Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([Cl:23])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17](Br)=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Li]CCCC.[CH3:31][C:32]1[C:37]([C:38]([C:40]2[N:44]([CH3:45])[N:43]=[N:42][CH:41]=2)=[O:39])=[CH:36][CH:35]=[C:34]([CH3:46])[N:33]=1>C1COCC1>[N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([Cl:23])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:38]([C:37]3[C:32]([CH3:31])=[N:33][C:34]([CH3:46])=[CH:35][CH:36]=3)([C:40]3[N:44]([CH3:45])[N:43]=[N:42][CH:41]=3)[OH:39])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cc1ccc(C(=O)c2cnnn2C)c(C)n1
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(O)(c2ccc3nc(Cl)c(Cc4ccc(-n5cccn5)cc4)c(Cl)c3c2)c2cnnn2C)c(C)n1
Temperature: -45 °C
Reaction time: 0.03 h

Procedure:
6-Bromo-2,4-dichloro-3-phenylquinoline (2.00 g, 4.62 mmol, Intermediate 3: step c) was dissolved in THF (250 mL) in a dry round bottom flask under an N2 atmosphere, then cooled to −45° C. in a dry ice acetone bath. n-BuLi (1.6 M in hexanes, 3.18 mL, 5.08 mmol) was then added dropwise via syringe over approximately 2 minutes and the resulting mixture was allowed to stir at that temperature for an additional 2 minutes. (2,6-Dimethylpyridin-3-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanone (1.10 g, 5.08 mmol, Intermediate 19: step b) in THF (15 mL) was then added to the reaction vessel via cannula over approximately 5 minutes. The reaction solution was stirred at −78° C. for approximately 5 minutes, then the dry ice bath was removed and replaced with an ice water bath and stirred at 0° C. for approximately 1 hour. The reaction was then quenched with a saturated, aqueous NH4Cl solution, then transferred to a separatory funnel with EtOAc. The organic phase was separated, then the aqueous layer was back extracted with EtOAc and the combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-10% DCM/(10% of a 2 M NH3 MeOH in DCM)) then further purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to afford the title compound. MS (ESI): mass calcd. For C30H25Cl2N7O, 570.5. m/z found, 570.5 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.27-8.22 (m, 1H), 8.07-8.02 (m, 1H), 7.84-7.77 (m, 1H), 7.73-7.67 (m, 1H), 7.61 (d, J=1.9 Hz, 1H), 7.18-7.13 (m, 2H), 7.04-6.98 (m, 3H), 6.86 (d, J=8.2 Hz, 1H), 6.76 (d, J=8.1 Hz, 1H), 5.91 (d, J=1.9 Hz, 1H), 4.51 (s, 2H), 3.94 (s, 3H), 2.40 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:28])[CH2:13][CH2:12][N:11]([C:14]3[N:15]=[N:16][C:17]([O:20]CC4C=CC=CC=4)=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H][H]>[Pd].COCCO>[OH:28][C:8]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[CH2:9][CH2:10][N:11]([C:14]2[N:15]=[N:16][C:17]([OH:20])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1
Reactant: [H][H]
Reactant: Cc1cccc(C2(O)CCN(c3ccc(OCc4ccccc4)nn3)CC2)c1
Agent: [Pd]
Solvent: COCCO
Product: Cc1cccc(C2(O)CCN(c3ccc(O)nn3)CC2)c1
Yield: 97 %

