Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([N:31]2[CH2:30][CH2:29][N:28]([C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[CH2:33][CH2:32]2)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diisopropylethylamine (4.00 ml) was added to a solution of 4-bromobenzenesulfonyl chloride (3.00 g) and 1-(tert-butoxycarbonyl)piperazine (2.40 g) in methylene chloride (50 ml) at room temperature. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was purified by chromatography on a silica gel column (hexane:ethyl acetate=4:1→1:1), followed by reprecipitation in a hexane—methylene chloride system, whereby the title compound (4.47 g) was obtained as a colorless solid.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8](Br)[CH:9]=[CH2:10]>C(OCC)C>[CH2:10]([N:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:9]=[CH2:8]
Reactant: C=CCBr
Reactant: C1CCCNCC1
Solvent: CCOCC
Product: C=CCN1CCCCCC1
Temperature: 5 °C

Procedure:
198.4 9 of homopiperidine dissolved in 280 mL of diethyl ether was added to a 1 L, 3-necked round-bottomed flask. The mixture was cooled to 5° C. with an ice bath and while stirring, 121 g of allyl bromide in 40 mL of diethyl ether was added slowly to this amine solution. After addition was complete, the reaction mixture was allowed to stir at room temperature for 18 hours. The white precipitate thus formed was filtered and ether was removed at room temperature using a rotary evaporator. The residual liquid was fractionally distilled yielding 72 9 of N-allylhomopiperidine. To a 500 mL 3-necked round-bottomed flask was added 41.8 g of N-allylhomopiperidine dissolved in 50 mL of diethyl ether. After cooling to 5° C. with an ice bath, 36.3 g of allyl bromide in 30 mL diethyl ether was added slowly. After completion of the addition of allyl bromide, the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 24 hours. The solid thus formed was collected by filtration and was washed twice with 1.5 L of diethyl ether. The washed solid was dried under vacuum yielding 67 g of N,N-diallyl-homopiperidinium bromide as a white solid.
Reaction SMILES: ClCCl.[CH2:4]([S:11][C:12]1[S:13][C:14]2[CH:20]=[C:19]([F:21])[C:18]([N:22]3[C:26](=[O:27])[N:25]([CH3:28])[C:24]([CH3:29])=[N:23]3)=[CH:17][C:15]=2[N:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.ClC1C=C(C=CC=1)C(OO)=[O:35]>O>[CH2:4]([S:11]([C:12]1[S:13][C:14]2[CH:20]=[C:19]([F:21])[C:18]([N:22]3[C:26](=[O:27])[N:25]([CH3:28])[C:24]([CH3:29])=[N:23]3)=[CH:17][C:15]=2[N:16]=1)=[O:35])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cc1nn(-c2cc3nc(SCc4ccccc4)sc3cc2F)c(=O)n1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: Cc1nn(-c2cc3nc(S(=O)Cc4ccccc4)sc3cc2F)c(=O)n1C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
10 mL of dichloromethane was charged with 0.001 mol 1-(2-(benzylthio)-6-fluorobenzo[d]thiazol-5-yl)-3,4-dimethyl-1H-1,2,4-triazol-5(4H)-one. The mixture was stirred for 10 mins and then 0.0011 mol m-chloroperoxybenzoic acid (MCPBA) were added. After stirring at room temperature for 2 hours, the mixture was poured into 30 mL of water, extracted with 15 mL dichloromethane twice. Organic phases were combined and dried over anhydrous sodium sulfate. Filtration and removal of solvent under vacuum gave the title compound as a white solid in a 91% yield.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:9]2[CH:10]=[N:11][C:12]([C:15]([OH:18])([CH3:17])[CH3:16])=[N:13][CH:14]=2)=[C:4]([F:19])[C:3]=1[CH:20]1[CH2:24][CH2:23][CH2:22][O:21]1.O1CCOCC1.[CH2:31]([NH:33][C:34]([NH:36][C:37](SC)=NC(=O)NCC)=[O:35])[CH3:32].C([O-])(O)=O.[Na+]>OS(O)(=O)=O>[CH2:31]([NH:33][C:34]([NH:36][C:37]1[NH:1][C:2]2[C:3]([CH:20]3[CH2:24][CH2:23][CH2:22][O:21]3)=[C:4]([F:19])[C:5]([C:9]3[CH:10]=[N:11][C:12]([C:15]([OH:18])([CH3:16])[CH3:17])=[N:13][CH:14]=3)=[CH:6][C:7]=2[N:8]=1)=[O:35])[CH3:32]
