Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.[CH3:15]OC1C=C2C(=CC=1)C(CCN)=CN2.C(O)(C(F)(F)F)=O>C1COCC1>[CH2:15]1[C:8]2[NH:7][C:6]3[C:13](=[CH:14][CH:3]=[CH:4][CH:5]=3)[C:9]=2[CH2:10][CH2:11][NH:12]1
Reactant: COc1ccc2c(CCN)c[nH]c2c1
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: c1ccc2c3c([nH]c2c1)CNCC3
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-Methoxy tryptamine 1a or 6-methoxy tryptamine 1b (0.524 mmol) and appropriate aryl or heteroaryl aldehyde 2 (0.63 mmol) were dissolved in THF (20 mL). The reaction mixture was cooled to 0° C. CF3COOH (0.2 ml) was then added at 0° C., and the reaction mixture was then allowed to stir at 0° C. for 1 hr. The ice bath was then removed and the reaction allowed to stir for a further 1 hr from 0° C. to r.t. The reaction mixture was quenched with aqueous saturated NaHCO3 (5 ml) and the organic phase separated. The mixture was extracted with EtOAc (2×10 ml). The combined organic phase was dried (anhydrous NaSO4), filtered and evaporated in vacuo to give the crude product tetrahydro β-carboline 3. The crude product was directly used for second step with out further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:21].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:21])[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccc2cc(OCc3ccccc3)ccc21
Reaction time: 0.5 h
Yield: 90 %

Procedure:
5-benzyloxyindole (2.00 g, 8.96 mmol) was dissolved in DMF (20 mL) and the solution cooled in ice. Sodium hydride (60% oil dispersion, 1.2 equivalent, 10.7 mmol, 0.43 g) was added and the mixture stirred for 30 min. Iodomethane (1.2 equivalent, 10.7 mmol, 0.67 mL) was added and the reaction stirred at room temperature overnight. The reaction was then poured into water (150 mL) and the precipitated solid collected by filtration. After washing with water and drying, 5-benzyloxy-1-methylindole (1.913 g, 90% yield) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]([F:32])([F:31])[C:14]1([CH2:17][CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=2)[CH2:19][NH2:20])[CH2:16][CH2:15]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=1)[CH2:17][C:14]1([C:13]([F:12])([F:31])[F:32])[CH2:16][CH2:15]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(CC1(C(F)(F)F)CC1)c1cnc(C(F)(F)F)nc1
Product: O=C(NCC(CC1(C(F)(F)F)CC1)c1cnc(C(F)(F)F)nc1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine. LCMS (MH+): m/z=486.1, tR (minutes, Method F)=2.77
Reaction SMILES: [C:1]1([P:7](=[O:10])([OH:9])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][S:12](O)(=[O:14])=[O:13].[Cl-].[Na+]>>[P:7]([C:1]1[CH:6]=[C:5]([S:12]([Cl:11])(=[O:14])=[O:13])[CH:4]=[CH:3][CH:2]=1)([OH:9])([OH:8])=[O:10]
Reactant: O=S(=O)(O)Cl
Reactant: O=P(O)(O)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: O=P(O)(O)c1cccc(S(=O)(=O)Cl)c1
Temperature: 140 °C

Procedure:
The preparation was undertaken as a modification of the process for forming 3-carboxybenzenesulfonyl chloride as reported in J. Chem. Soc. (C), page 11 et seq. (1968) by R. J. W. Cremlyn. Phenylphosphonic acid was added in portions to chlorosulfonic acid; about 10 moles of chlorosulfonic acid per mole of phenylphosphonic acid were employed. The initial mixing step was exothermic, causing the temperature of the mixture to rise to about 90° C. After completion of the addition of the phenylphosphonic acid to the chlorosulfonic acid, the reaction mixture was heated to about 140° C. for about two hours. Reaction proceeded according to the equation ##STR5## Attempts to lower the molar ratio of chlorosulfonic acid: phenylphosphonic acid, by addition of sodium chloride (to remove sulfuric acid from the reaction mixture), caused uncontrollable frothing.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17](=[O:18])[C:16]3[C@@H:15]4[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]4)[C:11]=3[NH:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.I[CH2:24][CH3:25].CCOCC>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17](=[O:18])[C:16]3[C@@H:15]4[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]4)[C:11]=3[N:10]2[CH2:24][CH3:25])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3cc(Cl)cc(Cl)c3)c(=O)c12
Reactant: CCI
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCn1c2c(c(=O)n1-c1cc(Cl)cc(Cl)c1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 95 °C
Yield: 6.8 %

