Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][SiH:2]([C:22]1[CH:27]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:25]([O:32][Si](C)(C)C)=[C:24]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:23]=1)[C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([O:13][Si](C)(C)C)=[C:5]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:4]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1>[CH3:1][SiH:2]([C:3]1[CH:4]=[C:5]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:6]([OH:13])=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:8]=1)[C:22]1[CH:23]=[C:24]([C:37]([CH3:40])([CH3:38])[CH3:39])[C:25]([OH:32])=[C:26]([C:28]([CH3:30])([CH3:31])[CH3:29])[CH:27]=1
Reactant: C[SiH](c1cc(C(C)(C)C)c(O[Si](C)(C)C)c(C(C)(C)C)c1)c1cc(C(C)(C)C)c(O[Si](C)(C)C)c(C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C[SiH](c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.4 %

Procedure:
To a solution of 6.0 g (10 mmol) of methylbis (3,5-di-tert-butyl-4-trimethylsilyloxyphenyl)silane in 30 ml of tetrahydrofuran is added dropwise a solution of 6.3 g (20 mmol) of tetrabutylammonium fluoride trihydrate in 35 ml of tetrahydrofuran. A vigorous evolution of gas is witnessed during the addition and the reaction mixture becomes green in color. The reaction mixture is stirred for 5 minutes at room temperature and to it is added dropwise a solution of 1.9 g (52 mmol) of concentrated hydrochloric acid in 10 ml of tetrahydrofuran. The solvent is removed in vacuo and the residue is recrystallized from n-propyl alcohol to give 2.7 grams of white solid which is a mixture of two products. The product mixture is separated by preparative HPLC (silica gel, 99:1, heptane, ethyl acetate) to give 0.4 g (9%) of the desired product as white crystals; mp. 191°-193.5° C.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]2[N:6]3[C:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)=[CH:9][C:8]([C:14]([OH:16])=O)=[N:7]3.[CH:19]([NH:22][CH2:23][CH2:24][OH:25])([CH3:21])[CH3:20].C(N(CC)CC)C>[Pd]>[OH:25][CH2:24][CH2:23][N:22]([CH:19]([CH3:21])[CH3:20])[C:14]([C:8]1[CH:9]=[C:10]2[N:6]([C:5]3[CH:17]=[CH:18][CH:2]=[CH:3][C:4]=3[O:13][CH2:12][CH2:11]2)[N:7]=1)=[O:16]
Reactant: O=C(O)c1cc2n(n1)-c1ccc(Br)cc1OCC2
Reactant: CC(C)NCCO
Agent: [Pd]
Solvent: CCN(CC)CC
Product: CC(C)N(CCO)C(=O)c1cc2n(n1)-c1ccccc1OCC2
Reaction time: 2.75 h
Yield: 68 %

Procedure:
Following the procedure for 116, 8-bromo-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-2-carboxylic acid was reacted with 2-isopropylamino-ethanol. The intermediate formed (145 mg, 0.37 mmol) was dissolved in IMS (10 mL) and triethylamine (50 L, 0.37 mmol) then 10% Pd/C (20 mg) added before the reaction mixture stirred under hydrogen (1 atmosphere) for 2.75 h. The reaction mixture was filtered through Celite® and the filtrate concentrated in vacuo. The resultant residue was partitioned between DCM and water, the aqueous layer was isolated and extracted with DCM. The combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was dissolved in diethyl ether and the solution washed with water, dried (Na2SO4), filtered and then concentrated in vacuo to give 140 (79 mg, 68%). 1H NMR (DMSO-d6, 400 MHz): δ 7.83 (dd, J=8.0, 1.6 Hz, 1H); 7.30 (td, J=7.6, 1.8 Hz, 1H); 7.26-7.16 (m, 2H); 6.54 (s, 1H); 4.67-4.53 (m, 1H); 4.46 (t, J=6.0 Hz, 2H); 4.35-4.27 (m, 1H); 3.64-3.56 (m, 2H); 3.55-3.46 (m, 2H); 3.13 (t, J=6.0 Hz, 2H); 1.22 (d, J=6.8 Hz, 6H). LCMS: RT=9.00 min, M+H+=316