Procedure:
A mixture of 6.1 parts of 4-(3-methylphenyl)-1-[6-(phenylmethoxy)-3-pyridazinyl]-4-piperidinol and 250 parts of 2-methoxyethanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was boiled in 2-propanol. The product was filtered off and dried, yielding 4.5 parts (97%) of 6-[4-hydroxy-4-(3-methylphenyl)-1-piperidinyl]-3-pyridazinol: mp. 264.6° C. (compound 269).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]=O)=[CH:4][N:3]=1.[NH2:11][NH2:12]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]2[NH:11][N:12]=[CH:9][C:5]2=[CH:4][N:3]=1
Reactant: NN
Reactant: O=Cc1cnc(Cl)nc1Cl
Solvent: C1CCOC1
Product: Clc1ncc2cn[nH]c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
A solution of 2,4-dichloropyrimidine-5-carbaldehyde (7.75 g, 43.8 mmol, Preparation #1) in THF (100 mL) was added to a 500 mL round-bottomed flask charged with anhydrous hydrazine (3.0 mL, 96 mmol) in THF (250 mL). The reaction mixture was allowed to stir at ambient temperature for about 1 h after which the reaction mixture was concentrated under reduced pressure. The crude product was suspended in DCM (100 mL) and filtered through a silica gel pad. The silica gel pad was washed with additional DCM (2×20 mL) and the combined organic layers were concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 30% EtOAc in heptane to provide 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (2.3 g, 34%) as a white solid. LC/MS (Table 2, Method a) Rt=1.29 min; MS m/z: 155 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:16])[CH:9]([OH:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.CO[C:19](OC)([CH3:21])[CH3:20].CC1C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:16][C:19]([CH3:21])([CH3:20])[O:15][CH:9]2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: COC(C)(C)OC
Reactant: CCOC(=O)C(O)C(O)c1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CCOC(=O)C1OC(C)(C)OC1c1ccc(Br)cc1

Procedure:
A solution of diol from step 1 (1 eq) in acetone (0.2M), dimethoxypropane (8 eq) and pTsOH (0.05 eq) was stirred at rt for 4 h. The solvent was evaporated, the residue dissolved in EtOAc and washed with aqueous NaHCO3 sol. The organic extract was washed with brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (hexane:EtOAc, 95:5 to 85:15) afforded the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][N:6]1[C:15](=[O:16])[CH2:14][C:9]2([CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:8][C:7]1=[O:17].[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(N(C(C)C)CC)(C)C>CC#N>[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][O:5][N:6]2[C:15](=[O:16])[CH2:14][C:9]3([CH2:13][CH2:12][CH2:11][CH2:10]3)[CH2:8][C:7]2=[O:17])[CH2:30][CH2:29]1
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: O=C1CC2(CCCC2)CC(=O)N1OCCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1CC2(CCCC2)CC(=O)N1OCCCN1CCN(c2ccc3ccccc3n2)CC1

Procedure:
A mixture of 8-(3-bromopropyloxy)-8-azaspiro[4.5]decan-7,9-dione (5.7 g), 1-(2-quinolinyl)piperazine (4.0 g) and diisopropylethylamine (6.6 ml) in 100 ml of dry CH3CN was heated to 80° with stirring under N2.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[NH:20][N:21]=[C:22]([CH3:24])[CH:23]=3)[CH:15]=[C:14]([C:25]3[CH:30]=[CH:29][C:28]([O:31]C)=[CH:27][CH:26]=3)[N:13]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].B(Br)(Br)Br>ClC(Cl)C.C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[NH:20][N:21]=[C:22]([CH3:24])[CH:23]=3)[CH:15]=[C:14]([C:25]3[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=3)[N:13]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2cc(Nc3cc(C)n[nH]3)nc(Sc3ccc(NC(C)=O)cc3)n2)cc1
Agent: BrB(Br)Br
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Sc2nc(Nc3cc(C)n[nH]3)cc(-c3ccc(O)cc3)n2)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
A solution of [2-(4-acetamido-phenyl-sulfanyl)-6-(4-methoxyphenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (100 mg, 2.24.10−4 mol) in dichloroethane (5 mL) is treated with 1M BBr3 in DCM (896 μL, 8.96.10−4 mol). The mixture is then heated at 80° C. for 4 hours before 1M BBr3 in DCM (896 μL, 8.96.10−4 mol) is added. The reaction mixture is then heated at 80° C. for a further 3 hours. The solvent is evaporated and methanol is added to the residue to quench any residual BBr3. The solvent is evaporated in vacuo and this evaporation step is repeated 3 times. 1M HCl(8 mL) is added to the solid residue and the suspension is stirred at room temperature for 15 hours. The solid is collected by filtration and suspended in a mixture of water/EtOH (3/1, 24 mL). The mixture is neutralized with NaHCO3 and stirred for 2 hours at room temperature. The solid is then collected by filtration, rinsed with water and with diethyl ether to give [2-(4-acetamido-phenyl-sulfanyl)-6-(4-hydroxyphenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N+:7]=2[O-:12])[CH:5]=[CH:4][N:3]=[CH:2]1.S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19].C(=O)([O-])[O-].[K+].[K+]>O>[N:1]1([C:6]2[CH:11]=[C:10]([N+:18]([O-:20])=[O:19])[CH:9]=[CH:8][N+:7]=2[O-:12])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])O
Reactant: [O-][n+]1ccccc1-n1ccnc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1cc[n+]([O-])c(-n2ccnc2)c1
Temperature: 130 °C

