Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)C.[Cl:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH2:31])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1>CCO>[Cl:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH:31][C:4]3[C:5](=[O:16])[C:6](=[O:15])[C:7]=3[NH:8][C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)=[CH:25][CH:24]=2)=[CH:20][CH:19]=1
Reactant: CCOc1c(Nc2cccnc2)c(=O)c1=O
Reactant: NCCc1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: CCO
Product: O=c1c(NCCc2ccc(Oc3ccc(Cl)cc3)cc2)c(Nc2cccnc2)c1=O
Temperature: 150 °C

Procedure:
3-Ethoxy-4-(pyridine-3-ylamino)-3-cyclobutene-1,2-dione (70 mg, 0.32 mmol) prepared according to example 1A and 2-[4-(4-chlorophenoxy)-phenyl]-ethylamine (105 mg, 0.45 mmol) in EtOH (1.5 mL) were stirred and heated to 150° C. in a sealed vessel in a microwave synthesizer for 1 min. After cooling to r.t. the precipitate was filtered off, washed with EtOH (3×3 mL) and dried in vacuo.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][F:19]>[I-].[K+].CS(C)=O>[F:19][CH2:18][CH2:17][O:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2]
Reactant: FCCBr
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1cccc(OCCF)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To a flame dried 50 mL round bottom flask was added 3-cyanophenol (1.0 g, 8.39 mmol) followed by 10 mL dimethyl sulfoxide. Potassium iodide (7.0 mg, 0.042 mmol) and potassium carbonate (1.74 g, 12.6 mmol) were added. The flask was immersed in an oil bath at 85° C. and 1-bromo-2-fluoroethane (1.17 g, 0.686 mL, 9.23 mmol) was added. The reaction was stirred at this temperature for 30 min, cooled to room temperature, filtered, and the filtrate was diluted with water (100 mL). The resulting solution was extracted with dichloromethane (3×30 mL). The organic layer was then washed with water (5×20 mL) and brine, and dried over magnesium sulfate. The solution was filtered and concentrated in vacuo to obtain 1.31 g (94%) of an oil as the product. 1H NMR (600 MHz, CDCl3): δ 7.37 (m, 1H), 7.26 (m, 1H), 7.15 (m, 2H), 4.75 (t of d, 2H, J=4.2, 46.8 Hz), 4.22 (t of d, 2H, J=4.2, 27.6 Hz). 13C NMR (75 MHz, CDCl3): δ 158.4, 130.4, 125, 119.8, 117.9, 117.5, 113.3, 81 (d, J=171 Hz), 67.4 (d, J=10.1 Hz).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)[CH:7]=[CH:6][N:5]=1.[CH:20]1([NH:23][C:24](=O)[O:25]C2C=CC=CC=2)[CH2:22][CH2:21]1.O>CN(C)C=O>[CH:20]1([NH:23][C:24]([N:16]2[C:17]3[C:13](=[CH:12][C:11]([O:10][C:8]4[CH:7]=[CH:6][N:5]=[C:4]([NH2:3])[CH:9]=4)=[CH:19][CH:18]=3)[CH:14]=[CH:15]2)=[O:25])[CH2:22][CH2:21]1
Reactant: O=C(NC1CC1)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc3[nH]ccc3c2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 1168.8 %

