Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[Cl:15].Br[CH2:17][CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:21]1(=[O:30])[N:20]([CH2:19][CH2:18][CH2:17][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][C:3]=2[Cl:15])[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: O=C1CCC(c2ccc(O)c(Cl)c2)=NN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCC(c2ccc(OCCCN3C(=O)c4ccccc4C3=O)c(Cl)c2)=NN1
Reaction time: 0.17 h
Yield: 87.6 %

Procedure:
A mixture of 3.4 g (15.1 mmol) of 6-(4-hydroxy-3-chlorophenyl)-4,5-dihydro-3(2H)-pyridazinone, prepared according to the methods described in Eur. Pat. Appl. 178,189A2, 4.87 g (18.2 mmol) of N-(3-bromopropyl)-phthalimide, and 2.30 g (16.6 mmol) of anhydrous K2CO3 in 80 ml of DMF is heated for 3 hrs at 100° C. The DMF is removed under vacuum and 150 ml of 1:1 EtOAc-H2O is added to the residue and stirred vigorously for 10 min. The solid precipitate is collected by suction filtration, washed with water (2×150 ml), washed with EtOAc (2. 50 ml), and dried under vacuum at 80° C. to give 5.45 g of 6-[4-(3-phthalimidopropyloxy)-3-chlorophenyl]-4,5-dihydro-3(2H)-pyridazinone as a white solid, m.p. 230°-232° C.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[C:9]3[CH2:12][CH:13]([C:15]([OH:17])=[O:16])[CH2:14][C:8]=3[CH:7]=[CH:6][C:5]=2[NH:4][C:3]1=[O:18].[N+:19]([O-])([OH:21])=[O:20]>FC(F)(F)C(O)=O>[N+:19]([C:7]1[C:8]2[CH2:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12][C:9]=2[C:10]2[NH:11][C:2](=[O:1])[C:3](=[O:18])[NH:4][C:5]=2[CH:6]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)C1Cc2ccc3[nH]c(=O)c(=O)[nH]c3c2C1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1Cc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A mixture of 2,3-dioxo-2,3,4,7,8,9-hexahydro-1H-cyclopenta[f]quinoxaline-8-carboxylic acid (4 g, 16 mmol) in trifluoroacetic acid (75 mL) was cooled to 0° C. and then treated with fuming nitric acid (5 mL). After stirring in an ice bath for 3 h, the mixture was warmed to room temperature for 1 h, the solvent evaporated, and the residue was suspended in water. A solid precipitate was collected by filtration, washed with ether and dried in vacuo (4 g). Calc'd for C12H9N3 O6.0.5 H2O: C, 48.00; H, 3.36; N, 14.00; found: C, 48.64; H, 3.13; N, 13.86. MS M+1 (292).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:10]=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O.[CH3:28][N:29]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=1)[C:30]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:31].[F-].[Cs+]>COCCOC.C(O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:10]=[CH:11][C:12]=1[C:42]1[CH:41]=[CH:40][CH:39]=[C:38]([N:29]([CH3:28])[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])[CH:43]=1
Reactant: CN(C(=O)N1CCOCC1)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCOC(=O)CCc1ccc(OS(=O)(=O)C(F)(F)F)c(OCCCOC)c1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CCO
Product: CCOC(=O)CCc1ccc(-c2cccc(N(C)C(=O)N3CCOCC3)c2)c(OCCCOC)c1
Temperature: 25 °C
Yield: 19.9 %

Procedure:
Ethyl 3-[3-(3-methoxypropoxy)-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl]propanoate (1.0 g, 2.40 mmol) was, dissolved in 1,2-dimethoxyethane (14.4 ml) and ethanol (1.6 ml). N-methyl-N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine-4-carboxamide (0.914 g, 2.64 mmol) was added and argon was bubbled in the solution for 10 minutes. Cesium fluoride (0.80 g, 5.28 mmol) and palladium tetrakistriphenylphosphine (0.139 g, 0.12 mmol) were added and the mixture was heated to reflux under an argon atmosphere for 14 hours. After cooling to room temperature, solvents were evaporated under reduced pressure and the residue was dissolved in ethyl acetate and water. The organic phase was washed with saturated aqueous ammonium chloride and brine, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 7/3) giving 0.232 g (20%) of the desired product.
Reaction SMILES: COC[CH2:4][C@@H:5]1[CH2:9][N:8]([C:10]2[CH:11]=[CH:12][C:13]3[O:14][CH2:15][C:16](=[O:20])[NH:17][C:18]=3[N:19]=2)[C:7](=[O:21])[CH2:6]1.[O:22]1CCCC1.Cl.C(=O)([O-])O.[Na+]>CO>[OH:22][CH2:4][C@@H:5]1[CH2:9][N:8]([C:10]2[CH:11]=[CH:12][C:13]3[O:14][CH2:15][C:16](=[O:20])[NH:17][C:18]=3[N:19]=2)[C:7](=[O:21])[CH2:6]1
Reactant: COCC[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Reactant: C1CCOC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C1COc2ccc(N3C[C@@H](CO)CC3=O)nc2N1
Temperature: 60 °C
Yield: 93 %

