Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)[O-].[Na+].[H+].[H+].Cl[Pt-2:9](Cl)(Cl)(Cl)(Cl)Cl.[CH2:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[Pt:9].[CH2:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [H+]
Agent: [Na+]
Solvent: C=Cc1ccccc1
Solvent: CCO
Product: [Pt]
Temperature: 55 °C

Procedure:
The platinum-styrene complex used in the examples is prepared by adding about 6 parts of sodium bicarbonate to a mixture containing 3 parts of chloroplatinic acid (H2PtCl6.6H2O), 6 parts of styrene and 50 parts of ethanol. The mixture is heated to reflux temperature, (about 55° C.) and refluxed for about 35 minutes with agitation, and then cooled to room temperature. The resultant mixture which contains orange crystals is filtered and the crystals washed with about 30 parts of acetone. After adding about 30 parts of xylene to the filtrate, crystals are again formed. The crystalline mixture is filtered and the orange crystals are recovered and dried. These crystals are then dissolved in isopropanol.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([C:13]3[CH:17]=[C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[S:15][C:14]=3[S:22]([NH:25]C(C)(C)C)(=[O:24])=[O:23])[CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.B(Cl)(Cl)Cl.N1(C2C=CC=CN=2)CCCC1.Cl[C:46]([O:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:47].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:49]([O:48][C:46]([NH:25][S:22]([C:14]1[S:15][C:16]([CH2:18][CH:19]([CH3:20])[CH3:21])=[CH:17][C:13]=1[C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:8]=1)(=[O:23])=[O:24])=[O:47])[CH2:50][CH2:51][CH3:52]
Reactant: CC(C)Cc1cc(-c2cccc(Cn3ccnc3)c2)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: CCCCOC(=O)Cl
Agent: ClB(Cl)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1ccc(N2CCCC2)nc1
Solvent: ClCCl
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(Cn2ccnc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
To a solution of 3-(3-imidazol-1-ylmethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (68.8 mg, 0.159 mmol; see step (f)) in CH2Cl2 (2 mL) was added BCl3 (0.6 mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was concentrated in vacuo. Water (5 mL) was added to the residue and this was then extracted with EtOAc. The combined organic phase was washed with water and brine and dried over anhydrous MgSO4, concentrated in vacuo. To the crude product dissolved in pyridine (1.5 mL) was added pyrrolidinopyridine (69.8 mg, 0.471 mmol) and butyl chloroformate (202.8 μL, 1.59 mmol) and the reaction mixture was stirred overnight. Citric acid (3 mL, 10% aq) was added to the reaction mixture, extracted with EtOAc, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue was purified by flash chromatography using MeOH:CH2Cl2 (6:94) as eluent to give the title compound in 59% yield, over two steps, (44.4 mg, 0.093 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[NH2:32][C:33]1[C:38]([NH2:39])=[CH:37][CH:36]=[CH:35][N:34]=1>C1COCC1>[NH2:32][C:33]1[C:38]([NH:39][C:14](=[O:16])[CH2:13][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH3:12])=[CH:37][CH:36]=[CH:35][N:34]=1
Reactant: CN(CC(=O)O)C(=O)OCc1ccccc1
Reactant: Nc1cccnc1N
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(CC(=O)Nc1cccnc1N)C(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 19.4 %