Procedure:
After adding 28 mg of sodium hydride (60% in oil) to a solution of 150 mg of 5-[(2-amino-4-pyridyl)oxy]-1H-indole in dimethylformamide at room temperature and stirring for 5 minutes, the mixture was cooled to 0° C., 124 mg of phenyl N-cyclopropylcarbamate was added and the mixture was further stirred for 30 minutes. Water was added, extraction was performed with ethyl acetate, the organic layer was washed 3 times with water and once with aqueous ammonium chloride solution, and then silica gel was added and the solvent was distilled off under reduced pressure. The silica gel was charged into a dry column packed with silica gel and purification was performed by column chromatography (hexane:ethyl acetate=1:1, followed by ethyl acetate), to obtain 2.4 g of a colorless powder.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:12]2[C:7](=[CH:8][C:9]([N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[Cl:19][C:20]1[CH:40]=[CH:39][C:23]([CH2:24][C@H:25]2[CH2:29]OS(=O)(=O)[N:26]2C(OC(C)(C)C)=O)=[CH:22][CH:21]=1.O>CN(C=O)C>[NH2:26][C@@H:25]([CH2:24][C:23]1[CH:22]=[CH:21][C:20]([Cl:19])=[CH:40][CH:39]=1)[CH2:29][NH:18][C:16]1[CH:15]=[N:14][N:13]([C:9]2[CH:8]=[C:7]3[C:12](=[CH:11][CH:10]=2)[CH:3]=[N:4][CH:5]=[CH:6]3)[CH:17]=1
Reactant: Nc1cnn(-c2ccc3cnccc3c2)c1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(Cl)cc2)COS1(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N[C@H](CNc1cnn(-c2ccc3cnccc3c2)c1)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 22.8 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (9.6 mg, 251 μmol) was added to a mixture of 1-(isoquinolin-6-yl)-1H-pyrazol-4-amine (44 mg, 209 μmol) and (S)-tert-butyl 4-(4-chlorobenzyl)-1,2,3-oxathiazolidine-3-carboxylate-2,2-dioxide (109 mg, 314 μmol) in DMF (1 mL) at ambient temperature and the mixture was stirred at ambient temperature for 1.5 hours. H2O (15 mL) was added, and the mixture was extracted with DCM (4×15 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting yellow solid was dissolved in DCM (3 mL), TFA (2 mL) was added, and the mixture was stirred at ambient temperature for 2 hours. Toluene (3 mL) was added, and the mixture was concentrated under reduced pressure. The resulting orange oil was dissolved in DCM, evaporated onto a silica gel plug, and purified by flash chromatography (Biotage Si 25+M, 5% to 10% 2 N NH3 in MeOH/DCM) to provide N-((S)-2-amino-3-(4-chlorophenyl)propyl)-1-(isoquinolin-6-yl)-1H-pyrazol-4-amine (18 mg, 23% yield) as an off-white solid. LCMS (API-ES) m/z (%): 412.2 (100%, M++H); 1H NMR (300 MHz, CDCl3) δ ppm 1.54 (br s, 3H), 2.62 (dd, J=13.1, 8.1 Hz, 1H), 2.79-2.94 (m, 2H), 3.15 (dd, J=11.8, 2.6 Hz, 1H), 3.25 (d, J=4.1 Hz, 1H), 7.17 (d, J=7.8 Hz, 2H), 7.31 (d, J=7.8 Hz, 2H) 7.45 (s, 2H), 7.64 (d, J=5.5 Hz, 1H), 7.89 (s, 1H), 8.00 (s, 2H), 8.51 (d, J=5.5 Hz, 1H), 9.20 (s, 1H). (S)-tert-Butyl 4-(4-chlorobenzyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide was prepared in a similar manner as that described for (S)-tert-butyl 4-(4-(trifluoromethyl)benzyl)-1,2,3-oxathiazolidine-3-carboxylate-2,2-dioxide in Scheme 1, using (S)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (commercially available from 3B Scientific Corporation Product List (Order Number 3B3-011434)) instead of (S)-2-(tert-butoxycarbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[N+:10]([O-])=O.C(O)(C)C.[Cl-].[NH4+]>[Fe].O>[NH2:10][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[CH:9][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1cc(CO)ccc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: Nc1cc(CO)ccc1F

Procedure:
A flask equipped with overhead stirrer was charged with 4-fluoro-3-nitrobenzyl alcohol (20 g, 0.117 mol) and 200 mL of 5:1 isopropanol:water. Ammonium chloride (62 g, 1.17 mol) was added followed by iron filings (65 g, 1.17 mol). The mixture was stirred at 70 C for 1.5H when it was shown to be complete by LC-MS. The liquid was decanted and the solids were washed with additional isopropanol: water. The isopropanol was removed and the residue was diluted with 0.5 N HCl and was extracted with ethyl acetate. The aqueous layer was brought to pH 12-14 with 2.5 N NaOH and was extracted with ethyl acetate. The organic layer was dried with anhydrous Na2SO4 and concentrated in vacuo. 3-Amino-4-fluorophenyl methanol was isolated as a brown solid (4.5 g, 27%) and was used without further purification. LC/MS, tr=2.40 minutes (5 to 95% acetonitrile/water over 8 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 142 (M+H). ES-HRMS m/z 142.0692 (M+H calcd for C7H8FNO requires 142.0663).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][CH2:12][Cl:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: ClCCCBr
Product: ClCCCOc1ccc(Cl)cc1

