CH:18]1[C:13]2[N:12]3[CH:19]=[CH:20][CH:21]=[C:11]3[CH2:10][CH2:9][N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:35](=[O:36])[C:34]4[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:33]=4[Cl:32])=[CH:3][C:4]=3[Cl:24])=[O:7])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)c(Cl)c1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a mixture of 0.10 g of 6,7-dihydro-5-(4-amino-2-chlorobenzoyl)-5H-pyrrolo[1,2-a][1,5]benzodiazepine and 0.06 g of triethylamine in 6 ml of dichloromethane is added 0.10 g of 2,4-dichlorobenzoyl chloride in 0.5 ml of dichloromethane. The mixture is stirred at room temperature for 2 hours and 2 ml of 1N NaOH is added. The volatiles are removed under vacuum and to the residue is added 2 ml of tetrahydrofuran and 1 ml of methanol. The mixture is stirred at room temperature for 2 hours and the volatiles removed. To the residue is added 2 ml of 1N NaOH and 5 ml of H2O. The mixture is extracted with ethyl acetate and the extract washed with brine and dried (Na2SO4). The solvent is removed and the solid triturated with diethyl ether-hexane to give 0.15 g of white solid, Mass Spectrum (CI): 510(M+H, Cl35).
Reaction SMILES: C(O)(C)C.[Cl:5][C:6]1[N:11]=[C:10]([C:12]([O:14]C)=O)[C:9]([O:16][CH3:17])=[N:8][C:7]=1[NH:18][CH2:19][CH3:20].[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25][NH2:26])[CH3:22]>CCOCC>[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25][NH:26][C:12]([C:10]1[C:9]([O:16][CH3:17])=[N:8][C:7]([NH:18][CH2:19][CH3:20])=[C:6]([Cl:5])[N:11]=1)=[O:14])[CH3:22]
Reactant: CCN(CC)CCN
Reactant: CCNc1nc(OC)c(C(=O)OC)nc1Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: CCNc1nc(OC)c(C(=O)NCCN(CC)CC)nc1Cl

Procedure:
In 14 ml. of isopropyl alcohol were dissolved 1.4 g. of methyl 6-chloro-5-ethylamino-3-methoxypyrazine-2-carboxylate and 1.4 g. of N,N-diethylethylenediamine and the solution was refluxed for 4 days. After the reaction was over, the solvent was distilled off under reduced pressure from the reaction mixture and the residue obtained was applied to a silica gel column chromatography. The column was then developed using a mixture of ether and N-hexane of 1:1 volume ratio as an eluting solution. From the 1st fraction 0.7 g. of methyl 5-ethylamino-6-chloro-3-methoxypyrazine-2-carboxylate used as the starting material was recovered and from the 2nd fraction 0.7 g. of colorless plate crystals of N-(2-diethylaminoethyl)-6-chloro-5-ethylamino-3-methoxypyrazine-2-carboxamide a melting at 142° C. were obtained. The product obtained by recrystallizing the crystals from a mixture of benzene and n-hexane melted at 142° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH2:11][N:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:13][CH2:14][C:15]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:21][O:22]C(Cl)Cl>C(Cl)Cl.O>[CH:21]([C:6]1[C:7]2[C:15]3[CH2:14][CH2:13][N:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][C:10]=3[O:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:22]
Reactant: COC(Cl)Cl
Reactant: CCOC(=O)N1CCc2c(oc3c(OC)cccc23)C1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)N1CCc2c(oc3c(OC)ccc(C=O)c23)C1
Yield: 97 %

Procedure:
To a solution of ethyl 8-methoxy-3,4-dihydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate (from step 5) (0.264 g, 0.96 mmol), in methylene chloride, was added stannic chloride (0.424 g, 1.6 mmol) and 1,1-dichloromethyl methyl ether (0.1655 g, 1.4 mmol) at −10° C. Reaction mass was diluted with dichloromethane, water was added to it and organic layer was thoroughly washed with water after separation. It was concentrated and purified to yield Ethyl 5-formyl-8-methoxy-3,4-dihydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate (97%).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1)=[NH:4].[CH3:26][C:27]([CH3:29])=O>>[CH3:26][C:27]1([CH3:29])[O:1][N:2]=[C:3]([C:5]2[CH:6]=[CH:7][C:8]([CH2:11][CH:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=3)[C:13]([OH:15])=[O:14])=[CH:9][CH:10]=2)[NH:4]1
Reactant: CC(C)=O
Reactant: N=C(NO)c1ccc(CC(C(=O)O)c2cccc(C(F)(F)F)c2)cc1
Product: CC1(C)NC(c2ccc(CC(C(=O)O)c3cccc(C(F)(F)F)c3)cc2)=NO1
Yield: 40 %