Procedure:
N-(Benzyloxycarbonyl)sarcosine (4.1 g, 18.5 mmol) was dissolved in dry THF, and triethylamine (3 mL, 21.6 mmol) was added, followed by isobutylchloroformate (2.5 mL, 19.27 mmol). The solution was cooled to about -20° C. for 15 minutes, then a solution of 2,3-diaminopyridine (2.0767 g, 19.03 mmol) in dry THF was added slowly. The reaction was kept stirring between -10° C. to -20° C. for 15 minutes, then was allowed to warm to RT. After 3 d, the reaction was evaporated under vacuum, and the residue was partitioned between EtOAc and 1N NaHCO3. The EtOAc phase was dried (MgSO4) and evaporated under vacuum. The residue was dissolved in glacial AcOH and was stirred in a oil bath at 70° C. After 24 h, the reaction was removed from the oil bath, allowed to cool to RT, and concentrated under vacuum. The residue was evaporated with toluene, then was chromatographed on silica gel (CHCl3, then 3% MeOH/CHCl3, then 5% MeOH/CHCl3) to afford the title compound (1.13 g, 19%): 1H NMR (250 MHz, CDCl3) δ 3.05 (s, 3H), 3.99 (s, 2H), 4.82 (br s, 1H), 6.5-6.65 (m, 1H), 7.32 (s, 5H), 7.87 (d, 1H), 8.84 (br s, 1H); MS (ES) m/e 315.4 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[CH2:9][CH2:8][C:7]1=[O:18].[CH2:19]1[NH:24][CH2:23][CH2:22][N:21]2[CH2:25][CH2:26][CH2:27][CH:20]12>>[CH2:19]1[N:24]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[CH2:9][CH2:8][C:7]2=[O:18])[CH2:23][CH2:22][N:21]2[CH2:25][CH2:26][CH2:27][CH:20]12
Reactant: C1CC2CNCCN2C1
Reactant: O=C1CCC(=O)N(CCCCCl)c2ccccc21
Product: O=C1CCC(=O)N(CCCCN2CCN3CCCC3C2)c2ccccc21
Yield: 35.2 %

Procedure:
Analogously to the method for Example 12b, reaction of 1-(4-chlorobutyl)-3,4-dihydro-1H-1-benzazepine-2,5-dione (0.40 mmol, 0.11 g) and octahydropyrrolo[1,2-a]pyrazine (0.40 mmol, 0.05 g) afforded 0.05 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[C:19](O)=[O:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:19]([C:16]2[C:17]3[C:12](=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:18]=3)[CH:13]=[CH:14][CH:15]=2)=[O:20])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1cccc2ccc(OCc3ccccc3)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc3ccc(OCc4ccccc4)cc23)CC1

Procedure:
To the product from Step C (3.58 mmol), N-tert-butoxycarbonylpiperazine (733 mg, 3.93 mmol), EDC hydrochloride (750 mg, 3.93 mmol), HOBT (483 mg, 3.58 mmol), and triethylamine (0.498 mL, 3.58 mmol) were stirred in dry DMF (15 mL) at room temperature for two days. After concentration in vacuo, the residue was partitioned between EtOAc and 50% NaHCO3 solution, washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (30% EtOAc/hexane) to yield the desired product as a white foam.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:38])=[C:21]([NH:26][S:27]([C:30]3[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=3[F:37])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=2[F:25])[CH:5]=[CH:4][N:3]=1.[NH4+:39].[OH-]>>[NH2:39][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:38])=[C:21]([NH:26][S:27]([C:30]3[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=3[F:37])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=2[F:25])[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1ccc(F)c(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1nccc(-c2sc(N3CCOCC3)nc2-c2c(F)ccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 21 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,6-difluorobenzenesulfonamide (150 mg, 0.256 mmol) and NH4OH (2.5 mL, 17.97 mmol) heated in the microwave at 130° C. for 15 min the title compound was obtained as a light yellow solid (124 mg, 81%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.85 (br. s., 1H), 7.90 (d, J=5.3 Hz, 1H), 7.60-7.74 (m, 1H), 7.49 (td, J=8.7, 6.1 Hz, 1H), 7.16-7.34 (m, 3H), 6.62 (s, 2H), 5.63 (d, J=5.3 Hz, 1H), 3.67-3.74 (m, 4H), 3.40-3.48 (m, 4H). MS (ESI): 566 [M+H]+.
Reaction SMILES: OO.[NH2:3][C:4]([CH3:22])([CH3:21])[CH2:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1.C([O-])([O-])=[O:24].[K+].[K+].CS(C)=O>O>[NH2:3][C:4]([CH3:22])([CH3:21])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]([NH2:16])=[O:24])=[CH:13][CH:12]=2)=[CH:19][CH:20]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(N)Cc1ccc(Oc2ccc(C#N)cc2)cc1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(N)Cc1ccc(Oc2ccc(C(N)=O)cc2)cc1
Reaction time: 1 h
Yield: 169.7 %