Procedure:
Prepared by Procedure U and Scheme AK using 4-chlorophenol and 1-bromo-3-chloropropane.
Reaction SMILES: C([C@@H]1CC[C@@H](C)C[C@H]1OCC([O:15][CH2:16][CH:17]1[CH:22]2[O:23][CH:21]2[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]1)=O)(C)C.[OH-:31].[K+]>>[OH:15][CH2:16][CH:17]1[CH2:18][NH:19][CH2:20][CH:21]([OH:23])[CH:22]1[OH:31]
Reactant: [OH-]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OCC(=O)OCC1CN(C(=O)OC(C)(C)C)CC2OC12
Agent: [K+]
Product: OCC1CNCC(O)C1O
Yield: 65 %

Procedure:
tert-Butyl 3-((1R,2S,5R)-2-isopropyl-5-methyl-1-cyclohexyloxy)acetoxymethyl-4,5-epoxypiperidine-1-carboxylate (0.25 g, 0.59 mmol) and 10% aqueous potassium hydroxide were refluxed for 3h. The reaction mixture was evaporated to dryness in vacuo and purified on a silica gel column (Eluent: isopropyl alkohol /26% ammonium hydroxide (3/1)) to give 5-hydroxymethyl-3,4-piperidinediol as an oil (Yield: 56 mg, 65%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23](/[CH:25]=[CH:26]/[C:27]#[N:28])[CH:22]=[C:21]([Cl:29])[CH:20]=2)[C:12]=1[F:30])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23](/[CH:25]=[CH:26]/[C:27]#[N:28])[CH:22]=[C:21]([Cl:29])[CH:20]=2)[C:12]=1[F:30])=[O:8]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(/C=C/C#N)c2)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#C/C=C/c1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.1 %

Procedure:
To a solution of 4-chloro-N-{[4-chloro-3-({3-chloro-5-[(E)-2-cyanoethenyl]phenyl}oxy)-2-fluorophenyl]methyl}-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (106 mg, 0.178 mmol) in DCM (5 ml) was added TFA (2.0 mL) and the reaction mixture was stirred at room temperature for 6 hours. The solvent was removed and the crude material was purified via reverse phase HPLC to give 4-chloro-N-{[4-chloro-3-({3-chloro-5-[(E)-2-cyanoethenyl]phenyl}oxy)-2-fluorophenyl]methyl}-1H-imidazole-5-carboxamide (72 mg, 0.155 mmol, 87% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.81-13.40 (m, 1H), 8.08-8.51 (m, 1H), 7.72 (s, 1H), 7.51-7.62 (m, 2H), 7.45 (d, 1H), 7.31 (t, 1H), 7.23 (s, 1H), 7.00 (s, 1H), 6.58 (d, 1H), 4.48 (d, 2H). LC-MS (ES+) m/z 464.94, [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[H-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[CH2:12]([N:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[C:3]([O:2][CH3:1])=[O:4])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc[nH]1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 56.3 %

