Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:18]3=4)[CH2:10][CH:9]2[CH3:33])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:38][C:39]([O:41][CH3:42])=[O:40]>CN(C)C=O>[CH3:42][O:41][C:39](=[O:40])[CH2:38][O:32][C:30]1[CH:29]=[CH:28][C:19]2[O:20][CH2:21][C:22]3[N:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:17](=[CH:16][CH2:15][CH2:14][N:11]3[CH2:12][CH2:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)([OH:34])[CH:9]([CH3:33])[CH2:10]3)[C:18]=2[CH:31]=1
Reactant: COC(=O)CBr
Reactant: CC1CN(CCC=C2c3cc(O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)C(C)C1)c1cccnc1CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.5 %

Procedure:
A solution of 5-{3-[4-(4-Chloro-phenyl)-4-hydroxy-3-methyl-piperidin-1-yl]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-ol (0.14 g, 0.28 mmol) in dimethylformamide (3 mL) was treated with sodium hydride (60% in mineral oil, 0.016 g, 0.4 mmol) and methyl bromoacetate (0.038 mL, 0.4 mmol). The mixture was allowed to stir at rt for 2 hr, then quenched with aqueous brine, and extracted with ethyl acetate (3×10 mL). The combined organics were washed several time with water, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate→487:10:3 ethyl acetate/methanol/triethylamine) to yield 0.07 g (50%) of the title compound, ESI-MS m/z: 549 [M+1].
Reaction SMILES: [N:1]1([C:10](=[O:22])[C:11](N2C3C=CC=CC=3N=N2)=[O:12])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.Cl.[F:24][C:25]([F:37])([F:36])[C:26]1[CH:27]=[N:28][C:29]2[CH2:30][CH2:31][NH:32][CH2:33][C:34]=2[CH:35]=1.CCN(CC)CC>C1COCC1>[N:1]1([C:10](=[O:22])[C:11]([N:32]2[CH2:31][CH2:30][C:29]3[N:28]=[CH:27][C:26]([C:25]([F:36])([F:24])[F:37])=[CH:35][C:34]=3[CH2:33]2)=[O:12])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: O=C(C(=O)n1nnc2ccccc21)n1nnc2ccccc21
Reactant: FC(F)(F)c1cnc2c(c1)CNCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(C(=O)n1nnc2ccccc21)N1CCc2ncc(C(F)(F)F)cc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.9 %

Procedure:
To a suspension of 1,2-bis-benzotriazol-1-yl-ethane-1,2-dione (0.100 g, 0.342 mmol) in THF (3.4 mL) was added 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,6]naphthyridine monohydrochloride (0.082 g, 0.342 mmol) and the reaction mixture was stirred at ambient temperature for about 4 h. Et3N (0.05 mL, 0.34 mmol) was added and stirring was resumed for about 1 hour. The reaction mixture was concentrated in vacuo and the residue triturated from hot iPrOAc. The solid was removed by filtration and the filtrate concentrated in vacuo then dissolved in EtOAc (10 mL), washed with 1N aq NaOH (2×5 mL), and saturated aqueous NaHCO3 (10 mL). The organic portion was separated, dried over MgSO4, filtered, and concentrated in vacuo to provide 1-benzotriazol-1-yl-2-(3-trifluoromethyl-7,8-dihydro-5H-[1,6]naphthyridin-6-yl)-ethane-1,2-dione as an orange oil (0.056 g, 0.15 mmol). The crude material was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].C([Sn](CCCC)(CCCC)[C:17]1[O:18][C:19]([Sn](CCCC)(CCCC)CCCC)=[CH:20][CH:21]=1)CCC>O1CCOCC1>[CH3:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[C:19]1[O:18][C:17]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[CH3:11])=[CH:21][CH:20]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc([Sn](CCCC)(CCCC)CCCC)o1
Reactant: Cc1cc([N+](=O)[O-])ccc1Br
Solvent: C1COCCO1
Product: Cc1cc([N+](=O)[O-])ccc1-c1ccc(-c2ccc([N+](=O)[O-])cc2C)o1
Yield: 84.8 %

