Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:5]([OH:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:14]([B:16](O)O)[CH:15]=1>C(OCC)C>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:14]([B:16]2[O:8][C:5]([CH3:7])([CH3:6])[C:2]([CH3:4])([CH3:3])[O:1]2)[CH:15]=1
Reactant: CC(C)(O)C(C)(C)O
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccccc1
Solvent: CCOCC
Product: CC1(C)OB(c2cc(Cl)ccc2OCc2ccccc2)OC1(C)C
Reaction time: 24 h

Procedure:
Pinacol (3.24 g) was added to a solution of [5-chloro-2-(phenylmethoxy)phenyl]-boronic acid (6 g) in diethyl ether, and stirred for 24 h. 4A molecular sieves and pinacol (1.5 g) were added, stirred for a further 24 h. The sieves were filtered and the filtrate was washed with water and brine, then dried (MgSO4) and concentrated in vacuo. Yield 6.8 g.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH:21]=[CH:20][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:8][CH:7]=1.C(N(CC)CC)C.[Cl:38][C:39]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:40]=1[S:46](Cl)(=[O:48])=[O:47].[N-]=C=O>C(Cl)Cl>[Cl:38][C:39]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:40]=1[S:46]([N:5]([CH2:4][C:3]1[CH:20]=[CH:21][C:22]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[CH:23][C:2]=1[Cl:1])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:8][CH:7]=1)(=[O:48])=[O:47]
Reactant: Clc1cc(OC2CCCCO2)ccc1CNc1ccc(OCCN2CCCC2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)cc1Cl)N(Cc1ccc(OC2CCCCO2)cc1Cl)c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 100 %

Procedure:
To a solution of [2-chloro-4-(tetrahydro-pyran-2-yloxy)-benzyl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (0.060 g, 0.15 mmol) in 0.4 mL methylene chloride was added triethylamine (0.06 mL, 0.45 mmol) and 2,4-dichlorobenzenesulfonyl chloride (0.074 g, 0.3 mmol). The reaction mixture was stirred at room temperature for 6 days. PS-isocyanate resin (0.050 g) and PStrisamine resin (0.050 g) were added and the reaction mixture was stirred for 2 hr. at room temperature. The resin was filtered off with the aid of methylene chloride. The filtrate was concentrated to afford the title compound of Step A (0.096 g). MS 639.3 (M+1)+
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@H:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:22][C:23]1[CH:31]=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=1>CN(C=O)C.C(OCC)(=O)C.N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>[NH2:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:22][C:23]3[CH:31]=[CH:30][C:26]4[O:27][CH2:28][O:29][C:25]=4[CH:24]=3)[CH2:8]2)=[CH:4][CH:3]=1
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: Nc1ccc(O[C@H]2CCCNC2)cc1
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc(O[C@H]2CCCN(Cc3ccc4c(c3)OCO4)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To an ice water-cooled solution of (3S)-3-(4-aminophenoxy)piperidine (3.5 g) in DMF (20 mL) was added K2CO3 (7.5 g) and Nal (0.2 g), followed by the addition of 5-chloromethyl-1,3-benzodioxole (4.7 mL). The resulting reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water (100 mL×3) and brine (100 mL), and dried (Na2SO4). The crude product was further purified by column chromatography (methanol:ethyl acetate 1:10), to afford (3S)-3-(4-aminophenoxy)-1-[(1,3-benzodioxol-5-yl)methyl]piperidine (4.4 g, 74% yield) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH:7]([CH3:15])[C:8](=O)[CH:9]=[CH:10][N:11](C)C)=[CH:4][CH:3]=1.N[N:19]1[CH:23]=[N:22][N:21]=[CH:20]1.O>C(O)(=O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH:7]([C:8]2[C:23]3[N:19]([CH:20]=[N:21][N:22]=3)[N:11]=[CH:10][CH:9]=2)[CH3:15])=[CH:4][CH:3]=1
Reactant: Nn1cnnc1
Reactant: CC(Oc1ccc(Cl)cc1)C(=O)C=CN(C)C
Solvent: CC(=O)O
Solvent: O
Product: CC(Oc1ccc(Cl)cc1)c1ccnn2cnnc12
Yield: 9.7 %