Reactant: CCNC(=O)N=C(NC(=O)NCC)SC
Reactant: CC(C)(O)c1ncc(-c2cc(N)c(N)c(C3CCCO3)c2F)cn1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)O)nc3)c(F)c(C3CCCO3)c2[nH]1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a stirring suspension of 2-[5-(4,5-diamino-2-fluoro-3-tetrahydrofuran-2-yl-phenyl)pyrimidin-2-yl]propan-2-ol (21) (111.3 g, 334.9 mmol) and 1,4-dioxane (556.5 mL, Sigma-Aldrich 360481) was added 1-ethyl-3-(N-(ethylcarbamoyl)-C-methylsulfanyl-carbonimidoyl)urea (10) (93.36 g, 401.9 mmol, CB Research and Development) followed by a pH 3.5 buffer (1.113 L), prepared by dissolving NaOAc trihydrate (158.1 g) in 1N aqueous H2SO4 (1.100 L). The reaction mixture was stirred at reflux overnight (HPLC showed complete conversion), cooled to room temperature, and poured portion-wise (to minimize frothing) into a stirring solution of aqueous saturated NaHCO3 (2.23 L) giving pH 8-9. The resulting mixture was stirred for 30 minutes, the solid was collected by filtration, washed copiously with water to neutral pH, and then more sparingly with EtOH. The solid was dried under reduced pressure giving 22 as an off-white yellowish solid (135.2 g, 94% yield; 99% HPLC purity). LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 429.58 (2.03 min). 1H NMR (300 MHz, MeOD) δ 8.95 (d, J=1.6 Hz, 2H), 7.45 (d, J=6.5 Hz, 1H), 5.38 (br.s, 1H), 4.27 (dd, J=14.9, 7.1 Hz, 1H), 4.01 (dd, J=15.1, 7.0 Hz, 1H), 3.37-3.29 (m, 2H), 2.55 (br.s, 1H), 2.19-2.07 (m, 2H), 2.02-1.82 (br.s, 1H), 1.63 (s, 6H), 1.21 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(OC(N(C)C)=[N+](C)C)[C:12]2[CH:13]=[CH:14][CH:15]=CC=2N=N1.[NH2:25][C:26]1[N:34]=[C:33]([C:35]([OH:37])=O)[N:32]=[C:31]2[C:27]=1[NH:28][C:29](=[O:45])[N:30]2[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(C(C)C)CC)(C)C.NCC1CC1>CC(N(C)C)=O>[CH:13]1([CH2:12][NH:8][C:35]([C:33]2[N:32]=[C:31]3[C:27]([NH:28][C:29](=[O:45])[N:30]3[CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[C:26]([NH2:25])[N:34]=2)=[O:37])[CH2:15][CH2:14]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Nc1nc(C(=O)O)nc2c1[nH]c(=O)n2Cc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: NCC1CC1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(C(=O)NCC2CC2)nc2c1[nH]c(=O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
O-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (48.1 g, 126.8 mmol) was added to a solution of the product of Preparation 12, 6-amino-9-benzyl-8-oxo-8,9-dihydro-7H-purine-2-carboxylic acid (32.88 g, 115.3 mmol) and diisopropylethylamine (40.2 ml, 230.6 mmol) in dimethylacetamide (250 ml) and the reaction mixture stirred at room temperature for 1 hour. Aminomethylcyclopropane (12.5 ml, 144.1 mmol) was added and the reaction mixture stirred at room temperature for a further 20 hours. The reaction mixture was concentrated in vacuo and water added. The resultant precipitate was collected by filtration, azeotroped with toluene and triturated with methanol to yield the title compound.