Procedure:
A mixture of (4S,7R)-2-(3,5-dichloro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 45; 400 mg, 1.2 mmol) and iodoethane (480 μL, 5.95 mmol) in dimethylformamide (5 mL) was heated at 95° C. for 7 h and then a further portion of iodoethane (480 μL, 5.95 mmol) was added. The solution was heated at 95° C. overnight. The solvent was evaporated, dichloromethane (100 mL) was added and the solution was washed with water (3×50 mL), saturated aqueous sodium thiosulfate (50 mL), and brine (50 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and purified by column chromatography, eluting with 20% ethyl acetate/petroleum ether, and dried under high vacuum over the weekend to give a pale orange solid. The solid was stirred in a small amount of ether, and the insoluble material was filtered off and dried under high vacuum overnight to give (4S,7R)-2-(3,5-dichloro-phenyl)-1-ethyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (30 mg, 7%). ES(+)-MS (M+H) 351.
Reaction SMILES: [CH:1]1([C:4]2[N:5]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]3[C:11]([CH:12]=2)=[C:10]([OH:13])[CH:9]=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.Br[CH2:22][C:23]([O:25][CH3:26])=[O:24].[H-].[Na+]>CN(C=O)C>[CH3:26][O:25][C:23](=[O:24])[CH2:22][O:13][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH:12]=[C:4]([CH:1]1[CH2:2][CH2:3]1)[N:5]2[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Oc1cccc2c1cc(C1CC1)n2Cc1ccccc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1cc(C1CC1)n2Cc1ccccc1
Yield: 62.9 %

Procedure:
2-Cyclopropyl-4-hydroxy-1-(phenylmethyl)-1H-indole (316 mg, 1.2 mmol) was alkylated by treating with 0.11 mL (1.2 mmol) of methyl bromoacetate and 48 mg (1.2 mmol) of 60% NaH/mineral oil in DMF as described in Example 1, Part E. The product was purified by chromatography over silica gel eluting with 20% EtOAc/hexane, to give 253 mg (63% yield) of [[2-cyclopropyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid methyl ester.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH:17]([CH3:19])[CH3:18])[CH:9]=2)=[CH:6][CH:7]=1.O.[NH2:21][NH2:22]>C(O)CCC>[NH:21]([C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH:17]([CH3:19])[CH3:18])[CH:9]=2)=[CH:6][CH:7]=1)[NH2:22]
Reactant: NN
Reactant: COc1ccc(-c2ccc(Cl)nn2)cc1OC(C)C
Solvent: O
Solvent: CCCCO
Product: COc1ccc(-c2ccc(NN)nn2)cc1OC(C)C
Temperature: 0 °C
Yield: 76.6 %