Procedure:
A solution of 4-(4-chlorophenoxy)-1-(dimethylamino)-1-penten-3-one (14.5 g) in glacial acetic acid (100 ml) was added dropwise to a solution of 4-amino-1,2,4-triazole (5.0 g) in glacial acetic acid (100 ml). The solution was boiled under reflux for 4 hours and then poured into water (400 ml). The mixture was extracted with toluene. The combined organic extracts were washed with 10% sodium bicarbonate solution, then with water, dried over anhydrous magnesium sulphate, filtered, and evaporated under reduced pressure. Flash column chromatography of the residue on silica gel, using ethyl acetate/petroleum ether 1:1 as the mobile phase, afforded 1.52 g of 8-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[4,3-b]pyridazine. A pure sample was obtained by recrystallisation from a mixture of ethyl acetate and hexane, m.p. 98-99° C.
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(C[Br:25])=CC=2C)=O)C(=O)C=1)C1C=CC=CC=1.O[CH:29]([C:31]1[CH:36]=[CH:35][C:34]([C:37](=[O:56])[CH2:38][N:39]2[C:44](=[O:45])[CH:43]=[C:42]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][N:49]=3)[CH:41]=[N:40]2)=[C:33]([CH3:57])[CH:32]=1)[CH3:30].C(OC1C=CN(CC(C2C=CC(CO)=CC=2C)=O)C(=O)C=1)C1C=CC=CC=1>>[Br:25][CH:29]([C:31]1[CH:36]=[CH:35][C:34]([C:37](=[O:56])[CH2:38][N:39]2[C:44](=[O:45])[CH:43]=[C:42]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][N:49]=3)[CH:41]=[N:40]2)=[C:33]([CH3:57])[CH:32]=1)[CH3:30]
Reactant: COc1ccc(COc2cnn(CC(=O)c3ccc(C(C)O)cc3C)c(=O)c2)nc1
Reactant: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Agent: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Product: COc1ccc(COc2cnn(CC(=O)c3ccc(C(C)Br)cc3C)c(=O)c2)nc1
Yield: 93 %

Procedure:
2-{2-[4-(1-Bromo-ethyl)-2-methyl-phenyl]-2-oxo-ethyl}-5-(5-methoxy-pyridin-2-ylmethoxy)-2H-pyridazin-3-one is prepared following preparation 1d employing 2-{2-[4-(1-Hydroxy-ethyl)-2-methyl-phenyl]-2-oxo-ethyl}-5-(5-methoxy-pyridin-2-ylmethoxy)-2H-pyridazin-3-one instead of preparation 1c.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[F:5][C:6]([F:19])([F:18])[C:7]1[CH:16]=[C:15]2[C:10]([C:11](=O)[CH2:12][CH2:13][NH:14]2)=[CH:9][CH:8]=1>N1C=CC=CC=1>[CH3:3][O:2][N:4]=[C:11]1[C:10]2[C:15](=[CH:16][C:7]([C:6]([F:19])([F:5])[F:18])=[CH:8][CH:9]=2)[NH:14][CH2:13][CH2:12]1
Reactant: O=C1CCNc2cc(C(F)(F)F)ccc21
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1CCNc2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methoxylamine hydrochloride (4.14 g, 49.5 mmol) was added to a solution of Example 16C (9.69 g, 45.0 mmol) in pyridine (40 mL), and mixture was stirred overnight at ambient temperature. Only one regioisomer, 7-(trifluoromethyl)-2,3-dihydroquinolin-4(1H)-one was converted to the oxime. The mixture was concentrated under reduced pressure and ethyl acetate (300 mL) was added. The organic layer was washed twice with water (300 mL) and brine, dried over sodium sulfate, and concentrate under reduced pressure. The residue was chromatographed on silica gel eluting with 20-70% ethyl acetate in hexane to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.70 (t, J=6.61 Hz, 2H), 3.19 (td, J=6.53, 1.86 Hz, 2H), 3.90 (s, 3H), 6.57 (s, 1H), 6.82 (dd, J=8.14, 1.70 Hz, 1H), 6.97 (s, 1H), 7.79 (d, J=8.14 Hz, 1H). MS (DCI) m/z 245.05 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.S(=O)(=O)(O)O.[CH3:14]O>>[S:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:14])=[O:7])=[CH:2]1
Reactant: O=C(O)c1ccsc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccsc1