Procedure:
A solution of 3-[4-(N-hydroxycarbamimidoyl)-phenyl]-2-(3-trifluoromethyl-phenyl)-propionic acid (200 mg, 0.57 mmol, example 258/259 b 1)) in acetone (50 ml) was refluxed for 8 hours per day for five days. The reaction mixture was evaporated in vacuo and the residue was purified by prep. HPLC (HPLC conditions: Purospher(R)Star HP-18e (10 μm), acetonitrile/water+1% TFA, 10% to 100% acetonitrile) to give 90 mg of the desired product (40%). MS m/z: 393.1 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([O:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][CH2:3]1.Br[C:18]1[CH:23]=[CH:22][C:21]([S:24]([C:27]([F:30])([F:29])[F:28])(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[F:29][C:27]([F:28])([F:30])[S:24]([C:21]1[CH:22]=[CH:23][C:18]([NH:1][CH:2]2[CH2:7][CH2:6][CH:5]([O:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][CH2:3]2)=[CH:19][CH:20]=1)(=[O:25])=[O:26]
Reactant: CC(C)(C)OC(=O)COC1CCC(N)CC1
Reactant: O=S(=O)(c1ccc(Br)cc1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)COC1CCC(Nc2ccc(S(=O)(=O)C(F)(F)F)cc2)CC1
Temperature: 100 °C
Yield: 98.2 %

Procedure:
A suspension of tert-butyl 2-(4-aminocyclohexoxy)acetate (0.5 g, 1.7 mmol, 1 eq.), 1-bromo-4-(trifluoromethylsulfonyl)benzene (0.4 g, 1.7 mmol, 1 eq.), cesium carbonate (1.4 g, 4.3 mmol, 2.5 eq.), and BINAP (54 mg, 0.08 mmol, 0.05 eq.), in toluene (15 mL), was bubbled with nitrogen for 10 minutes before the addition of Pd(OAc)2 (19 mg, 0.08 mmol, 0.05 eq.) to the reaction mixture. Nitrogen gas was bubbled through the reaction mixture for another 10 minutes and the contents were heated at 100° C. under nitrogen atmosphere for 3 hours. The contents were cooled to room temperature, diluted with ethyl acetate, filtered through Celite®, and concentrated. The crude material was purified by silica gel column chromatography using ethyl acetate/heptanes to elute. The product containing fractions were combined and concentrated to obtain tert-butyl 2-[4-[4-(trifluoromethylsulfonyl)anilino]cyclohexoxy]acetate (0.73 g, 77%); (CI, m/z): [M+H]+ 438; 1H NMR (400 MHz, CDCl3): δ 7.74 (d, J=8.9 Hz, 2H), 6.56-6.70 (m, 2H), 4.44 (d, J=7.4 Hz, 1H), 4.02 (s, 2H), 3.32-3.49 (m, 2H), 2.07-2.25 (m, 4H), 1.44-1.55 (m, 11H), 1.21-1.35 (m, 2H).
Reaction SMILES: CC(C)=O.[SH:5][C:6]1[N:7]([CH3:11])[CH:8]=[CH:9][N:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][Cl:21]>C(Cl)Cl>[Cl:21][CH2:20][CH2:19][S:5][C:6]1[N:7]([CH3:11])[CH:8]=[CH:9][N:10]=1
Reactant: Cn1ccnc1S
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cn1ccnc1SCCCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an acetone (40 ml) solution containing 2-mercapto-1-methylimidazole (4.0 g ) and anhydrous potassium carbonate (20 g) was added dropwise, under ice-cooling, 1-bromo-2-chloroethane (5.0 ml). The mixture was stirred for 2 hours at room temperature, to which was added methylene chloride (40 ml), followed by filtration. The filtrate was concentrated under reduced pressure to give 2-(2-chloroethyl thio)-1-methylimidazole (6.2 g ) as a colorless oily substance.
Reaction SMILES: C1(C(Cl)=O)CCCCCC1.C1(C(Cl)=O)CCCCC1.[C:20]([NH:24][CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([CH:37]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[O:36])=[C:30]([O:44][C:45]([CH:47]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)=[O:46])[CH:29]=1)=[O:27])([CH3:23])([CH3:22])[CH3:21]>>[CH:47]1([C:45]([O:44][C:30]2[CH:29]=[C:28]([CH:33]=[CH:32][C:31]=2[O:34][C:35]([CH:37]2[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]2)=[O:36])[CH:26]([OH:27])[CH2:25][NH:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:46])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]1
Reactant: CC(C)(C)NCC(=O)c1ccc(OC(=O)C2CCCCCC2)c(OC(=O)C2CCCCCC2)c1
Agent: O=C(Cl)C1CCCCC1
Agent: O=C(Cl)C1CCCCCC1
Product: CC(C)(C)NCC(O)c1ccc(OC(=O)C2CCCCCC2)c(OC(=O)C2CCCCCC2)c1

