Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:30]=[C:29]([Cl:31])[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:27][C:26]4[NH:25][N:24]=[CH:23][C:22]=4[CH2:21][CH2:20]3)[C:15]2=[O:28])=[C:11]([Cl:32])[CH:10]=1)C1C=CC=CC=1.CS(O)(=O)=O>CSC>[Cl:32][C:11]1[CH:10]=[C:9]([OH:8])[CH:30]=[C:29]([Cl:31])[C:12]=1[CH2:13][C@@H:14]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:27][C:26]3[NH:25][N:24]=[CH:23][C:22]=3[CH2:21][CH2:20]2)[C:15]1=[O:28]
Reactant: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1C1CCc2cn[nH]c2C1
Agent: CS(=O)(=O)O
Solvent: CSC
Product: O=C1[C@H](Cc2c(Cl)cc(O)cc2Cl)CCN1C1CCc2cn[nH]c2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 113.2 %

Procedure:
To a solution of (3R)-3-(4-benzyloxy-2,6-dichloro-benzyl)-1-(4,5,6,7-tetrahydro-1H-indazol-6-yl)-pyrrolidin-2-one (3.93 g, 8.36 mmol) in dimethylsulfide (45 mL), add methane sulfonic acid (13.23 g, 138 mmol) and stir the mixture vigorously under nitrogen atmosphere at room temperature for 18 hours. Remove the solvent in vacuo and dilute the residue with water, adjust the pH to pH=7 with 5 N NaOH, and extract the mixture several times with ethyl acetate and THF. After drying the combined organic layer (Na2SO4), filter and concentrate under vacuum to afford 3.60 g (100%) of the title compound. MS (m/z): 381 (M+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[O:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:21])[CH2:12][S:13]([CH2:15][C:16]1[O:20][CH:19]=[CH:18][CH:17]=1)=[O:14])=O.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.[BH4-].[Na+].Cl>C(O)C>[N:25]1([CH2:1][C:3]2[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=2)[O:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:21])[CH2:12][S:13]([CH2:15][C:16]2[O:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=Cc1cccc(OCCCNC(=O)CS(=O)Cc2ccco2)c1
Reactant: C1CCNCC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C(CS(=O)Cc1ccco1)NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 53 %

Procedure:
N-[3-(3-formylphenoxy)propyl]-2-(furfurylsulfinyl)acetamide (13.85 g) was dissolved in 150 ml of ethanol, and while 5.06 g of piperidine was added dropwise, the mixture was stirred at room temperature for 15 hours. The reaction solution was cooled with ice, and 1.5 g of sodium borohydride was added. The mixture was stirred for 5 hours. 1N-HCl was added to the reaction solution to make it acidic, and the solvent was evaporated. The residue was poured into water and extracted with ethyl acetate. The aqueous layer was made basic by adding anhydrous sodium carbonate, and extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=95/5) to give 8.80 g (yield 53%) of N-{3-[3-(piperidinomethyl)phenoxy] propyl]-2-(furfurylsulfinyl) acetamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([NH:16][CH:17]3[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]3)=[O:15])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl>CO.O1CCOCC1.CCOCC>[NH:19]1[CH2:20][CH:17]([NH:16][C:14]([C:11]2[CH:12]=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=2)=[O:15])[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)c2cnc(-c3cccc(F)c3)nc2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(NC1CNC1)c1cnc(-c2cccc(F)c2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
To a solution of tert-butyl 3-({[2-(3-fluorophenyl)pyrimidin-5-yl]carbonyl}amino)azetidine-1-carboxylate (570 mg, 1.53 mmol) in methanol (1 mL) was added 4N HCl in dioxane (3 mL). The reaction mixture was stirred at room temperature overnight and then diluted with ether to give a solid, which was filtered and collected to give the desired product as the hydrochloride salt, N-azetidin-3-yl-2-(3-fluorophenyl)pyrimidine-5-carboxamide (380 mg, 72%). LC/MS (M+H)=273.2 observed, 273.12 expected.
Reaction SMILES: [CH2:1]([O:8][N:9]([C@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([C:35](=[O:37])[NH2:36])[CH:24]=[C:23]1[CH2:38][CH2:39][N+:40]([O-:42])=[O:41])S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(ON[C@H]1CN[C@@H](C(N)=O)C=C1C)C=C>>[CH2:1]([O:8][NH:9][C@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([C:35](=[O:37])[NH2:36])[CH:24]=[C:23]1[CH2:38][CH2:39][N+:40]([O-:42])=[O:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])C(CC[N+](=O)[O-])=C[C@H]1C(N)=O
Agent: C=CCON[C@H]1CN[C@@H](C(N)=O)C=C1C
Product: CC(C)(C)OC(=O)N1C[C@H](NOCc2ccccc2)C(CC[N+](=O)[O-])=C[C@H]1C(N)=O