Procedure:
To a cooled (0° C.) solution of methyl-2-pyrrole carboxylate (8.00 g, 63.9 mmol) in DMF (320 mL) was added NaH (60% by weight 5.10 g, 128 mmol). After 20 min, benzylbromide (11.4 mL, 95.9 mmol) was added and the reaction was warmed to rt. Stirring was continued for 2 h before quenching with saturated aq NH4Cl (0.5 L). The mixture was extracted 3× with EtOAc and the combined organic layers were washed with H2O (3×) and brine, dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The crude product was chromatographed over silica gel (0 to 10% EtOAc in heptane over 25 min) to give methyl 1-benzyl-1H-pyrrole-2-carboxylate as a colorless oil (7.75 g, 56%). Rf=0.48 (25:75 heptane/EtOAc); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.28-7.34 (m, 2H) 7.23-7.27 (m, 1H) 7.09-7.13 (m, 2H) 7.01 (dd, J=4.0, 1.8 Hz, 1H) 6.88-6.91 (m, 1H) 6.19 (dd, J=4.0, 2.6 Hz, 1H) 5.57 (s, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH3:8][C:9]1([CH3:34])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19](O)=[O:20])[CH:16]=2)[NH:11][CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:32][CH2:31][O:30][C:29]2=[O:33])[CH:23]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH3:8][C:9]1([CH3:34])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:20])[CH:16]=2)[NH:11][CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:32][CH2:31][O:30][C:29]2=[O:33])[CH:23]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2CCOC2=O)c1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(C)(=O)=O)ccc2NC1c1cccc(N2CCOC2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a suspension of 60% sodium hydride (106 mg, 2.6 mmol) in N,N-dimethylformamide (2.5 mL) was added methanesulfonamide (257 mg, 2.7 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 3,3-dimethyl-2-[3-(2-oxo-oxazolidin-3-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.27 mmol) and 1,1′-carbonyldiimidazole (87 mg, 0.55 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-{3,3-dimethyl-2-[3-(2-oxo-oxazolidin-3-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-methanesulfonamide (24 mg, 20%) as a white solid: LC/MS m/e calcd for C22H25N3O5S (M+H)+: 444.53, observed: 444.1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][N:9]=[C:10](OCC)[CH2:11][CH2:12][CH2:13][CH3:14])=O.[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1)([O-:20])=[O:19].Cl>C(O)C>[CH2:11]([C:10]1[N:26]([CH2:25][C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:28][CH:27]=2)[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[N:8][N:9]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCC(=NNC(=O)c1ccco1)OCC
Reactant: NCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCO
Product: CCCCc1nnc(-c2ccco2)n1Cc1ccc([N+](=O)[O-])cc1

Procedure:
To 678 mg (2.85 mmole) of ethyl valerate 2-furoylhydrazone dissolved in 3 ml of ethanol was added a solution of 514 mg (2.16 mmole ) of 4-nitrobenzylamine (generated from the hydrochloride by partitioning between ether and saturated Na2CO3 solution) in 3 ml of ethanol. The resulting solution was heated at 45°-50° C. for two hours and then at 70° C. overnight. The solution was cooled and concentrated. Column chromatography of the residue on silica gel (gradient elution with 0.5-2.5% methanol in CH2Cl2) afforded some recovered starting material (ester hydrazone) followed by 432 mg (61%) of the product as a yellow oil which upon standing at 5° C. crystallized to a solid having mp 91°-92.5° C., homogeneous by TLC in 97:3 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 327 (M+1)+.
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH2:29][CH3:30])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[NH:12][C:11]2=[O:21])C=CC=CC=1.[CH3:32][N:33]1[CH2:38][CH2:37][CH:36]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:35][CH2:34]1>C1COCC1>[CH2:29]([O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:10]1([NH:9][C:8]([N:42]2[CH2:41][CH2:40][N:39]([CH:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)[CH2:44][CH2:43]2)=[O:7])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[NH:12][C:11]1=[O:21])[CH3:30]
Reactant: CCOc1ccccc1C1(NC(=O)Oc2ccccc2)C(=O)Nc2ccc(OC)cc21
Reactant: CN1CCC(N2CCNCC2)CC1
Solvent: C1CCOC1
Product: CCOc1ccccc1C1(NC(=O)N2CCN(C3CCN(C)CC3)CC2)C(=O)Nc2ccc(OC)cc21
Yield: 65.7 %

Procedure:
1.9 g (4.5 mmol) of the intermediate from step D and 1.75 g (9.5 mmol) 1-(1-methylpiperidine-4-yl)-piperazine were dissolved in 30 ml dry THF and refluxed for 90 minutes. The volatiles were removed in vacuo. The resulting residue was dissolved in ethyl acetate, washed with H2O and dried over magnesium sulfate and the solvent was removed in vacuo. The residue was treated with H2O and the resulting precipitate was separated to yield 1.5 g of the intermediate.
Reaction SMILES: [CH:1]([C:3]1[NH:4][CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1)=[O:2].Cl[CH2:13][O:14][CH3:15]>>[CH:1]([C:3]1[N:4]([CH2:13][O:14][CH3:15])[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1)=[O:2]
Reactant: COCCl
Reactant: COC(=O)c1c[nH]c(C=O)c1
Product: COCn1cc(C(=O)OC)cc1C=O

