Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[Li].O.[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([C:32](=[O:34])[NH2:33])([NH:17][C:18]([CH:20]2[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][C:28]([F:31])([F:30])[F:29])[CH2:22][CH2:21]2)=O)[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].[Cl-].[NH4+]>C(O)C>[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2([N:17]=[C:18]([CH:20]3[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][C:28]([F:31])([F:30])[F:29])[CH2:22][CH2:21]3)[NH:33][C:32]2=[O:34])[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)C2CCC(CCC(F)(F)F)CC2)(C(N)=O)CC1
Agent: [Cl-]
Agent: [Li]O
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)N=C(C1CCC(CCC(F)(F)F)CC1)NC2=O
Temperature: 85 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
LiOH.H2O (1.55 g, 36.9 mmol) was added to a solution of 4-carbamoyl-4-{[4-(3,3,3-trifluoro-propyl)-cyclohexanecarbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (5.53 g, 12.3 mmol) in ethanol (123 mL), and the mixture was stirred at 85° C. for two hours. A 50% saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was then dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by reprecipitation with hexane-ethyl acetate=3:1 to give 4-oxo-2-[4-(3,3,3-trifluoro-propyl)-cyclohexyl]-1,3,8-triaza-spiro[4.5]dec-1-ene-8-carboxylic acid tert-butyl ester (4.88 g, 92%).
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:15]2[NH:16][C:17](=[O:19])[O:18][C@H:14]2[CH2:13][C@H:12]([CH:20]=[O:21])[C@H:11]1[O:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](Cl)(=[O:33])[CH3:32].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:9][C@@H:10]1[C@H:15]2[N:16]([C:31](=[O:33])[CH3:32])[C:17](=[O:19])[O:18][C@H:14]2[CH2:13][C@H:12]([CH:20]=[O:21])[C@H:11]1[O:22][C:23](=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: O=C[C@H]1C[C@@H]2OC(=O)N[C@@H]2[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1C(=O)O[C@H]2C[C@H](C=O)[C@@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@H]21
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
To a solution of (3aS,4R,5R,6S,7aS)-6-formyl-2-oxooctahydrobenzo[d]oxazole-4,5-diyl dibenzoate (580 mg, 1.42 mmol) in dry DCM (10 mL) at 0° C. under N2 was added a solution of acetyl chloride (223 mg, 2.84 mmol) in dry DCM (2.84 mL) followed by a solution of DIPEA (330 mg, 2.56 mmol) in dry DCM (2.56 mL) dropwise. The mixture was stirred at 0° C. for 2 h. The reaction was further diluted with DCM (20 mL), washed with 0.1 N HCl and brine. The solvent was evaporated to give the crude (3aS,4R,5R,6S,7aS)-3-acetyl-6-formyl-2-oxooctahydrobenzo[d]oxazole-4,5-diyl dibenzoate (614 mg, 96%) which was carried onto next reaction without further purification. 1H NMR (400 MHz, CDCl3) δ 9.89 (s, 1H), 7.93 (d, J=7.8 Hz, 2H), 7.90 (d, J=7.8 Hz, 2H), 7.54-7.59 (m, 2H), 7.40-7.44 (m, 4H), 5.79 (dd, J=5.7 Hz, 4.1 Hz, 1H), 5.68 (t, J=5.7 Hz, 1H), 5.01-5.04 (m, 1H), 4.82 (dd, J=7.7 Hz, 4.0 Hz, 1H), 3.13-3.19 (m, 1H), 2.54-2.60 (m, 1H), 2.50 (s, 3H), 2.26-2.34 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>ClCCl.C(N(C(C)C)CC)(C)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:16]([F:15])=[CH:17][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 70.6 %