Reaction SMILES: F[B-](F)(F)F.N1(O[C:16](=[N+](C)C)[N:17](C)[CH3:18])C2C=CC=CC=2N=N1.[OH:23][C:24]([CH3:57])([CH3:56])[CH2:25][C@@:26]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[O:31][C:30](=[O:32])[N:29]([C@H:33]([C:35]2[CH:40]=[CH:39][C:38]([C:41]3[N:46]=[N:45][C:44]([C:47](O)=[O:48])=[CH:43][CH:42]=3)=[CH:37][CH:36]=2)[CH3:34])[CH2:28][CH2:27]1.C(N(C(C)C)C(C)C)C.CNC>CN(C)C=O>[CH3:16][N:17]([CH3:18])[C:47]([C:44]1[N:45]=[N:46][C:41]([C:38]2[CH:37]=[CH:36][C:35]([C@@H:33]([N:29]3[CH2:28][CH2:27][C@:26]([CH2:25][C:24]([OH:23])([CH3:56])[CH3:57])([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)[O:31][C:30]3=[O:32])[CH3:34])=[CH:40][CH:39]=2)=[CH:42][CH:43]=1)=[O:48]
Reactant: C[C@@H](c1ccc(-c2ccc(C(=O)O)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](c1ccc(-c2ccc(C(=O)N(C)C)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
[(Benzotriazol-1-yloxy)-dimethylamino-methylene]-dimethyl-ammonium tetrafluoroborate (TBTU, 110 mg) was added to a solution of 6-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridazine-3-carboxylic acid (140 mg) and ethyl-diisopropyl-amine (60 μL) in N,N-dimethylformamide (2 mL) at room temperature. The resulting solution was stirred for 20 min, before dimethylamine (2 mol/L in tetrahydrofuran, 300 μL) was added. After stirring the solution at room temperature for another 2 h, the solution was concentrated and the residue was purified by HPLC on reversed phase (methanol/water/NH4OH) to afford the title compound. Yield: 50 mg (34% of theory); Mass spectrum (ESI+): m/z=503 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:6]=1.[CH3:12]N(P(N(C)C)(N(C)C)=O)C.[Li+].CC([N-]C(C)C)C.CI>C1COCC1>[CH3:1][C:2]1[O:3][CH:4]=[C:5]([CH:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9])[N:6]=1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: COC(=O)Cc1coc(C)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)c1coc(C)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To the intermediate from Step A (1.35 g, 8.71 mmol) and HMPA (6.24 g, 34.8 mmol) in 10 mL of THF at −78° C. was added dropwise a LDA solution (2.0 M, 5.22 mL, 10.5 mmol). The mixture was stirred at −78° C. for 30 min and MeI (1.48 g, 10.45 mmol) was added dropwise. The resulting mixture was slowly warmed to room temperature. The reaction was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc. The organic phase was washed with brine, dried with MgSO4, and concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated compound (yellow oil). 1H NMR (CDCl3, 500 MHz) δ 7.48 (1H, s), 3.77 (3H, s), 3.76 (1H, q, J=7.5 Hz), 2.49 (3H, s), 1.55 (3H, d, J=7.5 Hz).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])#[N:2].CC(C)([O-])C.[K+].[NH:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](O)=[O:25].P(C#N)(=O)(OCC)OCC>CN(C)C=O.O>[O:25]=[C:24]([C:20]1[NH:19][CH:23]=[CH:22][CH:21]=1)[CH:3]([C:4](=[O:5])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:1]#[N:2]
Reactant: O=C(O)c1ccc[nH]1
Reactant: N#CCC(=O)Nc1ccccc1
Agent: CC(C)(C)[O-]
Agent: CCOP(=O)(C#N)OCC
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C(=O)Nc1ccccc1)C(=O)c1ccc[nH]1

Procedure:
