Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCCCC1.[CH2:7]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][C:15]=1[O:22][CH3:23])[CH2:8][CH2:9][CH2:10][C:11]#[CH:12].C([CH2:27][C:28]([NH:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([OH:35])=[O:34])=[O:29])(O)=O.Cl>C1(C)C=CC=CC=1>[CH2:7]([O:13][C:14]1[CH:21]=[CH:20][C:17](/[CH:18]=[CH:27]/[C:28]([NH:30][C:31]2[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=2[C:33]([OH:35])=[O:34])=[O:29])=[CH:16][C:15]=1[O:22][CH3:23])[CH2:8][CH2:9][CH2:10][C:11]#[CH:12]
Reactant: C#CCCCCOc1ccc(C=O)cc1OC
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: C#CCCCCOc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Yield: 73.4 %

Procedure:
Piperidine (0.30 mL, 3.0 mmol) was added to a suspension of 4-(hex-5-ynyloxy)-3-methoxybenzaldehyde (0.70 g, 3.0 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.61 g, 2.7 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. The crude product was recrystallised from EtOH/water providing (E)-2-[[3-(4-(Hex-5-ynyloxy)-3-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.78 g, 73%) as a yellow crystalline solid; mp 148-150° C.; δH (400 MHz, DMSO-d6) 1.59 (p, J=7.6 Hz, 2H, CH2), 1.81 (p, J=7.6 Hz, 2H, CH2), 2.24 (dt, J=7.6, 2.4 Hz, 2H, CH2CCH), 2.78 (t, J=2.4 Hz, 1H, CCH), 3.83 (s, 3H, OCH3), 4.01 (t, J=7.6 Hz, 2H, OCH2), 6.77 (d, J=15.6 Hz, 1H, CH═CHCO), 6.98 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.22 (d, J5′,6′=8.0 Hz, 1H, H6′), 7.37 (s, 1H, H2′), 7.55 (d, J=15.6 Hz, 1H, CH═CHCO), 7.61 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 11.27 (s, 1H, NH), 13.56 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 17.4, 24.6, 27.8, 55.7, 67.6, 71.4, 84.3, 110.7, 112.6, 116.6, 119.8, 120.3, 122.6, 122.7, 127.2, 131.1, 134.0, 141.1, 141.6, 149.1, 150.0, 164.2, 169.4; HRMS (ESI) calculated for C23H23NO5 [M+H]+ 394.1649. found 394.1649; vmax 755, 1237, 1508, 1609, 1669, 2944, 3424, 3567 cm−1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8]/[C:9]/2=[CH:12]\[C:13]#[N:14])=[CH:5][CH:4]=1.N.C(O)C>C(O)C.[Co]>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8]/[C:9]/2=[CH:12]\[CH2:13][NH2:14])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)/C(=C/C#N)CC2
Agent: [Co]
Agent: N
Solvent: CCO
Product: COc1ccc2c(c1)/C(=C/CN)CC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (E)-(6-methoxyindan-1-ylidene) acetonitrile (5.0 g, 27 mmol.) in ethanol (50 mL) were added a saturated ammonia/ethanol solution (250 mL) and Raney cobalt (10 g). The mixture was stirred for 5 hours at room temperature under hydrogen atmosphere (5 kgf/cm2). The Raney cobalt was filtered off, and the solvent was distilled off under reduced pressure to leave (E)-2-(6-methoxyindan-1-ylidene)ethylamine. This oily residue was dissolved in ethanol (20 mL). The solution was cooled to −40° C., to which was added a saturated hydrogen chloride/ethanol solution. The resulting crystalline precipitate was collected by filtration to obtain the title compound (yield 4.3 g, 71%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[C:4]([N+:12]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl.Cl>CO>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[C:4]([NH2:12])[CH:3]=1
Reactant: Cc1nc2c(Br)cc([N+](=O)[O-])cc2[nH]1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: Cc1nc2c(Br)cc(N)cc2[nH]1
Temperature: 65 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To a solution of 4-bromo-2-methyl-6-nitro-1H-benzo[d]imidazole (35 g, 137 mmol) and Tin(II) chloride dihydrate (185 g, 822 mmol) in methanol (800 mL) was added conc. HCl (10 mL), and the mixture was stirred at 65° C. for 2 h. Then the solvent was removed in vacuo, and the residue was diluted with 1N Na2CO3 solution (600 mL) and extracted with ethyl acetate (500 mL×3). The combined organic layers were washed with brine, dried over sodium sulphate and evaporated to give the crude product (30.2 g, 97%) as a brown solid; LC/MS: MS (ES+) m/e 226 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 2.38 (s, 3H), 4.98 (s, 2H), 6.52 (d, J=1.5 Hz, 1H), 6.66 (d, J=1.5 Hz, 1H), 11.86 (s, br, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[N:2]1.[CH3:14]COCC.Cl>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:2]1