Procedure:
To a solution of 6-{(4S)-4-[(methoxymethyl)methyl]-2-oxopyrrolidin-1-yl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (2.21 g, 7.20 mmol) in methanol (25 ml)/tetrahydrofuran (25 ml) was added 4N Hydrochloric acid (2.5 ml) at room temperature and the mixture was heated to 60° C. and stirred with heating for 16 hours. The reaction solution was poured into a saturated sodium hydrogen carbonate aqueous solution and extracted with a mixed solvent of chloroform/methanol (9:1) (3×). The organic layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. 1.76 g (93%) of a crude product of the title compound was obtained in the form of a light yellow solid.
Reaction SMILES: CI.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:11])=[C:6]([OH:19])[CH:5]=1.[C:20](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:11])=[C:6]([O:19][CH3:20])[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(c1ccc(F)cc1)c1ccc(Cl)cc1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(Cl)ccc1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93.1 %

Procedure:
Methyl iodide (1.10 mL) was added to a suspension of (4-chloro-2-hydroxyphenyl)(4-fluorophenyl)methanone (3.00 g) and potassium carbonate (3.30 g) in N,N-dimethylformamide (50 mL) and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was filtered through Celite and the filtrate was poured into an aqueous saturated ammonium chloride solution. The mixture was extracted with ethyl acetate and the organic layer was washed successively with water and brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (Solvent: n-hexane/ethyl acetate=30/1) to give the titled compound (2.95 g) as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([Br:15])=[C:11](Br)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=1.[OH-].[K+].O>CN(C)C=O>[Br:15][C:12]1[C:13](=[O:14])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[CH:10][C:11]=1[O:23][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: O=c1c(Br)c(Br)cnn1-c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c(Br)c(OCc2ccc(Cl)cc2)cnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.8 %

Procedure:
In 35 ml of N,N-dimethylformamide were dissolved 1.5 g (4.1 m mol) of 2-(4-chlorophenyl)-4,5-dibromo-3(2H)-pyridazinone and 0.59 g (4.1 m mol) of p-chlorobenzyl alcohol, and thereto was added 0.27 g of powdery potassium hydroxide. The reaction mixture was stirred for one day at room temperature. The resulting solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and freed of solvent by distillation under reduced pressure. The crystals thus obtained were recrystallized from ethyl acetate-benzene to give 1.4 g of the intended compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:15][O:16][C:17](=[O:23])[C:18](=O)[CH:19](Br)[CH3:20].C(OCC)(=O)C.[OH-].[Na+]>O1CCCC1>[CH3:15][O:16][C:17]([C:18]1[N:1]=[C:2]2[C:7]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[CH:6][CH:5]=[CH:4][N:3]2[C:19]=1[CH3:20])=[O:23]
Reactant: CC(C)(C)C(=O)Nc1cccnc1N
Reactant: COC(=O)C(=O)C(C)Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1nc2c(NC(=O)C(C)(C)C)cccn2c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 78 %

Procedure:
To a stirred solution of 30 g of 2-amino-3-pivaloylaminopyridine in 300 ml of dry tetrahydrofuran are added dropwise under argon 40 g of 3-bromo-2-oxobutanoic acid methylester. The brown solution is stirred at ambient temperature for 3 d. The resulting suspension is poured onto a mixture of icewater and ethyl acetate and the mixture is neutralised by adding 10 M sodium hydroxide solution. The organic phase is separated and the aqueous layer extracted two times with ethyl acetate. The combined organic phases are washed with water and dried over anhydrous sodium sulfate. The solvent is removed in vacuo and the blue coloured residue purified by column chromatography on silica gel to yield 35 g (78%) of a light brown solid (m.p. 132° C.).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[CH:21]=[O:22].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:21]([C:3]1[CH:4]=[C:5]([O:6][C:7]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])[CH:19]=[CH:20][C:2]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]
Reactant: OB(O)c1ccccc1
Reactant: N#Cc1ccc(C(F)(F)F)cc1Oc1ccc(Br)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Product: N#Cc1ccc(C(F)(F)F)cc1Oc1ccc(-c2ccccc2)c(C=O)c1
Yield: 98.9 %

