Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Zn:1].[Br:2]CCBr.C[Si](Cl)(C)C.Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1>C1COCC1>[Br-:2].[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][Zn+:1])=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: BrCCBr
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: [Zn]
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C[Zn+])cc1
Product: [Br-]
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
Zinc powder (2.81 g, 42.97 mmol) was suspended in THF (50 mL) under nitrogen and heated to 60° C. 1,2-dibromoethane (0.336 g, 1.79 mmol) was added and stirred for 15 min at 60° C. It was cooled to ambient temperature, TMSCl (0.156 g, 1.43 mmol) was added and stirred for 15 min at ambient temperature. 1-(Bromomethyl)-4-(methylsulfonyl)benzene (8.92 g, 35.81 mmol) dissolved in THF (50 mL) was added over 15 min and the resulting mixture was stirred at ambient temperature overnight. Stirring was stopped and the supernatant used in the next reaction.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>CS(C)=O>[CH3:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:3][CH:4]=1
Reactant: CNC(=O)c1ccc(F)cc1
Reactant: C1CNCCN1
Solvent: CS(C)=O
Product: CNC(=O)c1ccc(N2CCNCC2)cc1
Temperature: 120 °C
Reaction time: 68 h
Yield: 65.6 %

Procedure:
To a solution of 4-fluoro-N-methylbenzamide (6 g, 39.2 mmol) in DMSO (Volume: 24.0 mL) was added piperazine (16.87 g, 196 mmol) at 23° C. The reaction was stirred at 120° C. for 68 hr. The reaction mixture was poured into ice (261 g) and the reaction vessel was rinsed with H2O (˜50 mL). Next, celite (30 g) was added to aid the filtration. The resulting suspension was warmed to 100° C., cooled to ˜40° C., filtered, and rinsed with warm H20 (4×50 mL). The resulting solid was dried in vacuo. The filtrate was stirred at room temperature overnight affording a suspension. The suspension was filtered, rinsed with H2O (3×25 mL), and the resulting solid was dried in vacuo. The cloudy filtrate was filtered once again through a medium fitted funnel and rinsed with H2O (3×10 mL). Added NaCl (200.1 g) to the filtrate, cooled on ice, filtered, rinsed with cold H2O (3×25 mL), and dried the resulting solid in vacuo. Re-suspended the purified product in H2O (30 mL), stirred for 30 min at 23° C., filtered, rinsed with H2O (3×5 mL), and dried the resulting solid in vacuo. The purified product was re-suspended in ACN (25 mL), agitated for 10 min, and dried in vacuo. This procedure was repeated three times to provide N-methyl-4-(piperazin-1-yl)benzamide (5.64 g, 25.7 mmol, 65.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.29 (br. s., 1H) 2.74 (d, J=4.55 Hz, 3 H) 2.77-2.86 (m, 4 H) 3.08-3.18 (m, 4 H) 6.91 (m, 2 H) 7.69 (m, 2 H) 8.13 (q, J=4.04 Hz, 1 H). ESI-MS: m/z 220.2 (M+H)+. mp=153.9-156.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=O)[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][NH2:29])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO.C(Cl)Cl>ClC(Cl)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][NH:29][CH:10]2[CH2:9][CH2:8][C:7]3[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:11]2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc2C1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CNC2CCc3ccc([N+](=O)[O-])cc3C2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 7-nitro-3,4-dihydro-1H-naphthalen-2-one (600 mg, 2.98 mmol), prepared as described in J. Med. Chem., 1989, 32(9), 2128-34, and 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (700 mg, 3.3 mmol) in dichloroethane (50 mL) under a nitrogen atmosphere was added sodium triacetoxyborohydride (1.4 g, 6.5 mmol, 2 eq.) in a single portion. The reaction was stirred at room temperature for 24 h. The reaction was concentrated in vacuo and partitioned between EtOAc (100 mL) and 5% aq. KOH (50 mL). The aqueous layer was extracted twice more with EtOAc (2×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to afford a dark oil. Flash chromatography on silica gel eluting with 5% methanol/methylene chloride afforded 4-[(7-nitro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester, as an oil (790 mg).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[C:10](O)([CH3:13])([CH3:12])[CH3:11].C(OCC)C>CN(C)C1C=CN=CC=1.ClCCl>[C:10]([O:8][C:7]([CH:4]1[CH2:5][CH2:6][C:2](=[O:1])[CH2:3]1)=[O:9])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)O