Procedure:
To a solution of 2-bromo-5-nitrotoluene (4.32 g, 20 mmol) and tetrakis (triphenylphospine) palladium (0) (0.40 g) in anhydrous 1,4-dioxane (50 ml) was added 2,5-bis (tri-n-butylstannyl) furan (6.46 g, 10 mmol) and the mixture was heated overnight under nitrogen at 95–100° C. The resulting orange suspension was diluted with hexanes (15 ml), cooled to room-temperature, and filtered to give, after rinsing with hexanes, an orange solid (3.10 g), mp 241–243° C. The product was recrystallized from DMF (100 ml) to give a bright orange fluffy solid (2.87 g, 85%), mp 242–243° C. 1H NMR (DMSO-d6): 2.69 (s, 6H), 7.31 (s, 2H), 8.12 (m, 4H), 8.23 (s, 2H). Anal. Calcd. for C18H14N2O5 (338.31): C, H, N.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[C:25]([O:24][C:22]([NH:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[CH:14]=[C:15]([CH3:16])[C:7]2[CH:6]([CH2:5][C:4]([OH:29])=[O:3])[O:10][B:9]([OH:11])[C:8]=2[CH:12]=1)=[O:23])([CH3:27])([CH3:28])[CH3:26]
Reactant: CCOC(=O)CC1OB(O)c2cc(OCCCNC(=O)OC(C)(C)C)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OCCCNC(=O)OC(C)(C)C)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 3 h
Yield: 108.9 %

Procedure:
To a solution [6-(3-tert-butoxycarbonylamino-propoxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.445 g, 1.09 mmol) in THF (14 mL) was added a solution of LiOH (0.229 g, 5.44 mmol) in water (5 mL) at 0° C. The resulting mixture was stirred at room temperature for 3 hours then acidified to pH=2 with 6M HCl and extracted with EtOAc (3×25 mL). The organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (20% EtOAc/hexane) to give [6-(3-tert-butoxycarbonylamino-propoxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid (0.450 g, 80%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.08 (s, 1H), 7.00 (d, J=1.90 Hz, 1H), 6.87 (br. s., 1H), 6.81 (s, 1H), 5.41 (dd, J=9.52, 2.22 Hz, 1H), 3.93 (t, J=6.19 Hz, 2H), 3.06 (t, J=6.34 Hz, 2H), 3.00 (dd, J=15.55, 2.54 Hz, 1H), 2.23 (s, 3H), 2.03 (dd, J=15.39, 9.68 Hz, 1H), 1.80 (t, J=6.66 Hz, 2H), 1.35 (s, 9H).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[S:3].[OH-].[Na+].Cl[CH2:12][CH2:13][CH2:14][OH:15]>O>[NH2:6][C:5]1[CH:7]=[CH:8][N:1]=[C:2]([S:3][CH2:12][CH2:13][CH2:14][OH:15])[N:4]=1
Reactant: OCCCCl
Reactant: Nc1cc[nH]c(=S)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccnc(SCCCO)n1
Yield: 117 %

Procedure:
A mixture of 2-thiocytosine (0.88 g.), sodium hydroxide (0.32 g.), water (5 ml.) and 3-chloropropanol (0.8 g.) was heated at 90° for 1 hour and then cooled. The mixture was extracted with EtOAc and the extract dried and then evaporated to dryness to give 4-amino-2-(3-hydroxypropylthio)pyrimidine (1.5 g.) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[O-]CC.[Na+].[Br:26][CH2:27][CH2:28][CH2:29]Br>C(O)C>[Br:26][CH2:27][CH2:28][CH2:29][N:9]([O:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=1)[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:11])=[O:12]
Reactant: BrCCCBr
Reactant: COc1ccc(CONS(=O)(=O)c2ccc(C)cc2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(CON(CCCBr)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 87.8 %