to a solution of 1.6 g of α-cyanoacetanilide in 10 ml of dimethylformamide is added 3.4 g of potassium t-butoxide. The stirred cooled suspension is treated with a solution of 1.1 g of pyrrole-2-carboxylic acid and 1.4 ml of diethyl phosphorocyanidate in 6 ml of dimethylformamide. After standing for one half hour, solution is treated with 80 ml of cold water, filtered and acidified with 6N hydrochloric acid. The suspended product is collected, washed with water, dried, and dissolved in ethyl acetate. The ethyl acetate solution is filtered and evaporated to dryness. Recrystallization from ether-ethanol yields β-oxo-α-(phenylcarbamoyl)-β-(2-pyrrolyl)-propionitrile of Example 1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:12]([O-])=[O:13].[Na+].C(OCC)=O>C(O)C.C(O)(=O)/C=C/C(O)=O>[CH:12]([NH:11][NH:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)=[O:13]
Reactant: O=C[O-]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CCOC=O
Solvent: CCO
Product: O=CNNc1ccc([N+](=O)[O-])cc1

Procedure:
4-Nitrophenylhydrazine (9.2 g, 0.06 mole), sodium formate (4.08 g, 0.06 mole), and ethyl formate (148 g, 2.00 moles) were mixed in ethanol (40 ml) and fumaric acid (30 ml). The mixture was heated on a steam bath; the volume of the mixture was reduced to approximately 100 ml by continued boiling. The hydrazide product crystallized out of the concentrated reaction mixture upon cooling. The product was filtered off, washed with ethanol, and dried. Yield 10.2 g (94%), m.p. 183°-185° C.
Reaction SMILES: F[C:2]1C=C(C(N)C)C=C(F)C=1.[ClH:12].[NH2:13][C:14]1([C:19]([O:21][CH3:22])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15]1.NC1(C(O)=O)CCCCC1>>[ClH:12].[NH2:13][C:14]1([C:19]([O:21][CH3:22])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:2]1
Reactant: COC(=O)C1(N)CCCC1
Reactant: CC(N)c1cc(F)cc(F)c1
Agent: Cl
Agent: NC1(C(=O)O)CCCCC1
Product: COC(=O)C1(N)CCCCC1

Procedure:
Essentially following the procedures described in Intermediate 1 for methyl 1-aminocyclopentanecarboxylate hydrochloride, but using 1-aminocyclohexanecarboxylic acid in place of 1-aminocyclopentanecarboxylic acid, the title compound was obtained. MS: m/z=158 (M+1).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[CH:26]1([N:32]=[C:33]=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(CC)CC)C.Cl>C(#N)C>[CH:26]1([NH:32][C:33]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C=NC1CCCCC1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3cc(CNC(=O)NC4CCCCC4)ccc3C2=O)C(=O)N1
Reaction time: 2 h
Yield: 51.9 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.43 g, 1.16 mmol) and cyclohexylisocyanate (0.148 mL, 1.16 mmol) in acetonitrile (8 mL), was added triethylamine (0.32 mL, 2.33 mmol) at room temperature under nitrogen. After 2 h, dil. aq. HCl (10 mL) was added. The solids were collected by filtration and washed with dil. aq. HCl (20 mL) and acetonitrile (10 mL). The product was dried in vacuo to give 1-cyclohexyl-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.24 g, 52% yield): HPLC: Waters Nova-Pak C18 column, 3.9×150 mm, 4 μm; 25/75 CH3CN/0.1% aq H3PO4, 10 min, 1.0 mL/min, 5.94 min (99.50%); mp: 265-267° C.; 1H NMR (DMSO-d6) δ 0.99-1.36 (m, 5H, CH2, CH2, CH), 1.44-1.84 (m, 5H, CH2, CH2, CH), 1.92-2.06 (m, 1H, CH), 2.25-2.47 (m, 1H, CH), 2.59 (d, J=17.4 Hz, 1H, CH), 2.82-3.02 (m, 1H, CH), 3.33-3.47 (m, 1H, CH), 4.22-4.50 (m, 4H, CH2 and CH2), 5.10 (dd, J=5.0, 13.3 Hz, 1H, NCH), 5.88 (d, J=7.9 Hz, 1H, NH), 6.29 (t, J=5.9 Hz, 1H, NH), 7.38 (d, J=7.7 Hz, 1H, Ar), 7.44 (s, 1H, Ar), 7.67 (d, J=7.7 Hz, 1H, Ar), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 24.49, 25.28, 31.20, 33.28, 42.86, 47.09, 47.89, 51.55, 121.76, 122.84, 126.81, 130.13, 142.30, 145.51, 157.26, 167.98, 170.99, 172.85; LCMS: MH=399; Anal Calcd for C21H26N4O4: C, 63.30; H, 6.58; N, 14.06. Found: C, 63.30; H, 6.51; N, 13.76.
