Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]=[C:5]([CH3:25])[CH2:6][C:7]1[C:8](=[O:24])[NH:9][CH2:10][CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[C:13]=12)([CH3:3])[CH3:2]>C(O)C.[Pt](=O)=O>[CH:1]([NH:4][CH:5]([CH3:25])[CH2:6][C:7]1[C:8](=[O:24])[NH:9][CH2:10][CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[C:13]=12)([CH3:2])[CH3:3]
Reactant: COc1ccc2c(c1)CCC1CCNC(=O)C(CC(C)=NC(C)C)=C21
Agent: O=[Pt]=O
Solvent: CCO
Product: COc1ccc2c(c1)CCC1CCNC(=O)C(CC(C)NC(C)C)=C21

Procedure:
The solution of 1 g of 1-(2-isopropyliminopropyl)-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one in 50 ml of ethanol is hydrogenated at room temperature and atmospheric pressure for 2 hours in the presence of 0.1 g of platinum dioxide catalyst. The mixture is filtered, the filtrate evaporated and the residue crystallized from petroleum ether, to yield the 1-(2-isopropylaminopropyl)-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one as a mixture of the "slow" and "fast" moving isomers, melting at 118°-126°.
Reaction SMILES: OO.[CH2:3]([N:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]3[N+:17]([O-:18])=[N:16][C:15]([NH2:19])=[N:14][C:10]=3[CH:11]=2)[CH2:6]1)[CH3:4].C(O)(C(F)(F)F)=[O:21].O>N>[CH2:3]([N:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]3[N+:17]([O-:18])=[N:16][C:15]([NH2:19])=[N+:14]([O-:21])[C:10]=3[CH:11]=2)[CH2:6]1)[CH3:4]
Reactant: O=C(O)C(F)(F)F
Reactant: CCN1Cc2cc3nc(N)n[n+]([O-])c3cc2C1
Agent: N
Agent: OO
Solvent: O
Product: CCN1Cc2cc3c(cc2C1)[n+]([O-])c(N)n[n+]3[O-]
Temperature: 20 °C
Reaction time: 28 h
Yield: 19 %

Procedure:
H2O2 (70%, 0.50 mL, ca. 10 mmol) was added dropwise to a stirred mixture of 1-oxide 249 (328 mg, 1.4 mmol), TFA (4 mL) and water (0.3 mL) at 0° C. and the mixture was stirred at 20° C. Two more aliquots of H2O2 (70%, 0.50 mL, ca. 10 mmol) were added at 3 h and 20 h. After 28 h at 20° C., the mixture was diluted with aqueous NH3 solution (20 mL) and extracted with DCM (5×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 250 (68 mg, 19%) as a red solid which was crystallised as the hydrochloride salt: mp (MeOH/DCM) 230° C.; 1H NMR [(CD3)2SO] δ 11.84 (br s, 1H, HCl), 8.27 (s, 1H, H-9), 8.20 (s, 1H, H-5), 8.14 (br s, 2H, NH2), 4.88-5.05 (m, 2H, CH2N), 4.50-4.73 (m, 2H, CH2N), 3.42 (q, J=7.2 Hz, 2H, CH2N), 1.32 (t, J=7.2 Hz, 3H, CH3); 13C NMR [(CD3)2SO] δ 151.4, 143.0, 138.5, 134.0, 130.6, 115.6, 111.4, 56.5, 56.1, 49.1, 10.3; HRMS (FAB+) calcd for C11H14N5O2 (MH+) m/z 248.1148, found 248.1154.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:16][C:17]2[CH:18]=[N:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([O:14]C)=[O:13])=[CH:8]2.[OH-].[Na+]>O1CCCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:16][C:17]2[CH:18]=[N:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8]2
Reactant: COC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)nc3)cc(OC)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(=O)O)[nH]c12
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 94.4 %

Procedure:
Methyl 7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (0.99 g) was dissolved in a mixture of tetrahydrofuran (10 mL) and methanol (10 mL). 1M Aqueous sodium hydroxide solution (5 mL) was added and the mixture was stirred at 50° C. for 45 min. The mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1M hydrochloric acid was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residual amorphous solid was solidified with diethyl ether to give the title compound (0.9 g, 95%) as a pale yellow solid. MS 363 (MH+).
Reaction SMILES: [F-:1].[K+].[Cl-].C(CCCCCCCCCCCC[NH3+])C1C=CC=CC=1.[N+]([C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:28]=1[C:29]#[N:30])([O-])=O>O.C1(C)C=CC=CC=1>[Cl:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:27]([F:1])[C:28]=1[C:29]#[N:30]
Reactant: [F-]
Reactant: N#Cc1c(Cl)cccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH3+]CCCCCCCCCCCCCc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1c(F)cccc1Cl
Temperature: 105 °C
Yield: 22.5 %

