Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2Cl)=[CH:4][CH:3]=1.[NH:13]1[C:21]2[C:16](=[CH:17][C:18](B(O)O)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:13]1[C:21]2[C:16](=[CH:17][C:18]([C:9]3[C:10]4[C:5](=[CH:4][CH:3]=[C:2]([C:18]5[CH:17]=[C:16]6[C:21](=[CH:20][CH:19]=5)[NH:13][CH:14]=[CH:15]6)[CH:11]=4)[CH:6]=[CH:7][N:8]=3)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1
Reactant: Clc1nccc2ccc(Br)cc12
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cc2ccc(-c3ccc4[nH]ccc4c3)cc2c(-c2ccc3[nH]ccc3c2)n1
Temperature: 25 °C
Yield: 38.4 %

Procedure:
A mixture of 7-bromo-1-chloroisoquinoline (0.20 g, 2.1 mmol), 5-indoleboronic acid (0.80 g, 5.0 mmol), tetrakis(triphenylphosphene)palladium (0.19 g, 0.16 mmol), potassium carbonate (2.1 mL, 2 M, 4.1 mmol), N,N-dimethylformamide (11 mL) was stirred while purging the headspace with argon for 30 min. The mixture was then brought to reflux for 16 h before being allowed to cool to RT. The mixture was filtered through a bed of silica gel, diluted with water (50 mL), and extracted with ethyl acetate (50 mL). The organic layer was separated and washed with NaOH (2×20 mL, 10% aq.), water (5×30 mL, until refractive changes were no longer seen at the organic-aqueous interface), and ammonium chloride (20 mL, sat.). The organic layer was then adsorbed onto silica gel and flash-chromatographed (ethyl acetate/hexanes) to afford 0.29 g (39%) of a yellow solid. MS (ESI): calculated for C25H17N3, 359.1. Found 360.2 [M+H]+ 382.1 [M+Na]+, and 358.0 [M−H]−. 1H NMR (500 MHz, DMSO-d6) δ 6.46-6.50 (m, 1H) 6.52-6.59 (m, 1H) 7.34-7.36 (m, 1H) 7.36-7.41 (m, 2H) 7.42-7.52 (m, 3H) 7.58 (d, J=8.30 Hz, 1H) 7.81 (dd, J=5.49, 5.00 Hz, 2H) 7.92 (s, 1H) 8.08-8.17 (m, 2H) 8.33 (s, 1H) 8.54 (d, J=5.61 Hz, 1H) 11.18 (br. s., 1H) 11.30 (br. s., 1H) ppm.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C>[N:11]([CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1)=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: OCc1ccc(CCl)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc(CO)cc1

Procedure:
4-(Chloromethyl)-benzylalcohol (5.01 g, 32 mmol) and NaN3 (2.50 g, 38.4 mmol) were stirred in DMF (25 mL) at 90° C. for 17 h. The solvent was removed under reduced pressure and the residue was partitioned between water (50 mL) and Et2O (100 mL). The aqueous layer was extracted with Et2O (2×50 mL) and the combined org. layers were dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give (4-azidomethyl-phenyl)-methanol, pure enough for further reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH2:27])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[N:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37](OC)=[O:38])=[C:29]=[S:30]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][N:27]3[C:37](=[O:38])[C:32]4[C:31](=[CH:36][CH:35]=[CH:34][CH:33]=4)[NH:28][C:29]3=[S:30])[CH2:23][CH2:24]2)=[CH:4][CH:3]=1
Reactant: NCCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: COC(=O)c1ccccc1N=C=S
Solvent: C1CCOC1
Product: O=c1c2ccccc2[nH]c(=S)n1CCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 1 h
Yield: 46 %