Reaction SMILES: C([O:3][C:4](=O)[C:5]([NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([C:23](=[O:29])[N:24]([CH:26]([CH3:28])[CH3:27])[CH3:25])[CH:17]=2)=[C:10]([CH3:30])[CH:9]=1)=[O:6])C.S([O-])([O-])(=O)=O.[Mg+2].[NH3:38]>CCO.C(Cl)Cl>[OH:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:11]2[C:10]([CH3:30])=[CH:9][C:8]([NH:7][C:5]([C:4]([NH2:38])=[O:3])=[O:6])=[CH:13][C:12]=2[CH3:14])=[CH:17][C:18]=1[C:23](=[O:29])[N:24]([CH:26]([CH3:28])[CH3:27])[CH3:25]
Reactant: N
Reactant: CCOC(=O)C(=O)Nc1cc(C)c(Oc2ccc(O)c(C(=O)N(C)C(C)C)c2)c(C)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(NC(=O)C(N)=O)cc(C)c1Oc1ccc(O)c(C(=O)N(C)C(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of N-{4-[4-hydroxy-3-(isopropylmethylcarbamoyl)-phenoxy]-3,5-dimethyl-phenyl}-oxamic acid ethyl ester (7.1 mg, 0.017 mmol) in 1 mL of EtOH in the presence of magnesium sulfate (10 mg) at 0° C. was bubbled in NH3 gas for 10 min. The solution was allowed to warm to RT. After stirring at RT for 0.5 h, the solution was diluted with 2 mL of CH2Cl2 and filtered. The filtrate was concentrated to give the title compound as a white solid. MS Calc.: 399.5 Found: 398.4 (M−1).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:10]=[C:9]([F:11])[C:7]([NH2:8])=[C:6]([F:12])[CH:5]=1.[CH2:13]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](Cl)=[N:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:32][CH3:33])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:13]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([NH:8][C:7]3[C:9]([F:11])=[CH:10][C:4]([Br:3])=[CH:5][C:6]=3[F:12])=[N:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:32][CH3:33])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(F)cc(Br)cc3F)ncnc2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
Sodium hydride (60%, 612 mg, 15.3 mmol) was added to a solution of 4-bromo-2,6-difluoroaniline (2.77 g, 6.65 mmol) in DMF (80 ml). After stirring for 30 minutes at ambient temperature, 7-benzyloxy-4-chloro-6-methoxyquinazoline (2 g, 6.65 mmol), (prepared, for example, as described in WO 97/22596, Example 1, but the free base was generated prior to use), was added and stirring was maintained for 4 hours. The mixture was partitioned between ethyl acetate and water (200 ml). The organic layer was separated, washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was triturated with isopropanol, collected by filtration, washed with ether and dried under vacuum to give 7-benzyloxy-4-(4-bromo-2,6-difluoroanilino)-6-methoxyquinazoline (1.95 g, 62%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:11]([N:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:13])[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1)=[O:5])[CH3:2].[ClH:28]>C(OCC)(=O)C.O1CCOCC1>[ClH:28].[ClH:28].[CH2:1]([O:3][C:4]([C@H:6]1[C@H:11]([N:12]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:13])[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N(C)Cc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H]1CNCC[C@H]1N(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of trans-4-(benzyl-methyl-amino)-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (235 mg, 624 μmol) in ethyl acetate (2 mL) was stirred on an ice bath and treated with 4.0 N hydrogen chloride in dioxane (6 mL). The bath was removed, and the mixture was stirred at room temperature for 18 hours. The mixture was then concentrated under vacuum, and the residue was stirred in ether, and the ether was decanted. The ether treatment was repeated twice more, and the residue was dried under vacuum to provide a white powder (231 mg) which was used without purification. 