Procedure:
N-(p-methoxybenzyloxy)-p-toluenesulfonamide (61.4 g) was added to a solution of sodium ethoxide in absolute ethanol (Na:4.6 g, absolute C2H5OH:540 ml) and stirred at 70° C. for 1.5 hours. After cooling at ambient temperature, 1,3-dibromopropane (121.2 g) was added to the mixture, and then the mixture was refluxed with stirring for 2 hours and filtered. The filtrate was concentrated under reduced pressure. To the residue was added a mixture of ethyl acetate and water, and the organic layer was separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give an oil, which was crystallized from a mixture of ethyl acetate and n-hexane to give N-(3-bromopropyl)-N-(p-methoxybenzyloxy)-p-toluenesulfonamide (75.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=[O:18].C([O-])([O-])=O.[K+].[K+].[CH2:26](I)[CH3:27]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])=[CH:4][C:3]=1[CH2:16][C:17]([O:19][CH2:26][CH3:27])=[O:18]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)c(CC(=O)O)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)Cc1cc(NC(=O)OC(C)(C)C)ccc1Cl
Yield: 97.6 %

Procedure:
To a solution of (2-chloro-5-(Boc-amino)phenyl)acetic acid (2.8 g; 9.8 mmol; from step (iv) above) in acetone (100 mL) was added K2CO3 (2.1 g, 15 mmol). EtI (70.6 g; 150 mmol) was then added whilst the reaction mixture was stirred and refluxed. The solution was concentrated, and the resultant mixture was partitioned between ether and water (1:1; 60 mL). The organic layer was separated, and the water layer was extracted once with ether (30 mL). The combined organic phase was washed with water, dried (Na2SO4), and concentrated to yield 3.0 g (98%) of the sub-title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27](=O)[NH:26][N:25]=[N:24]2)=[CH:19][CH:18]=1.FC1C=C(F)C=CC=1[C@]1(OC1)[C@H](N1C(=O)N(C2C=CC(C(F)(F)F)=CC=2)N=N1)C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([O:14][C:27]2[N:23]([C:20]3[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:29])[F:30])=[CH:22][CH:21]=3)[N:24]=[N:25][N:26]=2)[CH3:13])[CH2:11][O:10]1
Reactant: O=c1[nH]nnn1-c1ccc(C(F)(F)F)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Agent: C[C@@H](n1nnn(-c2ccc(C(F)(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](Oc1nnnn1-c1ccc(C(F)(F)F)cc1)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 7.2 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.41 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.30 g of 1-(4-trifluoromethylphenyl)-5(1H,4H)-tetrazolone, 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-(4-trifluoromethylphenyl)-5-(1H,4H)-tetrazolone (1.38 g) and 0.168 g of (2R)-2-(2,4-difluorophenyl)-2-[(1R)-1-[1-(4-trifluoromethylphenyl)-1H-tetrazol-5-yloxy]ethyl]oxirane were obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([CH:16]2[CH2:25][C:24]3[CH:23]=[C:22]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([C:33]([NH:35][CH3:36])=[O:34])[CH:28]=4)[CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[CH2:38][CH2:39][OH:40]>CN(C=O)C.O>[OH:40][CH2:39][CH2:38][NH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([CH:16]2[CH2:25][C:24]3[CH:23]=[C:22]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([C:33]([NH:35][CH3:36])=[O:34])[CH:28]=4)[CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: OCCBr
Reactant: CNC(=O)c1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cc(CN)cc(C(F)(F)F)c2)CC3)ccn1
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cc(CNCCO)cc(C(F)(F)F)c2)CC3)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-{[7-({[3-(aminomethyl)-5-(trifluoromethyl)phenyl]amino}-carbonyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}-N-methylpyridine-2-carboxamide (0.459 g, 0.921 mmol) in DMF (10 mL) was added 2-bromoethanol (0.100 mL, 1.41 mmol) and TEA (0.300 mL, 2.15 mmol). The reaction mixture was allowed to stir at rt overnight, and then diluted with water. The mixture was extracted with EtOAc and the combined organic solutions were washed with 10% aqueous LiCl, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give 4-{[7-({[3-{[(2-hydroxyethyl)amino]methyl}-5-(trifluoromethyl)phenyl]amino}carbonyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}-N-methylpyridine-2-carboxamide I-276 (0.352 g, 71%) as a white solid. 1H NMR (400 MHz, d6-DMSO, HCl salt) δ: 10.65 (s, 1H), 9.19-9.09 (br s, 1H), 8.85-8.77 (m, 1H), 8.50 (d, 1H), 8.17-8.02 (m, 2H), 7.66 (s, 1H), 7.41-7.36 (m, 1H), 7.28-7.21 (m, 1H), 7.19-7.14 (m, 1H), 7.04-6.94 (m, 2H), 4.22 (t, 2H), 3.83-3.76 (m, 2H), 3.67 (t, 2H), 3.03-2.81 (m, 5H), 2.77 (d, 3H), 2.17-2.08 (m, 1H), and 1.89-1.75 (m, 1H). LCMS: (FA) ES+543.2, ES−541.2.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@@H:9](O)[CH2:8][N:7]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6]1)=[N+:2]=[N-:3].N12CCCN=C1CCCCC2.[F:32]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F>C1(C)C=CC=CC=1>[N:1]([CH2:4][C@@H:5]1[C@H:9]([F:32])[CH2:8][N:7]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1F
Reaction time: 1 h