Procedure:
To a stirred mixture of 5.5 parts of 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidineethanamine and 90 parts of tetrahydrofuran was added dropwise a solution of 3.8 parts of methyl 2-isothiocyanatobenzenecarboxylate in 18 parts of tetrahydrofuran (exothermic reaction). Upon completion, stirring was continued for 1 hour. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and recrystallized from methanol. The product was filtered off and dried, yielding 3.6 parts (46%) of 3-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]-2,3-dihydro-2-thioxo-4(1H)-quinazolinone; mp. 218.2° C. (460).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:6]3[CH2:5][C:4]=2[CH:3]=1>C1(C)C=CC=CC=1.[Pd]>[OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)CC1CCN2c3ccc(O)cc3CC12
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Temperature: 80 °C
Reaction time: 48 h
Yield: 42 %

Procedure:
tert-Butyl-2-(7-(benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-ylidene)acetate (1.391 g, 3.70 mmol) was dissolved in THF (25 mL) and 10% palladium on carbon (50% in water, 217 mg) was added. The reaction mixture was placed under 225 psi of hydrogen in a hydrogenation reactor for 24 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to provide tert-butyl 2-(7-(benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate. The above material was taken up in a mixture of THF (20 mL) and EtOH (20 mL) and Pd(OH)2/C (250 mg) was added. The reaction mixture was placed under 200 psi of hydrogen in a hydrogenation reactor for 2 days. Additional Pd(OH)2/C (250 mg) was added and the reaction mixture was placed under 300 psi of hydrogen in a hydrogenation reactor for 24 h. Pd(OH)2/C (250 mg) was again added and the vessel placed under 500 psi of hydrogen in a hydrogenation reactor for 24 h. The hydrogenation reactor was warmed to 50° C. for 8 h. The reaction mixture was cooled to room temperature and AcOH (5 mL) was added. The reaction mixture was placed under 500 psi of hydrogen for 16 h. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure to provide a mixture of the title compound and tert-butyl 2-(7-hydroxy-2,3,9,9a-tetrahydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate. The title compound (150 mg) was isolated by silica gel column chromatography. tert-Butyl 2-(7-hydroxy-2,3,9,9a-tetrahydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (600 mg) was dissolved in toluene (100 mL) and Pd/C (1.0 g) was added. The reaction mixture was warmed to 80° C. and stirred for 2 days. The reaction mixture was filtered through Celite® and the title compound (250 mg) was isolated as a white solid resulting from precipitation during concentration of the filtrate. LCMS m/z=288.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]2[CH:10]([CH:11]=1)[NH:9][C:8](=[O:12])[CH2:7][CH2:6]2.C1C(=O)N([Br:20])C(=O)C1>>[Br:20][C:3]1[C:2]([F:1])=[CH:11][CH:10]2[CH:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)[CH:4]=1
Reactant: O=C1CCC2C=CC(F)=CC2N1
Reactant: O=C1CCC(=O)N1Br
Product: O=C1CCC2C=C(Br)C(F)=CC2N1

Procedure:
This intermediate was obtained according to general procedure I from 7-fluoro-3,4,4a,8a-tetrahydro-1H-quinolin-2-one (92 mg, 0.56 mmol) and NBS (104 mg, 0.58 mmol) after flash chromatography on silica gel (hexanes/ethyl acetate, 5/1, Rf=0.27) as white solid (120 mg, 0.49 mmol, 88%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([CH2:13][C:14](=[O:28])[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[BH4-].[Na+].O.Cl>CO.O1CCCC1>[OH:3][CH2:4][CH2:5][N:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:13][C:14]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)=[O:28]
Reactant: CCOC(=O)CN(CC(=O)Nc1ccc(-c2ccncc2)cc1)c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(CN(CCO)c1ccccc1)Nc1ccc(-c2ccncc2)cc1
Yield: 48 %

