Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[CH2:22][CH2:21][CH2:20][C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6]1)[CH2:2][C:3]#[CH:4].C(N(CC)CC)C.[CH3:30][C:31]1([CH3:38])[C:35]([CH3:37])([CH3:36])[O:34][BH:33][O:32]1>[Cl-].[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Zr+2].ClCCl>[CH3:30][C:31]1([CH3:38])[C:35]([CH3:37])([CH3:36])[O:34][B:33](/[CH:4]=[CH:3]/[CH2:2][CH2:1][N:5]2[CH2:6][C:7]3([CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH2:11][CH2:12]3)[CH2:20][CH2:21][CH2:22]2)[O:32]1
Reactant: CC1(C)OBOC1(C)C
Reactant: C#CCCN1CCCC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: [Zr+2]
Agent: [Cl-]
Agent: c1cc[cH-]c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CCCN(CC/C=C/B3OC(C)(C)C(C)(C)O3)C2)CC1
Temperature: 65 °C
Reaction time: 24 h
Yield: 89.4 %

Procedure:
Tert-butyl 8-but-3-ynyl-3,8-diazaspiro[5.5]undecane-3-carboxylate (129.00 g, 420.95 mmoles), triethylamine (5.87 mL, 42.10 mmoles), and zirconocene chloride (10.86 g, 42.10 mmoles) are combined. To this is added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (64.13 mL 442.00 mmoles) via syringe. The reaction is then heated to 65° C. and stirred at this temperature for 24 hours. The heat is turned off and the reaction allowed to stir at ambient temperature for a further 24 hours. Dichloromethane (500 mL) is added and the resulting solution is filtered through a 10 cm pad of silica eluting with 20% ethyl acetate in dichloromethane (3×500 mL). The filtrate is concentrated under reduced pressure to provide the title compound (163.5 g; Yield 89%). Mass spectrum (m/z): 435.35 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8].P(Cl)(Cl)(Cl)(Cl)Cl.[Br:15]Br.S([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[Br:15][C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8]
Reactant: CC1CCCNC1=O
Reactant: BrBr
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=S([O-])O
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CC1(Br)CCCNC1=O
Temperature: 0 °C
Yield: 81 %

Procedure:
A mixture of 5.15 g of 3-methyl-2-piperidone (Ber. 24 page 2445) and 50 ml of chloroform is chilled to about 0° C. Then there are added while stirring at 0°-5° C. 19 g of phosphorus pentachloride, followed by 0.2 g of anhydrous zinc chloride. The mixture is heated to about 15° C., treated dropwise with a solution of 2.5 ml of bromine in 5 ml of chloroform and then heated to 40° C. for 5 hours, while stirring. After cooling the mixture is poured on ice and treated with sodium hydrogensulfite until it is discolored. The layers are separated and the aqueous phase is extracted with chloroform. The combined chloroform layers are dried over magnesium sulfate and then the solvent is distilled off in vacuo. The semi-solid residue is recrystallized from acetone to give 3-bromo-3-methyl-2-piperidone melting at 107° to 109° C. in a yield of 81% of the theoretical.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[N:13]=[N:12][NH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[K+].Br[CH2:19][CH2:20][CH3:21].O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[N:13]([CH2:19][CH2:20][CH3:21])[N:12]=[N:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCCBr
Reactant: O=c1nn[nH]n1-c1ccc([N+](=O)[O-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1nnn(-c2ccc([N+](=O)[O-])cc2)c1=O
Temperature: 55 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a stirred solution of 1-(4-nitrophenyl)-5-tetrazolone (6 g) in anhydrous N,N-dimethylformamide (30 mL) was added powdered 85% potassium hydroxide (1.9 g) and 1-bromopropane (3.9 g). The mixture was stirred at 55° C. for 2 hours and then poured into 300 mL of water. The biphasic mixture was extracted with ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, ethyl acetate:hexane) to afford 7.2 g of the title compound as a pale yellow solid. 1H NMR (CDCl3) δ 8.32 (ABq, JAB=9.6 Hz, 4H), 4.02 (t, J=7.2 Hz, 2H), 1.93 (m, 2H), 1.03 (t, J=7.5 Hz, 3H); MS (CI) m/z 250 (MH+); Rf=0.6 (25% ethyl acetate/hexane).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:14]2([CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[C:22]2[CH:29]=[CH:28][NH:27][C:23]=2[N:24]=[CH:25][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:1]([O:8][C:9]([N:11]1[C:14]2([CH2:19][CH2:18][CH2:17][N:16]([C:21]3[C:22]4[CH:29]=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:15]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: O=C(OCc1ccccc1)N1CCC12CCCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC12CCCN(c1ncnc3[nH]ccc13)C2
Temperature: 100 °C
Reaction time: 3 h
Yield: 74.2 %