Procedure:
Process B: (3R,4R)-3-Azidomethyl-1-benzyloxycarbonyl-4-hydroxypyrrolidine (1.79 g) was dissolved in toluene (56 mL). While this solution was chilled in an ice water bath, 1,8-diazabicyclo[5.4.0]undec-7-ene (2.03 mL) was added, followed by dropwise addition of perfluoro-1-octanesulfonyl fluoride (2.80 mL) and stirring for 1 hour. The insoluble material in the reaction mixture was filtered and washed with toluene. The filtrate and the washings were combined and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate=2:1) to give (3R,4S)-3-azidomethyl-1-benzyloxycarbonyl-4-fluoropyrrolidine as a pale brown syrup (1.58 g). This compound was identical to the compound obtained by Process A.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1.Br[CH2:27][C:28]([NH2:30])=[O:29]>CCN(CC)CC>[NH2:30][C:28](=[O:29])[CH2:27][NH:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[O:5][N:4]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Reactant: NC(=O)CBr
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CNCC(N)=O)no1

Procedure:
Method as for preparation 106 using tert-butyl(3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 18) (250 mg, 0.71 mmol) and 2-bromoacetamide (98 mg, 0.71 mmol) as starting materials and Et3N as the base.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:5][O:6][CH3:7])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:16][Si:17](Cl)([CH3:19])[CH3:18]>ClCCl>[CH3:1][C:2]([CH3:8])([CH2:3][O:4][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH2:5][O:6][CH3:7]
Reactant: COCC(C)(C)CO
Reactant: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(C)(C)CO[Si](C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1 g of 2,2-dimethyl-3-methoxy-1-propanol was dissolved in 20 ml of dichloromethane. The resultant solution was cooled in ice-water bath to below 5° C., and 1.65 ml of triethyl amine was added thereto. After stirring the mixture 5 minutes, 1.29 ml of trimethylsilyl chloride was added drop-wise to the reaction mixture, and the mixture was stirred in ice-water bath for further 2 hours, and at room temperature for further 1 hour. The reaction mixture was washed with water, and the organic layer separated was dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to give 1.33 g of concentrate. The crude product was purified by column chromatography using petroleum ether as eluent, to give colorless pure compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:10]=2)=[CH:7][CH:8]=1
Reactant: CCCCCI
Reactant: COc1ccc(-c2n[nH]c3c(C)cccc23)cc1
Agent: [H-]
Agent: [Na+]
Product: CCCCCn1nc(-c2ccc(OC)cc2)c2cccc(C)c21
Yield: 34 %