Procedure:
3-thiophenecarboxylic acid (2.0 g) was dissolved in MeOH (27 mL) and concentrated sulphuric acid (1.5 mL) was added. The reaction mixture was refluxed for 3 hours and 30 min., then concentrated under reduced pressure. A saturated NaHCO3 solution was added and the mixture was extracted with ethyl acetate. The organic phase was dried over Na2SO4 and concentrated in vacuo to give 1.98 g of the title compound as a colourless liquid which was used without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[O:68][C:67]([C:69]([O:71][CH3:72])=[O:70])=[CH:66][CH:65]=1>>[CH3:72][O:71][C:69]([C:67]1[O:68][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:36])([CH3:37])[CH3:35])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][CH:66]=1)=[O:70]
Reactant: COC(=O)c1ccc(N)o1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)o1
Yield: 1.6 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.3 g, 0.52 mmol), was reacted with diisopropylethylamine (0.34 g, 2.6 mmol), diphenylphosphinic chloride (0.25 g, 1 mmol), then reacted with methyl 5-aminofuran-2-carboxylate (Lancaster) (0.11 g, 0.78 mmol) to give rac-5-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-furan-2-carboxylic acid methyl ester as a yellow solid (Yield 5 mg, 2%).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]([CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)([OH:20])[CH3:19])[N:14]3[CH3:17])=[C:10]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[CH:36][C:5]=2[N:4]=1)[CH3:2].CCN(CC)CC.[CH:44]1([C:47](Cl)=[O:48])[CH2:46][CH2:45]1>C(Cl)Cl>[CH:44]1([C:47]([N:24]2[CH2:25][CH2:26][CH:21]([C:18]([C:13]3[N:14]([CH3:17])[C:15]4[C:11]([N:12]=3)=[C:10]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:9]=[C:8]([N:7]3[C:6]5[CH:33]=[CH:34][CH:35]=[CH:36][C:5]=5[N:4]=[C:3]3[CH2:1][CH3:2])[N:16]=4)([OH:20])[CH3:19])[CH2:22][CH2:23]2)=[O:48])[CH2:46][CH2:45]1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(C)(O)C3CCNCC3)n(C)c2n1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(C)(O)C3CCN(C(=O)C4CC4)CC3)n(C)c2n1
Reaction time: 0.25 h
Yield: 44 %

Procedure:
A solution of 1-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-1-piperidin-4-ylethanol and NEt3 (74 μL, 0.53 mmol) in DCM (5 mL) was cooled to −78° before the addition of cyclopropane carbonyl chloride (18 μL, 0.20 mmol). The resulting mixture was stirred for 15 min then quenched with H2O and extracted with DCM. The combined organics were dried (phase separator) and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% NH4OH in water on a gradient acetonitrile 10-70%) affording 865 as a white solid (44 mg, 44%). LCMS (method I): RT 3.51 min, [M+H]+ 559.4. 1H NMR (CDCl3, 400 MHz): δ 8.01-8.00 (1 H, m), 7.80 (1 H, d, J=7.13 Hz), 7.33-7.28 (2 H, m), 4.71 (1 H, brd s), 4.32 (4 H, brd s), 3.98 (3 H, s), 3.87 (4 H, t, J=4.69 Hz), 3.40 (2 H, q, J=7.47 Hz), 3.14-2.98 (1 H, m), 2.60-2.43 (1 H, m), 2.20-2.09 (1 H, m), 1.86-1.65 (6 H, m), 1.62-1.36 (3H, m), 1.47 (3 H, t, J=7.47 Hz), 1.00-0.93 (2 H, m), 0.75-0.74 (2 H, m)
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]O)=[CH:17][CH:16]=1.P(Br)(Br)[Br:28]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][Br:28])=[CH:17][CH:16]=1
Reactant: BrP(Br)Br
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCCCCO)cc1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCCCCBr)cc1

Procedure:
According to the method described for Reference Example 25, 5-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-1-pentanol was allowed to react with phosphorus tribromide to give 5-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]pentyl bromide. Recrystallization from ether-hexane gave colorless needles, m.p.58°-59° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([BH3-])#N>C(O)(=O)C.ClC(Cl)C>[CH2:11]([NH:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1sc(N)c(C#N)c1C
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1sc(NCc2ccccc2)c(C#N)c1C
Reaction time: 0.08 h

Procedure:
To a solution of 2-amino-4,5-dimethylthiophene-3-carbonitrile (151 mg, 1.0 mmol) and benzaldehyde (106 mg, 1 mmol) in 15 mL of 4% acetic acid in dichloroethane was added silica supported cyanoborohydride (2.0 g. 2.0 mmol). The reaction was placed in a microwave reactor for 5 minutes at 135° C. Silica supported cyanoborohydride was removed by filtration, and the product was purified by prep HPLC using acetonitrile/water as solvent. MS 243 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:7]2=[CH:8][C:9]3[C:14]([N:6]2[CH2:5][CH2:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=[CH:11][CH:10]=3.[C:20]([O:24][CH3:25])(=[O:23])[CH:21]=[CH2:22].CN(C)C(N(C)C)=N.Cl>C(#N)C.O>[CH2:18]([O:17][C:15]([C:3]1([CH2:22][CH2:21][C:20]([O:24][CH3:25])=[O:23])[CH2:4][CH2:5][N:6]2[C:14]3[C:9]([CH:8]=[C:7]2[C:2]1=[O:1])=[CH:10][CH:11]=[CH:12][CH:13]=3)=[O:16])[CH3:19]
Reactant: C=CC(=O)OC
Reactant: CCOC(=O)C1=C(O)c2cc3ccccc3n2CC1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C1(CCC(=O)OC)CCn2c(cc3ccccc32)C1=O
Reaction time: 8 h
Yield: 94.9 %