Procedure:
The desired product was prepared from (2S,5R)-tert-butyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-2-carbamoyl-4-(2-nitroethyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 223, 2 g, 3.30 mmol) following the procedure described for Intermediate 22. The desired product was obtained as yellow oil (0.8 g, 68%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[C:10]([S:20][CH3:21])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH:22]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([NH:28][C:2]2[CH:7]=[C:6]([C:8]3[N:9]=[C:10]([S:20][CH3:21])[NH:11][C:12]=3[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NC1CCCCC1
Reactant: CSc1nc(-c2ccnc(F)c2)c(-c2ccc(F)cc2)[nH]1
Product: CSc1nc(-c2ccnc(NC3CCCCC3)c2)c(-c2ccc(F)cc2)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Fluoro-4-[5-(4-fluorophenyl)-2-methylsulfanyl-1 H-imidazol-4-yl]pyridine (1.2 g, 4 mmol), which had been weighed out into a 25 ml one-necked flask which had been flushed with argon beforehand, was suspended in cyclohexylamine (3.97 g, 0.04 mol), covered with argon and then heated with reflux of the amine, in an oil bath at a temperature of 160° C., for 48 h. The brown suspension is allowed to cool to RT. 30 ml of Na citrate solution (10% strength citric acid solution pH 5 with conc. NaOH) are then added, and the mixture is stirred for 10 min. and extracted twice with 30 ml of ethyl acetate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15]2[CH2:22][C:18]3([CH2:21][CH2:20][CH2:19]3)[O:17][N:16]=2)[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH3:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C([O-])(O)=O.[Na+]>C1COCC1.O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:14]=[C:13]([C:15]3[CH2:22][C:18]4([CH2:21][CH2:20][CH2:19]4)[O:17][N:16]=3)[CH:12]=[C:4]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH:3]=2)=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(C2=NOC3(CCC3)C2)c1
Reactant: Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc(C3=NOC4(CCC4)C3)c2)cc1
Temperature: 120 °C
Yield: 90 %

Procedure:
To a solution of tert-butyl 3-bromo-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)benzoate (1.36 g, 3.71 mmol) in THF (8 mL) and water (8 mL) were added (4-methylphenyl)boronic acid (1.01 g, 7.43 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (82 mg, 0.11 mmol) and cesium carbonate (3.63 g, 11.1 mmol). The mixture was heated to 120° C. in a microwave reactor for 10 min. The mixture was cooled to ambient temperature and saturated aqueous NaHCO3 was added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water (2×), brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes 85% hexanes/ethyl acetate) gave the title compound (1.26 g). MS 378.3 (M+1).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:13]([O:15][P:16]([CH2:21][C:22]([OH:24])=O)([O:18][CH2:19][CH3:20])=[O:17])[CH3:14].[Br:25][C:26]1[CH:27]=[C:28]([NH:33][C:34]2[C:35]3[CH:43]=[C:42]([NH2:44])[N:41]=[CH:40][C:36]=3[N:37]=[CH:38][N:39]=2)[CH:29]=[CH:30][C:31]=1[Cl:32].CC(N(C)C)=O>C1COCC1.O.ClCCl.CO>[Br:25][C:26]1[CH:27]=[C:28]([NH:33][C:34]2[C:35]3[CH:43]=[C:42]([NH:44][C:22](=[O:24])[CH2:21][P:16](=[O:17])([O:15][CH2:13][CH3:14])[O:18][CH2:19][CH3:20])[N:41]=[CH:40][C:36]=3[N:37]=[CH:38][N:39]=2)[CH:29]=[CH:30][C:31]=1[Cl:32]
Reactant: CCOP(=O)(CC(=O)O)OCC
Reactant: Nc1cc2c(Nc3ccc(Cl)c(Br)c3)ncnc2cn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CCOP(=O)(CC(=O)Nc1cc2c(Nc3ccc(Cl)c(Br)c3)ncnc2cn1)OCC
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 94.4 %

