Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19]Cl)[C:10]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:22]([O:29]CC)([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25]>>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])[C:10]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(CCl)nc2ccccc2c1OCc1ccccc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1nc2ccccc2c(OCc2ccccc2)c1C)OCC
Temperature: 150 °C
Reaction time: 6 h
Yield: 83.5 %

Procedure:
A mixture of 4-(benzyloxy)-2-(chloromethyl)-3-methylquinoline (1.00 g) and triethyl phosphite (3.84 g) was stirred at 150° C. for 6 hours. The reaction mixture was allowed to cool to room temperature, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=98/2) to obtain diethyl {[4-(benzyloxy)-3-methylquinolin-2-yl]methyl}phosphonate (1.12 g).
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH2:14])=O)=[CH:8]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>O1CCCC1>[CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:32])[NH2:14])=[CH:8]2
Reactant: CN(c1cccc2cc(C(N)=O)[nH]c12)S(=O)(=O)c1cccs1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 4 h
Yield: 92.8 %

Procedure:
A mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (11.47 g), Lawesson's reagent (15.2 g) and tetrahydrofuran (150 mL) was stirred at 50° C. for 4 hr. The reaction mixture was concentrated, and the resulting crystals were filtrated, washed with toluene, and dried to give the title compound (11.16 g, yield 93%) as yellow crystals. melting point 239-240° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18]C)=[CH:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:6]=2[CH:17]=1.B(Br)(Br)Br>ClC(Cl)C>[Cl:1][C:2]1[C:3]([OH:18])=[CH:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:6]=2[CH:17]=1
Reactant: COc1cc2onc(-c3ccccc3F)c2cc1Cl
Agent: BrB(Br)Br
Solvent: CC(Cl)Cl
Product: Oc1cc2onc(-c3ccccc3F)c2cc1Cl

Procedure:
A solution of 5-chloro-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole (1 g) and boron tribromide (1.3 ml) in dichloroethane (30 ml) is refluxed for about 24 hours. The reaction mixture is poured onto ice-water and extracted with dichloromethane to give a solid of 5-chloro-3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole, mp 180°-182° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([OH:9])[C:3]=1[CH2:10][NH:11][CH3:12].[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][N:31]=2)[C:25]=1[C:36]#[N:37])[C:17](O)=[O:18].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>ClCCl.O>[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][N:31]=2)[C:25]=1[C:36]#[N:37])[C:17]([N:11]([CH2:10][C:3]1[C:4]([OH:9])=[N:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])[CH3:12])=[O:18]
Reactant: N#Cc1c(Oc2ccc(C(=O)O)cc2Cl)cccc1-c1ccncn1
Reactant: CNCc1c(C)cc(C)nc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)c(CN(C)C(=O)c2ccc(Oc3cccc(-c4ccncn4)c3C#N)c(Cl)c2)c(O)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 48.6 %

Procedure:
A mixture of 4,6-Dimethyl-3-((methylamino)methyl)pyridin-2-ol (28 mg, 0.17 mmol), 3-chloro-4-(2-cyano-3-(pyrimidin-4-yl)phenoxy)benzoic acid (50 mg, 0.14 mmol), triethylamine (42 mg, 0.42 mmol) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (65 mg, 0.17 mmol) in dichloromethane (20 mL) was stirred at room temperature for 15 hours. Water (20 mL) was added to the mixture. The organic phase was separated and concentrated in vacuo to give a residue. The residue was further purified by preparative-HPLC to provide 3-chloro-4-(2-cyano-3-(pyrimidin-4-yl)phenoxy)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-N-methylbenzamide (Compound I-17) as a white solid (34 mg, 49%). LRMS (M+H+) m/z: calcd 499.1. found 499. HPLC purity (214 nm): 94%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].[OH-].[Na+].[CH2:13]([OH:18])[CH2:14][CH2:15][CH2:16][CH3:17].C1(C)C=CC=CC=1>O>[CH2:13]([O:18][C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:4]([CH3:9])[C:3]=1[CH3:10])[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCO
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCOc1cc[n+]([O-])c(C)c1C
Temperature: 25 °C
Yield: 125.1 %