Procedure:
A solution of 120 g (2 mols) of potassium fluoride in 100 ml of water was treated first with 30 ml of a 50% strength aqueous solution of benzyldodecyl-ammonium chloride and then with a solution of 186 g (1 mol) of 2-nitro-6-chloro-benzonitrile in 250 ml of toluene. The reaction mixture was heated to 105° C. for 8 hours. After cooling, the organic phase was separated off and the aqueous phase was extracted with chloroform. The organic phase and the chloroform extracts were combined and washed and then freed from the organic solvent by distillation. On distillation of the residue, 35 g of 2-chloro-6-fluoro-benzonitrile (boiling point: 105°-108° C./15 mm Hg) were obtained.
Reaction SMILES: [NH:1]1[C:5]([NH:6][C:7](=[O:14])OCC(Cl)(Cl)Cl)=[N:4][N:3]=[N:2]1.[C:15]1([C:21]2[N:25]=[C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[S:23][N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:15]1([C:21]2[N:25]=[C:24]([N:26]3[CH2:31][CH2:30][N:29]([C:7]([NH:6][C:5]4[NH:1][N:2]=[N:3][N:4]=4)=[O:14])[CH2:28][CH2:27]3)[S:23][N:22]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1nnn[nH]1)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1nnn[nH]1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 27.9 %

Procedure:
A mixture of 2,2,2-trichloroethyl 1H-tetrazol-5-ylcarbamate (190 mg, 0.731 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.141 ml, 0.812 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 3 hours. Water was poured into the reaction mixture and a crystal was collected by filtration. They were recrystallized from a mixed solvent of hexane and tetrahydrofuran to obtain the desired product (72.9 mg, 27.9%) as a solid.
Reaction SMILES: [F:1][C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=O)[C:13]=2[O:20][CH3:21])=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6].CN.[C:24]([BH3-])#[N:25].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)(=O)C.CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[F:1][C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:25][CH3:24])[C:13]=2[O:20][CH3:21])=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6]
Reactant: [BH3-]C#N
Reactant: COc1c(C=O)cccc1Oc1c(C#N)ccc(C)c1F
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1cccc(Oc2c(C#N)ccc(C)c2F)c1OC
Yield: 57 %

Procedure:
3-Fluoro-2-(3-formyl-2-methoxyphenoxy)-4-methylbenzonitrile (0.10 g, 0.35 mmol), methylamine (33% in ethanol, 0.5 mL, 4.0 mmol) and sodium cyanoborohydride (30 mg, 0.48 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (25 mL) for 67 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (41 mg, 0.35 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 3-fluoro-2-(2-methoxy-3-(methylaminomethyl)phenoxy)-4-methyl-benzonitrile fumarate (83 mg, 57%) as a white solid.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[OH:14][CH:15]([CH3:26])[CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Si:1]([O:14][CH:15]([CH3:26])[CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(O)COc1ccc(C=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(COc1ccc(C=O)cc1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
5.39 g (35.7 mmol) of tert-butyldimethylsilyl chloride and 3.30 g (48.5 mmol) of imidazole are added successively to a solution of 4.60 g (25.5 mmol) of the compound from Example 40A in 120 ml of dry dimethylformamide, and the mixture is stirred at RT for 20 h. 100 ml of saturated sodium bicarbonate solution are then added, and the reaction mixture is extracted with diethyl ether (three times, 100 ml each). The combined organic phases are dried over magnesium sulphate. After removal of the solvent on a rotary evaporator, the crude product is purified chromatographically on silica gel 60 (mobile phase gradient cyclohexane/ethyl acetate 50:1→10:1).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[NH:6][C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[N+:10]([O-])=O)=[O:4]>CCOC(C)=O.[Pd]>[CH3:1][NH:2][C:3]([C:5]1[NH:6][C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH2:10])=[O:4]
Reactant: CNC(=O)c1[nH]c(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CNC(=O)c1[nH]c(C(C)(C)C)cc1N
Yield: 781 %