Procedure:
To a stirred mixture of CDI (1.20 g, 7.42 mmol) and dry THF (5 mL), at room temperature and under a nitrogen atmosphere, was added a solution of 2-(diethoxyphosphoryl)acetic acid (1.45 g, 7.42 mmol) in THF (4 mL). After addition the reaction mixture was stirred further at 40° C. (bath) for 15 min (whence evolution of gases ceased). A solution of compound 223 (2.00 g, 5.71 mmol) in a mixed solvents of dry THF (6 mL) and DMA (7 mL) was added and stirred further at 40° C. The reaction was monitored by TLC (dichloromethane-MeOH=10:1) and found only ca. 60% reaction occurred after 1 h. Thus, another batch of reagent was prepared from CDI [0.87 g, 5.37 mmol; dry THF (2.5 mL)] and 2-(diethoxyphosphoryl)acetic acid [0.72 g, 5.37 mmol); THF (3 mL)] and added to the reaction. It was stirred further for 3 h at 40° C. The reaction mixture was poured into water (300 mL) and stirred with petroleum ether (400 mL) at room temperature for 20 min. Petroleum ether layer was decanted. It was repeated once more with petroleum ether (400 mL). The solid was collected by suction filtration; washed with water (5×30 mL) and dried to give diethyl 2-(4-(3-bromo-4-chlorophenylamino)pyrido[3,4-d]pyrimidin-6-ylamino)-2-oxoethylphosphonate (232) (2.85 g, 94%); mp 113-116° C.; 1H NMR δ [(CD3)2SO]: 10.86 (s, 1H), 10.40 (s, 1H), 9.04 (s, 1H), 8.87 (s, 1H), 8.67 (s, 1 H), 8.34 (d, J=2.3 Hz, 1H), 7.94 (dd, J=8.8, 2.3 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 4.16-4.03 (m, 4H), 3.32 (d, partially obscured by water peak, 2H), 1.26 (t, J=7.1 Hz, 6H). Anal. Calcd for C19H20BrClN5O4P.H2O: C, 41.74; H, 4.06; N, 12.81%. Found C, 42.01; H, 3.90; N, 12.78%.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][CH2:7][O:8][P:9]([CH2:18][CH:19]([OH:32])[CH2:20][NH:21]C(OCC1C=CC=CC=1)=O)([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10])=[O:5])[CH3:2]>C(O)C.[H][H].[Pd]>[CH2:1]([O:3][C:4]([O:6][CH2:7][O:8][P:9]([CH2:18][C@H:19]([OH:32])[CH2:20][NH2:21])([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10])=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)OCOP(=O)(CC(O)CNC(=O)OCc1ccccc1)CC1CCCCC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)OCOP(=O)(CC1CCCCC1)C[C@H](O)CN
Yield: 100 %