Procedure:
17.0 g (0.11 mol, 1.0 eq.) of 4-chlor-2,3-dimethylpyridine-N-oxide, 8.6 g (0.225 mol, 2.0 eq.) of caustic soda, and 19.0 g (0.22 mol, 2.0 eq.) of 1-pentanol were added to 68 mL of toluene, and the mixture as heated to reflux for 5 hours, and then cooled to room temperature. 15 mL of water was added to the reaction liquid, and the mixture was concentrated, to obtain a residue in the form of a black paste. Subsequently, the residue was dissolved in 500 mL of water, and then the aqueous solution was extracted three times with 670 mL of chloroform. The extract was dried over anhydrous magnesium sulfate, and then concentrated to dryness under reduced pressure, to obtain 28.8 g of 4-pentyloxy-2,3-dimethylpyridine-N-oxide.
Reaction SMILES: CN(C)CCN(C)C.C([Li])CCC.[O:14]1[CH2:18][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]1=2.[C:23](=[O:25])=[O:24]>CCCCCC.O>[O:14]1[CH2:18][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:22]([C:23]([OH:25])=[O:24])[C:15]1=2
Reactant: O=C=O
Reactant: c1ccc2c(c1)CCO2
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Product: O=C(O)c1cccc2c1OCC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 28.4 %

Procedure:
N,N,N',N'-Tetramethylethylenediamine (231.4 g) was added at ambient temperature to a solution of n-butyl lithium (2.5M, 800 ml) in hexane (2.5 l) followed by a solution of 2,3-dihydrobenzo[b]furan (102 g) in hexane (25 ml). The mixture was stirred under nitrogen at ambient temperature for 5 hours. The resulting suspension was added slowly to dry ice (300 g) and hexane (500 ml) under nitrogen. After stirring at ambient temperature for 16 hours, the mixture was diluted with water (2 l), and the layers separated. The aqueous layer was washed with hexane, acidified to pH 1 with concentrated hydrochloric acid, cooled and the precipitate collected by filtration. This was washed with water and dichloromethane and dried at 80° C. in vacuo to give 2,3-dihydrobenzo[b]furan-7-carboxylic acid (39.6 g), m.p. 164°-165° C. The hexane layer was filtered, dried over sodium sulphate and concentrated. On cooling, further product was obtained (32.7 g), m.p. 170° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Br-].[CH2:13]([Zn+])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:13]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(Cc2ccccc2)c1
Temperature: 60 °C

Procedure:
Methyl 2-chloroisonicotinate (4.29 g, 25 mmol) and Pd(PPh3)4 (1.156 g, 1.00 mmol) were dissolved in THF (60 mL) to give a yellow solution. Then benzylzinc(II) bromide (0.5 M in THF) (75 mL, 37.50 mmol) was added. The resulting brown mixture was warmed to 60° C. in an oil-bath for 18 h. The reaction mixture was quenched by addition of methanol, then diluted with ethyl acetate and washed with satd NH4Cl and water. The combined organic layers were dried over MgSO4 and evaporated. The residue was purified via Biotage, Thompsson 160 g Silica, eluent isocratic heptanes/ethyl acetate 9:1 over 1 CV, then linear gradient 9:1-75:25 over 6 CV. Product containing fractions were evaporated to give methyl 2-benzylisonicotinate as an orange liquid. 1H NMR (400 MHz, cdcl3) δ 3.91 (s, 3H), 4.22 (s, 2H), 7.19-7.34 (m, 5H), 7.66 (dd, 1H), 7.69 (d, 1H), 8.70 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.C([Li])CCC.[CH2:15]1[O:17][CH2:16]1.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:15][CH2:16][OH:17])=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(Cl)cc1
Reactant: C1CO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OCCC#Cc1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Dissolve 14.2 g (0.104 mole) of 1-chloro-4-ethynylbenzene in 35 ml dry THF and cool to -78° C. Add 49 ml butyl lithium to cold reaction mixture and allow to warm to room temperature for 2 hours. After 2 hours, cool to -78° C. and then add 5.8 ml (0.114 mole) ethylene oxide in 20 ml THF. Allow to warm to room temperature. Monitor progress of reaction with thin-layer chromatography on silica gel (methylene chloride). After 18 hours, add 150 ml saturated aqueous ammonium chloride solution and extract with 150 ml diethyl ether. Wash organic layer with 2×100 ml saturated aqueous sodium chloride solution. Dry organic layer with magnesium sulfate and then filter, and evaporate solvent to obtain the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[N+:24]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31])([O-:26])=[O:25].C([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[N+:24]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH:6]=[CH:7][CH:8]=1)=[O:31])([O-:26])=[O:25]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CN)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cccc(CNC(=O)c2cccc([N+](=O)[O-])c2)c1
Temperature: 25 °C
Yield: 104.7 %