Reactant: CCOCC
Reactant: O=C(O)Cc1noc2ccccc12
Agent: Cl
Solvent: CO
Product: COC(=O)Cc1noc2ccccc12

Procedure:
A solution of 1,2-benzisoxazole-3-acetic acid (prepared according to G. Casini et al, J. Het. Chem. 6, 1969, 279) (18 g), ether saturated with dry HCl (150 ml) and methanol (200 ml) was stirred for 2 h at room temperature. Removal of the volatiles in vacuo gave methyl 1,2-benzisoxazole-3-acetate (17 g) as an oil. The oil was dissolved in tetrahydrofuran (100 ml) and added dropwise to a suspension of lithium aluminium hydride (6 g) in tetrahydrofuran (200 ml) at 0°-10° C. followed by stirring for 30 min at 15° C. Usual work-up gave 2-(1,2-benzisoxazol-3-yl)ethanol (13 g) as an oil.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13](=[O:14])[NH:12][C:10](=[O:11])[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>CC(C)=O>[C:1]1([NH:7][C:8]2[C:13](=[O:14])[N:12]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10](=[O:11])[CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C=C(Nc2ccccc2)C(=O)N1
Reactant: O=C(Cl)c1ccccc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C1C=C(Nc2ccccc2)C(=O)N1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1.88 g. (0.01 mole) of 3-phenylamino-maleinimide are dissolved in 70 ml. of acetone under stirring. To this mixture 2.1 g. (0.015 mole) of benzoyl chloride and 1.51 g. (0.015 mole) of triethylamine are added dropwise under simultaneous stirring. The temperature is maintained at 25°-30° C. during the addition. The mixture is then stirred for 2.5 hours at room temperature and heated for 1.5 hours. The mixture is allowed to stand overnight. The product is precipitating together with triethylaminechlorohydrate. The crystalline mixture is filtered and washed with 2×10 ml. of water. After drying a yellow crystalline product is obtained, which can be recrystallized from chloroform or acetone, if desired. 3-Phenylamino-N-benzoyl-maleinimide is obtained.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].Br[CH2:21][CH2:22][CH2:23][OH:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([N:5]1[C:9](=[O:10])[CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:21][CH2:22][CH2:23][OH:24])[CH:12]=2)[S:6]1(=[O:18])=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCCBr
Reactant: CC(C)(C)N1C(=O)C=C(c2cccc(O)c2)S1(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)N1C(=O)C=C(c2cccc(OCCCO)c2)S1(=O)=O
Yield: 88.4 %

Procedure:
A solution of 4.08-B (0.2 g, 0.7 mmol), 3-bromo-1-propanol (0.1 mL, 1.1 mmol), and potassium carbonate (147 mg, 1.1 mmol) in N,N-dimethylformamide (3 mL) was heated at 80° C. for 1 h. The reaction mixture was diluted with ethyl acetate (75 mL) and washed with 0.5 N HCl (50 mL) and brine (50 mL), dried with Na2SO4, filtered, and concentrated to give a crude residue which was purified using flash column chromatography (100% hexane to 50% ethyl acetate/hexane) to yield 4.08-C as a white solid (0.21 g, 88%). 1H NMR (500 MHz, CDCl3): δ 7.42 (dd, J=7.8, 7.8 Hz, 1H), 7.36–7.34 (m, 1H), 7.30 (dd, J=2.0, 2.0 Hz, 1H), 7.11–7.09 (m, 1H), 6.63 (s, 1H), 4.18–4.12 (m, 2H), 3.90–3.86 (m, 2H), 2.10–2.05 (m, 2H), 1.73 (s, 9H); LCMS found for C16H22NO5S (M+H)+: m/z=340.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][C:10]#[C:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1.N(C([O-])=O)=NC([O-])=O.[K+].[K+].C(O)(=O)C>N1C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1
Reactant: O=[N+]([O-])c1ccc(C#CCOCCCCCCBr)nc1
Agent: O=C([O-])N=NC(=O)[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(CCCOCCCCCCBr)nc1
Temperature: 25 °C
Yield: 5.9 %

Procedure:
A mixture of 2-[3-[(6-bromohexyl)oxy]-1-propynyl]-5-nitropyridine (5 g) and dipotassium azodicarboxylate (30 g) in pyridine (200 ml) was stirred at room temperature, and acetic acid (18 ml) added. The mixture was stirred overnight and evaporated in vacuo to give a residue oil which was partitioned between 8% sodium bicarbonate (20 ml) and ethyl acetate (20 ml). The organic phase was dried and concentrated to give an oil which was purified by FCC eluting with hexane-ether (1:2→methanol) to give the title compound as an orange oil (300 mg), t.l.c. (toluene:ethanol 0.88 ammonia 80:20:1) Rf 0.75.