Procedure:
To a solution of 2-(N-methylcarbamoyl)-5-tert-butyl-3-nitropyrrole (1.0 g, 0.4 mmol) in EtOAc (50 mL) under an Ar atmosphere was added 10% Pd/C (50 mg). The mixture was evacuated then placed under a static H2 atmosphere (1 atm.) for 24 h. The resulting slurry was filtered through a pad of Celite® with the aid of EtOAc, and the filtrate was concentrated under reduced pressure to afford 2-(N-methylcarbamoyl)-3-amino-5-tert-butylpyrrole (0.61 g, 70%): 1H-NMR (DMSO-d6) δ1.16 (s, 9H), 2.66 (d, J=4.41 Hz, 3H), 4.89 (br s, 2H), 5.27 (d, 2.58 Hz, 1H), 7.14-7.16 (m, 1H), 9.52 (br s, 1H).
Reaction SMILES: [I:1][C:2]1[O:6][C:5]([CH:7]([OH:22])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[N:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[I:1][C:2]1[O:6][C:5]([C:7](=[O:22])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[N:4][CH:3]=1
Reactant: COc1cccc(CCCCCCC(O)c2ncc(I)o2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: COc1cccc(CCCCCCC(=O)c2ncc(I)o2)c1
Reaction time: 1 h

Procedure:
Anhydrous dichloromethane (2 mL) was used to solubilize 1-(5-iodooxazol-2-yl)-7-(3-methoxyphenyl)heptan-1-ol (0.050 g, 0.120 mmol) under an atmosphere of argon with stirring. Dess-Martin periodinane (0.076 g, 0.181 mmol) was added and the reaction was allowed to proceed over 1 hour at ambient temperature. The reaction was then worked up with saturated sodium bicarbonate. Saturated sodium thiosulfate was added and the organic phase was separated. The organic phase was washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the product (60%, 0.030 g) was purified by preparative thin layer chromatography with silica (30% ethyl acetate:hexanes mobile phase) as a yellow oil: 1H NMR (600 MHz, CDCl3) δ 7.33 (s, 1H), 7.18 (m, 1H), 6.75 (d, J=7.2 Hz, 1H), 6.71 (m, 2H), 3.79 (s, 3H), 3.02 (t, 2H), 2.57 (t, 3H), 1.71-1.76 (m, 2H), 1.60-1.65 (m, 2H), 1.35-1.44 (m, 4H); 13C NMR (150 MHz, CDCl3) δ 187.11, 162.53, 159.53, 144.27, 137.40, 129.15, 120.80, 114.12, 110.85, 93.61, 55.09, 38.63, 35.87, 31.09, 28.91 (2 C), 23.75; HRMS (ES+) m/e calc'd for [M+H]+ C17H21INO3: 414.0561. found 414.0560.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[C:10]([CH3:13])([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C@H:18]([CH2:26][OH:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:6]([NH:8][C@H:9]([C:14]([NH:17][C@H:18]([CH2:26][OH:27])[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:16])[C:10]([CH3:11])([CH3:12])[CH3:13])([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N[C@H](CO)Cc1ccccc1)C(C)(C)C
Reaction time: 24 h

Procedure:
25 g of tert-butyloxycarbonyl-L-tert-leucine are dissolved in 250 ml of dry dimethylformamide, 16.36 g of phenylalaninol, 14.62 g of hydroxybenzotriazole and 24.9 g of N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride are added. The mixture is stirred for one day. The precipitate is filtered off, washed carefully with ethyl acetate and dried in vacuo (m.p. 198°-201°).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[CH:20][CH:19]=3)[N:9]=2)[CH2:3]1.CCN(CC)CC.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C1COCC1>[C:39]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[C:10]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[CH:22][CH:23]=3)[N:9]=2)[CH2:3]1)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: NC(=O)c1ccc(N2CCC[C@@H](N)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc(N2CCC[C@@H](NC(=O)c3ccccc3)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.9 %