Procedure:
To a mixture of 2-(4-bromo-3-formyl-phenoxy)-4-trifluoromethyl-benzonitrile (1.76 g, 4.76 mmol) and Pd(dba)3 (21.8 mg, 5 mole %) in dimethoxyethane (15 ml) was added a solution of phenylboronic acid (609 mg, 5 mmol), triphenylphosphine (15 mg, 12 mole %) and sodium carbonate (530 mg, 5 mmol) in water (10 ml). The mixture was refluxed for 3 h. The solvent was evaporated off and the aqueous layer was extracted with dichloromethane. The extracts were dried with MgSO4 and filtered through silica. Evaporation yielded a brown solid (1.73 g, 99%).
Reaction SMILES: O.[OH-].[Na+].[CH3:4][C:5]([C:7]1([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH2:8]1)=[O:6].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1>C(O)C>[C:11]1([S:10][C:7]2([C:5]([CH:4]=[CH:22][C:21]3[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=3)=[O:6])[CH2:9][CH2:8]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)C1(Sc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1ccc(Cl)cc1)C1(Sc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 98 %

Procedure:
50 ml of water and 8 pellets of solid sodium hydroxide are added at room temperature to a mixture of 75 g (0.39 mol) of 1-phenylmercaptocyclopropyl methyl ketone, 56 g (0.39 mol) of 4-chlorobenzaldehyde and 200 ml of ethanol. The mixture is stirred at room temperature for 14 hours. The precipitated solid is then filtered off with suction. In this manner, 120.3 g (98% of theory) of 4-chlorophenyl-ethenyl 1-phenylmercapto-cyclopropyl ketone are obtained in the form of a solid substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:36])[C:15]([O:28]CC2C=CC=CC=2)=[C:16]2[C:21](=[O:22])[N:20]3[C@H:23]([CH3:26])[CH2:24][O:25][C@H:19]3[CH2:18][N:17]2[CH:27]=1)=[O:12]>CO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:36])[C:15]([OH:28])=[C:16]2[C:21](=[O:22])[N:20]3[C@H:23]([CH3:26])[CH2:24][O:25][C@H:19]3[CH2:18][N:17]2[CH:27]=1)=[O:12]
Reactant: C[C@@H]1CO[C@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(OCc4ccccc4)c3C(=O)N12
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CO[C@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(O)c3C(=O)N12
Yield: 85.7 %

Procedure:
To a solution of (3R,11aS)—N-[(2,4-difluorophenyl)methyl]-3-methyl-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (396 mg, 0.80 mmol) in methanol (30 mL) was added 10% Pd/C (25 mg). Hydrogen was bubbled through the reaction mixture via a balloon for 2 h. The resultant mixture was filtered through Celite with methanol and dichloromethane. The filtrate was concentrated in vacuo to give (3R,11aS)—N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide as a pink tinted white solid (278 mg, 86%). 1H NMR (CDCl3) δ 11.47 (m, 1H), 10.29 (m, 1H), 8.32 (s, 1H), 7.36 (m, 1H), 6.82 (m, 2H), 5.31 (dd, J=9.6, 3.6 Hz, 1H), 4.65 (m, 2H), 4.47-4.38 (m, 3H), 3.93 (dd, J=12.0, 10.0 Hz, 1H), 3.75 (m, 1H), 1.49 (d, J=5.6 Hz, 3H); ES+ MS: 406 (M+1). The above material (278 mg, 0.66 mmol) was taken up in ethanol (10 mL) and treated with 1 N sodium hydroxide (aq) (0.66 ml, 0.66 mmol). The resulting suspension was stirred at room temperature for 30 min. Ether was added and the liquids were collected to provide the sodium salt of the title compound as a white powder (291 mg, 99%). 1H NMR (DMSO-d6) δ 10.68 (m, 1H), 7.90 (s, 1H), 7.35 (m, 1H), 7.20 (m, 1H), 7.01 (m, 1H), 5.20 (m, 1H), 4.58 (m, 1H), 4.49 (m, 2H), 4.22 (m, 2H), 3.74 (dd, J=11.2, 10.4 Hz, 1H), 3.58 (m, 1H), 1.25 (d, J=4.4 Hz, 3H).
Reaction SMILES: [Na].Cl.[C:3]1([CH2:9][C:10]([NH2:12])=[NH:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:13]1([CH2:19][C:20](=O)[CH2:21][C:22](OCC)=[O:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[C:3]1([CH2:9][C:10]2[N:12]=[C:20]([CH2:19][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:21]=[C:22]([OH:23])[N:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC(=O)Cc1ccccc1
Reactant: N=C(N)Cc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Oc1cc(Cc2ccccc2)nc(Cc2ccccc2)n1
Reaction time: 120 h
Yield: 34.3 %