Reaction SMILES: C([Li])(CC)C.[F:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)[CH:10]=[CH:11][CH:12]=1.[CH:23](N1CCOCC1)=[O:24].Cl>C1COCC1.C1CCCCC1>[F:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)[CH:10]=[CH:11][C:12]=1[CH:23]=[O:24]
Reactant: Fc1cccc(-c2ccc3ccccc3c2)c1
Reactant: O=CN1CCOCC1
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: O=Cc1ccc(-c2ccc3ccccc3c2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
A 86.86 ml cyclohexane solution of sec-butyl lithium in a concentration of 1.01M was dropped into a 300 ml THF solution of 15.00 g (=67.49 mmol) of 2-(3-fluorophenyl)naphthalene at −70° C. After the dropping was finished, the reaction solution was stirred at the same temperature for 1 hour, added with a 150 ml THF solution of 10.88 g (=94.49 mmol) of 4-formylmorpholine through dropping and then slowly heated to room temperature. After being stirred for 18 hours, 25 ml of 6N HCl(aq) was dropped into the reaction solution, and then the reaction mixture was extracted thrice with toluene. The extract was washed with water and an aqueous solution of NaHCO3, and then dried with anhydrous MgSO4. After the solvent was evaporated under a reduced pressure, the obtained yellow solid of 16.83 g was purified with silica gel chromatography using toluene as the eluent to obtain a yellowish solid of 13.26 g, which was further recrystallized with toluene to obtain 10.09 g of 2-fluoro-4-naphthalene-2-yl-benzaldehyde as yellowish crystals.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].C(C[N:11]1[CH:28]=[CH:27][C:15]([NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[N:14][C:12]1=[O:13])(O)=O>ClCCl>[Cl:4][C:2]([CH2:1][N:11]1[CH:28]=[CH:27][C:15]([NH:16][C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])=[N:14][C:12]1=[O:13])=[O:3]
Reactant: O=C(O)Cn1ccc(NC(=O)OCc2ccccc2)nc1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)Cn1ccc(NC(=O)OCc2ccccc2)nc1=O
Reaction time: 2 h

Procedure:
Oxalyl chloride (6.3 g, 50 mmol) is added dropwise over 5 minutes to a solution of 1-(carboxymethyl)-N4 -(benzyloxycarbonyl)cytosine (15.3 g, 50 mmol) dissolved in dichloromethane (200 mL). The reaction is stirred until gas evolution has ceased and then for an additional 2 hours. The reaction mixture is evaporated to an oil.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH:22]1[CH2:24][CH2:23]1>O1CCCC1>[CH:22]1([CH2:21][O:12][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=2[O:3][CH:2]([F:13])[F:1])[CH:8]=[O:9])[CH2:24][CH2:23]1
Reactant: BrCC1CC1
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 0 °C
Reaction time: 7 h
Yield: 94.7 %

Procedure:
4-Difluoromethoxy-3-hydroxybenzaldehyde (10 g, 52.8 mmol) was dissolved in tetrahydrofuran (100 ml) added with potassium carbonate (44 g, 105 mmol), cooled to 0° C. and added with a solution of bromomethylcyclopropane (11 ml, 116.6 mmol) in tetrahydrofuran (50 ml). The reaction mixture was heated to reflux under stirring for 7 hrs, then fresh bromomethylcyclopropane (5.5 ml, 58.3 mmol) was added and the heating continued for further 7 hrs. The solvent was removed by vacuum distillation, then the mixture was added with 2 N sodium hydroxide (100 ml) and extracted with dichloromethane (2×100 ml). The combined organic layers were dried over sodium sulphate (5 g) and the solvent removed under reduced pressure to afford 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde (12 g, 50 mmol, 97% yield), that was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][C:34]=1[CH2:35]Br>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:35][C:34]2[CH:37]=[C:38]([C:41]#[N:42])[CH:39]=[CH:40][C:33]=2[F:32])[C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:27]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(Oc2ccc(NC3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Reactant: N#Cc1ccc(F)c(CBr)c1