Procedure:
25 g (90 mmol) of 3-chloro-6-[4-methoxy-3-(1-methylethoxy)phenyl]pyridazine are boiled under reflux with 22.5 g (0.45 mol) of hydrazine hydrate in 200 ml of butanol for 12 hours. The reaction mixture is subsequently diluted to three to four times the volume with ice-water, and the precipitate is filtered off and recrystallized from isopropanol/cyclohexane. 18.9 g (76.8%) of 3-hydrazino-6-[4-methoxy-3-(1-methylethoxy)phenyl]pyridazine of m.p. 116° C. are obtained.
Reaction SMILES: [C:1]([C:3]1[N:11]=[CH:10][C:9]2[NH:8][C:7]3[N:12]=[CH:13][C:14]([C:16]4[CH:21]=[CH:20][C:19]([CH2:22][N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)=[CH:18][CH:17]=4)=[CH:15][C:6]=3[C:5]=2[CH:4]=1)#[N:2].C1(C2[O:37]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C(Cl)Cl>[C:1]([C:3]1[N:11]=[CH:10][C:9]2[NH:8][C:7]3=[N+:12]([O-:37])[CH:13]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([CH2:22][N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)=[CH:20][CH:21]=4)[CH:15]=[C:6]3[C:5]=2[CH:4]=1)#[N:2]
Reactant: N#Cc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClCCl
Product: N#Cc1cc2c(cn1)[nH]c1c2cc(-c2ccc(CN3CCCCC3)cc2)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
A mixture of 6-cyano-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (110 mg, 0.30 mmol) and 3-phenyl-2-(phenylsulfonyl)oxaziridine (102 mg, 0.39 mmol) in DCM (5.8 mL) was stirred at room temperature for 2 h. The solid was collected by filtration and washed with DCM (3×20 mL) to afford a bright yellow solid (100 mg, 90%). 1H NMR (400 MHz, DMSO-D6): 8.98 (s, 1H), 8.91 (s, 1H), 8.90 (s, 1H), 8.83 (s, 1H), 7.66 (m, 4H), 4.43 (s, 2H), 3.13 (m, 2H), 2.14 (m, 2H), 1.59 (m, 4H), 1.34 (m, 2H). LCMS (method D): RT=8.82 min, M+H+=384.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.Cl.[NH2:66][C@H:67]1[CH:72]2[CH2:73][CH2:74][N:69]([CH2:70][CH2:71]2)[CH2:68]1>C(Cl)Cl>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:13][CH2:14]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:66][C@H:67]5[CH:72]6[CH2:73][CH2:74][N:69]([CH2:70][CH2:71]6)[CH2:68]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N[C@@H]2CN3CCC2CC3)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 5) (0.11 g, 0.25 mmol, 1 eq), DIPEA (0.17 mL) and TBTU (88 mg, 0.28 mmol, 1.1 eq) were added to 5 mL DCM and the resulting solution stirred at rt for 30 min before the addition of (S)-(−)-3-aminoquinuclidine dihydrochloride (60 mg, 0.30 mmol, 1.2 eq). The RM was then stirred at rt for 16 hours before diluting with DCM and washing sequentially with water (×2), 50% saturated aqueous sodium hydrogen carbonate, saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was dissolved in the minimum quantity of EtOAc before addition of n-heptane to precipitate (S)-4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxy-N-(quinuclidin-3-yl)benzamide (white solid, 0.075 g, 55%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH2:14][C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[C:17]([O:31][CH3:32])[CH:16]=1)[CH2:10][C:11]#N)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[O:35]CC>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH2:14][C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[C:17]([O:31][CH3:32])[CH:16]=1)[CH2:10][CH:11]=[O:35])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCCOc1c(C)cc(CC[C@H](CC#N)NC(=O)OC(C)(C)C)cc1OC
Reactant: CCOCC
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1c(C)cc(CC[C@H](CC=O)NC(=O)OC(C)(C)C)cc1OC
Temperature: -60 °C
Reaction time: 1 h