Reaction SMILES: [ClH:1].Cl.[C:3]1([C:9]2[CH:10]=[C:11]([O:15][CH2:16][C@H:17]3[CH2:21][CH2:20][CH2:19][NH:18]3)[CH:12]=[N:13][CH:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C=O.[CH:24](O)=O.Cl>CCOCC>[ClH:1].[ClH:1].[C:3]1([C:9]2[CH:10]=[C:11]([O:15][CH2:16][C@H:17]3[CH2:21][CH2:20][CH2:19][N:18]3[CH3:24])[CH:12]=[N:13][CH:14]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(-c2cncc(OC[C@H]3CCCN3)c2)cc1
Reactant: O=CO
Agent: C=O
Agent: Cl
Solvent: CCOCC
Product: CN1CCC[C@@H]1COc1cncc(-c2ccccc2)c1

Procedure:
To 5-phenyl-3-(2-(R)-pyrrolidinylmethoxy)pyridine from Example 52 (150 mg, 0.59 mmol) was added formalin (38%, 5.0 mL) and formic acid (88%, 2.5 mL), and the mixture was refluxed for 16 hours. The reaction was quenched by the addition of saturated aqueous NaHCO3. The mixture was extracted with CHCl3, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with CHCl3 /MeOH 10:1.5 to afford the base. The salt was prepared by treatment with HCl in ether, as described above, to give the title compound. mp. 89°-90 ° C. MS (DCI/NH3) m/z 269 (M+H)+. 1H NMR (D2O, 300 MHz) δ: 2.05-2.29 (m, 2H), 2.38-2.47 (m, 1H), 3.07 (s, 3H), 3.23-3.32 (m, 1H), 3.64-3.82 (m, 1H), 3.92-4.00 (m, 1H), 4.44 (dd, J=7.7, 11.0 (1H), 4.61 (dd, J=3.0, 11.2, 1H), 7.51-7.62 (m, 3H), 7.70-7.74 (m, 2H), 7.88 (s, 1H), 8.36 (br s, 1H), 8.56 (br s, 1H). Anal. Calcd for C17H20N2OCl·2 HCl·0.5 H2O: C, 58.29; H, 6.62; N, 8.00. Found: C, 58.16; H, 6.76; N, 8.18. [α]25D =+9.2° (c 0.39, MeOH).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([O:11][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[C:8]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:9]=1
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Yield: 160.4 %

Procedure:
A mixture of 25.0 g (0.15 mol) of 3,5-dihydroxybenzoic acid methyl ester, 44 ml (0.37 mol) of benzyl bromide and 82 g (0.60 mol) of potassium carbonate in 300 ml of DMF was stirred and heated at 85° under argon for 45 hours. The cooled reaction mixture was filtered and the filtrate was concentrated at reduced pressure. The residue was treated with methylene chloride and the extract was filtered again to remove salts. Crystallization from methylene chloride-methanol gave 41.9 g (81% yield, mp 64°-66°) of 3,5-bis(phenylmethoxy)benzoic acid methyl ester.