Procedure:
To a stirring solution of tert-butyl [3-(aminomethyl)phenyl]carbamate (2.0 g, 9.0 mmol) and triethylamine (1.3 mL, 9.4 mmol) in dry tetrahydrofuran (25 mL) at 0° C. slowly added a solution of 3-nitrobenzoyl chloride (1.75 g, 9.45 mmol) in tetrahydrofuran (7.3 mL). The resulting mixture was slowly warmed up to rt and stirred for one additional hour at rt. The reaction mixture was treated with Na2CO3 (aq), separated. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated to give the desired product as an off-white powder (3.5 g, 100%). LCMS for C19H21N3O5 (M-tBu+H)+: m/z=316.0. 1H NMR (400 MHz, CD3OD): δ 8.71 (t, J=2.0 Hz, 1H), 8.38 (ddd, J=8.4, 1.6, 1.2 Hz, 1H), 8.23 (ddd, J=8.0, 1.6, 0.8 Hz, 1H), 7.70 (t, J=8.0 Hz, 1H), 7.44 (s, 1H), 7.28 (m, 1H), 7.20 (t, J=7.6, 1H), 7.00 (d J=7.6 Hz, 1H), 4.90 (s, 2H), 1.49 (s, 9H).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH2:7][CH2:8][CH:9]([OH:12])[CH2:10][OH:11]>>[C:4]([NH:7][CH2:8][CH:9]([OH:12])[CH2:10][OH:11])(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: NCC(O)CO
Reactant: C=C1CC(=O)O1
Product: CC(=O)CC(=O)NCC(O)CO

Procedure:
Diketene is reacted at a temperature of about 25 to 35° C. with 1-amino-2,3-propane diol in an aqueous solution to produce 1-acetoacetamido-2,3-propane diol, as illustrated below: ##STR1##
Reaction SMILES: [CH2:1]([N:8]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:9](=[O:29])[CH2:10][C:11]1[CH:28]=[CH:27][C:14]([CH2:15][O:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21]C)=[O:20])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH-].[K+]>CCO>[CH2:1]([N:8]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:9](=[O:29])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][O:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([OH:21])=[O:20])=[CH:27][CH:28]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCN(CCc1ccccc1)C(=O)Cc1ccc(COc2ccccc2C(=O)OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCN(CCc1ccccc1)C(=O)Cc1ccc(COc2ccccc2C(=O)O)cc1
Yield: 11.2 %

Procedure:
Methyl 2-[(4-{2-[heptyl(2-phenylethyl)amino]-2-oxoethyl}benzyl)oxy]benzoate (0.229 g, 0.457 mmol) was dissolved in EtOH (5 ml, 95%) and potassium hydroxide (0.051 g, 0.913 mmol) was added. The reaction was performed in an single node microwave oven (7 min, 150° C.). Work-up was by removing the solvent by evaporation and addition of HCl (2 ml, 1 M). The water-phase was extracted with two portions of EtOAc (20 ml) and the organic phase was dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by flash chromatography (started with isocratic DCM 100% and then the MeOH concentration was increased from 0.5% to 20%, (silica gel 60 0.004-0.063 mm). The product containing fractions were pooled and the EtOAc was removed by evaporation. The product was not pure and was therefore purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). The solvent was removed by evaporation to give 0.025 g of 2-[(4-{2-[heptyl(2-phenylethyl)amino]-2-oxoethyl}benzyl)oxy]benzoic acid (yield 11.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=2)[N:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Br.[F:48][C:49]([F:67])([F:66])[C:50]1[CH:51]=[C:52]([C:56]2[CH:65]=[CH:64][C:59]3[NH:60][C:61]([NH2:63])=[N:62][C:58]=3[CH:57]=2)[CH:53]=[CH:54][CH:55]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[F:67][C:49]([F:48])([F:66])[C:50]1[CH:51]=[C:52]([C:56]2[CH:65]=[CH:64][C:59]3[NH:60][C:61]([NH:63][C:11]([C:9]4[N:10]=[C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][N:6]5[CH:8]=4)=[O:13])=[N:62][C:58]=3[CH:57]=2)[CH:53]=[CH:54][CH:55]=1
Reactant: O=C(O)c1cn2nc(Cl)ccc2n1
Reactant: Nc1nc2cc(-c3cccc(C(F)(F)F)c3)ccc2[nH]1
Agent: Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nc2cc(-c3cccc(C(F)(F)F)c3)ccc2[nH]1)c1cn2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.6 %