Procedure:
A solution of 220 mg (0.49 mmol) of 3-(R)-[N-(tert-butoxycarbonyl)amino]-5-(3-methoxy-5-methyl-4-octyloxyphenyl)-pentanenitrile (from Step D) in 10 mL of Et2O at −60° C. was treated with 2.0 mL (2.0 mmol) of 1M Dibal in toluene over 4 h via a syring pump. After stirring for 1 h additional at −60° C., the reaction was quenched with MeOH and warmed to room temperature. The mixture was poured into 50 mL of saturated NH4Cl (pH adjusted to 3 with 2 N HCl). After separating phases, the aqueous layer was extracted with 2×50 mL of EtOAc (aqueous pH maintained at 3 to avoid an emulsion). The combined organics were dried over Na2SO4 and concentrated. The residue was purified by flash chromatography eluting with 4/1 v/v hexane/EtOAc to afford 95 mg of the title compound as a colorless film. RF: 0.20 (4/1 v/v hexane/EtOAc); 1H-NMR (500 MHz) δ 0.91 (t, J=6.9, 3H), 1.27-1.86 (m, 23H), 2.25 (s, 3H), 2.54-2.70 (m, 4H), 3.84 (s, 3H), 3.89 (t, J=6.8, 2H), 4.08 (m, 1H), 4.72 (m, 1H), 6.57-6.58 (m, 2H), 9.77 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:12]=[C:13]=[O:14].[NH2:15][C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1)=[O:14]
Reactant: COc1cc([N+](=O)[O-])ccc1N=C=O
Reactant: Nc1cnccn1
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1NC(=O)Nc1cnccn1

Procedure:
A mixture of 2-methoxy-4-nitrophenyl isocyanate (15.0 g, 77 mmol) and aminopyrazine (7.35 g, 77 mmol) in THF (600 mL) was stirred at reflux for 24 hours. The product precipitated from the cooled reaction mixture and was collected by filtration, washed with ethyl acetate, triturated with hot ethanol, and dried in vacuo (16.3 g, 73%). 1H NMR (300 Mhz, d6DMSO) δ: 10.50 (br s, 1H), 10.42 (s, 1H), 8.94 (s, 1H), 8.48 (d, 1H), 8.39 (s, 1H), 8.32 (d, 1H), 7.95 (dd, J=9.1, 2.4 Hz, 1H), 7.84 (d, J=2.4 Hz, 1H), 4.08 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].OS(O)(=O)=O.[N+:17]([O-])([OH:19])=[O:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([N+:17]([O-:19])=[O:18])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(Cl)cc1C(=O)O
Agent: O=S(=O)(O)O
Product: Cc1c(C(=O)O)cc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
A stirred solution of 5-chloro-2-methylbenzoic acid (1 mmol) in cone. H2SO4 (2 mL) was cooled to −10° C. and nitrating mixture (0.4 mL of conc. H2SO4+0.1 mL of conc. HNO3) was added to it in dropwise manner. The reaction mixture was stirred at the same temperature for 20 min then warmed to room temperature. The solid precipitate was filtered and dried to obtain 5-chloro-2-methyl-3-nitrobenzoic acid which was used in next step without further purification (yield 60-70%).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:22])=[C:14]1[N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)=[O:5])C.C(O)C.[OH-].[Na+].Cl>O>[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:22])=[C:14]1[N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)([OH:5])=[O:3]
Reactant: CCOC(=O)CCCCCCCn1c(-n2ccnc2)c(C)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(-n2ccnc2)n(CCCCCCCC(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1-(7-ethoxycarbonylheptyl)-2-(1-imidazolyl)-3-methylindole (0.75 g), absolute ethanol (2 ml), and 3N sodium hydroxide (10 ml) is stirred at room temperature for 18 hours. The resulting clear solution is concentrated in vacuo and the residue obtained is diluted with water (40 ml) and acidified to pH 5.9 with 1N hydrochloric acid. The mixture is extracted with ethyl acetate (3×25 ml) and the extract is washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to give an oil which crystallizes on standing. The solid is purified by trituration with ether (10 ml) to give 1-(7-carboxyheptyl)-2-(1-imidazolyl)-3-methylindole; m.p. 101°-103°.
Reaction SMILES: [NH2:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([NH:12][C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=4)=[O:14])([CH2:5]3)[CH2:3]1)[CH2:9]2.CCN(C(C)C)C(C)C.[CH3:31][N:32]1[CH:36]=[CH:35][C:34]([C:37](Cl)=[O:38])=[N:33]1>C(Cl)Cl>[CH3:31][N:32]1[CH:36]=[CH:35][C:34]([C:37]([NH:1][C:2]23[CH2:11][CH:6]4[CH2:7][CH:8]([CH2:10][C:4]([NH:12][C:13]([C:15]5[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=5)=[O:14])([CH2:5]4)[CH2:3]2)[CH2:9]3)=[O:38])=[N:33]1
Reactant: Cc1cccc(C(=O)NC23CC4CC(CC(N)(C4)C2)C3)n1
Reactant: Cn1ccc(C(=O)Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(C(=O)NC23CC4CC(C2)CC(NC(=O)c2ccn(C)n2)(C4)C3)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.3 %