Procedure:
(3-Benzyloxycarbonylamino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid ethoxycarbonyloxymethyl ester (0.263 g, 0.56 mmol) was dissolved in absolute ethanol (28 mL) and hydrogenated at RT via a hydrogen Paar shaker for 1 h at 55 psi with 10% Pd/C (0.127 g). The reaction mixture was filtered through celite and concentrated in vacuo to yield the title compound (187 mg, 0.56 mmol) as a foamy white solid. 1H NMR (CDCl3, 300 MHz): 7.90 (bs, 2H), 5.69 (m, 2H), 4.51 (bs, 1H), 4.23 (q, 2H), 3.27 (m, 1H), 3.17 (m, 1H), 2.20 (m, 2H), 1.88-1.64 (m, 8H), 1.34-1.00 (m, 6H), 1.32 (t, 3H). 31P NMR (CDCl3, 300 MHz): 61.14, 59.63. LC/MS m/z: [M+H]+=338.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:18])=[C:12]2[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)([CH3:7])[CH3:6])[CH3:2].[Na].[H-].[Na+].[CH2:32](Br)[CH:33]=[CH2:34]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:28])[C:5]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:34][CH:33]=[CH2:32])[C:13]([CH3:18])=[C:12]2[CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: C=CCBr
Reactant: CCOC(=O)C(C)(C)Oc1ccc2[nH]c(C)c(CCc3ccc(Cl)cc3)c2c1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: C=CCn1c(C)c(CCc2ccc(Cl)cc2)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
Two grams (5 m mole) of 2-{3-[2-(4-chloro-phenyl)-ethyl]-2-methyl-1H-indole-5-yloxy}-2-methyl-propanoic acid ethylester in 20 ml of absolute dimethylformamide were converted to the sodium salt in the present of 0.24 g (~5 m mole) of 55% sodium hydride immersion in oil, and the mixture was alkylated with 1.2 g (10 m mole) of allylbromide at room temperature. After the solvent was distilled off in vacuo, the evaporation residue was dissolved in toluene, filtered, and purified over a silicagel column (solvent: toluene).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=[O:12])[CH2:7][CH:6]([CH2:14][OH:15])[CH2:5]2.[N:16]#[C:17][NH2:18].[CH]Cl.[OH-].[Na+]>O>[NH2:18][C:17]1[N:16]=[N+:11]([O-:12])[C:10]2[CH:9]=[C:8]3[C:4]([CH2:5][CH:6]([CH2:14][OH:15])[CH2:7]3)=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1cc2c(cc1[N+](=O)[O-])CC(CO)C2
Reactant: N#CN
Agent: [CH]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2cc3c(cc2[n+]([O-])n1)CC(CO)C3
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 88.8 %

Procedure:
A mixture of nitroaniline 123 (4.43 g, 17.8 mmol) and cyanamide (3.51 g, 83.6 mmol) were mixed together at 100° C., cooled to 50° C., cHCl (8.21 mL) added carefully and the mixture stirred at 65-70° C. for 90 min. A solution of 7.5 M NaOH (72 mL) was added until the mixture was strongly basic and the mixture stirred at 90-98° C. for 45 min. The mixture was cooled, diluted with water (50 mL), filtered, washed with water (3×20 mL) and dried to give 1-oxide 124 (3.67 g, 89%) as a green-yellow solid: mp (DCM/MeOH) 255-257° C.; 1H NMR [(CD3)2SO] δ 7.93 (s, 1H, H-9), 7.33 (s, 1H, H-5), 7.10 (s, 2H, NH2), 4.67 (t, J=5.2 Hz, 1H, OH), 3.40 (dd, J=6.5 Hz, 5.2 Hz, 2H, CH2O), 2.99-3.10 (m, 2H, CH2), 2.73-2.85 (m, 2H, CH2), 2.52-2.63 (m, 1H, CH); 13C NMR [(CD3)2SO] δ 159.9, 153.5, 148.6, 141.9, 128.8, 120.1, 114.1, 63.7, 41.6, 35.3, 34.6. Anal. calcd for C11H12N4O2.¼CH3OH: C, 56.2; H, 5.5; N, 23.3. Found: C, 56.7; H, 5.4; N, 23.2%.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[N:14]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:13]=[C:12]([CH3:21])[C:11]=2[CH2:22][C:23]([O:25]C)=[O:24])[CH:7]=[CH:8][CH:9]=1>CO>[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[N:14]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:13]=[C:12]([CH3:21])[C:11]=2[CH2:22][C:23]([OH:25])=[O:24])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)Cc1c(C)nn(-c2cccnc2)c1-c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nn(-c2cccnc2)c(-c2cccc(Cl)c2)c1CC(=O)O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
0.053 g (1.334 mmol) of 2 molar aqueous sodium hydroxide solution was added to 0.114 g (0.334 mmol) of methyl [5-(3-chlorophenyl)-3-methyl-1-pyridin-3-yl-1H-pyrazol-4-yl]acetate (see A1), and the mixture was stirred at 20° C. for 1 h. The methanol formed during the reaction was removed under reduced pressure, and the residue was poured onto a mixture of 10 ml of water and 15 ml of dichloromethane. The aqueous phase was extracted with 15 ml of dichloromethane, acidified with concentrated hydrochloric acid (pH=3) and extracted three times with in each case 15 ml of dichloromethane. Drying of the combined organic phases and removal of the solvent under reduced pressure give 0.050 g (43% of theory) of a light-beige solid of melting point 163° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1COCC1.[F:25][C:26]1[CH:52]=[CH:51][C:29]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][N:35]([C:38]3[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH2:46][N:47]=[N+]=[N-])=[CH:40][CH:39]=3)[C:34](=[O:50])[CH:33]=2)=[CH:28][CH:27]=1.Cl>O>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][N:35]([C:38]3[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH2:46][NH2:47])=[CH:40][CH:39]=3)[C:34](=[O:50])[CH:33]=2)=[CH:51][CH:52]=1
Reactant: [N-]=[N+]=NCCOc1ccc(-n2ccc(OCc3ccc(F)cc3)cc2=O)cc1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCCOc1ccc(-n2ccc(OCc3ccc(F)cc3)cc2=O)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
Triphenylphosphine (50 mg) was added to THF (5 mL)-water (1 mL) solution of 4-(4-fluorobenzyloxy)-1-[4-(2-azidoethoxy)phenyl]-1H-pyridin-2-one (50 mg), and stirred at 80° C. for 2 hours. Allowing the reaction liquid to cool off, 1N hydrochloric acid was added, followed by washing with diethyl ether. The aqueous layer was rendered basic by addition of 1N aqueous sodium hydroxide, extracted with chloroform and dried over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the residue was reprecipitated from diethyl ether-hexane to provide the title compound (9.8 mg, 21%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](O)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4](C(=O)C2C=CC=CC=2)[CH2:3]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1C=CC=CC=1>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCC(O)(c2ccccc2)C(C(=O)c2ccccc2)C1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CN1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 45 °C
Reaction time: 0.42 h