Procedure:
Aqueous 30% H2O2 (62.1 mL, 548 mmol) was added dropwise to a mixture of 4-(4-(2-amino-2-methylpropyl)phenoxy)benzonitrile (53.2 g, 200 mmol), K2CO3 (15.78 g, 114 mmol) and DMSO (270 mL) over 20 min while the temperature was held at 20° C. with a cooling bath. The mixture was stirred at this temperature for 1 h after the addition was complete, and then water (209 mL) was added slowly. The slurry was cooled in an ice bath with stirring for 1 h, and the product was then filtered, washed with water and dried in vacuo at 50° C. to yield 55.0 g (97%) of white solid. Analysis by HPLC indicated purity of >99%. NMR.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH3:27])[C:13]=3[NH:17][C:18](=[O:26])[CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:8]=2)[CH2:3]1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>ClCCl>[CH3:27][C:12]1[C:13]([NH:17][C:18](=[O:26])[CH2:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:4]1[CH2:5][CH2:6][C@@H:2]([O:1][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:3]1)[CH:16]=[CH:15]2
Reactant: Cc1ccc2nc(N3CC[C@@H](O)C3)ccc2c1NC(=O)CC1CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2nc(N3CC[C@@H](OS(C)(=O)=O)C3)ccc2c1NC(=O)CC1CCCCC1

Procedure:
Prepared according to the method of example 33(a), using N-[2-[(3R)-3-hydroxy-1-pyrrolidinyl]-6-methyl-5-quinolinyl]-cyclohexaneacetamide (Example 84) (0.545 g), methanesulfonyl chloride (0.23 mL), triethylamine (0.62 mL) and dichloromethane (20 mL) to afford the sub-title compound (0.4 g).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20].[OH-].[Na+].O1CCCC1>O>[CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: NCCCCC(=O)O
Reactant: CN(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)c1ccc(S(=O)(=O)NCCCCC(=O)O)cc1
Reaction time: 4 h
Yield: 61.7 %

Procedure:
4.4 g of 4-dimethylaminobenzenesulphonyl chloride (Chem. Ber. 43, 3038, (1910)) are added to a solution comprising 2.34 g of 5-aminovaleric acid and 2.4 g of sodium hydroxide dissolved in 24 cm3 of water, followed by the addition of 24 cm3 of tetrahydrofuran in order to obtain a solution. The temperature rises to 36° C. The mixture is kept stirring for 4 hours, the tetrahydrofuran is evaporated off, the reaction medium is acidified using acetic acid and extracted with chloroform, the organic phase is dried and the solvents are removed under reduced pressure. 3.7 g of expected product are obtained. M.p. 105°-110° C. After crystallization in an isopropanol/water mixture (1:1), the product, melting point 118°-120° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:21]=[C:12]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:19](=[O:20])[N:11]3[N:10]=2)=[CH:5][CH:4]=1.[OH2:22].[OH-].[Na+].Cl>CO>[C:19]([C:18]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:12]1[CH:21]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[NH:10][N:11]=1)([OH:22])=[O:20]
Reactant: COc1ccc(-c2cc3n(n2)C(=O)c2ccccc2-3)cc1
Reactant: O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-c2cc(-c3ccccc3C(=O)O)n[nH]2)cc1
Reaction time: 0.08 h