Procedure:
A 3.22 g portion of 2-(1-imidazolyl)pyridine N-oxide was added to 7.6 g of concentrated sulfuric acid, a mixed solution of 5.2 g of fuming nitric acid and 2.6 g of concentrated sulfuric acid was gradually added dropwise thereto, and then the mixture was heated at 130° C. for about 2.5 hours. The reaction mixture was spontaneously cooled, poured into 150 g of ice-cooled water, neutralized with potassium carbonate and then extracted with 300 ml of ethyl acetate. The organic layer was dried and then concentrated, and the thus obtained mixture was subjected to a silica gel column chromatography and eluted with chloroform-methanol-28% aqueous ammonia (200:0.9:0.1, v/v/v) to obtain 0.12 g of the title compound as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:15][CH3:16])[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:28][CH2:29][CH:30]=[C:31]1[C:37]2[CH:38]=[CH:39][CH:40]=[N:41][C:36]=2[CH2:35][O:34][C:33]2[CH:42]=[CH:43][C:44]([C:46]([OH:49])([CH3:48])[CH3:47])=[CH:45][C:32]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:15][CH3:16])[CH:9]2[CH2:14][CH2:13][N:12]([CH2:28][CH2:29][CH:30]=[C:31]3[C:37]4[CH:38]=[CH:39][CH:40]=[N:41][C:36]=4[CH2:35][O:34][C:33]4[CH:42]=[CH:43][C:44]([C:46]([OH:49])([CH3:48])[CH3:47])=[CH:45][C:32]3=4)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: CCN(c1ccc(Cl)cc1)C1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: Cc1cccc(C)n1
Solvent: CC(C)O
Product: CCN(c1ccc(Cl)cc1)C1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CC1
Temperature: 80 °C
Reaction time: 14 h
Yield: 33.8 %

Procedure:
To a solution of the (4-chloro-phenyl)-ethyl-piperidin-4-yl-amine (0.150 g, 0.63 mmol) in isopropanol was added 2,6-lutidine (0.24 mL, 2.1 mmol) and catalytic potassium iodide. This mixture was heated to 80° C., and treated with 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a, d]cyclohepten-7-yl]-propan-2-ol (0.221 g, 0.6 mmol), added in portions over 1 h. The solution was then stirred at 80° C. for an additional 14 h. The reaction was concentrated in vacuo, then purified by Isco flash chromatography (15% methanol/85% methylene chloride) to yield the title compound (0.108 g, 34%). 1H-NMR (CDCl3): δ 1.12 (t, 3H), 1.57 (s, 6H), 2.67–2.80 (m, 4H), 2.00 (m, 2H), 2.34–2.41 (m, 2H), 2.43–2.54 (m, 2H), 2.88 (d, 2H), 3.22 (q, 2H), 3.37–3.51 (m, 1H), 5.28 (bs, 2H), 6.12 (t, 1H), 6.60 (d, 2H), 6.80 (d, 1H), 7.13 (d, 2H), 7.21–7.30 (m, 2H), 7.45 (s, 1H), 7.56 (d, 1H), 8.48 (dd, 1H). ESI-MS m/z: 532 (M+1), retention time 2.47.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:29][O:30][C:31]([CH:33]1[CH2:38][CH2:37][CH:36]([CH2:39][NH:40][C:41](N2C=CN=C2)=[O:42])[CH2:35][CH2:34]1)=[O:32]>C(Cl)Cl>[CH3:29][O:30][C:31]([CH:33]1[CH2:38][CH2:37][CH:36]([CH2:39][NH:40][C:41]([N:9]2[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C@@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:42])[CH2:35][CH2:34]1)=[O:32]
Reactant: COC(=O)C1CCC(CNC(=O)n2ccnc2)CC1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Product: COC(=O)C1CCC(CNC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 85.7 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (70.2 mg, 0.165 mmol) and 4-{[(imidazole-1-carbonyl)-amino]-methyl}cyclohexanecarboxylic acid methyl ester (509.6 mg, 1.921 mmol) in CH2Cl2 (9 mL) was stirred at rt for 17 hrs and at reflux for 7 hrs. The reaction mixture was then purified by flash column to give rac 4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-cyclohexanecarboxylic acid methyl ester (87.7 mg, 85.1%). HRMS (ES+) m/z Calcd for C32H37Cl2F2N3O3+H [(M+H)+]: 620.2253; Found: 620.2254.
Reaction SMILES: [Cl:1][CH2:2][C:3](O)=[O:4].[CH3:6][O:7][C:8](=[O:13])[C:9]([NH2:12])([CH3:11])[CH3:10].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:6][O:7][C:8](=[O:13])[C:9]([NH:12][C:3](=[O:4])[CH2:2][Cl:1])([CH3:11])[CH3:10]
Reactant: O=C(O)CCl
Reactant: COC(=O)C(C)(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)NC(=O)CCl
Reaction time: 0.5 h