Procedure:
Ethyl[(2-oxo-2-{[4-(4-pyridinyl)phenyl]amino}ethyl) (phenyl)amino]acetate (50.0 mg) was dissolved in methanol/tetrahydrofuran (1:1, 1.0 mL) and sodium borohydride (14.6 mg) was added portionwise to the mixture cooled with ice bath stirring. The mixture was stirred at 0° C. for 5 hours and water (2.0 mL) was added to the resulting mixture. The mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate (3.0 mL). The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography (2 g, 10% methanol in chloroform) to afford 2-[(2-hydroxyethyl) (phenyl)amino]-N-[4-(4-pyridinyl)phenyl]acetamide (21.4 mg) as white crystals.
Reaction SMILES: [C:1]([O:6][C:7]([C:10]12[CH2:19][C:14]3([O:20]COCCOC)[CH2:15][CH:16]([CH2:18][C:12]([O:27]COCCOC)([CH2:13]3)[CH2:11]1)[CH2:17]2)([CH3:9])[CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].Cl.[Cl-].[NH4+]>CC(C)=O>[OH:20][C:14]12[CH2:19][C:10]3([C:7]([O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])([CH3:9])[CH3:8])[CH2:17][CH:16]([CH2:18][C:12]([OH:27])([CH2:11]3)[CH2:13]1)[CH2:15]2
Reactant: C=C(C)C(=O)OC(C)(C)C12CC3CC(OCOCCOC)(CC(OCOCCOC)(C3)C1)C2
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)=O
Product: C=C(C)C(=O)OC(C)(C)C12CC3CC(O)(CC(O)(C3)C1)C2

Procedure:
A mixture of 10 mmole of 1-(1-methacryloyloxy-1-methylethyl)-3,5-bis(2-methoxyethoxymethoxy)adamantane thus obtained, 1 mmole (in terms of HCl) of 6N-HCl and 40 ml of acetone was stirred at room temperature for 5 hours. The resulting reaction mixture was incorporated with an aqueous ammonium chloride solution, was extracted with ethyl acetate, the organic layer was concentrated, and the concentrate was subjected to column chromatography on a silica gel to thereby yield the title compound.
Reaction SMILES: [CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=[C:13]3B2OC(C)(C)C(C)(C)O2)=[N:8][N:9]=1)([CH3:3])[CH3:2].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Cl[C:73]1[N:78]=[C:77]([CH:79]2[CH2:81][CH2:80]2)[C:76]([C:82]([O:84][CH3:85])=[O:83])=[CH:75][N:74]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:79]1([C:77]2[C:76]([C:82]([O:84][CH3:85])=[O:83])=[CH:75][N:74]=[C:73]([C:13]3[C:12]4[C:16](=[CH:17][CH:18]=[C:10]([C:7]5[O:6][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:9][N:8]=5)[CH:11]=4)[N:15]([S:19]([C:22]4[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=4)(=[O:20])=[O:21])[CH:14]=3)[N:78]=2)[CH2:80][CH2:81]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Reactant: COC(=O)c1cnc(Cl)nc1C1CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COC(=O)c1cnc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccc(-c4nnc(NC(C)C)o4)cc23)nc1C1CC1
Temperature: 130 °C
Yield: 40.2 %