Procedure:
Prepared according to Method D step B from 3-(4-methoxyphenyl)-7-methyl-1H-indazole (0.23 g, 1.0 mmol), sodium hydride (60% in oil, 0.048 g, 1.2 mmol) and 1-iodopentane (0.26 mL, 2.0 mmol) to give the title compound (0.105 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[NH2:12][CH2:13][C:14]1([N:20]([CH3:28])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:12][CH2:13][C:14]1([N:20]([CH3:28])[CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:6]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CN(Cc1ccccc1)C1(CN)CCCCC1
Solvent: c1ccccc1
Product: CN(Cc1ccccc1)C1(CNC(=O)c2ccc(Cl)c(Cl)c2)CCCCC1
Yield: 98.8 %

Procedure:
A solution of 3,4-dichlorobenzoyl chloride (2.095 g.) in benzene (50 ml) was added to a solution of 1 -aminomethyl-N-methyl-N-benzylcyclohexylamine (2.32 g.) in benzene (50 ml) and the mixture heated under reflux for 1 hr. The solution was allowed to cool, washed with 2N sodium hydroxide solution (3 × 50 ml), water (4 × 100 ml), dried (Na2SO4) and evaporated to give a white crystalline solid (4.0 g). Recrystallisation from cyclohexane afforded 1-[3,4-dichlorobenzoylaminomethyl]-N-methyl-N-benzylcyclohexylamine (110/39) as white prisms (3.589 g. 89%) m.p. 139°-145°.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:20][NH:21][CH3:22]>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([N:21]([CH3:22])[CH3:20])=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(CC(=O)c2ccc(F)cc2)CC1
Reactant: CNC
Product: CC(=O)N1CCC(CC(=O)c2ccc(N(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 1.84 g of 1-acetyl-4-(4-fluorobenzoylmethyl)piperidine and 6 ml of a 50% aqueous solution of dimethylamine was stirred at room temperature for 3 days and the reaction mixture was worked up as in Example 1 to give 1.8 g of colorless crystals melting at 136° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]2[NH:12][CH:11]=[N:10][N:9]=2)=[C:4]([NH2:7])[S:5][CH:6]=1.Cl.[F:14][C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:25][C:26](O)=[O:27].[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[C:4]([NH:7][C:26](=[O:27])[CH2:25][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[N:17]=[CH:16][C:15]([F:14])=[CH:24]3)[S:5][CH:6]=1
Reactant: O=C(O)Cc1cccc2cc(F)cnc12
Reactant: Nc1scc(Br)c1-c1nnc[nH]1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1cccc2cc(F)cnc12)Nc1scc(Br)c1-c1nc[nH]n1
Reaction time: 1 h