Procedure:
100 g. of 1-methyl-3-benzoyl-4-hydroxy-4-phenylpiperidine are suspended in 600 ml. of anhydrous benzene while stirring. 200 g. of finely pulverized, anhydrous aluminum chloride are added in portions thereto within 25 minutes. The reaction temperature increases to about 45° C. when adding the first portion of aluminum chloride. After about 20 minutes the reaction temperature of the reaction mixture is maintained at 50° to 55° C. for about 1 hour. The reaction mixture is then cooled to room temperature and is introduced into a mixture of ice and concentrated hydrochloric acid while stirring. After heating the mixture to room temperature, the benzene layer is separated from the hydrochloric acid and oil layer which is washed with benzene. The hydrochloric acid and oil layer is diluted, while stirring, with an amount of water sufficient to cause substantially all the oil to be dissolved. The resulting aqueous solution is then rendered alkaline by the addition of 40% sodium hydroxide solution, while stirring, and the alkaline solution is extracted with ether. The combined ether extracts are dried over anhydrous potassium carbonate and are concentrated by evaporation of the ether. 83.5 g. of the crude base are obtained as residue in the form of a dark oil. A light oil boiling at 98° to 103° C./0.01 mm. Hg is recovered by distillation of said crude oil in a high vacuum. The oil solidifies to crystals on standing for a short period of time. After recrystallization from aqueous dimethylformamide, the resulting 1-methyl-4,4-diphenylpiperidine has a melting point of 71° to 73° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:16])=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[CH:17]1([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[O:32])=[CH:27][CH:26]=2)=[O:23])[CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C>O1CCCC1>[C:9]([NH:8][C:6](=[O:7])[C:5]1[CH:13]=[CH:14][CH:15]=[C:3]([CH2:2][N:36]2[CH2:37][CH2:38][N:33]([C:31](=[O:32])[C:28]3[CH:29]=[CH:30][C:25]([NH:24][C:22]([NH:21][CH:17]4[CH2:18][CH2:19][CH2:20]4)=[O:23])=[CH:26][CH:27]=3)[CH2:34][CH2:35]2)[C:4]=1[F:16])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)NC(=O)c1cccc(CBr)c1F
Reactant: O=C(Nc1ccc(C(=O)N2CCNCC2)cc1)NC1CCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(NC(=O)NC4CCC4)cc3)CC2)c1F
Temperature: 70 °C
Yield: 44 %