Procedure:
A mixture of 6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid (2.5 g), HBTU (4.41 g) and DIEA (4.0 mL) in DMF (20 mL) were stirred at room temperature for 10 minutes. To this reaction mixture was added 5-(3-trifluoromethyl-phenyl)-1H-benzoimidazol-2-ylamine hydrobromide salt (3.61 g), and the mixture was heated at 80° C. for 30 minutes. After cooling the reaction mixture to room temperature, an aqueous sodium bicarbonate solution (200 mL) was added, and the mixture was stirred for 30 minutes. The mixture was then filtered, washed with water, dried, and purified on an 80 g pre-packaged silica gel column with a gradient of 0 to 10% 2M ammonia-methanol in DCM. 4.4 g of 6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide was obtained. LCMS (m/z): 457.8. 1H NMR (400 MHz, DMSO-d6) δ 11.85-12.45 (2H, m) 9.08 (1H, s) 8.36 (1H, d) 7.93-8.04 (2H, m) 7.83 (1H, s) 7.67-7.75 (2H, m) 7.49-7.64 (3H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>[N+](C)([O-])=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[O:9][C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:7][C:6]=2[CH:11]=1
Reactant: Cc1cc(C)c2oc(S)nc2c1
Reactant: C1CNCCN1
Solvent: C[N+](=O)[O-]
Product: Cc1cc(C)c2oc(N3CCNCC3)nc2c1

Procedure:
A 50 mg portion of 5,7-dimethyl-2-mercaptobenzoxazole was dissolved in 5 ml of nitromethane, and the solution was mixed with 240 mg of piperazine and heated under reflux for 12 hours. The solvent was concentrated under a reduced pressure, and the residual oily matter was mixed with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate, and then the solvent was evaporated under a reduced pressure. Thereafter, the thus obtained mixture was purified by a silica gel column chromatography (chloroform:methanol=20:1) to obtain the title compound (35 mg) in white color.
Reaction SMILES: C[CH:2]([CH:6]([S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH3:7])[C:3](O)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([S:8]([CH:6]([CH3:7])[CH2:2][CH2:3][OH:4])(=[O:9])=[O:10])=[CH:16][CH:15]=1
Reactant: COc1ccc(S(=O)(=O)C(C)C(C)C(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(S(=O)(=O)C(C)CCO)cc1
Reaction time: 1.5 h
Yield: 85 %

Procedure:
Part B: To a solution of 3.5 g (13 mmol) of methyl 3-[(4-methoxyphenyl)sulfonyl]-butanoic acid from Part A in 50 mL of anhydrous THF at zero° C. under nitrogen, was added 14.2 mL (0.5 g, 13 mmol) of a 1.0 M solution of lithium aluminum hydride in THF. After 1.5 hours, the reaction mixture was cooled to zero° C. and z0.6 mL of water was added, followed by 0.6 mL of 2.5 N sodium hydroxide solution and 1.8 mL of water, the reaction was filtered, the filtrate concentrated in vacuo, ethyl acetate and 5% citric acid solution were added, the organic layer was separated and washed with saturated sodium bicarbonate solution and brine, dried with magnesium sulfate, filtered and concentrated to afford 2.7 grams of pure 3-[(4-methoxyphenyl)-sulfonyl]butan-1-ol, m/z=251 (M+Li).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[C:12]([NH2:16])(=[O:15])[CH:13]=[CH2:14].C1(C=CC(O)=CC=1)O>S(=O)(=O)(O)O>[OH:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:1][CH2:14][CH2:13][C:12]([NH2:16])=[O:15]
Reactant: C=CC(N)=O
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Agent: O=S(=O)(O)O
Agent: Oc1ccc(O)cc1
Product: NC(=O)CCNc1ccc([N+](=O)[O-])cc1O