Procedure:
To a solution of 6-methyl-pyridine-2-carboxylic acid (3-amino-adamantan-1-yl)-amide (Intermediate 1, 20 mg, 0.07 mmol) in DCM (5 mL) was added DIEA (30 mg, 0.2 mmol) and 1-methyl-1H-pyrazole-3-carbonyl chloride (20 mg, 0.1 mmol, Maybridge Chemical Co., Cornwall, UK). After stirring at room temperature for 16 h, the reaction mixture was partitioned into dichloromethane and saturated sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified on a RP-HPLC/MS purification system (Gradient: acetonitrile in water, 25-95%, in 3.9 minutes with a cycle time of 5 min. Flow rate: 100 mL/min. Mobile phase additive: 25 mM of ammonium formate. Column: Inertsil® C8, 30×50 mm, 5 μm particle size (GL Sciences, Tokyo, Japan)) to afford 10 mg (30%) of the title compound, 6-methyl-pyridine-2-carboxylic acid {3-[(1-methyl-1H-pyrazole-3-carbonyl)-amino]-adamantan-1-yl}-amide, as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.07 (s, br, 1H), 7.95 (d, J=7.7 Hz, 1H), 7.69 (t, J=7.8 Hz, 1H), 7.33 (d, J=2.3 Hz, 1H), 7.26-7.21 (m, 1H), 6.76-6.72 (m, 2H), 3.89 (s, 3H), 2.55 (s, 3H), 2.54-2.52 (m, 2H), 2.35-2.08 (m, 10H), 1.72-1.69 (m, 2H). ESI-MS m/z: 394.1 (M+H)+.
Reaction SMILES: [Na].[C:2]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].[C:11](Cl)(=[O:13])[CH3:12]>C1(C)C=CC=CC=1>[C:4]([CH:3]([C:11](=[O:13])[CH3:12])[C:2]([O:8][CH2:9][CH3:10])=[O:7])(=[O:5])[CH3:6]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)CC(C)=O
Agent: [Na]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(C)=O)C(C)=O
Temperature: 85 °C
Reaction time: 0.33 h

Procedure:
5 g of sodium salt of ethyl acetoacetate was mixed with 30 ml of toluene. Over 20 minutes, 5 g of acetic acid chloride was added dropwise, and the mixture was stirred for one hour at room temperature and at 85° C. for 3 hours. The solid was filtered off and washed with diethyl ether. Fractional distillation of the liquid phase yielded ethyl 2-acetyl-3-oxo-butyrate.
Reaction SMILES: FC1C=CC([C:8]2[C:9](=[O:23])[N:10]([CH3:22])[C:11](SC)=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=CC=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1C(N)CCN>>[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:11]2[N:10]([CH3:22])[C:9](=[O:23])[CH:8]=[C:13]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)[N:12]=2)=[CH:27][CH:26]=1
Reactant: NCCC(N)c1ccccc1F
Reactant: CSc1nc(-c2ccncc2)c(-c2ccc(F)cc2)c(=O)n1C
Product: Cn1c(-c2ccc(F)cc2)nc(-c2ccncc2)cc1=O
Reaction time: 3 h