Procedure:
reacting a methyl 2-formyl-4-pyrrolcarboxylate with chloromethyl-methyl-ether in the presence of a base and a suitable organic solvent, obtaining as a reaction product methyl 2-formyl-N-methoxymethyl-4-pyrrolcarboxylate;
Reaction SMILES: F[C:2]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][CH2:9][C:10](=[O:28])[NH:11][CH:12]2[CH2:15][N:14]([CH:16]3[CH2:21][CH2:20][CH:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)[CH2:13]2)=[O:7])=[CH:4][C:3]=1[C:31]([F:34])([F:33])[F:32].[NH2:35][CH2:36][CH2:37][OH:38]>>[OH:38][CH2:37][CH2:36][NH:35][C:2]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][CH2:9][C:10](=[O:28])[NH:11][CH:12]2[CH2:13][N:14]([CH:16]3[CH2:21][CH2:20][CH:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)[CH2:15]2)=[O:7])=[CH:4][C:3]=1[C:31]([F:34])([F:33])[F:32]
Reactant: NCCO
Reactant: O=C(CNC(=O)c1ccc(F)c(C(F)(F)F)c1)NC1CN(C2CCC(c3ccccc3)CC2)C1
Product: O=C(CNC(=O)c1ccc(NCCO)c(C(F)(F)F)c1)NC1CN(C2CCC(c3ccccc3)CC2)C1

Procedure:
The title compound was prepared as a white solid from the coupling of 4-fluoro-N-{[1-(4-phenyl-cyclohexyl)-azetidin-3-ylcarbamoyl]-methyl}-3-trifluoromethyl-benzamide (as prepared in Example 71) and 2-amino-ethanol (Aldrich) using the procedure described in Example 65.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:8]=3[CH:7](O)[C:5]=2[N:6]=1.[CH3:18][N:19]1[CH:26]=[CH:25][C:23](=[O:24])[NH:22][C:20]1=[O:21]>>[Cl:1][C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:8]=3[CH:7]([C:25]3[C:23](=[O:24])[NH:22][C:20](=[O:21])[N:19]([CH3:18])[CH:26]=3)[C:5]=2[N:6]=1
Reactant: Cn1ccc(=O)[nH]c1=O
Reactant: OC1c2ccc(Cl)cc2C=Cc2sc(Cl)nc21
Product: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(Cl)nc32)c(=O)[nH]c1=O

Procedure:
The title product was prepared from the product of step (vii) (1.27 g) and 1-methyluracil (1 g) according to the method of example 38 step (iv). Purification was by chromatography eluting with 50-60% ethyl acetate in isohexane.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:6]2([CH2:9][C:10](=O)[CH3:11])[CH2:7][CH2:8][CH:3]1[CH2:4][CH2:5]2.C(O)(=O)C.[CH3:18][NH2:19]>[Pt]=O.C(O)C>[CH3:18][NH:19][CH:10]([CH3:11])[CH2:9][C:6]12[C:2]([CH3:13])([CH3:1])[CH:3]([CH2:8][CH2:7]1)[CH2:4][CH2:5]2
Reactant: CN
Reactant: CC(=O)CC12CCC(CC1)C2(C)C
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: CCO
Product: CNC(C)CC12CCC(CC1)C2(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 7,7-dimethyl-1-(2-oxo-n-propyl) norbornane (4.69 g), glacial acetic acid (10 ml), methylamine (10g) and ethanol (100 ml) was heated under reflux for 1 hour, cooled to room temperature and hydrogenated for 4 hours at 4 atmospheres using platinum oxide (0.25 g) as catalyst. The catalyst was removed by filtration and the filtrate evaporated to low volume before extracting with ether. The aqueous phase was basified with 2N-sodium hydroxide solution and the liberated base extracted into ether. The combined extracts were washed with water, dried (MgSO4) and evaporated in vacuo to yield the title product (4.15 g) which was characterised as the hydrochloride salt.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[C:20](=[O:21])[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])=[N:11][O:12][C:8]=2[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C.[F:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)=[CH:40][CH:39]=1.[I-].[K+]>CN(C=O)C>[F:37][C:38]1[CH:39]=[CH:40][C:41]([N:44]2[CH2:49][CH2:48][N:47]([CH2:2][CH2:3][CH2:4][CH:5]3[C:20](=[O:21])[C:9]4[C:10]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=5[F:19])=[N:11][O:12][C:8]=4[CH2:7][CH2:6]3)[CH2:46][CH2:45]2)=[CH:42][CH:43]=1
Reactant: O=C1c2c(-c3ccccc3F)noc2CCC1CCCCl
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1c2c(-c3ccccc3F)noc2CCC1CCCN1CCN(c2ccc(F)cc2)CC1
Temperature: 80 °C
Yield: 47 %