1H NMR (300 MHz, methanol-d4) δ7.60 (m, 2H), 7.54 (m, 3H), 4.6-3.8 (m, 6H), 3.68 (m, 2H), 3.4-3.0 (m, 2H), 2.90 (s, 3H), 2.52 (m, 1H), 2.28 (m, 1H), 1.35 (m, 3H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH:5]([O:7][CH3:8])[CH2:4][C@H:3]1[OH:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([O:1][C@@H:2]1[CH2:6][CH:5]([O:7][CH3:8])[CH2:4][C@H:3]1[O:9][S:18]([CH3:17])(=[O:20])=[O:19])(=[O:20])=[O:19]
Reactant: COC1C[C@@H](O)[C@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1C[C@@H](OS(C)(=O)=O)[C@H](OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 1.33 h

Procedure:
(1R*,2R*)-1,2-Dihydroxy-4-methoxycyclopentane (1.21 g) and triethylamine (7.66 ml) were dissolved in dichloromethane (20 ml), and methanesulfonyl chloride (2.13 ml) was added dropwise over 20 minutes at −78° C. After completion of drop addition, the mixture was warmed to 0° C. and stirred for 80 minutes to obtain crude (1R*,2R*)-1,2-bis(methanesulfonyloxy)-4-methoxy-cyclopentane. This product was dissolved in N,N-dimethylformamide (20 ml), and sodium azide (3.57 g) was added. The mixture was stirred at 65° C. for 22 hours. Sodium azide (3.57 g) was additionally added to stir the mixture at 70° C. for 2 days. The reaction mixture was allowed to cool, and water and diethyl ether was added to separate an organic layer. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate 2:1) to obtain the title compound (584 mg) as a colorless liquid.
Reaction SMILES: C(O)(=[O:3])C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[N:23]1[CH:28]=[CH:27][C:26]([S:29][C:30]2[CH2:31][C@@H:32]3[C@H:42]([C@H:43]([C:49](C)(C)C)CO[SiH](C)C)[C:41](=[O:53])[N:33]3[C:34]=2[C:35]([O:37][CH2:38][CH:39]=[CH2:40])=[O:36])=[CH:25][CH:24]=1>C1COCC1>[N:23]1[CH:28]=[CH:27][C:26]([S:29][C:30]2[CH2:31][C@@H:32]3[C@@H:42]([C@H:43]([OH:3])[CH3:49])[C:41](=[O:53])[N:33]3[C:34]=2[C:35]([O:37][CH2:38][CH:39]=[CH2:40])=[O:36])=[CH:25][CH:24]=1
Reactant: C=CCOC(=O)C1=C(Sc2ccncc2)C[C@@H]2[C@H]([C@@H](CO[SiH](C)C)C(C)(C)C)C(=O)N12
Reactant: CC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCOC(=O)C1=C(Sc2ccncc2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reaction time: 62 h
Yield: 21 %

Procedure:
3.69 ml (64.5 mmol - 10 equivalents) of glacial acetic acid and 19.3 ml (19.3 mmol - 3 equivalents) of a 1M solution of tetrabutylammonium fluoride in THF were added to a solution, which had been cooled to 0° C., of 2.97 g (6.5 mmol) of allyl (5R,6S)-2-(4-pyridylthio)-6-[(1R)-1-tert.-butyldimethylsilyloxyethyl]carbapen-2-em-3-carboxylate in 60 ml of THF. The cooling bath was removed and the reaction solution was allowed to stand at room temperature for 62 h. To work up, it was poured a into a mixture of cold, saturated NaHCO3 solution and ethyl acetate, extraction with ethyl acetate was carried out, followed by washing with saturated NaHCO3 and NaCl solutions and drying over MgSO4. After evaporation of the solvent in vacuo and chromatography of the residue on 360 g of silica gel (toluene:ethyl acetate 9:1), 472 mg (21%) of the title compound were obtained as an oil, Rf: 0.24 (toluene:ethyl acetate 9:1).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:2]1=[O:3].[C:12]1(=[O:17])[O:16][CH2:15][CH2:14][CH2:13]1>>[OH:17][CH2:12][CH2:13][CH2:14][C:15]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[NH:1][C:2](=[O:3])[CH2:4][CH2:5]2)=[O:16]