Procedure:
2-34 2-((3-Amino-3-(2-fluorophenyl)propyl-amino)-5-(4-fluorophenyl-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone was prepared from 5-(4-fluorophenyl)-3-methyl-2-methylthio-6-(4-pyridyl)-4(3H)-pyrimidinone and 1-(2-fluorophenyl)-1,3-propanediamine according to the General Procedure. The reaction was done at 190μ C. for 3 h. MS (m/z): 448.1 (M+H)+; C25H23F2N5O requir. 447.5 (free base).
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>O1CCCC1>[Cl:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][C:28]2[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=2)=[CH:45][CH:44]=1
Reactant: Clc1ccc(Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(Cc2ccc(Cl)cc2)cc1O

Procedure:
Prepared in the same way as 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(4-chlorophenyl)methyl]pyridazine (Intermediate 49) except that the solvent used for the hydrogenation was ethyl acetate and tetrahydrofuran and the product was recrystallised from ethyl acetate.
Reaction SMILES: C(=N[C@H](C)C(C1C=CC=CC=1)(C1C=CC=CC=1)O)C1C(=CC=CC=1)O.[CH3:26][C:27](=[CH:29][CH:30]=[C:31]([CH3:33])[CH3:32])[CH3:28].C1(NN)C=CC=CC=1.[N+](=[CH:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])=[N-]>O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:49][CH2:48][O:47][C:45]([CH:44]1[C:31]([CH3:33])([CH3:32])[CH:30]1[CH:29]=[C:27]([CH3:28])[CH3:26])=[O:46]
Reactant: CC(C)=CC=C(C)C
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: C[C@@H](N=Cc1ccccc1O)C(O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: NNc1ccccc1
Product: CCOC(=O)C1C(C=C(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
19.64 mg (0.05 mmol) of a copper complex prepared from 9.98 mg (0.05 mmol) of copper acetate monohydrate and 18.23 mg (0.055 mmol) of (R)-N-salicylidene-2-amino-1,1-diphenylpropanol, and 6.09 (55 mmol) of 2,5-dimethyl-2,4-hexadiene were charged in a 50 ml Schlenk's tube wherein the atmosphere is substituted with nitrogen. After 5.4 mg of phenylhydrazine was further added, 1.14 g (10 mmol) of ethyl diazoacetate was added dropwise at 50° C. over 2 hours. After the completion of the dropwise addition of ethyl diazoacetate, the mixture was further stirred at 25° C. for 1 hour. The amount of chrysanthemic acid ethyl ester formed was determined by gas chromatography. As a result, it was 1.52 g and the yield was 77.7% based on ethyl diazoacetate and, furthermore, the trans/cis ratio was 61/39. After 2,5dimethyl-2,4-hexadiene (boiling point: 51° C./30 mmHg) was distilled off from the reaction mixture, 1 g of the concentrated solution was taken out. Then, 10 ml of an aqueous 1N sodium hydroxide solution and 5 ml of ethanol were added and alkali hydrolysis was performed by stirring at 100° C. for 1 hour. The resulting chrysanthemic acid was reacted with 1-menthol and the formed diastereomer ester was analyzed by gas chromatography. As a result, the optical purity of the (+)-trans isomer was 69% e.e., whereas, the optical purity of the (+)-cis isomer was 68% e.e.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=O)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:9]1[O:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: O=c1[nH]c(-c2ccccc2)c(-c2ccccc2)o1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Clc1nc(-c2ccccc2)c(-c2ccccc2)o1

Procedure:
4,5-Diphenyloxazolone from Step 1 (30 g, 0.126 mol), triethylamine (12.8 g, 0.126 mol), and phosphorous oxychloride (96.6 g, 0.63 mol) were stirred at reflux for 4.0 hours. The mixture was concentrated in vacuo, dissolved in ether (250 mL), washed with 1N HCl, brine, and water, dried over MgSO4 and concentrated to a light yellow oil which was used in the next step without further purification or characterization.