Procedure:
To a solution of 1-benzyl-4-aminopiperidine (1.13 g) in dichloromethane (10 ml) were added a solution of 4-fluorobenzoyl chloride (0.99 g) in dichloromethane (1 ml) and diisopropylethylamine (1.09 ml) under cooling on an ice-water bath. The mixture was warmed to ambient temperature slowly under stirring. The mixture was diluted with dichloromethane and washed with water, saturated aqueous sodium hydrogen carbonate, water, and brine. After drying with magnesium sulfate, the solvents were removed under reduced pressure. A residue was purified by column chromatography (silica gel 100 ml, dichloromethane:methanol=15:1). After rinse with diisopropyl ether-n-hexane (1:1), N-(1-benzylpiperidin-4-yl)-4-fluorobenzamide (1.31 g) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[C:16](Cl)(=[O:18])[CH3:17].C(N(C(C)C)CC)(C)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:16](=[O:18])[CH3:17])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC1CCCc2c1[nH]c1ccc(Br)cc21

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)acetamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and acetyl chloride in the presence of diisopropylethylamine to give a tan solid (52% yield). 1H-NMR (CDCl3): δ 8.86 (s, 1H), 7.59 (m, 1H), 7.22 (m, 1H), 7.16 (d, 1H), 5.80 (m, 1H), 5.10 (m, 1H), 2.67 (m, 2H), 2.22 (m, 1H), 2.04 (s, 3H), 1.91 (m, 2H), 1.81 (m, 1H); MS m/z 306 (M−1).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]([N:16]1[C:20]([CH2:21][CH2:22][CH2:23][C:24]([O:26]CC)=O)=[CH:19][N:18]=[CH:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:9]([N:16]1[C:20]([CH2:21][CH2:22][CH2:23][C:24]([OH:26])([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:19][N:18]=[CH:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Brc1ccccc1
Reactant: CCOC(=O)CCCc1cncn1Cc1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(CCCc1cncn1Cc1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Magnesium turnings (0,49 g) are covered with 4 ml of dry tetrahydrofuran. Brombenzene (3,18 g) in 7 ml of dry tetrahydrofuran is added dropwise to the mixture at such a rate that a smooth reaction is maintained. The reaction mixture is refluxed for an additional hour. Ethyl 4-(1-benzyl-1H-imidazol-5-yl)butyrate (1,10 g) in 15 ml of dry tetrahydrofuran is then added dropwise to the Grignard reagent and the reaction mixture is refluxed for 2 hours. Saturated ammonium chloride is added to the cooled reaction mixture. Tetrahydrofuran is evaporated and the precipitated product is collected. Yield 1,41 g. Melting point of the hydrochloride salt is 197°-201° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:11]2[C:12]([CH3:26])=[N:13][N:14]3[C:19](C(CC)CC)=[CH:18][C:17]([CH3:25])=[N:16][C:15]=23)=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[CH3:27][NH:28][CH3:29]>CO>[CH2:5]([CH:4]([C:15]1[N:14]2[N:13]=[C:12]([CH3:26])[C:11]([C:4]3[S:3][C:2]([N:28]([CH3:29])[CH3:27])=[N:6][C:5]=3[C:7]([F:8])([F:10])[F:9])=[C:19]2[CH:18]=[C:17]([CH3:25])[N:16]=1)[CH2:11][CH3:15])[CH3:7]
Reactant: CNC
Reactant: CCC(CC)c1cc(C)nc2c(-c3sc(Br)nc3C(F)(F)F)c(C)nn12
Solvent: CO
Product: CCC(CC)c1nc(C)cc2c(-c3sc(N(C)C)nc3C(F)(F)F)c(C)nn12
Yield: 194.4 %