Procedure:
To a solution of sodium (1.84 g, 80 mmol) in ethanol (200 ml) was added phenylacetamidine hydrochloride (16.2 g, 95.0 mmol) and ethyl 4-phenylacetoacetate (15 g, 72.9 mmol). The mixture was heated under reflux with stirring for 5 days followed by cooling and evaporation in vacuo. Water (150 ml) was added to the residue causing a solid to precipitate which was filtered off and washed thoroughly with water and diethyl ether. Recrystallisation of the solid from a chloroform/hexane mixture afforded 6.9 g 2,4-di(phenylmethyl)-6-hydroxypyrimidine as a white solid. m.pt., 158°-160° C., M+ found: 276.
Reaction SMILES: [C:1]([N:9]=C=O)(=[O:8])C1C=CC=CC=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=1.[OH-].[Na+]>C(Cl)Cl>[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:1]([NH2:9])=[O:8])[CH:13]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Nc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)Nc1cccnc1
Temperature: -10 °C
Yield: 120.4 %

Procedure:
Benzoyl isocyanate (3.28 g, 22.3 mmol, 1.05 equiv.) was taken up in CH2Cl2 (30 mL) and cooled to −10° C. Pyridin-3-amine (2 g, 21.2 mmol, 1 equiv.) was added in portions while stirring. The mixture was allowed to stir for 3 h at room temperature. After the reaction was deemed complete, it was concentrated and then taken up in a 1:1 mixture of CH3OH and H2O (100 mL) followed by the addition of NaOH (4.25 g, 106.3 mmol, 5 equiv.). The reaction was allowed to stir overnight at room temperature, concentrated to dryness, and then azeotroped three times with toluene. A mixture of 10% CH3OH in EtOAc (100 mL) was added to the solid and stirred for 10 minutes followed by filtration. The solid was suspended and filtered two additional times. The combined filtrates were filtered once more to remove any solids that passed through the filter and concentrated. The residue was triturated with EtOAc (5 mL) and dried under vacuum to yield 3.5 g of crude material (off-white solid) that was utilized without further purification. LC/MS: m/z (ES+) 138 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[O:25]1[CH2:30][CH2:29][CH2:28][CH:27]([C:31](O)=[O:32])[CH2:26]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:31]([CH:27]3[CH2:28][CH2:29][CH2:30][O:25][CH2:26]3)=[O:32])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Reactant: O=C(O)C1CCCOC1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCCOC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound [(3S,4R)-4-(4-chloro-phenyl)-1-(tetrahydro-pyran-3-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of [(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using rac-tetrahydro-pyran-3-carboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white foam. MS m/e: 461.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH:9]1[CH:13]=[C:12]([CH:14]=[O:15])[N:11]=[CH:10]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH:13]=[C:12]([CH:14]=[O:15])[N:11]=[CH:10]2)=[N:6][CH:7]=1
Reactant: Fc1ccc(Br)cn1
Reactant: O=Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cn(-c2ccc(Br)cn2)cn1
Temperature: 70 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
A mixture of 5-bromo-2-fluoropyridine (630 mg, 3.58 mmol), 4-imidazolecarboxaldehyde (355 mg, 3.70 mmol) and K2CO3 (1.00 g, 7.25 mmol) in DMF (10 mL) was stirred at 70° C. overnight. After being cooled down, H2O was added to induce precipitation. The precipitate was collected and dried on vacuum to give 1-(5-bromopyridin-2-yl)-1H-imidazole-4-carbaldehyde (738 mg).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:28])[C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:15][CH2:14][NH:13][CH2:12][C@H:11]2[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:6][CH:5]=1.Br[CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.C([O-])([O-])=O.[K+].[K+]>>[ClH:1].[CH:30]1([N:13]2[CH2:14][CH2:15][C@@H:10]([C:7]3[CH:8]=[CH:9][C:4]([N:3]([CH3:28])[CH3:2])=[CH:5][CH:6]=3)[C@H:11]([CH2:16][O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=3)[CH2:12]2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CN(C)c1ccc([C@@H]2CCNC[C@H]2COc2ccc(C(F)(F)F)cc2)cc1
Reactant: BrC1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(C)c1ccc([C@@H]2CCN(C3CCCC3)C[C@H]2COc2ccc(C(F)(F)F)cc2)cc1