Procedure:
A 20 mL microwave vial was charged with N-isopropyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (300 mg, 0.574 mmol), Xphos (Stem Chemicals, Newburyport, Mass., 16.4 mg, 0.034 mmol), Pd2(dba)3 (Strem Chemicals, Newburyport, Mass., 15.8 mg, 0.017 mmol), methyl 2-chloro-4-cyclopropylpyrimidine-5-carboxylate (147 mg, 0.689 mmol) and potassium phosphate (366 mg, 1.723 mmol) followed by purging with argon. The solids were treated with dioxane (3 mL) and water (1.0 mL) and heated in the microwave at 130° C. for 20 min. The reaction mixture was treated with water and extracted with EtOAc, dried over MgSO4, filtered and concentrated. Purification of the crude residue on the ISCO (12 g Redisep column, using a gradient of 0-100% EtOAc in hexanes) afforded methyl 4-cyclopropyl-2-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)pyrimidine-5-carboxylate (132.4 mg, 0.231 mmol, 40.3% yield) as light yellow amorphous solid. MS (ESI, pos. ion) m/z: 573.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 9.11 (1H, s), 9.04 (1H, d, J=1.2 Hz), 8.59 (1H, s), 8.08 (1H, d, J=8.8 Hz), 8.01 (1H, dd, J=8.8, 1.6 Hz), 7.86 (2H, d, J=8.4 Hz), 7.28 (2H, s), 4.55 (1H, br. s.), 4.00-4.08 (1H, m), 3.98 (3H, s), 3.24-3.34 (1H, m), 2.36 (3H, s), 1.32-1.39 (6H, m), 1.21-1.30 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:36][CH:11]3[C:12](=[O:35])[N:13]([C:16]4[CH:21]=[CH:20][C:19]([O:22][Si](C(C)C)(C(C)C)C(C)C)=[C:18]([O:33][CH3:34])[CH:17]=4)[CH:14]=[CH:15][CH:10]3[CH:9]=2)=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:36][CH:11]3[C:12](=[O:35])[N:13]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:33][CH3:34])[CH:17]=4)[CH:14]=[CH:15][CH:10]3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(N2C=CC3C=C(c4ccc(Cl)cc4)SC3C2=O)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(N2C=CC3C=C(c4ccc(Cl)cc4)SC3C2=O)ccc1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
Dissolve 2-(4-chloro-phenyl)-6-(3-methoxy-4-triisopropylsilanyloxy-phenyl)-3a,7 a-dihydro-6H-thieno[2,3-c]pyridin-7-one (2.86 g, 5.29 mmol) in THF (55 mL), cool to 0° C., and treat with 1.0 M TBAF (5.8 mL, 5.8 mmol). Stir the reaction at 0° C. for 10 min and at RT for 2 h. Dilute the reaction with EtOAc (150 mL), wash with saturated NH4Cl (100 mL), water (100 mL), and brine (100 mL). Dry the organic portion over Na2SO4, filter, and concentrate. Wash the resulting crude material with refluxing hexanes (2×40 mL) and dry in vacuo to give 1.95 g (96%) of the title compound. LC-MS/ES m/z (35Cl) 384.0 [M−H]−.
Reaction SMILES: II.Br[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:10]([N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(=O)(O)[O-].[Na+]>C1COCC1.[Zn].C(OCC)(=O)C>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][C:20]1([OH:23])[CH2:19][CH2:18][N:17]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:22][CH2:21]1)[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOC(=O)CBr
Agent: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Yield: 90.8 %

Procedure:
Iodine (12.7 g) was added to the suspension of zinc dust (20 g) in dry THF (200 ml) under nitrogen. An exothermic reaction takes place within 2 minutes and iodine disappeared in less the 10 minutes (a cold water bath is ready to cool the reaction down, but not used). To above mixture was then added by syringe a solution of mixture of ethyl bromoacetate (10.9 g) and N-Boc-4-piperidinone (10 g) in THF (50 ml) on the speed to maintain the reaction at gentle reflux. After stirring for 2 more hours, this mixture was then poured to the mixture of aqueous sodium bicarbonate (200 ml) and ethyl acetate (500 ml). Organic layer was seperated, washed with brine (200 ml), dried over sodium sulphate, solvent removed, the residue was columned on silica gel using heptane:EtOAc (10:1) as eluant to give expected product as a colourless oil (13.1 g). 1H NMR (CDCl3) δ: 4.18 (q, 2H), 3.80 (br, 2H), 3.57 (s, 1H), 3.22 (t, br, 2H), 2.46 (s, 2H), 1.67 (m, 2H), 1.47 (m, 2H), 1.46 (s, 9H), 1.28 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[C:16]([F:19])=[C:15]([CH3:20])[NH:14][C:13]2=[O:21])=[C:4]([F:22])[CH:3]=1.S(OC)(O[CH3:27])(=O)=O>>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[C:16]([F:19])=[C:15]([CH3:20])[N:14]([CH3:27])[C:13]2=[O:21])=[C:4]([F:22])[CH:3]=1
Reactant: Cc1[nH]c(=O)n(-c2cc(OC(C)C)c(Cl)cc2F)c(=O)c1F
Reactant: COS(=O)(=O)OC
Product: Cc1c(F)c(=O)n(-c2cc(OC(C)C)c(Cl)cc2F)c(=O)n1C