Procedure:
An optically-active compound of 1,6-diazaspiro[3.5]nonane-1-carboxylic acid benzyl ester (2.37 g) was mixed with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.4 g), potassium carbonate (3.8 g) and water (71 ml), and heated to 100° C. to stir for 3 hours. The mixture was cooled to room temperature. Then, thereto was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and concentrated under reduced pressure. The resulting residue was slurry-washed with n-hexane/ethyl acetate (1/1) solution to give the titled compound (2.55 g).
Reaction SMILES: C[O:2][C:3]([C:5]1([N:13]([CH3:26])[C:14](=[O:25])[CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])[CH2:10][CH2:9][N:8]([O:11][CH3:12])[CH2:7][CH2:6]1)=O.C[O-].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[OH:2][C:3]1[C:5]2([CH2:10][CH2:9][N:8]([O:11][CH3:12])[CH2:7][CH2:6]2)[N:13]([CH3:26])[C:14](=[O:25])[C:15]=1[C:16]1[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=1[CH3:24]
Reactant: COC(=O)C1(N(C)C(=O)Cc2c(C)cc(C)cc2C)CCN(OC)CC1
Agent: C[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CON1CCC2(CC1)C(O)=C(c1c(C)cc(C)cc1C)C(=O)N2C
Reaction time: 0.5 h