Reactant: O=C1CCc2ccccc2N1
Reactant: O=C1CCCO1
Product: O=C1CCc2cc(C(=O)CCCO)ccc2N1
Temperature: 0 °C
Reaction time: 10 h

Procedure:
14.4 Grams of 3,4-dihydrocarbostyril and 10 g of γ-butyrolacton were mixed into 120 g of polyphosphoric acid and stirred at 80°-90° C. for 10 hours. The reaction mixture was poured into 300 ml of ice-water and was allowed to stand overnight. Then the precipitates thus formed were collected by filtration and washed with water, then recrystallized from ethanol-ethyl acetate to obtain 9.5 g of 6-(4-hydroxy-1-oxobutyl)-3,4-dihydrocarbostyril, having the melting point of 175°-176° C. in colorless prism-like crystals. Next, 5 g of 6-(4-hydroxy-1-oxobutyl)-3,4-dihydrocarbostyril and 0.5 g of palladium black wre mixed in 160 ml of ethanol and the mixture was subjected to catalytic reduction under 3 kg/cm2 of hydrogen gas at 60° C. for 6 hours. The reaction mixture was then cool and was added 1 ml of concentrated hydrochloric acid thereinto. Further the reaction mixture was subjected to the catalytic reduction under 3 kg/cm2 of hydrogen gas for 6 hours. The reaction mixture was filtered and the mother liquor was concentrated under a reduced pressure. The residue was recrystallized from ligroin to obtain 3.2 g of 6-(4-hydroxybutyl)-3,4-dihydrocarboxtryril, having the melting point of 133°-134° C. Next, 3.2 g of 6-(4-hydroxybutyl)-3,4-dihydrocarbostyril and 5 ml of thionyl chloride were mixed into 50 ml of chloroform and the mixture was stirred at a room temperature for 24 hours. The reaction mixture was concentrated under a reduced pressure. The residue was then recrystallized from ligroin to obtain 1.8 g of 6 -(4-chlorobutyl)-3,4-dihydrocarbostryl, having the melting point of 119°-121° C., in colorless prism-like crystals.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[N:12]=3)=[CH:9][N:8]=[C:7](SC)[N:6]=2)[CH2:3][CH2:2]1.[CH:26]([NH2:29])([CH3:28])[CH3:27]>CS(C)=O>[CH:1]1([CH2:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[N:12]=3)=[CH:9][N:8]=[C:7]([NH:29][CH:26]([CH3:28])[CH3:27])[N:6]=2)[CH2:3][CH2:2]1
Reactant: CSc1ncc(-c2ccnc(Nc3ccncc3)n2)c(CC2CC2)n1
Reactant: CC(C)N
Solvent: CS(C)=O
Product: CC(C)Nc1ncc(-c2ccnc(Nc3ccncc3)n2)c(CC2CC2)n1
Yield: 39.4 %

Procedure:
To a solution of 4′-(cyclopropylmethyl)-2′-(methylsulfanyl)-N-pyridin-4-yl-4,5′-bipyrimidin-2-amine (11) (35 mg, 0.096 mmol) in DMSO (1 mL), isopropylamine (24.55 μl, 0.287 mmol) was added and the reaction was microwaved for 20 minutes at 160° C. The crude product was purified by reverse-phase HPLC [30-100% organic phase over 15 minutes] followed by Biotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 10% MeOH/DCM] to afford the title compound as a pale-yellow solid (13.67 mg, 39.6% yield). 1H NMR (400 MHz, MeOD) δ ppm 0.04-0.17 (m, 2 H) 0.31-0.50 (m, 2 H) 0.97-1.17 (m, 1 H) 1.27 (d, J=6.57 Hz, 6 H) 2.88 (d, J=7.07 Hz, 2 H) 4.22 (ddd, J=13.01, 6.44, 6.32 Hz, 1 H) 7.10 (d, J=5.05 Hz, 1 H) 7.84 (d, J=7.07 Hz, 2 H) 8.30 (d, J=6.57 Hz, 2 H) 8.42 (s, 1 H) 8.55 (d, J=5.05 Hz, 1 H). HRMS (ES+) for C20 H23N7.H+ [MH+]: calcd, 362.2093. found, 362.2083. UV-LC: 100% UV purity at 254/214 nm; tR=3.39 minutes over 7.75 minutes.