Procedure:
To a solution of 0.95 g chloro acetic acid in 20 ml of dry THF 1.78 g N,N′-carbonyl-diimidazole were added. After 0.5 h at room temperature and under argon atmosphere 1.69 g 2-amino-2-methyl-propionic acid methyl ester and 1.29 g N,N-diisopropyl-ethyl-amine were added and it was stirred for 3 h. Then the solvent was evaporated, the residue taken up in ethyl acetate and washed with 2 M hydrochloric acid, water and sat. aqueous sodium hydrogen carbonate solution. The combined organic fractions were dried over sodium sulphate, filtrated and concentrated. The resulting residue was crystallized from diethylether to yield 2-(2-chloro-acetylamino)-2-methyl-propionic acid methyl ester.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]=[C:8]1[CH:16]([CH2:17][CH2:18][C:19](OC)=[O:20])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9]1>O1CCCC1>[OH:20][CH2:19][CH2:18][CH2:17][CH:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]1=[O:7]
Reactant: COC(=O)CCC1C(=O)Nc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1CCCO
Temperature: 25 °C
Yield: 85.6 %

Procedure:
Lithium aluminum hydride (0.5M solution in diglyme, 13.8 mL, 6.9 mmol) was added dropwise at 0° C. to methyl 3-(2-oxoindolin-3-yl)propanoate (1.51 g, 6.90 mmol) in tetrahydrofuran (30 mL). The mixture was allowed to warm to room temperature and then quenched with 2N aqueous hydrochloric acid. The reaction was extracted with ethyl acetate. The extract was weashed with brine, dried (MgSO4) and evaporated. The residue was purified by Biotage flash column chromatography (50% ethyl acetate/hexanes) to give product as a white solid (1.13 g, 86%); 1H NMR (DMSO-d6); δ1.38 (m, 2H); 1.85 (m, 2H); 3.32-3.38 (t, J=6.4 Hz, 1H); 4.38 (t, J=5.2 Hz, 1H); 6.80 (d, J=8 Hz, 1H); 6.94 (m, 1H); 7.16 (m, 1H); 7.22 (d, J=7.2 Hz, 1H); 10.3 (s, 2H)
Reaction SMILES: [CH3:1][O:2][C:3]1([CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3]1([CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:4][CH2:5][N:6]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=[O:25])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:7][CH2:8]1
Reactant: COC1(CNC(=O)OC(C)(C)C)CCNCC1
Reactant: O=C(CCCCCBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC1(CNC(=O)OC(C)(C)C)CCN(CCCCCC(=O)c2ccccc2)CC1
Yield: 85 %

Procedure:
4-Methoxy-4-tert-butoxycarbonylaminomethylpiperidine (2.3 g), 6-bromo-1-phenyl-1-hexanone (2.52 g) and potassium carbonate (2.6 g) were reacted and treated in the same manner as in Preparation Example 138(1) to give 3.35 g of 4-methoxy-1-(6-oxo-6-phenylhexyl)-4-tert-butoxycarbonylaminomethylpiperidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[C:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)#[N:11]>>[C:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:17])=[CH:14][CH:13]=1)#[N:11]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NC(=O)c2ccc(C#N)cc2)cc1
Yield: 91.6 %