Reactant: O=C1CCC(C(=O)O)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C1CCC(=O)C1
Temperature: 2 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
To a cold (ice bath) solution of 3-oxo-1-cyclopentanecarboxylic acid (1.50 g), tert-butylalcohol (1.05 g) and 4-dimethylaminopyridine (140 mg) in dichloromethane (9 mL) was added a solution of dicyclocarbodiimide in dichloromethane (9 mL). The mixture was stirred 3 hours at ca. 2° C. then diethylether (30 mL) was added and the precipitate was filtered off and discarded. The solution was concentrated in vacuo. The residue was purified by flash chromatography on silica gel with cyclohexane/ethyl acetate (9:1 v/v) as eluant to afford the title compound (1.80 g, 96%) as colorless oil. MS (EI): 111 (M-OtBu.)+.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[N+:14]([C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19])([O-:16])=[O:15].Cl.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N+:14]([O-:16])=[O:15])=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: CSc1ncnc2cc(N)ncc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1cc2ncnc(Nc3ccccc3[N+](=O)[O-])c2cn1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 33.3 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (220 mg, 1.15 mmole) and 2-nitroaniline (2.00 g, 14.5 mmole) is heated to 100° C., then excess dry HCl gas is added to the hot stirred solution, and the mixture stirred at 160° C. for 20 min. The resulting product is neutralized with excess NaHCO3, dissolved in MeOH/CHCl3, dried onto silica gel and chromatographed over silica gel (2-4% MeOH/CH2Cl2) to give 7-amino-4-(2-nitroanilino)pyrido[4,3-d]pyrimidine (108 mg, 33%) as a yellow brown solid. 1H NMR (DMSO) δ 10.40 (1H, brs), 9.24 (1H, brs), 8.20 (1H, brs), 8.12 (1H, brs), 8.01 (2H, brs), 7.75 (1H, brs), 6.70 (2H, brs), 6.43 (1H, brs).
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)[CH2:5][CH3:6])[CH3:3].O1CCOCC1.[CH:23]1([N:28]2[C:32]3=[N:33][C:34]([CH2:38][C:39]4[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=4)=[N:35][C:36](=[O:37])[C:31]3=[C:30]([CH2:46][CH3:47])[NH:29]2)[CH2:27][CH2:26][CH2:25][CH2:24]1.O>C(OCC)(=O)C>[CH:23]1([N:28]2[C:32]3=[N:33][C:34]([CH2:38][C:39]4[CH:40]=[CH:41][C:42]([O:13][C:12]([C:11]5[CH:10]=[CH:9][C:8]([CH2:7][N:4]([CH2:5][CH3:6])[CH2:2][CH3:3])=[CH:16][CH:15]=5)=[O:14])=[CH:43][CH:44]=4)=[N:35][C:36](=[O:37])[C:31]3=[C:30]([CH2:46][CH3:47])[NH:29]2)[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CCN(CC)Cc1ccc(C(=O)O)cc1
Reactant: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccc(O)cc3)nc(=O)c1-2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccc(OC(=O)c4ccc(CN(CC)CC)cc4)cc3)nc(=O)c1-2
Temperature: 25 °C
Yield: 58.1 %

Procedure:
A mixture of 4-diethylaminomethyl benzoic acid hydrochloride (360 mg, 1.5 mmol), N,N'-carbonyldiimidazole (264 mg, 1.5 mmol) and dioxane (20 ml) was heated on an oil bath for 1 hour. The reaction mixture was cooled to room temperature and 1-cyclopentyl-3-ethyl-6-(4-hydroxyphenylmethyl)pyrazolo[3,4-d]pyrimidin-4-one (500 mg, 105 mmol) and dioxane (10 ml) were added and the reaction mixture was heated at 100° C. overnight. The reaction mixture was cooled, the solvent was stripped and then water and ethyl acetate were added. The ethyl acetate layer was separated, then washed with 2N HCl (4×150 ml). The aqueous layers were combined, treated with concentrated NH4OH and then extracted with ethyl acetate (2×). The ethyl acetate layer was washed with brine, dried over MgSO4, filtered and stripped to afford crude product. The crude product was combined with the crude product from a similar experimental run and the mixture was recrystallized from ether to afford 0.46 g of 1-cyclopentyl-3-ethyl-6-[4-[4-(diethylaminomethyl)phenylcarbonyloxy]phenylmethyl]pyrazolo[3,4-d]pyrimidin-4-one, m.p. 143°-145° C.
Reaction SMILES: [CH3:1][C:2]1[C:19]([CH3:20])=[CH:18][C:5]2[NH:6][C:7]([C:9]3[C:13]4[CH2:14][NH:15][CH2:16][CH2:17][C:12]=4[NH:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1.[CH:21]([N:24]([CH:27](C)C)CC)([CH3:23])[CH3:22].CN(C)C(Cl)=[O:33]>CN(C)C=O>[CH:21]([NH:24][C:27]([N:15]1[CH2:16][CH2:17][C:12]2[NH:11][N:10]=[C:9]([C:7]3[NH:6][C:5]4[CH:18]=[C:19]([CH3:20])[C:2]([CH3:1])=[CH:3][C:4]=4[N:8]=3)[C:13]=2[CH2:14]1)=[O:33])([CH3:23])[CH3:22]
Reactant: CN(C)C(=O)Cl
Reactant: Cc1cc2nc(-c3n[nH]c4c3CNCC4)[nH]c2cc1C
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2nc(-c3n[nH]c4c3CN(C(=O)NC(C)C)CC4)[nH]c2cc1C
Reaction time: 1 h