Reaction SMILES: O.[Cl:2][C:3]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:6]([N+:19]([O-])=O)=[C:5]([F:22])[CH:4]=1>C(O)(=O)C.[Fe]>[Cl:2][C:3]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:6]([NH2:19])=[C:5]([F:22])[CH:4]=1
Reactant: CCCCCOC(=O)COc1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CCCCCOC(=O)COc1cc(N)c(F)cc1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
A mixture of iron powder (115 g), acetic acid (29 g) and water (551 g) was heated at 80° C., and a solution of the compound (III) (132 g) in acetic acid (200 g) was dropwise added thereto in 1 hour, followed by heating under reflux for 5 hours. The reaction mixture was filtered to remove insoluble materials, and the filtrate was extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was distilled off under reduced pressure to give 4-chloro-2-fluoro-5-(pentyloxycarbonylmethyloxy)aniline (Compound (II)) (90 g). Yield, 75 b.p., 145°-149° C./0.4 mmHg. m.p., 32°-3420 C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH:16]([N+:18]([O-])=O)[CH3:17])[CH:12]=[CH:11][C:10]=1[O:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>[Ni].CO>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH:16]([NH2:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[O:21][CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CC(C)[N+](=O)[O-])cc1OCc1ccccc1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: COc1ccc(CC(C)N)cc1OCc1ccccc1
Temperature: 40 °C
Yield: 75.7 %

Procedure:
Raney nickel (50%, slurry in water, 2.0 g) was washed with MeOH (3×). To this was added MeOH (70 ml) and 209 (3.05 g, 10.1 mmol). The mixture was cooled (ice-bath) and hydrazine hydrate (2.53 g, 50.5 mmol) was added dropwise. The mixture was heated to 40° C. for 1 h, then further Raney nickel (50% slurry in water, 1.0 g) was added as a suspension in MeOH (10 ml). The reaction mixture was heated at 40° C. for a further 18 h. The resulting solution was cooled to rt and filtered through celite, washing through with MeOH (200 ml). The filtrate was concentrated in vacuo and purification (flashmaster: 50 g, EtOAc/MeOH) afforded the title compound (2.074 g, 76%) as a pale yellow oil. 1H NMR (270 MHz; CDCl3) 1.04 (3H, d, J=6.4 Hz, CH3), 2.36 (1H, dd, J=13.3, 8.2 Hz, CHH), 2.58 (1H, dd, J=13.3, 5.2 Hz, CHH), 2.98-3.1 (1H, m, CH), 3.86 (3H, s, OCH3), 5.13 (2H, s, CH2), 6.67-6.83 (3H, m, 3×CH), 7.25-7.43 (5H, m, 5×CH, phenyl). LC/MS (ES+) tr=1.82 min, m/z 272.19 (M++H).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:25]1[CH2:30][CH2:29][CH2:28][C@H:27]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26]1.CCN(C(C)C)C(C)C>ClCCCl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:25]3[CH2:30][CH2:29][CH2:28][C@H:27]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@H]1CCCNC1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCOC(=O)[C@H]1CCCN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (300 mg, 0.80 mmol) in DCE (5 mL) was slowly added to a solution of ethyl (3S)-piperidine-3-carboxylate (140 mg, 0.88 mmol) and DIPEA (1.4 mL, 8.0 mmol) in DCE (25 mL). The reaction mixture was stirred overnight at ambient temperature and the solvent was concentrated. The product was purified by MPLC on silica gel using 60-90% EtOAc/heptane as eluent to provide the title compound as white solid. Yield: 276 mg (69%). 1H NMR (400 MHz, CDCl3) δ 1.26 (t, J=7.13 Hz, 3 H), 1.33 (td, J=12.21, 3.32 Hz, 1 H), 1.50-1.57 (m, 3 H), 1.59 (s, 9 H), 1.62-1.73 (m, 2 H), 1.73-1.83 (m, 1 H), 1.91-2.01 (m, 1 H), 2.30 (td, J=11.43, 2.93 Hz, 2 H), 2.44 (t, J=11.13 Hz, 1 H), 2.58-2.69 (m, 1 H), 3.28-3.40 (m, 2 H), 3.65-3.74 (m, 1 H), 3.91 (dd, J=11.43, 3.81 Hz, 1 H), 4.01 (dd, J=11.33, 2.93 Hz, 2 H), 4.13 (q, J=7.23 Hz, 2H), 4.25 (d, J=7.42 Hz, 2 H), 7.43 (d, J=8.59 Hz, 1 H), 7.64 (dd, J=8.59, 1.76 Hz, 1 H), 8.19 (d, J=1.76 Hz, 1 H). MS (ESI) (M+H)+=492.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[C:14](F)[CH:13]=[C:12]([F:17])[C:11]=1[N+:18]([O-:20])=[O:19].[CH3:21][O-:22].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[C:14]([O:22][CH3:21])[CH:13]=[C:12]([F:17])[C:11]=1[N+:18]([O-:20])=[O:19]