Procedure:
using 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5-fluoro-6 methyl-2,4(1H,3H)-pyrimidinedione and dimethyl sulphate there is obtained 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-1,6-dimethyl-5-fluoro-2,4(1H,3H)pyrimidinedione, m.p. 139°-141° C.;
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][NH2:8])=[CH:2]1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH4-].[Na+].[OH-].[Na+]>CO>[CH2:9]([NH:8][CH2:7][CH2:6][C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: NCCc1ccoc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: c1ccc(CNCCc2ccoc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the above crude 2-(3-furyl)ethylamine and 4.24 g (39.9 mmol) of benzaldehyde in 50 ml of methanol was stirred at room temperature for 0.5 hours. The reaction mixture was cooled with ice-water; 1.89 g (49.9 mmol) of sodium borohydride was added portionwise followed by stirring at room temperature for 1 hour. The reaction mixture was poured into aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 to ethyl acetate) to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:11]=[C:10]([CH:21]3[CH2:26][C:25]([CH3:28])([CH3:27])[O:24][C:23]([CH3:30])([CH3:29])[CH2:22]3)[CH:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:38])C(=O)C1>C(Cl)Cl>[Br:38][C:9]1[C:10]([CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[O:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)=[N:11][N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1-c1ccc(Cl)cc1
Solvent: ClCCl
Product: COc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)c(Br)c1-c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
To a solution of 5-(4-chlorophenyl)-1-(2-methoxyphenyl)-3-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazole (80 mg, 0.19 mmol)(Example 1) in 2 mL of DCM was added NBS (33 mg, 0.19 mmol) and the mixture stirred for 30 mins at Rt. The crude product was purified by silica gel chromatography (Thomson Scientific 12-g cartridge, 2-20% EtOAc/heptane) to give 40 mg (40%) of the title compound.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[C:8]([C:9](I)=[CH:10][C:11]([F:14])([F:13])[F:12])=[CH:7][S:6][CH:5]=1>C(O)C.O>[Br:3][C:4]1[C:8]([C:9]#[C:10][C:11]([F:13])([F:12])[F:14])=[CH:7][S:6][CH:5]=1
Reactant: FC(F)(F)C=C(I)c1cscc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: FC(F)(F)C#Cc1cscc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydroxide (1.2 g, 30 mmol) dissolved in a 50/50 mixture of ethanol and water was added to the product of Example 2. The reaction was stirred overnight at room temperature. The product was extracted with pentane and purified by distillation at 25° C., 300 mTorr. MS: m/z 256, 254, 236, 234, 206, 204, 175, 131, 106, 99, 69 1H-NMR: δ (ppm) 7.3 (d, 1), 7.7 (d, 1); 19F-NMR: δ (ppm) −50 (s, 3)
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:21])=[C:4]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([Br:20])[CH:18]=3)[NH:13][CH:12]=2)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl:29][C:30]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:31]=1[C:32](Cl)=[O:33]>CN(C)C1C=CN=CC=1.CC1CCCO1>[NH2:1][C:2]1[C:3]([F:21])=[C:4]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([Br:20])[CH:18]=3)[N:13]([C:32](=[O:33])[C:31]3[C:30]([Cl:29])=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:39])[CH:12]=2)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC1CCCO1
Product: Nc1ccc(F)c(C(=O)c2cn(C(=O)c3c(Cl)cccc3Cl)c3ncc(Br)cc23)c1F
Temperature: 9.300000190734863 °C
Yield: 92.93 %