Procedure:
Heat a sealed tube containing 3-(2-bromo-4-trifluoromethyl-thiazol-5-yl)-7-(1-ethyl-propyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (313 mg, 0.7 mmol), and dimethyl amine (2 M in THF, 4 mL, 8 mmol) in methanol (4 mL) to 80° C. for 2 h. Cool the reaction and concentrate under vacuum. Purify the resulting residue by silica gel chromatography, eluting with 0-30% ethyl acetate in CH2Cl2, to give the title compound (0.28 g, 97%). HR-ToF-MS m/z calcd for C19H24F3N5S+H+ 412.1770, found: 412.1783.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][OH:8])(=[O:4])=[O:3].Cl[C:10]([O:12][CH3:13])=[O:11]>N1C=CC=CC=1>[C:10](=[O:11])([O:12][CH3:13])[O:8][CH2:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: COC(=O)Cl
Reactant: CS(=O)(=O)CCCO
Solvent: c1ccncc1
Product: COC(=O)OCCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 70.6 %

Procedure:
A 100 ml 3-neck round bottom flask, fitted with a magnetic stir bar, rubber septum and hose adapter, was flushed with dry nitrogen and was charged via syringe with 17.53 g (0.127 mol) 3-(methylsulfonyl)-1-propanol and 19 ml anhydrous pyridine. The resulting mixture was cooled in an ice-water bath. Methyl chloroformate (13.3 g; 0.141 mol) was added dropwise to the mixture via syringe over 45 minutes. The ice-water bath was then removed, and the mixture was allowed to stir at room temperature. After 3.5 hours, the resulting white opaque mixture was poured into 120 ml of ice cold 10% aqueous HCl in a separatory funnel, and the resulting solution was extracted four times with 50 ml aliquots of CH2Cl2. The resulting organic extracts were combined and dried over Na2SO4. Solvent removal under reduced pressure on a rotary evaporator left a clear pale yellow liquid, which solidified as it cooled. The resulting solid was purified by recrystallization from t-butyl methyl ether to give 17.6 g of white needles, m.p. 55-56.5° C., and a filtrate that was then concentrated to provide a second batch of crystals (1.9 g), m.p. =55-57° C., to yield a total of 19.5 g (78% yield) of 3-(methylsulfonyl) propyl methyl carbonate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][CH:13]([CH3:23])[CH2:14][CH2:15][NH:16][C@H:17]([C:19]([O:21][CH3:22])=[O:20])[CH3:18].C(=O)(O)[O-].[K+]>CCOCC>[Cl:1][C:2]1[N:7]=[C:6]([N:16]([CH2:15][CH2:14][CH:13]([CH3:23])[CH3:12])[C@H:17]([C:19]([O:21][CH3:22])=[O:20])[CH3:18])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: COC(=O)[C@H](C)NCCC(C)C
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Product: COC(=O)[C@H](C)N(CCC(C)C)c1nc(Cl)ncc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 51 %