Procedure:
To a solution of (R)-6-(3-aminopiperidin-1-yl)-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (27.5 mg, 0.065 mmol) and Et3N (0.014 mL, 0.097 mmol) in THF (2 mL) was added benzoyl chloride (10.93 mg, 0.078 mmol). The reaction mixture was stirred at rt for 10 min, quenched with satd. NaHCO3, extracted twice with CH2Cl2, separated, and concentrated. The residue was purified by ISCO (100% ethyl acetate, 12 g column) to obtain 24 mg of (R)-6-(3-benzamidopiperidin-1-yl)-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide as a white solid. LCMS: (M+H)+=529.38. 1H NMR (400 MHz, CDCl3) δ ppm 11.22 (1H, s), 7.66 (2H, d, J=8.56 Hz), 7.59-7.64 (2H, m), 7.53 (1H, d, J=9.06 Hz), 7.42-7.49 (1H, m), 7.37 (1H, d, J=7.81 Hz), 7.31 (1H, d, J=8.56 Hz), 6.55 (1H, d, J=6.80 Hz), 6.11-6.18 (1H, m), 5.60 (2H, s), 4.17-4.28 (1H, m), 3.86-3.94 (1H, m), 3.53-3.83 (11H, m), 1.96-2.06 (1H, m), 1.88-1.95 (1H, m), 1.74-1.85 (1H, m), 1.67-1.73 (1H, m).
Reaction SMILES: C([N:8]1[CH2:27][CH2:26][C:11]2[N:12]=[CH:13][N:14]=[C:15]([O:16][C@H:17]3[CH2:21][CH2:20][N:19]([C:22](=[O:25])[CH2:23][CH3:24])[CH2:18]3)[C:10]=2[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[N:12]1[C:11]2[CH2:26][CH2:27][NH:8][CH2:9][C:10]=2[C:15]([O:16][C@H:17]2[CH2:21][CH2:20][N:19]([C:22](=[O:25])[CH2:23][CH3:24])[CH2:18]2)=[N:14][CH:13]=1
Reactant: CCC(=O)N1CC[C@H](Oc2ncnc3c2CN(Cc2ccccc2)CC3)C1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCC(=O)N1CC[C@H](Oc2ncnc3c2CNCC3)C1
Temperature: 70 °C

Procedure:
Pd(OH)2 (150 mg, 1.070 mmol) was put into a round flask and flushed under argon for 5 minutes. A solution of 1-[(S)-3-(6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidin-1-yl]-propan-1-one (560 mg, 1.528 mmol) in 22 mL of MeOH was added followed by ammonium formate (482 mg, 7.64 mmol). The reaction mixture was stirred under reflux (70° C.) for 2 h. The mixture was filtered over a pad of celite and dried under high vacuum to give 1-[(S)-3-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidin-1-yl]-propan-1-one. No further purification (m=420 mg, quantitative yield). MS: [M+H]+=277.5 Rt(6)=0.71 min.
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)[C:10]2=[O:19])[CH2:5][CH2:4]1.Br[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.O1CCOCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][CH2:16][N:15]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)[CH2:14]3)[C:10]2=[O:19])[CH2:5][CH2:4]1
Reactant: O=C1N([C@H]2CC[C@H](O)CC2)CCC12CCCNC2
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1COCCO1
Product: O=C1N([C@H]2CC[C@H](O)CC2)CCC12CCCN(c1ccc(C(F)(F)F)cc1)C2
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one hydrochloride (25 mg, 0.000086 mol), 1-bromo-4-(trifluoromethyl)benzene (29 mg, 0.00013 mol), sodium tert-butoxide (28 mg, 0.00029 mol), palladium acetate (0.6 mg, 0.000002 mol), and 2-(di-tert-butylphosphino)biphenyl (0.8 mg, 0.000002 mol) in 1,4-dioxane (1.0 mL, 0.013 mol) was heated at 100° C. with stirring for 16 h. LCMS indicated that most of the desired product was oxidized to the ketone so the crude reaction mixture was cooled to −10° C. and 1.0 M of L-Selectride® in tetrahydrofuran (0.2 mL) was added and the mixture was stirred for 20 min. LCMS indicated that the ketone was converted to the alcohol. The crude mixture was purified by prep.-HPLC to afford 5.2 mg of the desired product. LC-MS: 397.2 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([Br:19])=[CH:11][CH:10]=2)=[O:8])[CH2:3][CH2:2]1.Cl.N1CCC(C(C2C=CC3C(=CC=C(Cl)C=3)C=2)=O)CC1>>[Br:19][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([CH:7]([CH:4]2[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]2)[OH:8])=[CH:10][CH:11]=1
Reactant: O=C(c1ccc(Br)c2ccccc12)C1CCNCC1
Agent: Cl
Agent: O=C(c1ccc2cc(Cl)ccc2c1)C1CCNCC1
Product: OC(c1ccc(Br)c2ccccc12)C1CCNCC1