Procedure:
A mixture of 5 g of ethyl 6,7-dihydro-9-hydroxypyrido[1,2-a]indole-8-carboxylate. 1.85 g of methyl acrylate and 250 mg of 1,1,3,3-tetramethylguanidine was dissolved in 250 ml of acetonitrile and the solution was stirred overnight, poured into 500 ml of water containing 20 ml of 2M hydrochloric acid and extracted with diethyl ether. The ethereal extracts were washed with water, dried and concentrated. There were obtained 6.33 g of methyl 8-(ethoxycarbonyl)-6,7,8,9-tetrahydro-9-oxopyrido[1,2-a]indole-8-propionate.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[C:9]([NH2:11])[CH:10]=1.Cl.[N:27]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]2[C:8]([C:12]([S:13]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])=[N:27][NH:11]2)=[CH:7][CH:6]=1
Reactant: O=N[O-]
Reactant: Nc1cc(OCCCl)ccc1CS(=O)(=O)c1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2cc(OCCCl)ccc12
Temperature: 3 °C

Procedure:
A mixture of 5-(2-chloro-ethoxy)-2-(naphthalene-1-sulfonylmethyl)-phenyl amine (0.74 g, 1.99 mmoles) in THF (5 mL), and 4M HCl (10 mL) was stirred in a round bottom flask, under nitrogen, at 3° C. A solution of sodium nitrite (0.14 g, 2.08 mmoles) in H2O (1 mL) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.74 g, 1.93 mmoles).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[CH2:35][C:36]([OH:38])=O.CCN(C(C)C)C(C)C.[CH3:48][C:49]1[S:50][C:51]([CH:60]([NH2:68])[CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[C:52]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[N:53]=1>CN(C=O)C>[OH:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[CH2:35][C:36]([NH:68][CH:60]([C:51]1[S:50][C:49]([CH3:48])=[N:53][C:52]=1[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:61][C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1)=[O:38]
Reactant: Cc1nc(-c2ccccc2)c(C(N)Cc2ccccc2)s1
Reactant: O=C(O)Cc1c[nH]c2ccc(O)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2ccccc2)c(C(Cc2ccccc2)NC(=O)Cc2c[nH]c3ccc(O)cc23)s1
Reaction time: 0.17 h