Procedure:
Prepared from (41) (1.5 g), bromocyclopentane (0.80 g) and K2CO3 (1 g). Reflux for 21 h. Purification of the crude product on silica gel column. Yield of (68) 11%. M.p. 205.8°-206.2° C.
Reaction SMILES: [CH2:1]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([N+:20]([O-])=O)[CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H][H]>[Pd].O1CCCC1>[CH2:1]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([NH2:20])[CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCc1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1ccc(O)c(N)c1
Yield: 99.5 %

Procedure:
5.80 g of the 4-dodecyl-2-nitrophenol obtained in (2) above was mixed with 500 mg of 5% active carbonsupported palladium, and 150 ml of tetrahydrofuran and the resulting mixture was contacted with hydrogen at room temperature for 7 hours to reduce the nitro group. The reaction mixture was filtered, and then the solvent was distilled off to obtain 5.21 g of 4-dodecyl-2-aminophenol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:10][CH:11]=[CH:12][C:13]=1[C:14]#[N:15].[C:16](Cl)(=[O:18])[CH3:17].[Cl-].[Cl-].[Cl-].[Al+3].Cl>ClCCl.C(O)(C)C>[C:16]([C:11]1[NH:10][C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[C:13]([C:14]#[N:15])[CH:12]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: N#Cc1cc[nH]c1-c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(=O)c1cc(C#N)c(-c2ccc(Cl)cc2Cl)[nH]1
Reaction time: 3 h
Yield: 92.2 %

Procedure:
To a mixture of 2-(2,4-dichloro-phenyl)-1H-pyrrole-3-carbonitrile (6.00 g, 25.30 mmol, see EP 0312,723) in 120 mL of dichloromethane was added acetyl chloride (3.18 g; 40.49 mmol) at room temperature, under nitrogen. The resulting mixture was cooled to +2° C. and anhydrous aluminum trichloride (8.10 g, 60.73 mmol) was added in small portions during a period of 20 minutes, keeping the internal temperature below 5° C. Upon complete addition, the mixture was brought to room temperature and allowed to stir for 3 hours. Then, the mixture was slowly poured in a solution of ice-cooled 2M HCl (120 mL) and isopropanol (28 mL). The aqueous layer was separated and extracted twice with a mixture of dichloromethane (120 mL) and isopropanol (28 mL). The combined organic extracts were concentrated under reduced pressure to slurry, which was treated under stirring with isopropanol (30 mL) and diluted with water (60 mL) at room temperature. The solid was collected by suction and dried under vacuum at +50° C. to afford the 6.51 g of product as white, fluffy crystals. Yield=92%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[CH3:23])=[C:13]([C:24]([OH:26])=O)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].Cl.[F:28][C:29]1[CH:34]=[CH:33][C:32]2[C:35]3([CH2:41][O:42][C:31]=2[CH:30]=1)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[CH3:23])=[C:13]([C:24]([N:38]3[CH2:39][CH2:40][C:35]4([C:32]5[CH:33]=[CH:34][C:29]([F:28])=[CH:30][C:31]=5[O:42][CH2:41]4)[CH2:36][CH2:37]3)=[O:26])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)O)cnc12
Reactant: Fc1ccc2c(c1)OCC21CCNCC1
Agent: Cl
Product: CCOC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc12
Yield: 75.5 %

Procedure:
In the same manner as in Example 21, step 5 and using 3-ethoxycarbonyl-7-(4-fluoro-2-methylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.130 g, 0.363 mmol) obtained in step 2 and 6-fluoro-2H-spiro[benzofuran-3,4′-piperidine]hydrochloride (0.082 g, 0.399 mmol), the title compound (0.150 g, 75%) was obtained.