Procedure:
When cycloheptanecarbonyl chloride is substituted for the cyclohexanecarbonyl chloride in the procedure described in Example 15A above, the acylation product obtained is 3,4-bis(cycloheptanecarbonyloxy)phenyl tert-butylaminomethyl ketone; and when this product is catalytically hydrogenated using the procedure described in Example 15B above, there is obtained 3,4-bis(cycloheptanecarbonyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])O.[Na+].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CN(C)C=O>[CH2:21]([N:11]1[CH2:12][CH2:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)([CH3:14])[CH2:9][CH2:10]1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CC1(c2cccc(O)c2)CCNCC1
Reactant: CCCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCN1CCC(C)(c2cccc(O)c2)CC1
Temperature: 100 °C
Yield: 89.4 %

Procedure:
To 4-(3-hydroxyphenyl)-4-methylpiperidine (776 mg, 4.06 mmol) in N,N-dimethylformamide (5 ml) was added sodium hydrogen carbonate (341 mg, 4.06 mmol) and 1-bromohexane (0.57 ml, 4.06 mmol). The reaction mixture was heated at 100° C. for 4 h and then allowed to cool to room temperature. The solution was poured onto water (20 ml) and extracted with diethyl ether (3×10 ml). The combined extracts were washed with water (20 ml), dried (MgSO4) and concentrated in vacuo to give the title compound as a clear oil (1.0 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([O:17]C)[CH:14]=[CH:13][C:12]=2[NH:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)=[O:21])=[O:10])=[N:6][CH:7]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:12]([NH:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=3)=[O:21])=[CH:13][CH:14]=[C:15]([OH:17])[CH:16]=2)=[O:10])=[N:6][CH:7]=1
Reactant: COc1ccc(NC(=O)c2ccc(C#N)cc2)c(C(=O)Nc2ccc(Cl)cn2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)Nc2ccc(O)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Reaction time: 72 h
Yield: 90 %