Procedure:
A solution of 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine [0.150 g, Example 251(a)] in dimethyl formamide (4 ml) was treated with diisopropylethylamine (0.54 ml) and then with dimethyl carbamyl chloride (0.122 ml). After stirring for 1 hour the reaction mixture was quenched by the addition of methanol (0.1 ml) and then diluted with ethyl acetate. This mixture was washed five times with brine and then evaporated. The residue was treated with tetrahydrofuran (9 ml) and methanol (3 ml) and the resulting solution was then treated with potassium hydroxide (50 mg). This mixture was stirred for 1 hour, then acidified by addition of hydrochloric acid (1M) and then extracted three times with ethyl acetate. The aqueous layer was basified by addition of sodium carbonate and the resulting suspension was filtered, then washed with water, then dried in air and then azeotroped with toluene to yield 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid isopropylamide as a pale brown solid. MS: 339 (M+H)+. HPLC (METHOD F1): RT=8.67 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9]1.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH3:19][C:17]1([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9][CH:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:31]([CH3:30])(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1N)N2
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1NS(C)(=O)=O)N2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of methyl 2-(2-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (1.0 g, 3.22 mmol, 1.0 eq.) in pyridine (5 mL, 0.0644 mL, 20.0 eq.) and dichloro methane (20 mL) at 0 C was added dropwise a solution of methanesulfonyl chloride in dichloromethane (30 mL). The mixture was stirred at room temperature for 4 h. Thin layer chromatography and LC-MS showed the reaction was complete. The mixture was quenched with 50 mL water and extracted with ethyl acetate (100 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and evaporated to afford 1.475 g of methyl 3,3-dimethyl-2-(2-(methylsulfonamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (pyridine included) as light yellow solid, which was used in next step without further purification.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:12]1[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]1[OH:14].Cl.[NH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]1>C(O)(C)C>[OH:29][C@H:26]1[CH2:27][CH2:28][C@H:23]([NH:22][C:2]2[C:3]3[N:4]=[CH:5][N:6]([C:7]=3[N:8]=[C:9]([CH3:11])[N:10]=2)[C@@H:12]2[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]2[OH:14])[CH2:24][CH2:25]1
Reactant: Cc1nc(Cl)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Solvent: CC(C)O
Product: Cc1nc(N[C@H]2CC[C@H](O)CC2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reaction time: 17 h

Procedure:
A mixture of 6-chloro-2-methyl-9-(β-D-ribofuranosyl)-9H-purine (902 mg), trans-4-aminocyclohexanol hydrochloride (1.14 g) and DEA (1.94 g) in isopropanol (50 ml) was heated at reflux with stirring under nitrogen for 17 h. The resulting cooled reaction mixture was adsorbed onto silica (Merck 9385) and purified by column chromatography on silica (Merck 9385) eluting with System B (10:1 then 8:1) to give the title compound (0.9 g) as a solid.
Reaction SMILES: [N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]([NH2:26])=[NH:25])[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1.CN(C)[CH:29]=[C:30]([CH3:41])[C:31](=O)[CH:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:33].C(N(CC)CC)C>CN1CCCC1=O>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]2[N:26]=[C:31]([CH:32]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH3:33])[C:30]([CH3:41])=[CH:29][N:25]=2)[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1
Reactant: CC(=CN(C)C)C(=O)C(C)c1ccccc1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc(C)c(C(C)c3ccccc3)n2)ccc1-n1cnc(C)c1
Reaction time: 0.5 h