Reaction SMILES: C(NC(C)C)(C)C.[CH3:8][O:9][C:10](=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1.Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>O1CCCC1>[CH3:8][O:9][C:10](=[O:20])[CH:11]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(CC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
2.5M nButyllithium in hexanes (37.5 ml, 0.094 mol) was added, in a dropwise fashion, to a solution of diisopropylamine (14.45 ml, 0.103 mol) in tetrahydrofuran (300 ml) at 0° C. The solution was stirred at 0° C. for 20 minutes. The mixture was then cooled to −70° C. and a solution of (3,4-dichloro-phenyl)-acetic acid methyl ester (20.54 g, 0.094 mol) in tetrahydrofuran (50 ml) was added dropwise via cannula. The reaction mixture was stirred at −70° C. for 30 minutes. After this time, tert-butyl bromoacetate (45.42 ml, 0.281 mol) was added in a dropwise fashion. The cooling bath was removed and the reaction mixture was allowed to warm up to room temperature. The reaction mixture was quenched with a saturated solution of NH4Cl (100 ml). THF was partially removed in vacuo and the mixture was extracted with EtOAc (3×200 ml). The combined organic extrats were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by silica gel column chromatography using as eluent petrol: ether (9:1) to give the title compound in 92% yield.). 1H NMR (400 MHz, DMSO-d6) δ 1.34 (9H, s), 2.65 (1H, dd), 2.98 (1H, dd), 3.60 (3H, s), 4.08 (1H, m), 7.31 (1H, m), 7.58–7.62 (2H, m); MS (ES+): m/e=333.2 (5%); MS (ES−): m/e=331.2 (100%), 333.2 (65%), 335.2 (10%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:20]=O)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:22]=1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH2:20][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:22]=1
Reactant: C1CCNC1
Reactant: COC(=O)c1nc2n(c1C=O)C1CC(C1)c1ccc(Br)cc1-2
Product: COC(=O)c1nc2n(c1CN1CCCC1)C1CC(C1)c1ccc(Br)cc1-2
Yield: 70 %

Procedure:
Methyl 10-bromo-3-formyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was reacted with pyrrolidine similarly to as described in Example 7 to afford 320 mg (70%) of methyl 10-bromo-3-(pyrrolidin-1-ylmethyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate as a white solid. methyl 10-bromo-3-(pyrrolidin-1-ylmethyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was subjected to General Procedure L to afford 130 mg (47%) of 10-bromo-3-(pyrrolidin-1-ylmethyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide. 10-bromo-3-(pyrrolidin-1-ylmethyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford 14 mg (19%) of 10-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-3-(pyrrolidin-1-ylmethyl)-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[H-].[Na+].O.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Cl>O1CCCC1>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:10])[CH3:1]
Reactant: COc1ccccc1CCl
Reactant: CN(C)CCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1COCCCCCCN(C)C
Reaction time: 0.75 h

Procedure:
6-(Dimethylamino)hexanol (8.80 g, 60.6 mmol) was dissolved in an anhydrous 2:1 mixture of tetrahydrofuran and dimethylfornamide (150 mL) and the solution was cooled in an ice bath. Sodium hydride (60% in oil, 3.23 g, 80.8 mmol) was added in portions and after 5 min. the water bath was removed. After 45 min., 2-methoxybenzyl chloride (6.28 g, 40.4 mmol) was added. After 4 h, the reaction mixture was quenched with 1 M sodium thiosulfate and tetrahydrofuran was removed in vacuo. The reaction mixture was washed with ethyl acetate and the aqueous phase was basified with 3 M sodium hydroxide, followed by extraction with ether. The ether layer was dried over potassium carbonate, filtered and acidified with 4 M hydrochloric acid in dioxane. The reaction mixture was concentrated in vacuo and the residue was crystallized form ethanol/ether to give O-(2-methoxybenzyl)-6-dimethylaminohexanol as the hydrochloride salt (10.4 g, 85%). MS (M-Cl)+266.3.