Procedure:
A solution of 2,4-dichloro-5-nitropyrimidine (27.8 g, 144 mmol) in ether (350 mL) was cooled to −10° C. and was treated with methyl N-(3-methylbutyl)alaninate (20.8 g, 120 mmol). A solution of potassium bicarbonate (25.0 g in 180 mL water) was added drop wise maintaining the temperature below 0° C. Reaction mixture was then allowed to come to room temperature and stirred for 2 h. Ether layer was separated, the aq. layer was extracted with ether (3×100 mL). Combined ether solution was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate-hexane mixture (v:v=5:95) to give titled product (yield: 51%). 1HNMR (300 MHz, CDCl3): δ 0.90-1.01 (m, 6H), 1.40-1.61 (m, 6H), 3.10-3.21 (m, 1H), 3.39-3.45 (m, 1H), 3.78 (s, 3H), 4.41-4.50 (s, 1H), 8.71 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[NH:8][C:9](=[O:24])[C:10]1[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[C:12]([O:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:11]=1.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.[Xe](F)[F:42]>ClCCl>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[NH:8][C:9](=[O:24])[C:10]1[CH:15]=[CH:14][C:13]([S:16][CH2:17][F:42])=[C:12]([O:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:11]=1
Reactant: F[Xe]F
Reactant: CSc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1OC1CCCC1
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Solvent: ClCCl
Product: O=C(Nc1c(Cl)cncc1Cl)c1ccc(SCF)c(OC2CCCC2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-(methylthio)benzamide (1 g; that is prepared as described in Example 20) in dichloromethane (100 mL), containing molecular sieve 4A, under nitrogen, is treated with 2,6-di-tert-butyl-4-methylpyridine (1.28 g). The resulting mixture is stirred at room temperature for 1.5 hours, and then it is cooled to 0° C. (in an ice/salt bath) and treated with xenon difluoride (0.51 g) in one portion. After stirring for a further 2 hours in the cold, the mixture is filtered, and the flitrate is washed with saturated aqueous ammonium chloride solution. The organic phase is dried over sodium sulfate and evaporated. The resulting residue is subjected to flash chromatography, eluting with a mixture of ethyl acetate and pentane (2:3 v/v), to give impure N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-(fluoromethylthio)-benzamide (600 mg). It is further purified by reversed phase HPLC on octadecylsilyl silica gel, eluting with a mixture of methanol and water (7:3 v/v), to give N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-(fluoromethylthio)benzamide (519 mg), in the form of a white solid, m.p. 111°-113° C. [Elemental analysis: C,51.50; H,4.12; N,6.74%; calculated: C,52.05; H,4.12; N ,6.74%].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[CH:16]=[CH:15][C:14]4[CH2:18][CH2:19][CH2:20][CH2:21][C:13]=4[C:12]=3[NH:11][C:10](=[O:22])[C:9]2=[O:23])[CH:5]=[CH:6][CH:7]=1.[C:24]1([S:34](Cl)(=[O:36])=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>>[O:22]=[C:10]1[NH:11][C:12]2[C:13]3[CH2:21][CH2:20][CH2:19][CH2:18][C:14]=3[CH:15]=[CH:16][C:17]=2[N:8]([C:4]2[CH:3]=[C:2]([NH:1][S:34]([C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)(=[O:36])=[O:35])[CH:7]=[CH:6][CH:5]=2)[C:9]1=[O:23]
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: Nc1cccc(-n2c(=O)c(=O)[nH]c3c4c(ccc32)CCCC4)c1
Product: O=c1[nH]c2c3c(ccc2n(-c2cccc(NS(=O)(=O)c4cccc5ccccc45)c2)c1=O)CCCC3
Yield: 29 %

Procedure:
4-(3-Aminophenyl)-1,4,7,8,9,10-hexahydrobenzo[f]quinoxaline-2,3-dione (30 mg, 0.097 mmol) and 1-naphthalenesulfonyl chloride (33 mg, 0.146 mmol) were used in a process similar to Example 9 to give the titled compound (a white crystal, 14 mg, yield 29%).
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[CH:12]=[C:11]([O:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]2[OH:20])[N:10]=[CH:9][N:8]=1.Cl[Si:22]([CH3:25])([CH3:24])[CH3:23].[Cl-].[NH4+]>C(N(CC)CC)C>[Cl:6][C:7]1[CH:12]=[C:11]([O:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]2[O:20][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:10]=[CH:9][N:8]=1
Reactant: O[C@H]1CCCC[C@H]1Oc1cc(Cl)ncn1
Reactant: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)O[C@H]1CCCC[C@H]1Oc1cc(Cl)ncn1
Temperature: 0 °C