Procedure:
Using p-anisidine (1.35 g, 11.0 mmol) and 4-cyanobenzoic acid (1.47 g, 10.0 mmol), the procedure of Reference Example 16 was repeated to obtain 2.31 g (91.7%) of the title compound in the form of colorless needle crystals.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:11])[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+].[Br:23]Br.O>C(Cl)Cl>[CH2:1]([NH:8][C:9](=[O:10])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:23][C:16]1[CH:15]=[CH:14][NH:13][N:12]=1
Reactant: c1cn[nH]c1
Reactant: BrBr
Agent: O=C(O)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Brc1cc[nH]n1
Reaction time: 6 h

Procedure:
To a solution of pyrazole benzyl carbamate (115.0 mg, 0.38 mmol), prepared in step A, in 6 mL of CH2Cl2 at room temperature was added solid potassium carbonate in one portion. A solution of bromine was added dropwise to the stirred mixture. After 6 h, 30 mL of H2O was added, and the mixture was extracted with CH2Cl2 (30 mL×3). The combined organic extracts were washed with a 10% Na2S2O3 aqueous solution (20 mL), a saturated NaHCO3 aqueous solution (20 mL) and brine (20 mL), and dried with Na2SO4. Evaporation of solvent gave a slightly yellow oil, which was purified by preparative TLC (CH2Cl2—MeOH=20:1). The silica was extracted with CH2Cl2 and methanol, the extracts were filtered and concentrated under reduced pressure to afford an oil, which was further dried on high vacuum, yielding 134.2 mg (93%) of the bromo-pyrazole benzyl carbamate (MH+=381).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([OH:11])=[CH:3][CH:2]=1.Br[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([F:24])=[C:18]([CH:23]=1)[C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:24][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[CH:3]=[CH:2]2)=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: Oc1ccnc2ccccc12
Reactant: COC(=O)c1cc(CBr)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cn2ccc(=O)c3ccccc32)ccc1F
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of quinolin-4-ol, methyl 5-(bromomethyl)-2-fluorobenzoate (prepared as described in US 2007/0021427 A1, 1 eq) and potassium carbonate (1.2 eq) in dry DMF (0.1 M solution) was stirred at 100° C. for 1 h. After solvent evaporation, the residue was dissolved in DCM and washed twice with H2O and once with brine. The organic phase was dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting crude was purified by flash-chromatography (EtOAc/PE 9:1) to give the title compound. The O-alkylated isomer is eluted before the title compound.
Reaction SMILES: [CH2:1]([C:4]1([CH2:29][CH:30]=[CH2:31])[N:13]2[CH2:14][CH2:15][C:16]3[C:21]([CH:12]2[CH2:11][C:10]2[CH:9]=[CH:8][C:7]([O:25][CH3:26])=[C:6]([O:27][CH3:28])[C:5]1=2)=[CH:20][C:19]1[O:22][CH2:23][O:24][C:18]=1[CH:17]=3)C=C>ClCCl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[CH3:28][O:27][C:6]1[C:5]2[C:4]3([CH2:1][CH:31]=[CH:30][CH2:29]3)[N:13]3[CH2:14][CH2:15][C:16]4[C:21]([CH:12]3[CH2:11][C:10]=2[CH:9]=[CH:8][C:7]=1[O:25][CH3:26])=[CH:20][C:19]1[O:22][CH2:23][O:24][C:18]=1[CH:17]=4
Reactant: C=CCC1(CC=C)c2c(ccc(OC)c2OC)CC2c3cc4c(cc3CCN21)OCO4
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: COc1ccc2c(c1OC)C1(CC=CC1)N1CCc3cc4c(cc3C1C2)OCO4
Temperature: 58 °C
Yield: 4 %