Procedure:
To a suspension of compound N-(5-chloro(2-pyridyl)){2-[(4-cyanophenyl)-carbonylamino]-5-methoxyphenyl}carboxamide (500 mg, 1.2 mmol) in DCM (100 mL) at −78° C. was added BBr3 (2 mL). The mixture was stirred at ambient temperatures for 72 hours. The solid was collected by filtration and was washed by DCM and water, dried under vacuum. The filtrate was concentrated and extracted with EtOAc. The organic extract was washed with brine, dried and evaporated. The resulting solid was combined with the solid obtained from filtration to give the title compound. Total yield is 90% (430 mg). MS found for C20H13ClN4O3 (M+H)+: 393.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][O:10][CH3:11])[CH:3]=1.BrC1C=C(O)C=CC=1.C([Li])CCC.CCCCCC.[C:31]([O:35][C:36](=[O:46])[NH:37][CH2:38][CH2:39][C:40](=[O:45])N(OC)C)([CH3:34])([CH3:33])[CH3:32].C(OC(NCCC(O)=O)=O)(C)(C)C.Cl.CNOC.[Cl-].[NH4+]>O1CCCC1.O>[CH3:11][O:10][CH2:9][O:8][C:4]1[CH:3]=[C:2]([C:40](=[O:45])[CH2:39][CH2:38][NH:37][C:36](=[O:46])[O:35][C:31]([CH3:32])([CH3:33])[CH3:34])[CH:7]=[CH:6][CH:5]=1
Reactant: COCOc1cccc(Br)c1
Reactant: CON(C)C(=O)CCNC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CNOC
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: COCOc1cccc(C(=O)CCNC(=O)OC(C)(C)C)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
1-Bromo-3-(methoxymethoxy)benzene (3.938 g, 18.14 mmol) prepared from 3-bromophenol by the method described in Shin-Jikken-Kagaku-Koza (New Experiment Chemistry Lecture) Vol. 14, p. 568 (Maruzen, 1978) was dissolved in tetrahydrofuran (8 mL), and to the solution was gradually added a 1.56 mol/L solution of n-butyl lithium in hexane (12.2 mL, 19.0 mmol) under cooling at −78° C. Subsequently, to the mixture was added THF (16 mL), and then the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was gradually added to tert-butyl[2-(N-methoxy-N-methylcarbamoyl)ethyl]carbamate (this compound is prepared by condensation of N-tert-butoxycarbonyl-β-alanine and N,O-dimethylhydroxylamine hydrochloride) (2.010 g, 8.653 mmol) dissolved in THF (10 mL) at −18° C. The mixture was stirred at the same temperature for 1 hour, then to the mixture was added water and saturated aqueous ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/4) to give tert-butyl {3-[3-(methoxymethoxy)phenyl]-3-oxopropyl}carbamate (1.568 g, 59%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10]([C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1)#[N:11]>>[CH3:9][C:4]1[CH:5]=[C:6]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:10]#[N:11])[CH:17]=2)[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: N#Cc1cccc(B(O)O)c1
Product: Cc1cc(-c2cccc(C#N)c2)nc(N)n1

Procedure:
The title compound is synthesized according to general procedure GP4 starting from 2.0 g (14 mmol) 2-amino-4-chloro-6-methylpyrimidine and 2.7 g (18 mmol) 3-cyano-phenyl boronic acid. Yield after extraction and crystallization from diethylether: 3.2 g (100%).
Reaction SMILES: Cl[C:2]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][CH2:6][CH2:5][N:4]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[O:21][C:20]([CH3:22])=[N:19][CH:18]=4)=[C:13]([O:23][CH3:24])[CH:12]=3)=[N:9][N:10]=[C:3]12.[F:30][C:31]1[CH:32]=[C:33]([OH:38])[CH:34]=[C:35]([F:37])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[F:30][C:31]1[CH:32]=[C:33]([CH:34]=[C:35]([F:37])[CH:36]=1)[O:38][C:2]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][CH2:6][CH2:5][N:4]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[O:21][C:20]([CH3:22])=[N:19][CH:18]=4)=[C:13]([O:23][CH3:24])[CH:12]=3)=[N:9][N:10]=[C:3]12
Reactant: Oc1cc(F)cc(F)c1
Reactant: CCOC(=O)C1(Cl)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(Oc2cc(F)cc(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 38.6 %

Procedure:
A mixture of ethyl 8-chloro-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (671 mg), 3,5-difluorophenol (220 mg), potassium carbonate (667 mg) and DMF (6 mL) was stirred at 100° C. for 1 hr, the reaction mixture was diluted with ethyl acetate, and the mixture was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and purified by silica gel chromatography (NH, ethyl acetate). The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (317 mg).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26](O)=[O:27])[CH:24]=4)[NH:19][CH:18]=3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.O>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([CH:26]=[O:27])[CH:24]=4)[NH:19][CH:18]=3)[CH2:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc2[nH]cc(CCCCN3CC=C(c4ccccc4)CC3)c2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc2[nH]cc(CCCCN3CC=C(c4ccccc4)CC3)c2c1
Reaction time: 2 h

Procedure:
4.04 g of 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-indole-5-carboxylic acid are suspended in 25 ml of toluene, and a 3-fold molar amount of a 20% strength solution of diisobutylaluminum hydride in toluene is added dropwise, under N2 and with stirring, the mixture is boiled for 2 hours and cooled and is decomposed with water, and the product is worked up in the customary manner to give 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-5-formylindole, m.p. 131°.