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:26][O:27][CH3:28])[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([O-:23])=[O:22])=[C:15]([CH2:18][O:19][CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].FC(F)(F)C([O-])=O.[C:37]([O:43][CH2:44]I)(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39].C(OCC)(=O)C>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:26][O:27][CH3:28])[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([O:23][CH2:44][O:43][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[O:22])=[C:15]([CH2:18][O:19][CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(C)C(=O)OCI
Reactant: COCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COCC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Yield: 90.4 %

Procedure:
To a solution of 45 mg of sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylate (prepared from the corresponding trifluoroacetate) in 1 ml of dimethylacetamide were added, at -15° C., 27 mg of iodomethyl pivalate and the mixture was allowed to react for 15 minutes. At the end of this time, 20 ml of ethyl acetate were added to the reaction mixture, and the mixture was washed, in turn, with water, an aqueous solution of potassium bisulphate and an aqueous solution of sodium bicarbonate. The organic phase was separated and concentrated by evaporation under reduced pressure, and the residue was subjected to column chromatography through silica gel eluted with a 3:1 by volume mixture of ethyl acetate and hexane, to give 49 mg of the title compound, whose properties were identical with those of the compound obtained in Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=3)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[CH2:30][C:31](=O)[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C(#N)C>[CH2:35]([O:34][C:32]([C:31]1[N:1]=[C:2]2[CH:7]=[C:6]([NH:8][C:9]([C:11]3[N:12]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=4)=[O:10])[CH:5]=[CH:4][N:3]2[CH:30]=1)=[O:33])[CH3:36]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1cc(NC(=O)c2cc3cc(F)ccc3n2Cc2cccc(F)c2)ccn1
Solvent: CC#N
Product: CCOC(=O)c1cn2ccc(NC(=O)c3cc4cc(F)ccc4n3Cc3cccc(F)c3)cc2n1
Yield: 27.8 %

Procedure:
The compound is prepared according to a process similar to that described in step 4.3, by reacting 0.2 g (0.53 mmol) of N-[2-aminopyrid-4-yl]-5-fluoro-1-[(3-fluorophenyl)-methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 10.1, with 0.21 g (1.06 mmol) of ethyl 3-bromo-2-oxopropionate in 8 mL of acetonitrile. 70 mg of the expected product are thus obtained.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[CH:20][CH:19]=[CH:18]4)=[O:14])=[CH:11][N:12]=2)[N:9]=1.O>C(O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([CH:13]([C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[CH:20][CH:19]=[CH:18]4)[OH:14])=[CH:11][N:12]=2)[N:9]=1
Reactant: O=C(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium borohydride (103 mg, 2.62 mmol) was added to a solution of (6-chloro-imidazo[1,2-b]pyridazin-3-yl)-quinolin-6-yl-methanone (Stage 1.2, 1.62 g, 5.25 mmol) in ethanol (17 mL) and the solution was stirred at rt for 4 h. Water was then added and the mixture extracted with 9:1 DCM/MeOH. The organic extracts were dried, filtered and concentrated to afford the title compound as a brown solid (tR 1.0 min (conditions 1), MH+=311).