Procedure:
A mixture of 2 -(4-methoxyphenyl)-8H-pyrazolo[5,1-a]isoindol-8-one (100 mg), water (5 ml) and methanol (5ml) was stirred for one hour with sodium hydroxide (0.5 g). Within 5 minutes, a colorless solution has been produced. The mixture was then acidified to pH 3 with concentrated hydrochloric acid, cooled to 0° and filtered. The colorless crystalline residue was rinsed with water and air-dried. It was recrystallized from 33% aqueous ethanol (15 ml), recovery 80.7 mg (79%) of colorless crystals, mp 223°-225° dec, of 3-(2-carboxyphenyl)-5-(4-methoxyphenyl)pyrazole.
Reaction SMILES: [CH3:1][C:2]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:3]=1[NH:4][CH2:5][C:6]1[NH:7][CH2:8][CH2:9][N:10]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1>C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([N:10]2[CH2:9][CH2:8][N:7]=[C:6]2[CH2:5][NH:4][C:3]2[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:2]=2[CH3:1])=[O:25])=[CH:19][CH:18]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Cc1cccc(NCC2=NCCN2)c1C
Solvent: ClCCl
Product: Cc1cccc(NCC2=NCCN2C(=O)Nc2ccc(Cl)cc2)c1C
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
2-(2,3-Dimethylanilinomethyl)-2-imidazoline (4.20 g; 0.024 moles) was stirred in methylene chloride (90 ml), cooled to 0° C. and a solution of 4-chlorophenyl isocyanate (3.66 g; 0.024 moles) in methylene chloride (10 ml) was then added dropwise. A white precipitate formed rapidly. Stirring was continued for 2 to 3 hours after the addition at 0° C., the reaction mixture then allowed to reach ambient temperature and stirring was continued overnight. The reaction mixture was then evaporated to dryness under reduced pressure and the solid residue so obtained recrystallised from propan-2-ol to yield white crystals of 1-(N-(4-chlorophenyl)-carbamoyl)-2-(2,3-dimethylanilinomethyl)-2-imidazoline m.p. 153°-155° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH:6]2[O:8][CH:5]2[CH2:4]1)[CH3:2].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[OH:17].[OH-].[Na+].O>Cl.C(Cl)Cl>[ClH:9].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[O:17][C@@H:6]1[CH2:7][N:3]([CH2:1][CH3:2])[CH2:4][C@H:5]1[OH:8]
Reactant: Oc1c(Cl)cccc1Cl
Reactant: CCN1CC2OC2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCN1C[C@@H](O)[C@H](Oc2c(Cl)cccc2Cl)C1

Procedure:
A mixture of 11.3 g. (0.10 mole) of 1-ethyl-3,4-epoxypyrrolidine, 18.0 g. (0.11 mole) of 2,6-dichlorophenol and 2 drops concentrated hydrochloric acid was heated on a steam bath overnight. The oil was dissolved in methylene chloride and wahed with three 50-ml. portions of 5% sodium hydroxide an one 50-ml. portion of water. The methylene chloride solution was dried over anhydrous sodium sulfate, concentrated and chromatogrpahed on silica gel to give 12.9 g. (47%) of and oil residue. The oil was converted to the hydrchloride and recrystallized from isopropyl alcohol-diethyl ether to yield 12.3 g. (39%), m.p. 160°-162° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:17])[C:10]([C:14]([OH:16])=[O:15])=CNC=2)=[CH:4][CH:3]=1.F[C:19]1C=CC(CC(Cl)=O)=C[CH:20]=1.CC1(C)OC(=O)CC(=O)O1.N1C=CC=CC=1>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9](=[O:17])[CH2:10][C:14]([O:16][CH2:19][CH3:20])=[O:15])=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: O=C(O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Agent: CC1(C)OC(=O)CC(=O)O1
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)CC(=O)Cc1ccc(F)cc1