Procedure:
To a solution consisting of 5-(3-chloropropyl)-3-(2-fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one (5.8 g) and DMF (100 ml) was added anhydrous potassium carbonate (1.3 g), diisopropylethyl amine (4.9 ml), 1-(4-fluorophenyl)piperazine (4.1 g) and potassium iodide (0.3 g) at room temperature with stirring. The flask was flushed with nitrogen and warmed to 80° C. for 13.5 hours. Upon cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous phase was extracted 3 times with ethyl acetate. The combined organic layers were washed with water twice, brine, and then dried (MgSO4). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel, 2% triethylamine/ether) afforded 4.0 g of 6,7-dihydro-5-[3-(4-(4-fluorophenyl)-1-piperazinyl)-propyl]-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-one as an oil. The product was flushed thru alumina with ether. The hydrochloride was prepared in ether with ethereal HCl. The precipitate was filtered and washed with pentane, m.p. 161°-164° C.
Reaction SMILES: [C:1]([O:11][C:12](=[C:14]([F:16])[F:15])[F:13])([C:4]([C:7]([F:10])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].CO.[C:19]([O:24]OC(=O)C1C=CC=CC=1)(CC)(C)C>>[C:1]([O:11][CH:12]([C:14]([CH2:19][OH:24])([F:15])[F:16])[F:13])([C:4]([C:7]([F:10])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: FC(F)=C(F)OC(F)(F)C(F)(F)C(F)(F)F
Reactant: CCC(C)(C)OOC(=O)c1ccccc1
Solvent: CO
Product: OCC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F

Procedure:
C3F7OCFHCF2CH2OH was prepared by the reaction of C3F7OCF═CF2 (53 g, 0.2 mol) with methanol (63.7 g, 2.0 mol) using t-amylperoxybenzoate (1.0 g) as free radical initiator at 106° C. The product reaction mixture was washed with water and distilled and the distillation fraction of b.r.=115-117° C. used in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([F:24])=[C:21]([CH:23]=3)[NH2:22])=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH:25]1[CH:29]=[C:28]([CH2:30][C:31](Cl)=[O:32])[S:27][CH:26]=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([F:24])=[C:21]([NH:22][C:31](=[O:32])[CH2:30][C:28]4[S:27][CH:26]=[CH:25][CH:29]=4)[CH:23]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)ccc1F
Reactant: O=C(Cl)Cc1cccs1
Product: O=C(Cc1cccs1)Nc1cc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)ccc1F
Yield: 92.5 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]-2-fluoroaniline (690 mg, 2.0 mmol) and thiophene-2-acetyl chloride (0.26 mL, 2.1 mmol) were coupled according to the procedure of Example 56, Step G to give the desired product (858 mg, 92%). 1H NMR (400 MHz, d6-DMSO) δ 10.21 (s, 1H), 8.93 (d, J=9.2 Hz, 1H), 8.49 (d, J=7.6 Hz, 1H), 8.44 (d, J=12.0 Hz, 1H), 8.29-8.27 (m, 1H), 7.70-7.65 (m, 1H), 7.49-7.41 (m, 3H), 7.27-7.22 (m, 1H), 7.13 (d, J=7.2 Hz, 1H), 7.02-6.98 (m, 2H), 4.02 (s, 2H) ppm.