Product: COC(=O)c1ccc(Oc2ccc(N(Cc3cc(C#N)ccc3F)C3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Yield: 89.3 %

Procedure:
Using general procedure H, 4-[4-(4-methoxycarbonyl-phenoxy)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 96) (430 mg, 1.04 mmol) and 2-fluoro-5-cyanobenzyl bromide (289 mg, 1.35 mmol) afforded 4-{(5-cyano-2-fluoro-benzyl)-[4-(4-methoxycarbonyl-phenoxy)-phenyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester as a white solid (520 mg, 89%).
Reaction SMILES: C(OCC)C.[CH3:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])=[O:8].[Br-].CO.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>>[Cl:16][C:10]1[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[C:7](=[O:8])[CH2:6][N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: CC(=O)c1ccc(Cl)cc1Cl
Reactant: c1c[nH]cn1
Agent: [Br-]
Solvent: CCOCC
Solvent: CO
Product: O=C(Cn1ccnc1)c1ccc(Cl)cc1Cl
Reaction time: 1 h
Yield: 80 %

Procedure:
A 300 ml solution of diethyl ether containing 100 g (0.53 mole) of 2,4-dichloroacetophenone was cooled to 0°-5° C., and treated with 85.0 g (0.53 mole) of bromide and stirred one hour. The organic layer was washed with 3×500 ml portions of saturated sodium bicarbonate solution followed by 3×500 ml portions of water. The aqueous layer was removed and the organic layer treated with a 200 ml portion of methanol containing 108.0 g (1.6 mole) of imidazole and stirred in the cold overnight. The solution was concentrated, poured into 1600 ml of H2O with separation of an oil, the aqueous layer decanted, and the oil extracted 2×300 ml of methylene chloride. The combined organic phase was washed 2×300 ml of H2O, dried over magnesium sulfate and concentrated to give 108.8 g (80%) of a red oil. The nitrate salt was formed by treatment of the oil in acetone/ether solution with excess nitric acid, m.p. 161°-163° C. The free base obtained by neutralization was recrystallized from ethanol/water, m.p. 80°-82° C.
Reaction SMILES: [Na].[C:2]([O:11][CH3:12])(=[O:10])[C:3]1[C:4](=[CH:6][CH:7]=[CH:8][CH:9]=1)S.S([O-])(=O)(=O)C.Cl>CO.O>[CH3:12][O:11][C:2](=[O:10])[C:3]1[CH:4]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccccc1S
Agent: CS(=O)(=O)[O-]
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccccc1
Reaction time: 0.08 h

Procedure:
To a cooled (0° C.) solution of 27 mg (1.17 m atoms) of sodium in 4 ml of absolute methanol there were added 78 mg (0.47 mmol) of methyl thiosalicylate. After stirring 5 minutes, a solution of 128 mg (0.39 mmol) of the foregoing mesylate in 3 ml of methanol was added. The reaction mixture was stirred at room temperature for 1 hour, diluted with 5 ml of water, acidified with 10% hydrochloric acid, and extracted with methylene chloride (3×6 ml). The combined extracts were washed with brine (5 ml), dried and evaporated in vacuo. The residue was purified by thin layer chromatography, using hexane-ethyl acetate (95:5) as gradient, to afford the title compound, as an oil.