Procedure:
To a solution of 1-methoxy-4-{methyl-[2-(2,4,6-trimethyl-phenyl)-acetyl]amino}-piperidine-4-carboxylic acid methyl ester (85.0 g, 234.5 mmol) in dimethylformamide (800 ml) at 0° C. was added sodium methoxide (38.0 g, 703.5 mmol) in four portions and stirring continued at 0° C. for 30 minutes, then at room temperature for 1 hour. The reaction mixture was poured on ice and saturated aqueous ammonium chloride, acidified to pH 5-6 with concentrated HCl and thoroughly extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate, concentrated and the residue dried in vacuo. Yield: 72.7 g of 4-hydroxy-8-methoxy-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (title compound P2.2) as a solid. The spectral data of this crude material were identical to those described above under preparation example 1, step 1.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:33])=[C:10]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:11]=2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:6](=[O:34])[C:5]([C:35]([OH:37])=O)=[CH:4]1)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:71]1([CH2:76][CH2:77][NH2:78])[CH2:75][CH2:74][CH2:73][CH2:72]1>CN(C)C=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:33])=[C:10]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[C:11]=2[O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[C:6](=[O:34])[C:5]([C:35]([NH:78][CH2:77][CH2:76][N:71]2[CH2:75][CH2:74][CH2:73][CH2:72]2)=[O:37])=[CH:4]1)[CH3:2]
Reactant: NCCN1CCCC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)NCCN2CCCC2)c(=O)c2cc(F)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
To a solution of 1-ethyl-6-fluoro-7,8-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 40a) (8 g, 15.76 mmol) in N,N-Dimethylformamide (DMF) (15 mL) was added HATU (8.99 g, 23.64 mmol) and DIPEA (8.26 mL, 47.3 mmol), the resulting mixture was stirred at r.t. for 30 min. 2-(Pyrrolidin-1-yl)ethanamine (2.98 mL, 23.64 mmol) was added and the resulting mixture was stirred at r.t. for 3 h. The mixture was concentrated and the residue was purified by normal phase automatic silica column chromatography (Combiflash RF) eluting with MeOH/DCM (0-20%) to afford 1-ethyl-6-fluoro-7,8-bis((4-methoxybenzyl)oxy)-4-oxo-N-(2-(pyrrolidin-1-yl)ethyl)-1,4-dihydroquinoline-3-carboxamide (6.6 g, 10.93 mmol, 69.4% yield) as a pale yellow solid. LCMS: (M+H)+: 604.5.
Reaction SMILES: CN(C=[C:5]1[C:9](=[O:10])[N:8]([C:11](OC(C)(C)C)=[O:12])[CH:7]2[C:18]3[C:23]([CH2:24][CH:6]12)=[CH:22][CH:21]=[C:20]([C:25]([O:27][CH3:28])=[O:26])[CH:19]=3)C.Cl>O1CCOCC1.C(OCC)(=O)C>[OH:10][CH:9]=[C:5]1[C:11](=[O:12])[NH:8][CH:7]2[C:18]3[C:23]([CH2:24][CH:6]12)=[CH:22][CH:21]=[C:20]([C:25]([O:27][CH3:28])=[O:26])[CH:19]=3
Reactant: COC(=O)c1ccc2c(c1)C1C(C2)C(=CN(C)C)C(=O)N1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)C1NC(=O)C(=CO)C1C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
To a solution of tert-butyl 7-methyl 3-(dimethylaminomethylene)-2-oxo-4,8b-dihydro-3aH-indeno[1,2-b]pyrrole-1,7-dicarboxylate (610 mg, 1.6 mmol) in dioxane (20 mL) was added HCl (36%, 2.9 mL, 32 mmol). The solution was stirred overnight at room temperature. The solution was diluted with ethyl acetate and washed twice with water, brine, dried over magnesium sulphate and concentrated to give title compound (0.300 g, 73%). This compound was used without extra purification. LC/MS (method B) RT: 0.65 min; ES−: 258, M−H+.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[CH:24]=[CH:23][C:11]([O:12][CH:13]([CH3:22])[C:14](=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>C(O)C.C(Cl)Cl>[F:1][C:2]([F:27])([F:28])[C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:24]=[CH:23][C:11]([O:12][CH:13]([CH3:22])[CH:14]([OH:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)CC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CC(O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of ethyl 4-[4-(4trifluoromethylphenoxy) phenoxy]-3-oxopentanoate (450 mg) in ethanol (5 ml) is added NaBH4 (150 mg) at 0°. The resulting mixture is then stirred at 0° for about 10 minutes. The mixture is diluted with CH2Cl2, washed with saturated NaCl solution, dried and evaporated to dryness to give ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-hydroxypentanoate, in quantitative yield, MS m/e 398 (M+).
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([C:14]([O:16]CC)=[O:15])=[CH:12][S:13][C:7]=2[N:6]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:5]1=[O:23].O>CO.O1CCCC1>[CH3:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([C:14]([OH:16])=[O:15])=[CH:12][S:13][C:7]=2[N:6]([CH2:19][CH:20]([CH3:21])[CH3:22])[C:5]1=[O:23]
Reactant: CCOC(=O)c1csc2c1c(=O)n(C)c(=O)n2CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)O)csc21
Reaction time: 6 h
Yield: 92.6 %

Procedure:
2M Sodium hydroxide solution (30 ml) was added to a solution of ethyl 1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate (16.13 g) in methanol (25 ml) and tetrahydrofuran (50 ml). After 6 hours, further 2M sodium hydroxide solution (30 ml) was added. After a further 2 hours, water (500 ml) was added and the mixture was extracted with ether (250 ml). The aqueous layer extracts were acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3×250 ml). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was redissolved in tetrahydrofuran (100 ml) and evaporated to give the subtitle compound (13.58 g) as a solid.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[Cs+].[Cs+].C(=O)(OO)N.S(=O)(=O)(O)O.[F:17][C:18]1[CH:19]=[C:20]([CH:25]([NH2:29])[CH:26](O)[CH3:27])[CH:21]=[CH:22][C:23]=1[F:24]>O>[F:17][C:18]1[CH:19]=[C:20]([C@H:25]2[C@H:26]([CH3:27])[O:2][C:1](=[O:4])[NH:29]2)[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: O=C([O-])[O-]
Reactant: CC(O)C(N)c1ccc(F)c(F)c1
Agent: NC(=O)OO
Agent: O=S(=O)(O)O
Agent: [Cs+]
Solvent: O
Product: C[C@@H]1OC(=O)N[C@H]1c1ccc(F)c(F)c1