Procedure:
HATU (40 mg, 0.105 mmol) was added to a solution of 2-(5-hydroxy-1H-indol-3-yl)acetic acid (19.2 mg, 0.1 mmol) and DIPEA (0.02 mL, 0.12 mmol) in DMF (0.3 mL). After 10 minutes, 15B (29.4 mg, 0.1 mmol) in 0.2 mL of DMF was added to the reaction. The reaction was stirred for 2 hours. LC/MS shows desired product with a small amount of acid. Purified reaction mixture on prep reverse phase HPLC using 20-80% B over 20 min. (A=0.1% TFA/H2O; B=0.1% TFA/Acetonitrile). Combined pure fractions as determined by LC/MS and lyophilized to provide the desired product. 1H NMR (400 MHz, DMSO) δ 10.46 (s, 1H), 8.59 (d, J=7.6 Hz, 1H), 7.44-7.22 (m, 5H), 7.07 (dd, J=5.5, 3.2 Hz, 4H), 6.92 (dd, J=6.5, 2.9 Hz, 3H), 6.80 (d, J=2.2 Hz, 1H), 6.55 (dd, J=8.6, 2.3 Hz, 1H), 5.34 (dd, J=15.0, 7.5 Hz, 1H), 3.36 (s, 2H), 3.07 (dd, J=13.8, 7.9 Hz, 1H), 2.84 (dd, J=13.5, 7.0 Hz, 1H), 2.60 (s, 3H); MS (m/z) 468 [M+H]+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([N:32]1[CH2:37][CH2:36][CH:35]([NH:38][CH3:39])[CH2:34][CH2:33]1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(N(CC)CC)C.[C:47](O)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C(Cl)Cl>[CH3:39][N:38]([C:47]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:54])[CH:35]1[CH2:36][CH2:37][N:32]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:33][CH2:34]1
Reactant: O=C(O)c1ccccc1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)c1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a round bottomed flask benzoic acid (0.627 g, 5.13 mmol, commercially available from e.g. Sigma-Aldrich) and HATU (2.129 g, 5.60 mmol) were dissolved in DCM (10 mL). The reaction mixture was stirred at room temperature for 30 minutes before 1-boc-4-methylaminopiperidine (1 g, 4.67 mmol, commercially available from e.g. Apollo, Fluorochem or Astatech) was added followed by triethylamine (1.626 mL, 11.67 mmol). The reaction was stirred at room temperature overnight. Solvent was removed in vacuo and the crude dissolved in DCM then organic phase was extracted with a saturated NaHCO3 solution (twice), a 10% citric acid solution (twice) then washed with brine and dried over MgSO4. Solvent was removed in vacuo and the crude purified on a silica column (40+M) eluting with DCM/MeOH; 90/10. Fractions containing desired compound were joined and solvents were removed in vacuo, to give title compound D14 as a pale yellow oil in 1.66 g. LCMS [M+H]+319.13 [M+H-tBu]+263.03@1.01 min (2 min run)
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH2:16])=O.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:16]
Reactant: COc1ccc2ncc(C(N)=O)c(Cl)c2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2ncc(C#N)c(Cl)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To a solution of 4-chloro-6-(methyloxy)-1,5-naphthyridine-3-carboxamide (647 mg, 2.7 mmol) in anhydrous DCM (2 mL) with triethyamine (2 mL) at 0° C. was added trifluororacetic anhydride (1 mL) slowly. The resulting solution was warmed up to 25° C. and stirred for 1 h. The mixture was partitioned between CHCl and H2O. The aqueous layer was extracted several times with CHCl. The organic fractions were combined, concentrated and purified with column chromatography (silica, 0-25% ethyl acetate/hexane) affording the title compound as an off-white solid (540 mg, 91%): LC/MS (ES) m/e 220 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:7]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19].[NH:28]1[CH:32]=[CH:31][CH:30]=[N:29]1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]2[N:7]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:19])=[O:20])[CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:28]3[CH:32]=[CH:31][CH:30]=[N:29]3)[CH2:10][CH2:9]2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCCCl)CCC2c2ccc(F)cc2)cc1
Reactant: c1cn[nH]c1
Product: Cc1ccc(S(=O)(=O)N2C(CCCCn3cccn3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=442.4 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(4-chloro-butyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 1H-pyrazole.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([O:26][CH3:27])[N:20]=2)=[CH:12][C@@H:13]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([O:26][CH3:27])[N:20]=2)[CH2:12][C@@H:13]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14]2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1nc(C(=C[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)ccc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1nc(C(C[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 7 h

Procedure:
5% palladium-activated carbon (30 mg) was added to a solution of (5R)-5-[2-(4-tert-butylphenyl)-2-(5-chloro-6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one (E:Z=2:8) (150 mg) in methanol in a hydrogen gas stream, and the mixture was stirred at room temperature for seven hours. The reaction solution was filtered through celite, and the solvent was evaporated under reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (chloroform) and further purified by preparative TLC (chloroform) to give (5R)-5-[2-(4-tert-butylphenyl)-2-(5-chloro-6-methoxypyridin-2-yl)ethyl]pyrrolidin-2-one as a pale brown amorphous (110 mg, 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH2:13][CH2:14][C:15]([OH:17])=[O:16].[Li]CCCC.[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1.Cl>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[C:6]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[C:7]2[CH3:12])=[CH:26][CH:25]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: COc1ccc2[nH]c(C)c(CCC(=O)O)c2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1ccc2c(c1)c(CCC(=O)O)c(C)n2Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 32.5 %

Procedure:
To a cold (-78° C.) solution of the indole from Step 1 (877 mg, 4.04 mmol) in 40 mL of THF and 2.5 mL of HMPA was added n-BuLi (1.45M solution in hexanes, 5.6 mL, 8.12 mmol), giving a thick slurry. The mixture was warmed to 0° C., then cooled to -78° C. A solution of p-bromobenzyl bromide (1.18 g, 4.72 mmol) in 8 mL of THF was then added, and the mixture was warmed to room temperature. After 30 min, the reaction was poured into 1M HCl and extracted with ether. The organic layer was washed thrice with water, then with brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash chromatography (30% ethyl acetate/hexanes) to give 529 mg of the title compound as a crystaline solid.