Reactant: C[O-]
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1Nc1ccc(I)cc1F
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(F)c([N+](=O)[O-])c(Nc2ccc(I)cc2F)c1
Reaction time: 1 h
Yield: 53.3 %

Procedure:
To a solution of 2-fluoro-N-(3,5-difluoro-2-nitrophenyl)-4-iodobenzenamine (Intermediate 14, 1.05 g, 2.7 mmol) in THF (25 mL) was added NaOMe solution (prepared by dissolving Na metal (61 mg, 2.7 mmol) in 6 mL of methanol)-78° C. The reaction mixture was brought to rt and stirred for 1 h at same temperature. The progress of reaction was monitored by TLC. After completion, the reaction mixture was quenched with water and extracted with ether. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography to yield 2-fluoro-N-(3-fluoro-5-methoxy-2-nitrophenyl)-4-iodobenzenamine as yellow solid (584 mg). 1H-NMR (400 MHz, CDCl3): δ 3.91 (3H, s), 6.23 (1H, d, J=10.4), 6.35 (1H, d, J=10.8), 7.04-7.08 (1H, m), 7.45-7.52 (2H, m), 7.83 (1H, s).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][C:19]([CH3:34])([S:30]([CH3:33])(=[O:32])=[O:31])[C:20]([NH:22][O:23]C3CCCCO3)=[O:21])[C:13](=[O:35])[CH:12]=2)=[CH:7][CH:6]=1.Cl>O1CCOCC1.CO>[OH:23][NH:22][C:20](=[O:21])[C:19]([CH3:34])([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:18][CH2:17][N:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][OH:1])=[CH:6][CH:7]=2)=[CH:12][C:13]1=[O:35]
Reactant: CC(CCn1ccc(-c2ccc(CCCO)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(CCn1ccc(-c2ccc(CCCO)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
To 4-{4-[4-(3-hydroxypropyl)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (213 mg, 0.420 mmol) was added 4 N hydrogen chloride in dioxane (5.0 mL) and methanol (0.50 mL). The reaction was stirred for 30 minutes and then evaporated to dryness. The residue was dissolved in minimal dichloromethane (2.0 mL) and diluted with ether to produce a precipitate. The suspension was stirred overnight at room temperature. The resulting solid was allowed to settle and the liquid was decanted off. The solid was rinsed twice with ether and dried on a vacuum pump to give the title compound as a white solid (164 mg, 92.4%). 1H NMR (400 MHz, CD3OD, δ ppm 1.72 (s, 3H), 1.83-1.91 (m, 2H), 2.41 (ddd, J=13.4, 10.9, 5.4 Hz, 1H), 2.66 (ddd, J=13.6, 10.8, 5.4 Hz, 1H), 2.76 (m, 2H), 3.10 (s, 3H), 3.59 (t, J=6.4 Hz, 2H), 4.05 (ddd, J=12.5, 10.5, 5.2 Hz, 1H), 4.38 (ddd, J=12.9, 10.7, 5.0 Hz, 1H), 6.95 (d, J=1.8 Hz, 1H), 7.00 (m, 1H), 7.38 (br d, J=8.3 Hz, 2H), 7.66 (br d, J=8.3 Hz, 2H), 7.87 (d, J=7.1 Hz, 1H). LCMS: 423.3 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[C:19]([S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[CH:21][C:22]=3[OH:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][C:4]=1[F:28])#[N:2].[CH3:29][CH:30]([CH3:33])[CH2:31]O.C1(P(C2C=CC=CC=2)C2C=CC=CN=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:18]=[C:19]([S:24]([NH2:27])(=[O:25])=[O:26])[CH:20]=[CH:21][C:22]=3[O:23][CH2:29][CH:30]([CH3:33])[CH3:31])=[O:16])[CH2:13][CH2:14]2)=[CH:5][C:4]=1[F:28])#[N:2]
Reactant: CC(C)CO
Reactant: N#Cc1ccc(N2CCN(C(=O)c3cc(S(N)(=O)=O)ccc3O)CC2)cc1F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccn2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)COc1ccc(S(N)(=O)=O)cc1C(=O)N1CCN(c2ccc(C#N)c(F)c2)CC1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To 0.1 mmol (3-[4-(4-cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-4-hydroxy-benzenesulfonamide (compound 6.38), 0.5 mmol 2-methyl-1-propanol and 0.3 mmol diphenyl-2-pyridylphosphine in 4 ml THF was added 0.3 mmol di-tert-butyl azodicarboxylate, and the mixture was stirred at 60° C. for 4 h. The mixture was then diluted with ethyl acetate and washed twice with 5 M aq HCl and then with saturated aq NaCl solution. The organic phase was then dried with Na2SO4, and concentrated in vacuo. The residue was triturated in ether to afford the title compound. MS (m/e): 459.2 ([M−H]−, 100%)