Procedure:
Compound 4 (2.5 kg, 7.114 mol) obtained from Example 2 was added into a 50-liter flask and cooled to 9.3° C. To compound 4 in the 50-liter flask was added triethylamine (0.864 kg, 8.537 mol), followed by 4-dimethylaminopyridine (DMAP) (0.087 kg, 0.7114 mol) and 2,6-dichlorobenzoyl chloride (1.34 kg, 6.40 mol) in 2-methyl-THF (25 L) over a period of 2 hrs. The reaction was quenched with methanol (0.30 L at room temperature and added an aqueous NaCl solution (12.5 L, 15%) and celite (0.5 kg). The mixture was stirred and filtered through celite. The filtrate was concentrated and added 5 volumes of heptanes. The resulting solution was stirred for about 1 hr and dried with sodium sulfate (1 kg) and filtered. Compound 5 was isolated by removing the solvents under vacuum (3.47 kg, 92.93% yield). MS (ESI): M+H+=524, 525.8, 527.8. 1H NMR (DMSO-d6, δ ppm): 5.36 (2H, s), 7.01 (2H, m), 7.68 (3H, s), 8.34 (1H, brs), 8.61 (1H, brs), 8.72 (1H, d J=2.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].Cl.Cl[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]Cl>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:5]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: ClCCNCCCl
Reactant: Nc1ccc(F)c(Cl)c1
Agent: Cl
Solvent: Cc1ccccc1C
Product: Fc1ccc(N2CCNCC2)cc1Cl

Procedure:
A xylene (20 ml.) solution of 3-chloro-4-fluoroaniline (5.0 g., 34.3 mmol) and bis-(2-chloroethyl)amine hydrochloride (6.13 g., 34.3 mmol) is heated to reflux for 64 hrs. The mixture is extracted with warm water and the aqueous phase then extracted with methylene chloride. The aqueous phase is made basic with 50% sodium hydroxide and extracted with methylene chloride which is dried over potassium carbonate and concentrated under reduced pressure. Residual material is distilled and the fraction having a b.p. of about 100° C. at 0.25 mmHg collected. Conversion of the amine to the hydrochloride salt and crystallization from ethanol affords N-(3-chloro-4-fluorophenyl)piperazine.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[O:5][CH2:4][C@@H:3]1[NH:10][C:11](=[O:19])[O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C.[S:27](Cl)([CH3:30])(=[O:29])=[O:28]>ClCCl>[CH3:30][S:27]([O:1][C@@H:2]1[C@@H:3]([NH:10][C:11]([O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:16])[CH3:18])=[O:19])[CH2:4][O:5][C:6]([CH3:9])([CH3:8])[CH2:7]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)C[C@H](O)[C@@H](NC(=O)OCC[Si](C)(C)C)CO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C[C@H](OS(C)(=O)=O)[C@@H](NC(=O)OCC[Si](C)(C)C)CO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 124.4 %

Procedure:
To a solution of 2-(trimethylsilyl)ethyl (3S,4S)-4-hydroxy-6,6-dimethyl-tetrahydro-2H-pyran-3-ylcarbamate (1.0 g, 3.5 mmol) and triethylamine (1.4 mL, 10 mmol) in dichloromethane (10 mL) at 0° C. was dropwise added mesyl chloride (600 mg, 5.20 mmol). The reaction mixture was stirred at room temperature for 4 hours and then diluted with dichloromethane (100 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated to afford the title compound (1.6 g, crude) as a yellow oil which was directly used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[O:11]1[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]1.C(N(CC)CC)C>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Br:1][C:2]1[CH:3]=[C:4]([NH:16][C:13]2[CH:14]=[CH:15][O:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccon1
Reactant: OB(O)c1cccc(Br)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Brc1cccc(Nc2ccon2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 13.9 %

Procedure:
To a solution of 3-bromophenylboronic acid (2.00 g, 9.96 mmol) in CH2Cl2 (80 mls) was added Isoxazol-3-ylamine (0.84 g, 19.92 mmol), Cu(OAc)2 (0.9 g, 0.46 mmol) and triethylamine. (14 mls). The reaction mixture was stirred at room temperature for 18 h, filtered and the resulting precipitate purified by silica column chromatography (20-80% EtOAc in hexane) to afford the title compound (0.33 g). MS: [M+H]+=239, 241