Procedure:
A stirred mixture of 3-(bromomethyl)-N-tert-butyl-2-fluorobenzamide (0.36 mmol, 105 mg), 1-cyclobutyl-3-(4-(piperazine-1-carbonyl)phenyl)urea (0.33 mmol, 620 mg) and triethylamine (2.5 mmol, 0.35 mL, 253 mg) in tetrahydrofuran (2 mL) was heated to 70° C. for 16 hours. After this time the volatiles were removed under vacuum. The residue was purified by strong cation exchange chromatography and basic reverse phase HPLC to yield the title compound (74 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[CH3:21][NH:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][CH:24]=1>>[CH:13]1([C:9]2[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6](=[O:20])[N:5]3[C:10]=2[C:11]([CH3:12])=[C:2]([C:26]2[CH:27]=[CH:28][C:23]([NH:22][CH3:21])=[CH:24][CH:25]=2)[CH:3]=[CH:4]3)[CH2:15][CH2:14]1
Reactant: CNc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: CNc1ccc(-c2ccn3c(=O)c(C(=O)OC)cc(C4CC4)c3c2C)cc1
Yield: 89.4 %

Procedure:
Methyl 1-cyclopropyl-9-methyl-8-(4-(methylamino)-phenyl)-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (74 mg, 0.25 mmol) and N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (71 mg, 0.31 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (81 mg, 81%). ESI-MS m/z: 363 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:13])[C@@H:4]1[CH2:8][C:7]([O:11][CH3:12])([O:9][CH3:10])[CH2:6][NH:5]1.N1NN=NC=1C1C=CC=CC=1C1C=CC2N(C(CCCCCC)C(O)=O)C=NC=2C=1.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:10][O:9][C:7]1([O:11][CH3:12])[CH2:6][NH:5][C@H:4]([C:3]([OH:13])=[O:2])[CH2:8]1
Reactant: COC(=O)[C@@H]1CC(OC)(OC)CN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCCCCC(C(=O)O)n1cnc2cc(-c3ccccc3-c3nn[nH]n3)ccc21
Agent: Oc1cccc2[nH]nnc12
Product: COC1(OC)CN[C@H](C(=O)O)C1

Procedure:
4,4-Dimethoxy-L-proline methyl ester (1.35 moles, 0.257 g) and 2-[5-[2-(2H-tetrazol-5-yl)phenyl]-1H-benzimidazol-1-yl]octanoic acid (1.23 mmoles, 0.5 g) were reacted in the presence of hydroxybenzotriazole and dicyclohexylcarbodiimide as in Example 15 to yield 0.220 g of 1-[1-oxo-2-[5-2-(2H-tetrazol-5-yl)phenyl]-1H-benzimidazol-1-yl]octyl]-4,4-dimethoxy-L-proline. (MS).
Reaction SMILES: [C:1]1([C:7]([SH:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:23]([CH:27]([O:37][SiH:38]([CH3:40])[CH3:39])[C@@H:28]1[C@@H:31](S(C)(=O)=O)[NH:30][C:29]1=[O:36])([CH3:26])([CH3:25])[CH3:24]>CO.CC(C)=O.O>[C:23]([CH:27]([O:37][SiH:38]([CH3:40])[CH3:39])[C@@H:28]1[C@@H:31]([S:20][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:30][C:29]1=[O:36])([CH3:26])([CH3:24])[CH3:25]
Reactant: C[SiH](C)OC([C@H]1C(=O)N[C@@H]1S(C)(=O)=O)C(C)(C)C
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CO
Product: C[SiH](C)OC([C@H]1C(=O)N[C@@H]1SC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At 0°, 12.5 g of triphenylmethyl mercaptan are suspended in 70 ml of methanol and there is added in portions, over a period of 10 minutes, a total of 2.2 g of a 55% sodium hydride suspension in oil. There is then added dropwise, over a period of 30 minutes, an emulsion of 11.1 g of (3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-methylsulphonylazetidin-2-one (European Patent Application No. 82113) in 70 ml of acetone and 70 ml of water. After being stirred for 30 minutes at 0° and for 1 hour at room temperature, the reaction mixture is concentrated in a rotary evaporator, methylene chloride is added thereto, and the aqueous phase is separated off. The organic solution is washed with brine and dried over sodium sulphate. After concentration, the crude title compound is purified by chromatography over silica gel (eluant toluene/ethyl acetate 19:1). TLC (toluene/ethyl acetate 19:1): Rf =0.64; IR (methylene chloride): 3390, 1760, 1117, 835 cm-1.