Procedure:
The title compound was prepared in analogous manner described in example 4c) from N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate, 1-dimethylamino-2-methyl-4-phenyl-pent-1-en-3-one and triethylamine using 1-methyl-2-pyrrolidinone as the solvent. The reaction was performed in a microwave at 200° C. for 30 min. The title compound was isolated as a pale-yellow solid in 39% yield.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>ClCCCl.CO>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH2:21][CH2:20]3)=[CH:8][C:6]=2[N:7]=1
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CO
Solvent: ClCCCl
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCC(N4CCOCC4)CC3)cc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.6 %

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (2.0 g, 7.1 mmol) and 4-piperidin-4-yl-morpholine (1.4 g, 8.5 mmol) in DCE (40 mL) was stirred at room temperature for 1.5 hour then triacetoxyborohydride (2.2 g, 10.6 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours then diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge (70 g). The cartridge was washed with MeOH/DCM (1/1: v/v) and the desired product was eluted with (2M NH3 in MeOH)/DCM (1/1: v/v). The solvents were removed and the residue was triturated in hot IMS, filtered and dried at 60° C. for 1 hour under vacuum to give 2-Chloro-4-morpholin-4-yl-6-(4-morpholin-4-yl-piperidin-1-ylmethyl)-thieno[3,2-d]pyrimidine as a white solid (2.6 g, 84%). LCMS (Method C): RT 0.34 min and 1.67 min; [M+H]+ 438
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:11][O:12][C:6]=2[CH:5]=1)=[O:3].[CH:13]1([Mg]Br)[CH2:15][CH2:14]1.C1(C(C2C=CC(Cl)=CC=2)(O)C)CC1>O1CCCC1>[O:10]1[C:7]2[CH:8]=[CH:9][C:4]([C:2]([CH:13]3[CH2:15][CH2:14]3)([OH:3])[CH3:1])=[CH:5][C:6]=2[O:12][CH2:11]1
Reactant: CC(=O)c1ccc2c(c1)OCO2
Reactant: Br[Mg]C1CC1
Agent: CC(O)(c1ccc(Cl)cc1)C1CC1
Solvent: C1CCOC1
Product: CC(O)(c1ccc2c(c1)OCO2)C1CC1

Procedure:
The title compound was prepared starting from 1.50 g (9.14 mmol) of 3,4-(methylenedioxy)acetophenone and 36.5 ml (18.28 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran in analogy to the synthesis of the compound from Example 138A. 1.32 g (70% of theory) of the title compound were obtained.
Reaction SMILES: C(O[C:4](=[O:20])[C:5](=[CH:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC.C(OCC)(=O)C>[CH2:9]([O:8][C:6]([C:5]1[C:4](=[O:20])[C:18]2[C:13](=[N:14][C:15]([CH3:19])=[CH:16][CH:17]=2)[NH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1cccc(C)n1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c[nH]c2nc(C)ccc2c1=O
Temperature: 25 °C
Yield: 67.6 %

Procedure:
Add 2-[(6-methyl-pyridin-2-ylamino)-methylene]-malonic acid diethyl ester (14.8 g) to the refluxing phenyl ether (100 ml) over a period of 5 min under nitrogen. After the addition is complete, keep the reaction under reflux for 3 h. Cool it to room temperature, and then pour the reaction mixture into 1:1 hexane/ethyl acetate (2000 ml). Collect the brown precipitate by filtration to obtain 7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester (8.35 g, 72% for two steps). MS (ES+): 233 (M+H); (ES−): 231 (M−H).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:12][NH2:13]>>[C:1]1([S:7]([NH:12][NH2:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NN
Solvent: O
Product: NNS(=O)(=O)c1ccccc1

Procedure:
Benzenesulfonohydrazide is prepared from benzenesulfonyl chloride (500 mg, 2.83 mmol) and hydrazine monohydrate (0.42 mL, 8.49 mmol) according to the experimental provided in Tetrahedron 2002, 58, 5513. The product is recrystallized from EtOAc/Hexane. The yield is 136 mg of benzenesulfonohydrazide, 28%.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]#[C:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].O.[OH-].[Li+]>CO>[CH3:15][C:14]([CH3:17])([CH3:16])[C:13]#[C:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[CH:11]=1
Reactant: COC(=O)c1ccc(C#CC(C)(C)C)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)C#Cc1ccc(C(=O)O)c(F)c1
Temperature: 25 °C