Procedure:
4-Bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine (17 mg, 69.4 umol), 2-(3-fluoroquinolin-8-yl)acetic acid hydrogen chloride (22 mg, 91.0 umol), 2-chloro-1-methylpyridinium iodide (101 mg, 395 umol) and triethylamine (0.2 ml) in methylene chloride (1 ml) was heated to reflux. After stirring for 1 h, the solution was concentrated and the residue was purified by HPLC to yield N-(4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(3-fluoroquinolin-8-yl)acetamide. Method [7] retention time 5.67 min by HPLC (M+432 and 434) and (M+Na 454 and 456). 1H NMR (300 MHz, CDCl3) δ 12.25 (s, 1H), 8.83 (d, J=3.3 Hz, 1H), 7.87 (m, 2H), 7.80 (d, J=6.0 Hz, 1H), 7.73 (s, 1H), 7.66 (t, J=7.8 Hz, 1H), 6.90 (s, 1H), 6.70 (broad s, 2H), 4.56 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.[F:14][C:15]([F:21])([F:20])[C:16](=[O:19])[CH2:17][CH3:18]>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]([OH:19])([CH2:17][CH3:18])[C:15]([F:21])([F:20])[F:14])=[CH:3][CH:4]=1
Reactant: CCC(=O)C(F)(F)F
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(O)(c1ccc(Br)cc1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1,4-dibromobenzene (2.5 g, 10.6 mmol) in THF (50 mL) at −78° C. was added n-BuLi (6.5 mL, 10 mmol; 1.6 M in hexanes) and the mixture was stirred at −78° C. for 15 min. 1,1,1-Trifluoro-2-butanone (1.3 g, 10 mmol) was then added. After further stirring for 15 min., the mixture was quenched with aqueous NH4Cl and extracted with Ethyl acetate. Purification by combi-flash chromatography (40 g column; eluted with hexanes—Ethyl acetate (10% -20%) in 20 min.; flow rate: 35 mL/min and collected 18 mL/fraction) to yield the title compound as a colorless liquid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][N:12]1[C:16](=[O:17])[CH:15]=[C:14]([Br:18])[NH:13]1.[F:19][C:20]([F:35])([C:31]([F:34])([F:33])[F:32])[C:21]([F:30])([F:29])[C:22]([F:28])([F:27])[S:23](F)(=[O:25])=[O:24]>O1CCCC1.O>[CH3:11][N:12]1[C:16]([O:17][S:23]([C:22]([F:27])([F:28])[C:21]([F:29])([F:30])[C:20]([F:19])([F:35])[C:31]([F:34])([F:33])[F:32])(=[O:25])=[O:24])=[CH:15][C:14]([Br:18])=[N:13]1
Reactant: Cn1[nH]c(Br)cc1=O
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(Br)cc1OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.6 %

Procedure:
A solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (1M, 0.70 mL, 0.70 mmol) was added at −78° C. under nitrogen to a stirred solution of 1-methyl-3-bromo-5-pyrazolone from Step 1 (0.10 g, 0.565 mmol) in dry tetrahydrofuran (2 mL). After 10 min, nonafluorobutanesulfonyl fluoride (0.13 mL, 0.70 mmol) was added dropwise. The resulting gel was warmed to room temperature and stirred for 1 hour. The solution was diluted with water (10 mL) and extracted with ethyl acetate (2×10 mL). The extracts were dried (Na2SO4) and concentrated. Flash column chromatography on silica, eluting with 10% ethyl acetate-isohexane, gave 1-methyl-3-bromo-5-(nonafluorobutanesulfonyloxy)pyrazole (0.204 g, 79%) as a colourless oil.
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1.[NH:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1>[Br:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]([N:18]2[CH2:22][CH2:21][CH2:20][C@H:19]2[CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:17])=[CH:15][CH:14]=1
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(Br)cc1
Reactant: C1CN[C@H](CN2CCCC2)C1
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cc1)N1CCC[C@H]1CN1CCCC1
Temperature: 25 °C
Yield: 71 %

Procedure:
To a stirring solution of 4-bromobenzoic acid-2,5-dioxo-pyrrolidin-1-yl ester (3.5 g, 11.7 mmol) [CAS: 80586-82-9] in tetrahydrofuran (0.15M), is added (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (1.9 mL, 11.7 mmol) and the mixture heated to reflux for 4 h. The reaction is allowed to cool to room temperature and washed with water while extracting with 10% isopropanol/dichloromethane. The organic portion is dried with sodium sulfate, filtered; and concentrated in vacuo. The resulting residue is purified on a silica gel column, eluting with 2M ammonia in methanol and dichloromethane to obtain 2.80 g (71%) of the title compound. MS (ES+) m/e 337.1 (M+1)+.