Procedure:
15 g (0.1 mol) of 2-amino-5-nitrophenol, 7.8 g (0.11 mol) of acrylamide, 3 drops of 96% sulfuric acid and 20 mg of hydroquinone were maintained at 100° C. for 45 minutes. The mixture dissolved and an insoluble material was then formed, which was filtered off. This precipitate was taken up in 100 ml of refluxing toluene; after filtering while hot, 18 g of powder were obtained after re-slurrying in hot ethyl acetate (m.p.=194° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22]N3C4C=CC=CC=4N=N3)=O)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:43]1([NH2:49])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:17][CH2:16][C:15]([C:20]([NH:49][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)=[O:22])([CH2:18][CH2:19]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCCCC1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)NC3CCCCC3)(CC1)CC2

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and cyclohexylamine (13.0 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(N-cyclohexylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (35.0 mg).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C@H:22]1[C@H:31]([C:32]([O:34][CH3:35])=[O:33])[C:30]2[C:25](=[CH:26][C:27]([O:38][CH3:39])=[C:28]([O:36][CH3:37])[CH:29]=2)[C:24](=[O:40])[N:23]1[CH3:41])=[O:14].C1([Se]Cl)C=CC=CC=1>C1COCC1>[CH3:37][O:36][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:38][CH3:39])[C:24](=[O:40])[N:23]([CH3:41])[C:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][C:13]([O:12][CH3:11])=[O:14])=[C:31]2[C:32]([O:34][CH3:35])=[O:33]
Reactant: COC(=O)Nc1ccccc1[C@H]1[C@H](C(=O)OC)c2cc(OC)c(OC)cc2C(=O)N1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl[Se]c1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Nc1ccccc1-c1c(C(=O)OC)c2cc(OC)c(OC)cc2c(=O)n1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
NaHMDS (1 M solution in THF-heptanes, 1.8 mL, 1.8 mmol) was slowly added to a solution of 11 (320 mg, 0.75 mmol) in dry THF (20 mL) at −78° C. The reaction mixture was stirred at −78° C. for 1 h, and then a solution of phenylselenyl chloride (216 g, 1.13 mmol) in dry THF (5 mL) was added dropwise and the mixture was stirred at −78° C. for 2 h. The reaction mixture was allowed to warm to room temperature and stirred at this temperature for 3 h. The reaction mixture was quenched by slow addition of 1N HCl (5 mL) at 0° C., diluted with water (50 mL) and extracted with chloroform (4×50 mL). The combined extracts were washed with water and brine, dried with sodium sulfate, and evaporated under reduced pressure. The residue was dissolved in THF (10 mL). Acetic acid (1 mL) and hydrogen peroxide (30%, 5 mL) were added sequentially at 0° C. The reaction mixture was warmed to room temperature and stirred for 6 h. Saturated aqueous sodium bicarbonate (5 mL) was added to the mixture at 0° C. Chloroform (3×10 mL) was used to extract the product. The combined extracts were washed with water and brine, dried with sodium sulfate, and evaporated to afford the product (198 mg, 62%): mp 165-170° C. IR (film) 1730, 1718, 1638 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.05 (d, J=6.2 Hz, 1 H), 7.86 (s, 1 H), 7.49 (t, J=7.9 Hz, 1 H), 7.22-7.16 (m, 2 H), 7.16-7.11 (m, 1 H), 6.53 (s, 1 H), 4.04 (s, 3 H), 3.99 (s, 3 H), 3.72 (s, 3 H), 3.45 (s, 3 H), 3.24 (s, 3 H); 13C NMR (126 MHz, CDCl3) δ 167.39, 162.03, 154.22, 154.07, 150.14, 139.65, 136.41, 130.97, 129.29, 128.59, 124.49, 119.35, 112.69, 108.14, 104.80, 56.52, 56.37, 52.75, 52.26, 33.18; ESIMS m/z (rel intensity) 449 (18), 427 (MH+, 100), 395 (78); ESIHRMS m/z MH+ calcd. for C22H22N2O7, 427,1505; found, 427.1507.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:8]=[C:9]([Cl:11])[CH:10]=1.[Li+].[OH-]>O1CCOCC1>[Cl:11][C:9]1[CH:10]=[C:5]([CH2:4][C:3]([OH:26])=[O:2])[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:8]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(Cl)cc(CC(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cc(Cl)cc(CC(=O)O)c1

Procedure:
(5-Chloro-2′-ethylaminomethyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.010 g, 0.03 mmol) in 1,4-dioxane (2 mL) was treated with 1N aqueous LiOH (1 mL) at room temperature for 1 hour. The solution was neutralized to pH 6 and extracted with EtOAc, and the combined organic layers were concentrated and purified by preparative HPLC to give the title compound.