Procedure:
Recovery Procedure B. Cesium carbonate (2 g) was added to another portion of the hydroxy carbamate mixture, and after about thirty minutes at room temperature the reaction mixture was diluted with water (50 ml). Sulfuric acid (10 eq.) was then added, and the mixture was refluxed for 30 minutes to obtain a mixture of the title compound plus 1-(3,4-difluorophenyl)-2-hydroxy-propylamine. Isolation by neutralization with NaOH to a pH=8-9, and extraction with MTBE afforded the title compound, which was obtained in 90% ee by evaporative removal of the MTBE.
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.Cl.[C:21](Cl)(Cl)(Cl)[Cl:22].CCCCCC>C(O)(=O)C>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:21][Cl:22])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=C(c1ccccc1)N1CCc2ccccc21
Agent: C=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CCCCCC
Product: O=C(c1ccccc1)N1CCc2cc(CCl)ccc21
Yield: 60 %

Procedure:
1-Benzoyl-2,3-dihydro-1H-indole (Beilstein, 20, 257) (5.58 g, 25 mmole) is dissolved in 50 ml of glacial acetic acid, then 56 ml (ca 70 mmoles) of 40% formaldehyde are added, and dry hydrogen chloride passed into the solution which is maintained at 70° for 3 hours. The solution is evaporated, and the residue dissolved in benzene, and again evaporated to dryness to give 6.53 g of crude product. This residue is treated with carbon tetrachloride-hexane to give 4.05 g (60%) of 1-benzoyl-5-chloromethyl-2,3-dihydro-1H-indole, m.p. 107.5 - 110.0°.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([CH3:44])[CH2:5][C:6]([CH3:43])([CH3:42])[CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]3[C:17]=2[CH2:18][CH2:19][C@H:20]3[O:26][C:27]2[CH:40]=[CH:39][C:30]3[C@H:31]([CH2:34][C:35]([O:37]C)=[O:36])[CH2:32][O:33][C:29]=3[CH:28]=2)=[C:11]([CH3:41])[CH:10]=1.Cl>CO>[CH3:44][N:4]([CH3:3])[CH2:5][C:6]([CH3:42])([CH3:43])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH3:41])[C:12]([C:16]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]3[C:17]=2[CH2:18][CH2:19][C@H:20]3[O:26][C:27]2[CH:40]=[CH:39][C:30]3[C@H:31]([CH2:34][C:35]([OH:37])=[O:36])[CH2:32][O:33][C:29]=3[CH:28]=2)=[C:13]([CH3:15])[CH:14]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCC(C)(C)CN(C)C)cc5C)ccc(F)c43)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(OCC(C)(C)CN(C)C)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1 M Aqueous NaOH solution (70 μL) is added to a solution of methyl 2-((S)-6-((R)-4-(4-(3-(dimethylamino)-2,2-dimethylpropoxy)-2,6-dimethylphenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (20 mg) in methanol (2 mL) at room temperature. The mixture is stirred at room temperature for 48 hours, treated with 1 M aqueous NaOH solution (70 μL) and heated for 4 hours at 50° C. The mixture is neutralized by addition of 1 N aqueous HCl solution and purified by HPLC on reversed phase to give the title compound. Yield: 11 mg; LC (method 14): tR=0.95 min; Mass spectrum (ESI+): m/z=562 [M+H]+.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[NH:53]1[CH2:58][CH2:57][CH:56]([NH:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[C:66]([F:69])([F:68])[F:67])[CH2:55][CH2:54]1>CN(C=O)C.O>[O:13]=[C:11]([N:53]1[CH2:54][CH2:55][CH:56]([NH:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[C:66]([F:67])([F:68])[F:69])[CH2:57][CH2:58]1)[CH2:10][NH:9][C:7]([C:4]1[CH:3]=[CH:2][C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][CH:5]=1)=[O:8]
Reactant: O=C(O)CNC(=O)c1ccc(-c2ccccc2)cc1
Reactant: FC(F)(F)c1ccccc1NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2C(F)(F)F)CC1)c1ccc(-c2ccccc2)cc1
Reaction time: 8 h
Yield: 72.7 %