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][CH2:5][N:6]([CH3:13])[CH2:7][CH2:8][C:9]([CH3:12])([NH2:11])[CH3:10].C1COCC1.C(=O)([O-])O.[Na+].[C:25](ON1C(=O)CCC1=O)([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>O>[CH3:14][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]([CH3:13])[CH2:7][CH2:8][C:9]([NH:11][C:25](=[O:26])[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:10])[CH3:12]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CN(C)CCCN(C)CCC(C)(C)N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCCN(C)CCC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
Crude N1-(3-(Dimethylamino)propyl)-N1,3-dimethylbutane-1,3-diamine (18.0 g, 31.9 mmol) was dissolved into THF (200 mL). Sodium hydrogen carbonate (14.0 g, 0.167 mol) dissolved in water (200 mL) was added to reaction to give a solution. CbzOSu (7.95 g, 1 equiv, 31.9 mmol) was added in one portion to the reaction and left to stir at room temperature for 16 h. The organic solvent was removed via rotovap and the aqueous concentrated to ˜100 mL. The aqueous was extracted with DCM (2×200 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a pale yellow oil. The crude oil was purified on a Shimadzu Prep-LC utilizing water/acetonitrile and 0.05% acetic acid as modifier. Fractions were collected monitoring UV absorbance at 215 nm. The desired fractions were collected and lyophilized to give a colorless oil (5.57 g, yield: 52.1%). LRMS (ESI+) for C19H33N3O2 (335.3); Found: 336 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12](=[C:17]1[CH2:20][O:19][CH2:18]1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])C1C=CC=CC=1.C(OC(OC)=O)(OC)=O.[H][H]>C(OCC)(=O)C.C(Cl)Cl.[Pd]>[CH3:1][O:8][C:9]([NH:11][CH:12]([CH:17]1[CH2:20][O:19][CH2:18]1)[C:13]([O:15][CH3:16])=[O:14])=[O:10]
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)=C1COC1
Reactant: [H][H]
Agent: [Pd]
Agent: COC(=O)OC(=O)OC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)NC(C(=O)OC)C1COC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114 %

Procedure:
A solution of methyl 2-(benzyloxycarbonylamino)-2-(oxetan-3-ylidene)acetate (intermediate LS28; Source: Moldes et al, Il Farmaco, 2001, 56, 609 and Wuitschik et al, Ang. Chem. Int. Ed. Engl, 2006, 45, 7736; 200 mg, 0.721 mmol) in ethyl acetate (7 mL) and CH2Cl2 (4.00 mL) was degassed by bubbling nitrogen for 10 min. Dimethyl dicarbonate (0.116 mL, 1.082 mmol) and Pd/C (20 mg, 0.019 mmol) were then added, the reaction mixture was fitted with a hydrogen balloon and allowed to stir at ambient temperature overnight. The reaction mixture was filtered through diatomaceous earth (Celite®) and concentrated. The residue was purified via Biotage (load with dichloromethane on 25 samplet; elute on 25S column with dichloromethane for 3CV then 0 to 5% methanol/dichloromethane over 250 mL then hold at 5% methanol/dichloromethane for 250 mL; 9 mL fractions). Fractions containing the desired product were concentrated to provide 167 mg methyl 2-(methoxycarbonylamino)-2-(oxetan-3-yl)acetate as a colorless oil which solidified on standing. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 3.29-3.40 (m, 1H) 3.70 (s, 3H) 3.74 (s, 3H) 4.55 (t, J=6.41 Hz, 1H) 4.58-4.68 (m, 2H) 4.67-4.78 (m, 2H) 5.31 (br s, 1H). MS: Anal. Calcd. for [M+H]+ C8H13NO5: 204.1. found 204.0. To methyl 2-(methoxycarbonylamino)-2-(oxetan-3-yl)acetate (50 mg, 0.246 mmol) in THF (2 mL) and Water (0.5 mL) was added lithium hydroxide monohydrate (10.33 mg, 0.246 mmol). The resultant solution was allowed to stir overnight at ambient temperature then concentrated to dryness to provide intermediate LS29 as a colorless powder. 1H NMR (500 MHz, CH3OD) δ ppm 3.38-3.50 (m, 1H) 3.67 (s, 3H) 4.28 (d, J=7.63 Hz, 1H) 4.57-4.79 (m, 4H).