Procedure:
The intermediate, 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (8) can be obtained using the chemistry described in Scheme 2. Thus, 2-(4-fluorophenyl)acetyl chloride (10) can be treated with 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) in the presence of pyridine and the resulting adduct can be refluxed in ethanol to afford ethyl 4-(4-fluorophenyl)-3-oxobutanoate (12). Treatment of intermediate 12 with triazine and sodium ethoxide in ethanol can furnish the requisite ester intermediate, which can be readily hydrolyzed in the presence of sodium hydroxide at elevated temperature to furnish intermediate 8.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]([CH3:13])[N:5]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1.C(N(CC)CC)C.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:7](=[O:12])[CH:6]([CH3:13])[N:5]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1
Reactant: CC(C)CCN1c2nc(Cl)ncc2NC(=O)C1C
Reactant: OB(O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CCN1c2nc(Cl)ncc2N(c2ccccc2)C(=O)C1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 39 %

Procedure:
To a stirred solution of 2-chloro-7-methyl-8-(3-methylbutyl)-7,8-dihydropteridin-6(5H)-one (2.0 g, 7.4 mmol) in dichloromethane (100 mL) was added triethylamine (10.4 ml, 74 mmol), cupric acetate (2.70 g, 14.8 mmol) and phenylboronic acid (1.81 g, 14.8 mmol) followed by 4 Å molecular sieves (3.0 g). The reaction mixture was stirred for 48 h at room temperature with an air balloon. The mixture was then filtered over celite. The filtrate was washed with aqueous saturated sodium bicarbonate (2×50 ml), dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel using 2% methanol in dichloromethane as eluent to give the titled product. (yield: 39%). 1HNMR (300 MHz, CDCl3): δ 0.91-1.01 (m, 6H), 1.49-1.75 (m, 6H), 3.12-3.20 (m, 1H), 4.18-4.21 (m, 1H), 4.30-4.45 (m, 1H), 7.10 (s, 1H), 7.20-7.39 (m, 2H), 7.42-7.65 (m, 3H).
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19]C(OC(C)(C)C)=O)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.C(OC(=O)NC1C=CC=C(C=O)C=1)(C)(C)C.[C:43]([NH:47]C(C1CCNCC1)=O)([CH3:46])([CH3:45])[CH3:44]>>[C:43]([NH:47][C:4]([CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)[CH2:10][CH2:11]1)=[O:5])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)NC(=O)C1CCNCC1
Reactant: CCOC(=O)C1CCN(Cc2cccc(NC(=O)OC(C)(C)C)c2)CC1
Agent: CC(C)(C)OC(=O)Nc1cccc(C=O)c1
Product: CC(C)(C)NC(=O)C1CCN(Cc2cccc(N)c2)CC1

Procedure:
The title compound is prepared according to the reaction 1.001a and 1.001d described above using (3-formyl-phenyl)-carbamic acid tert-butyl ester and piperidine-4-carboxylic acid tert-butylamide: LC-MS A: tR=0.44 min; [M+H]+=289.92.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][OH:16])O[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1>Cl>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][OH:16])[N:24]([C:20]2[CH:19]=[C:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:23]=[CH:22][CH:21]=2)[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(CO)occ1OCc1ccccc1
Reactant: Nc1cccc(-c2ccccc2)c1
Agent: Cl
Product: O=c1cc(CO)n(-c2cccc(-c3ccccc3)c2)cc1OCc1ccccc1

Procedure:
To a suspension of 5-(benzyloxy)-2-(hydroxymethyl)-4H-pyran-4-one (92.9 g, 0.40 mol) in dilute aq hydrochloric acid (0.5 N, 800 mL) was added biphenyl-3-amine (74.4 g, 0.44 mol). The resulting mixture was heated under refluxed for 16 h. Concentration of the solvent gave a residue which was purified by silica gel chromatography (EtOAc:MeOH/20:1) to afford 5-(benzyloxy)-1-(biphenyl-3-yl)-2-(hydroxymethyl)pyridin-4(1H)-one as pale solid MS (ESI) (M+H)+ 384.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:12]O.P(Br)(Br)[Br:15]>C(OCC)C.O>[Br:15][CH2:12][C:3]1[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=1[Cl:1]
Reactant: CS(=O)(=O)c1ccc(CO)c(Cl)c1
Reactant: BrP(Br)Br
Solvent: O
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc(CBr)c(Cl)c1
Temperature: 0 °C