Procedure:
When in the procedure of Example 9, 4-bromo-1-naphthyl 4-piperidyl ketone is substituted for 6-chloro-2-naphthyl 4-piperidyl ketone hydrochloride, α(4-bromo-1-naphthyl)-4-piperidinemethanol is obtained.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][P:9](=O)([O:18]CC2C=CC=CC=2)[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:27][C@@H:28]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:29]([NH:31][C@H:32]([C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30]>>[C:12]1([CH2:11][O:10][P:9]([CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([O:27][C@@H:28]([CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:29]([NH:31][C@H:32]([C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])=[O:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=P(CCc1ccccc1)(OCc1ccccc1)OCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](O)Cc1ccccc1)C(=O)OCc1ccccc1
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)OP(=O)(CCc1ccccc1)OCc1ccccc1)C(=O)OCc1ccccc1

Procedure:
This (2-phenylethyl)phosphonic acid, dibenzyl ester is reacted with N-[(S)-2-hydroxy-3-phenyl-1-oxopropyl]-L-leucine, phenylmethyl ester according to the procedure described in Example 76 to give N-[(S)-2[[(phenylmethoxy)(2-phenylethyl)phosphinyl]oxy]-1-oxo-3-phenylpropyl]-L-leucine, phenylmethyl ester as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:24])[C@:9]([C@@H:17]2[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18]2)([OH:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.[CH3:25][C:26]1[N:31]=[C:30]([CH:32]=O)[CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(O)(=O)C.C(OCC)(=O)C>[CH3:32][C:30]1[N:31]=[C:26]([CH2:25][N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:24])[C@:9]([C@@H:17]3[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18]3)([OH:16])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:3][CH2:2]2)[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1cccc(C=O)n1
Reactant: O=C(NC1CCNCC1)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1cccc(CN2CCC(NC(=O)[C@](O)(c3ccccc3)[C@@H]3CCC(F)(F)C3)CC2)n1
Reaction time: 8 h
Yield: 40.4 %

Procedure:
To a solution of 17 mg of (2R)-N-(piperidin-4-yl)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide in 2 ml of tetrahydrofuran, 3 μl of acetic acid, 12 mg of 6-methylpyridine-2-carbaldehyde and 21 mg of sodium triacetoxyborohydride were added sequentially at room temperature, and stirred overnight at the same temperature. The reaction mixture was diluted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, the residue was purified by preparative thin layer chromatography (Kieselgel™ 60F254, Art 5744 (Merck) chloroform/methanol=10/1) to provide 9 mg of the title compound as a solid substance.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:16][C:17]1[CH:18]=[C:19]([C:23]2([CH2:29][CH2:30][N:31]3[CH:36]4[CH2:37][CH2:38][CH:32]3[CH2:33][CH:34]([N:39]3[C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=5[N:41]=[C:40]3[CH3:48])[CH2:35]4)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.ClC1C(C(N2CCC(C3C=CC=C(F)C=3)(CCN3C4CCC3CC(N3C5C=CC=CC=5N=C3C)C4)CC2)=O)=C(Cl)C=CC=1S(NC)(=O)=O>>[F:11][C:9]1[CH:10]=[C:2]([F:1])[C:3]([C:4]([N:26]2[CH2:25][CH2:24][C:23]([C:19]3[CH:20]=[CH:21][CH:22]=[C:17]([F:16])[CH:18]=3)([CH2:29][CH2:30][N:31]3[CH:32]4[CH2:38][CH2:37][CH:36]3[CH2:35][CH:34]([N:39]3[C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=5[N:41]=[C:40]3[CH3:48])[CH2:33]4)[CH2:28][CH2:27]2)=[O:6])=[CH:7][C:8]=1[S:12]([OH:15])(=[O:14])=[O:13]
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2cccc(F)c2)CCNCC1
Reactant: O=C(O)c1cc(S(=O)(=O)O)c(F)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNS(=O)(=O)c1ccc(Cl)c(C(=O)N2CCC(CCN3C4CCC3CC(n3c(C)nc5ccccc53)C4)(c3cccc(F)c3)CC2)c1Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)c2cc(S(=O)(=O)O)c(F)cc2F)CC1
Yield: 20.7 %

Procedure:
Prepared from a mixture of 2,4-difluoro-5-sulfobenzoic acid 885-6b (580 mg, 0.58 mmol, 2 equiv), 1-(8-{2-[4-(3-fluorophenyl)-4-piperidinyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole (150 mg, 0.29 mmol, 1 equiv), DIEA (260 μL, 1.45 mmol, 5 equiv) and HATU (110 mg, 0.29 mmol, 1 equiv) following the general procedure for 2,4-dichloro-3-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-N-methylbenzenesulfonamide, example 880. The crude product was purified by prep HPLC (HPLC Method C) to afford 2,4-difluoro-5-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]benzenesulfonic acid (example 885) as a white solid (40 mg, 22% yield).