Procedure:
To a stirred solution of [(biphenyl-4-carbonyl)-amino]-acetic acid (0.03219 g, 0.00012 mol) in DMF (1 mL), was added, DIPEA (0.065 g, 0.0005 mol), HOBt (0.017 g, 0.00012 mol) and EDCI.HCl (0.2689 g, 0.00013 mol) at ambient temperature. After 2 minutes piperidin-4-yl-(2-trifluoromethyl-phenyl)-amine dihydrochloride (0.04 g, 0.00012 mol) was and the resulting mixture was stirred at the same temperature overnight. The reaction mixture was diluted with cold water, and the resulting precipitate was isolated by filtration. The solid was recrystallized from a mixture of ethyl acetate and hexane to afford 0.042 g (61%) of biphenyl-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-phenylamino)-piperidin-1-yl]-ethyl}-amide. LCMS: 482.1 (M+1)+, 97.99%, 1H NMR (DMSO-d6): δ 8.6 (t, 1H), 8.0 (m, 2H), 7.78-7.5 (m, 4H), 7.6-7.4 (m, 5H), 7.0 (d, 1H), 6.7 (t, 1H), 4.7 (d, 1H), 4.3 (m, 1H), 4.2 (d, 2H), 4.0-3.7 (m, 2H), 3.2 (m, 2H), 2.8 (m, 2H), 2.0 (m, 3H), 1.6-1.2 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].C[C:12](C(Cl)Cl)=[O:13]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:12]=[O:13])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1ccc(F)c(F)c1
Reactant: CC(=O)C(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(F)c(F)cc1C=O
Temperature: 0 °C
Yield: 85.1 %

Procedure:
7.29 ml (66.3 mmol) of titanium tetrachloride were added while stirring to a solution, cooled to 0°, of 5.73 g (39.8 mmol) of 3,4-difluoroanisole in 30 ml of anhydrous dichloromethane. Subsequently, the mixture was treated dropwise over 10 minutes with 3.51 ml (39.6 mmol) of 1,1-dichloromethyl methyl ketone and stirred at room temperature for one hour. The mixture was poured into 100 ml of ice-water, extracted twice with 150 ml of dichloromethane each time and the combined organic phases were washed once with 100 ml of water and once with 100 ml of saturated sodium chloride solution. After drying over magnesium sulfate concentration was carried out in a vacuum. The crude product obtained was purified by column chromatography on silica gel (hexane/ethyl acetate 4:1). There were obtained 5.8 g (84%) of 4,5-difluoro-2-methoxybenzaldehyde as a white solid with m.p. 74°.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH:7]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:6]=2[C:5]([CH3:24])=[N:4]1)[CH3:2].CCN(C(C)C)C(C)C.[CH3:34][NH:35][C:36]([CH:38](OS(C1C=CC(C)=CC=1)(=O)=O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:37]>CC(C)C(C(C(C(C)C)C)=O)C>[CH2:1]([N:3]1[C:11]2[CH2:10][CH2:9][N:8]([CH:38]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:36]([NH:35][CH3:34])=[O:37])[CH:7]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=3)[C:6]=2[C:5]([CH3:24])=[N:4]1)[CH3:2]
Reactant: CNC(=O)C(OS(=O)(=O)c1ccc(C)cc1)c1ccccc1
Reactant: CCn1nc(C)c2c1CCNC2CCc1ccc(C(F)(F)F)cc1
Agent: CC(C)C(C)C(=O)C(C)C(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCn1nc(C)c2c1CCN(C(C(=O)NC)c1ccccc1)C2CCc1ccc(C(F)(F)F)cc1
Temperature: 90 °C
Yield: 96.3 %

Procedure:
In an inert atmosphere, 1-ethyl-3-methyl-4-[2-(4-trifluoromethyl-phenyl)-ethyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (51 mg, 0.15 mmol) was dissolved in 3-methyl-2-butyl-ketone (MIBK) (1 ml) followed by the addition of DIPEA (21.3 mg, 0.165 mmol) and toluene-4-sulfonic acid methylcarbamoyl-phenyl-methyl ester (71.8 mg, 0.225 mmol). The reaction mixture was heated to 90° C. for 24 h, concentrated in vacuo and the crude product was purified by prep. HPLC to give 70 mg (95%) of 2-{1-ethyl-3-methyl-4-[2-(4-trifluoromethyl-phenyl)-ethyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-N-methyl-2-phenyl-acetamide. LC-MS: tR=0.84 min; [M+H]+=485.28.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[CH3:13][S:14]([O-:16])=[O:15].[Na+]>>[CH3:13][S:14]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)(=[O:16])=[O:15]
Reactant: CS(=O)[O-]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: [Na+]
Product: CS(=O)(=O)CCc1ccc([N+](=O)[O-])cc1