Procedure:
A cooled (0° C.), stirred suspension of (2-chloro-4-methanesulfonyl-phenyl)-methanol (19.1 g, 0.087 mol) in diethyl ether (250 ml) under an inert atmosphere, is treated with phosphorus tribromide (5.2 ml, 0.029 mol) and allowed to stir and warm to room temperature overnight. The resulting mixture is diluted with water (100 ml) and the organic portion is separated and dried over NaOH pellets for 5 minutes. The solvent is removed in vacuo and the resulting crude residue is loaded on a pre-packed Isolute™ silica column and eluted with iso-hexane/ethyl acetate (4:1) to yield the titled compound as a white powder.
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.N1C=CC=CC=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]([NH:28][C:29]([C:31]2([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:30])[CH3:27])=[CH:22][CH:21]=1.[Na+].[Cl-]>ClCCl>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]([NH:28][C:29]([C:31]2([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:32][CH2:33][N:34]([C:7]([Cl:10])=[O:6])[CH2:35][CH2:36]2)=[O:30])[CH3:27])=[CH:22][CH:21]=1
Reactant: C[C@H](NC(=O)C1(c2ccccc2)CCNCC1)c1ccc(F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H](NC(=O)C1(c2ccccc2)CCN(C(=O)Cl)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.9 %

Procedure:
To a solution of triphosgene (172 mg, 0.6 mmol) in dichloromethane (6 mL) at 0° C. under an argon atmosphere was added a solution of pyridine (106 μL, 1.32 mmol) in dichloromethane (3 mL) and a solution of 4-phenyl-piperidine-4-carboxylic acid [(S)-1-(4-fluoro-phenyl)-ethyl]-amide (195 mg, 0.6 mmol) in dichloromethane (6 ml). After stirring at room temperature for 12 h the reaction mixture was poured into ice water, the aqueous layer was saturated with NaCl, then extracted 6 times with dichloromethane, the combined organic layers were dried over Na2SO4 and the solvents were evaporated. The residue was purified by flash chromatography over a 10 g silica gel column with n-heptane and ethyl acetate to yield 233 mg 4-[(S)-1-(4-fluoro-phenyl)-ethylcarbamoyl]-4-phenyl-piperidine-1-carbonyl chloride. MS ISN (m/e): 387.4 [(M−H)−].
Reaction SMILES: [Cl:1][C:2]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][NH:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])[CH3:8].ClC1C=CC=CC=1C(C)CN([CH2:47][CH2:48][CH2:49][O:50][C:51]1[CH2:52][C:53](=[CH:57][C:58]([O:60][CH3:61])=[O:59])[CH:54]=[CH:55][CH:56]=1)CC1C=CC=C(C(F)(F)F)C=1Cl>>[CH3:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:7]([CH3:8])[CH2:6][N:5]([CH2:47][CH2:48][CH2:49][O:50][C:51]1[CH2:52][C:53](=[CH:57][C:58]([O:60][CH3:61])=[O:59])[CH:54]=[CH:55][CH:56]=1)[CH2:4][C:3]1[CH:17]=[CH:18][CH:19]=[C:20]([C:21]([F:22])([F:23])[F:24])[C:2]=1[Cl:1]
Reactant: COc1ccccc1C(C)CNCc1cccc(C(F)(F)F)c1Cl
Reactant: COC(=O)C=C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(C)c2ccccc2Cl)C1
Product: COC(=O)C=C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(C)c2ccccc2OC)C1
Yield: 90 %

Procedure:
The titled compound was prepared from N-(2-Chloro-3-trifluoromethylbenzyl)-2-(2-methoxyphenyl)propylamine in 90% yield in the same manner as the preparation of N-(2-[2-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylamine in Example 184f. MS (ESI) 564 (MH+).