Procedure:
To 3.2 ml of tetrahydrofuran were added 0.37 g of 4-chloro-6-(cis-2-hydroxycyclohexyloxy)pyrimidine and 0.45 ml of triethylamine, to which 0.25 ml of chlorotrimethylsilane was slowly added dropwise with stirring at 0° C. After stirring at room temperature for 3 hours, the reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.5 g of 4-chloro-6-(cis-2-trimethylsilanyloxycyclohexyloxy)pyrimidine.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([B:10]([OH:12])[OH:11])[CH:7]=[CH:8][CH:9]=1)([OH:3])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:65][O:66][C:67]1[CH:72]=[CH:71][C:70]([CH2:73][NH2:74])=[CH:69][CH:68]=1>CN(C=O)C>[CH3:65][O:66][C:67]1[CH:72]=[CH:71][C:70]([CH2:73][NH:74][C:1]([C:4]2[CH:5]=[C:6]([B:10]([OH:12])[OH:11])[CH:7]=[CH:8][CH:9]=2)=[O:3])=[CH:69][CH:68]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)c2cccc(B(O)O)c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3-Carboxyphenylboronic acid (140 mg, 0.84 mmol), PyBOP (376 mg, 0.72 mmol) and HOBt (97.7 mg, 0.72 mmol) were dissolved in DMF (3.18 mL) and treated with DIPEA (420 μL, 2.41 mmol). After 5 min at ambient temperature, 4-methoxybenzenemethanamine (78 μL, 0.60 mmol) was added. The homogeneous reaction mixture was stirred at ambient temperature for 16 h, the solvent was removed under reduced pressure, and the residue purified by preparative HPLC (5-40% MeCN over 40 min, 35 mL/min) to afford the product as a white solid.
Reaction SMILES: [O:1]1[C:5]([C:6](OCC)=[O:7])=[CH:4][C:3]2[CH:11]=[CH:12][C:13]3[CH:14]=[CH:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:22]=3[C:2]1=2>C(Cl)Cl.CCCCCC>[O:1]1[C:5]([CH2:6][OH:7])=[CH:4][C:3]2[CH:11]=[CH:12][C:13]3[CH:14]=[CH:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:22]=3[C:2]1=2
Reactant: CCOC(=O)c1cc2ccc3ccc4ccccc4c3c2o1
Solvent: CCCCCC
Solvent: ClCCl
Product: OCc1cc2ccc3ccc4ccccc4c3c2o1
Yield: 91 %

Procedure:
Using the procedure outlined in Example 14A, ethyl phenanthro[4,3-b]furan-2-carboxylate (H. C. Pars Pharmaceutical Laboratories, Inc.) gave a 91% yield of phenanthro[4,3-b]furan-2-methanol, mp 125°-126°, (C,H), (CH2Cl2 /hexane).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][N:7]([CH:11]([CH:15]([CH3:17])[CH3:16])[C:12]([OH:14])=[O:13])[C:6]1=[O:18].[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.[K].[I-].[K+]>CN(C)C=O>[O:24]=[C:22]1[C:21]2[C:20](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19](=[O:29])[N:23]1[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][N:7]([CH:11]([CH:15]([CH3:17])[CH3:16])[C:12]([OH:14])=[O:13])[C:6]1=[O:18]
Reactant: CC(C)C(C(=O)O)N1CCCN(CCCCl)C1=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: CC(C)C(C(=O)O)N1CCCN(CCCN2C(=O)c3ccccc3C2=O)C1=O