Procedure:
To a solution of 8,8-diallyl-9,10-dimethoxy-5,8,13,13a-tetrahydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (68 mg, 0.16 mmol) in dry dichloromethane (50 mL) was added Grubbs' catalyst I (32 mg, 0.04 mmol) under nitrogen. The mixture was heated to reflux for 72 h at 58° C. The reaction mixture was cooled and concentrated in vacuo. Purification by Waters Automated Flash System (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 9′,10′-dimethoxy-5′,6′,13′,13a′-tetrahydrospiro[cyclopent-3-ene-1,8′-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline] (2.5 mg, 4%). LC/MS m/e calcd for C24H25NO4 (M+H)+: 392.47, observed: 392.3; 1H NMR (400 MHz, MeOD) δ ppm 2.34-2.43 (m, 2 H) 2.55-2.68 (m, 1 H) 2.68-2.75 (m, 1 H) 2.75-2.81 (m, 1 H) 2.85-2.92 (m, 1 H) 2.92-2.99 (m, 1 H) 3.03-3.10 (m, 1 H) 3.11 (d, J=3.03 Hz, 1 H) 3.14-3.18 (m, 1 H) 3.79 (s, 3 H) 3.84 (s, 3 H) 3.93-4.00 (m, 1 H) 5.78-5.83 (m, 1 H) 5.83-5.88 (m, 1 H) 5.90 (s, 2 H) 6.58 (s, 1 H) 6.78 (s, 1 H) 6.83 (m, 1 H) 6.91 (m, 1 H).
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH:6]([CH3:14])[CH2:7][CH:8]([CH3:13])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:3]Br.[NH2:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1>>[CH3:1][CH:2]([CH2:5][CH:6]([CH3:14])[CH2:7][CH:8]([CH3:13])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:3][NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=1
Reactant: CC(C)CC(C)CC(C)CC(C)CBr
Reactant: CCOC(=O)c1ccc(N)cc1
Product: CCOC(=O)c1ccc(NCC(C)CC(C)CC(C)CC(C)C)cc1
Temperature: 120 °C
Reaction time: 17 h

Procedure:
A solution of 9 g. (34.2 m moles) 2,4,6,8-tetramethylnonylbromide, 6 g. (1.06 eq) ethyl 4-aminobenzoate, and 5 g. (1.05 eq) dry, powdered potassium carbonate in 50 ml. hexamethylphosphoramide is stirred at 120° C. for 17 hours. The cooled solution is diluted with 100 ml. water, the precipitate is filtered and washed with 100 ml. 50% aqueous ethanol. The product is dried and crystallized twice from ethanol to colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)=[O:12].C1C(=O)N([Br:25])C(=O)C1>C1COCC1>[Br:25][C:16]1[CH:17]=[C:13]([C:11]([C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[Cl:1])=[O:12])[NH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(c1ccc[nH]1)c1cc([N+](=O)[O-])ccc1Cl
Solvent: C1CCOC1
Product: O=C(c1cc(Br)c[nH]1)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
A mixture of (2-chloro-5-nitro-phenyl)-(1H-pyrrol-2-yl)-methanone (600 mg, 2.4 mmol) (from Aldrich, Milwaukee, Wis.) and NBS (504 mg, 2.8 mmol) in THF (60 mL) was stirred at room temperature for overnight. The reaction was concentrated, diluted with ethyl acetate (100 mL), washed wit 1N NaOH, brine and concentrated. The residue was recrystallized to give 310 mg (39%) of (4-bromo-1H-pyrrol-2-yl)-(2-chloro-5-nitro-phenyl)-methanone.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([C:14]([C:17]#[N:18])([CH3:16])[CH3:15])[CH:13]=1)[CH2:9]Br)([CH3:5])[CH3:4])#[N:2].[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:4][C:3]([C:6]1[CH:7]=[C:8]([CH2:9][N:19]2[N:20]=[CH:21][N:22]=[CH:23]2)[CH:11]=[C:12]([C:14]([C:17]#[N:18])([CH3:16])[CH3:15])[CH:13]=1)([C:1]#[N:2])[CH3:5]
Reactant: CC(C)(C#N)c1cc(CBr)cc(C(C)(C)C#N)c1
Reactant: c1nc[nH]n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: CC(C)(C#N)c1cc(Cn2cncn2)cc(C(C)(C)C#N)c1

Procedure:
In yet another embodiment of the present invention, the purified bromo compound (formula (III)) is alkylated with 1,2,4-triazole in a suitable solvent using a suitable base in the presence of a phase transfer catalyst such as tetrabutyl ammonium bromide to obtain anastrozole, which is further purified using column chromatography, followed by precipitation/crystallization using ethyl acetate and diisopropyl ether to obtain pure anastrozole in high yield.