Procedure:
Methyl 2-fluoro-4-(3,3-dimethylbut-1-ynyl)benzoate (8.2 g, 0.035 mol) was suspended in a 3:1 mixture of H2O and methanol to which was added lithium hydroxide (2.5 g, 0.10 mol) all at once and the mixture was agitated over-night at ambient temperature. The mixture was then concentrated to ¾ the volume and acidified with 1N HCl until the pH read just acidic. The white precipitate was filtered, washed with water and vacuum dried at 80° C. for several hours. m/z=218.9 (M−1).
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].CN(C)C=O.N1C=CN=C1.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[C:23]([I:27])=[CH:22][C:21]=1[OH:28]>O>[C:2]([Si:5]([O:28][C:21]1[CH:22]=[C:23]([I:27])[C:24]([Cl:26])=[CH:25][C:20]=1[Cl:19])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cc(I)c(Cl)cc1Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cc(I)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
TBDMSCl (5.22 g) was added to a dimethylformamide solution (50 mL) of imidazole (2.83 g) and 2,4-dichloro-5-iodophenol (10 g), which was synthesized according to the production method described in WO 2001/027088. The mixture was stirred at room temperature for 4 hours. Water (150 mL) was added and extracted with hexane (200 mL). The extract was then washed in succession twice with water (100 mL) and once with brine (100 mL), and was pre-dried over anhydrous sodium sulfate, and then filtered. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (developing solvent: hexane) to give tert-butyl-(2,4-dichloro-5-iodophenoxy)-dimethyl-silane as pale yellow oil (11.39 g).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:16]([OH:19])([CH3:18])[CH3:17])[CH:11]=3)[N:6]=[C:5]2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:23][CH:22]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCCCc1nc(=O)c2cc(C(C)(C)O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCc1nc2ccc(C(C)(C)O)cc2c(=O)n1Cc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a solution of 1.37 g of 2-butyl-6-(1-hydroxy-1-methylethyl)-4(1H)-quinazolinone in 115 ml of acetone is added 1.58 g of 4-bromobenzyl bromide and 2.18 g of anhydrous potassium carbonate. The resulting suspension is heated to reflux for 16 hours. The reaction mixture is then allowed to cool to room temperature, filtered and the filtrate is concentrated vacuo. The residue is purified by HPLC eluting with ethyl acetate/hexanes (1:3) to provide the desired product.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([C:11]1[S:12][CH:13]=[C:14]([C:16]([N:18]2[CH2:23][C:22]3([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[O:21][CH2:20][CH2:19]2)=[O:17])[N:15]=1)([CH3:10])[CH3:9].[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][C:31]=1[CH2:38][CH2:39][OH:40].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CN1C(=O)CCC1.C(O)(=O)C>[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][N:26]2[CH2:25][CH2:24][C:22]3([O:21][CH2:20][CH2:19][N:18]([C:16]([C:14]4[N:15]=[C:11]([CH:8]([CH3:10])[CH3:9])[S:12][CH:13]=4)=[O:17])[CH2:23]3)[CH2:28][CH2:27]2)=[CH:32][C:31]=1[CH2:38][CH2:39][OH:40]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: O=Cc1ccc(Cl)c(CCO)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4ccc(Cl)c(CCO)c4)CC3)C2)cs1
Reaction time: 0.08 h

Procedure:
A solution of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 22, step b) (0.178 g) in NMP (2 mL) was treated with acetic acid (0.032 mL) and stirred for 5 minutes. A solution of 4-chloro-3-(2-hydroxyethyl)benzaldehyde (example 75, step c) (0.154 g) in NMP (3 mL) was then added, the resulting solution was stirred for 1 hour and was then treated with sodium triacetoxyborohydride (0.181 g) and stirred overnight at room temperature. More sodium triacetoxyborohydride (0.404 g) was added and the mixture was stirred for an additional 6 hours, then poured into saturated sodium bicarbonate and extracted twice with ethyl acetate. The combined extracts were washed three times with water, once with brine, then dried over anhydrous magnesium sulphate and purified by flash chromatography on silica eluted with 1:2:97 triethylamine:methanol:dichloromethane to afford the subtitled compound as a colourless gum. Yield 0.157 g.