Procedure:
This compound was prepared in a similar manner from 1-(2-bromoethyl)-4-nitrobenzene and sodium methanesulfinate.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].[Cl:11][C:12]1[CH:13]=[C:14]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:15]=[CH:16][CH:17]=1.[Na+].[I-]>CN(C=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([N:18]2[CH2:23][CH2:22][N:21]([CH2:2][CH2:3][CH2:4][N:5]3[CH2:9][CH2:8][CH2:7][C:6]3=[O:10])[CH2:20][CH2:19]2)[CH:15]=[CH:16][CH:17]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: O=C1CCCN1CCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCN1CCCN1CCN(c2cccc(Cl)c2)CC1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
A mixture of 1-chloro-3-[2-oxopyrrolidin-1-yl]propane (1 g, 6.2 mmol),, 1-(3-chlorophenyl)piperazine (1.22 g, 6.2 mmol) anhydrous Na2CO3 (0.33 g, 3.1 mmol) and NaI (0.093 g, 0.6 mmol) in dry DMF (5 ml) was stirred at 70° C. for 14 hrs. The reaction mixture was cooled, poured on water (20 ml) and the separated residue was extracted with CHCl3 (2×25 ml). The extracts were dried over Na2SO4 and concentrated under reduced pressure to give 1-[4-(3-chlorophenyl)piperazin-1-yl]-3-[2-oxopyrrolidin-1-yl]propane as an oil which was purified by flash column chromatography over silica gel using chloroform as eluent, yield 1.50 g (75%). IR (Neat): 3020, 2820, 1660, 1590, 1450, 1210, 730. 1H NMR (CDCl3): 1.30-2.60(m, 12H, 3', 4', 2, 1 & 2×N-CH2), 2.40-3.50(m, 8H, 5', 3 & 2×N-CH2), 6.40-7.20(m, 4H, ArH). MS: m/z 321
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][N:5]=1.BrCC1CCCCO1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@@:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:20]1=[O:40].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[F:10][C:9]1[C:4]([CH2:3][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C@@:21]3([C:39]4[C:30](=[CH:31][C:32]5[O:37][CH2:36][CH2:35][O:34][C:33]=5[CH:38]=4)[O:29][CH2:28]3)[C:20]2=[O:40])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: Fc1cccnc1CCl
Agent: BrCC1CCCCO1
Agent: Cl
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: O=C1N(Cc2ncccc2F)c2ccccc2[C@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(chloromethyl)-3-fluoropyridine hydrochloride to replace 2-(bromomethyl)tetrahydro-2H-pyran, and (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, (8S)-1′-[(3-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (33%) as a colorless solid: mp 125-126° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) 8.38-8.32 (m, 1H), 7.43-7.34 (m, 1H), 7.28-7.11 (m, 3H), 7.02-6.95 (m, 1H), 6.78 (d, J=7.6 Hz, 1H), 6.48 (s, 1H), 6.44 (s, 1H), 5.31 (d, J=16.2 Hz, 1H), 5.04 (d, J=16.2 Hz, 1H), 4.95 (d, J=8.9 Hz, 1H), 4.67 (d, J=8.9 Hz, 1H), 4.21-4.07 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.5, 159.6, 156.2, 155.2, 145.4, 144.5, 142.9, 142.8, 142.2, 138.3, 132.6, 128.6, 124.3, 123.8, 123.3, 123.1, 121.3, 112.2, 109.0, 99.2, 80.2, 64.5, 63.9, 58.1, 40.7; MS (ES+) m/z 404.9 (M+1). Anal. Calcd. for C23H17FN2O4: C, 68.31; H, 4.24; N, 6.93. Found: C, 67.27; H, 4.24; N, 6.93.