Procedure:
As a further illustration, Scheme 28, Example 2 depicts the reaction of the chloro-propyl tetrahydropyrimidine derivative 28.13 with potassium phthalimide 28.16. Equimolar amounts of the reactants are combined in dimethylformamide at ca 80°, in the presence of a catalytic amount of potassium iodide, to afford 2-{3-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-2-oxo-tetrahydro-pyrimidin-1-yl}-3-methyl-butyric acid 28.17. The product is then reacted under reductive amination conditions, as described above (Scheme 10) with a dialkyl formylphenyl phosphonate 28.19 (Epsilon) to yield the phosphonate ester product 28.20.
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[O:7][CH:8]1[CH2:11][N:10]([C:12](=[O:20])[CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>C(O)C>[C:1]([C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[O:7][CH:8]1[CH2:9][N:10]([C:12](=[O:20])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCC(=O)N1CC(Oc2ccccc2C(C)(C)C)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1ccccc1OC1CN(C(=O)CCC(=O)O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a solution of ethyl 4-(3-(2-tert-butylphenoxy)azetidin-1-yl)-4-oxobutanoate (0.47 g, 1.41 mmol) obtained in Example 11 in ethanol (20.0 mL) was added lithium hydroxide (1.0M aqueous solution, 4.23 ml, 4.23 mmol) under ice-cooling, and the mixture was stirred at room temperature. After 2 hr, the reaction mixture was adjusted to about pH 1 with 1.0M hydrochloric acid, and the mixture was concentrated under reduced pressure. The obtained residue was partitioned to between ethyl acetate and water, and the organic layer was washed with saturated sodium chloride, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was recrystallized from heptane/ethyl acetate to give the title compound (0.28 g, 65%) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(-c2ccncc2)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)cc(-c2ccncc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a solution of methyl 3-nitro-5-(pyridin-4-yl)benzoate (45.1.B) (5.60 g, 21.62 mmol) in methanol (50 mL) was added 10% Pd on carbon by weight (2.50 g). The air was evacuated from the reaction flask and was replaced with hydrogen. The resulting slurry was stirred overnight at room temperature. The reaction mixture was then filtered and the mother liquor condensed to afford methyl 3-amino-5-(pyridin-4-yl)benzoate (45.1.C) (4.70 g, 95% yield) which was used in the next step without any further purification.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13]>C1(C)C=CC=CC=1>[CH3:9][O:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1/[N:13]=[CH:1]/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1N
Reactant: O=Cc1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccccc1/N=C/c1ccccc1

Procedure:
A mixture of 31.8 g (0.30 mol) of benzaldehyde, 36.9 g (0.30 g) of 2-methoxyaniline and 450 mL of toluene was refluxed using a Dean-Stark head for 1 hr. 15 granules of 4A molecular sieves were added. This mixture was refluxed for 4 hr, then filtered off, and the filtrate was evaporated to dryness. The residue was dried in vacuum at 70° C. This crude product was further used without an additional purification, since it is unstable on silica gel 60 and decomposes when dried under vacuum. Yield 52.0 g (82%) of the title material.
Reaction SMILES: CC(OC([N:8]([CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)[NH:9]C(OC(C)(C)C)=O)=O)(C)C.[ClH:28]>O1CCOCC1>[ClH:28].[CH3:25][O:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][C:18]([CH2:17][NH:8][NH2:9])=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(CN(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(CNN)cc1
Yield: 80 %

Procedure:
A solution of methyl 4-[[(2-methylpropan-2-yl)oxycarbonyl-[(2-methylpropan-2-yl)oxycarbonylamino]amino]methyl]benzoate (Intermediate #54) (3.3 g, 8.67 mmol) in 4M to HCl in Dioxane (100 mL) was stirred overnight at ambient temperature. The solvent was removed under reduced pressure and the resulting solid was dissolved in hot MeOH. The hot suspension was filtered then evaporated in vacuo to give a solid. This solid was triturated with ether, filtered then dried under high vac to yield the title compound as a yellow solid (1.5 g, 80%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:27]C=O)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].Cl>CO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:27])[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(CN4CCCCC4)cc3)cc2[C@H](NC=O)C[C@@H]1C
Agent: Cl
Solvent: CO
Product: CC(=O)N1c2ccc(-c3ccc(CN4CCCCC4)cc3)cc2[C@H](N)C[C@@H]1C
Yield: 70 %

Procedure:
To a suspension of {(cis)-1-acetyl-2-methyl-6-[4-(1-piperidinylmethyl)phenyl]-1,2,3,4-tetrahydro-4-quinolinyl}formamide (for a preparation see Intermediate 30) (109 g, 0.27 mol) in MeOH (1 L) was added 6N HCl (136 mL, 0.8 mol). The resulting homogenous mixture was stirred at reflux for 2 hours and concentrated under vacuo. The residue was taken up in water (1 L) and washed with DCM (100 mL). The aqueous phase was basified with NaHCO3 and the organic materials were extracted with DCM (2×0.5 L) dried over Na2SO4 and concentrated to dryness. After heating of the residue in DCM (100 mL) and iPr2O (1 L) and filtration the title compound was obtained as a white precipitate (70 g, 70%)