Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([O:13]C)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Cl.N1C=CC=CC=1>O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: COc1ccc(C2=CCCCC2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Oc1ccc(C2=CCCCC2)cc1
Temperature: 180 °C

Procedure:
56.5 Grams of p-(1-cyclohexenyl)-anisol and 125 g of pyridine-hydrochloride are thoroughly mixed and heated for 3 hours in an atmosphere of nitrogen to 180° C. The reaction mixture is cooled to room temperature, treated with water and extracted with 3 × 400 ml of benzene. The benzene extracts are washes with 3 × 300 ml of water, dried over sodium sulphate and evaporated in vacuo. The solid residue yields the crude p-(1-cyclohexenyl)-phenol (m.p. 115-119° C), which can be purified by recrystallisation from benzene and then melts at 120°-122° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([I:11])[CH:3]=1.[CH3:12]C(C)([O-])C.[Na+].CI>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]#[N:10])=[C:4]([I:11])[CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: N#CCc1ccc(Cl)cc1I
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C#N)c1ccc(Cl)cc1I
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
2-(4-Chloro-2-iodophenyl)acetonitrile (1.070 g, 3.9 mmol) was dissolved in THF (50 mL) and cooled to 0° C. Sodium tert-butoxide (0.74 g, 7.7 mmol) was added, and the solution was stirred for 10 minutes (the reaction color changed from colorless to orange.) MeI (0.24 mL, 3.9 mmol) was then added dropwise as a solution in THF (10 mL). The reaction was complete in ten minutes as determined by TLC. The crude residue was purified by silica flash chromatography using 0-15% EtOAc/hexanes. MS m/e=292 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[F:9].C([Li])CCCCC.[Cl:17][CH2:18][C:19]([CH2:21][Cl:22])=[O:20].[Cl-].[NH4+]>C(OCC)C>[Cl:17][CH2:18][C:19]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[F:9])([OH:20])[CH2:21][Cl:22]
Reactant: Fc1c(Cl)cccc1Br
Reactant: O=C(CCl)CCl
Agent: [Cl-]
Agent: [Li]CCCCCC
Agent: [NH4+]
Solvent: CCOCC
Product: OC(CCl)(CCl)c1cccc(Cl)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
To a solution of 1-bromo-3-chloro-2-fluorobenzene (1.4 g, 6.7 mmol) in dry diethyl ether (25 mL), at −78° C. under nitrogen was added n-hexyllithium (2.5 M in hexane, 3.2 ml, 8.0 mmol) dropwise. The mixture was stirred for 10 min after which a solution of 1,3-dichloroacetone (1.1 g, 7.3 mmol) in dry diethyl ether (10 ml) was added dropwise. The resulting mixture was stirred at −78° C. for 0.5 h and then brought to ambient temperature and stirred for 2 h. Aqueous saturated ammonium chloride (25 ml) was added and the mixture was extracted with ethylacetate (3×25 ml). The combined organic phase was dried (Na2SO4), filtered and evaporated to dryness. The crude product was purified by flash column chromatography on silica gel (ethylacetate/isooctane, 1:9 to 1:1) to give the title compound (0.88 g, 51%). MS m/z (rel. intensity, 70 eV) 257 (M+, 1), 209 (64), 207 (bp), 143 (44), 77 (13).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20]C(C)(C)C)=O)[CH2:14][C@H:13]2[O:25][CH3:26])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.C(OCC)(=O)C.[CH2:34]([O:36][C:37](=[O:43])/[CH:38]=[CH:39]/C(O)=O)[CH3:35].CCN=C=NCCCN(C)C.Cl.Cl>CO.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:20])/[CH:39]=[CH:38]/[C:37]([O:36][CH2:34][CH3:35])=[O:43])[CH2:14][C@H:13]2[O:25][CH3:26])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)/C=C/C(=O)O
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)/C=C/C(=O)N1CC[C@H](NC(=O)c2nc(Cl)c(CC)[nH]2)[C@H](OC)C1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1g) (133 mg, 0.34 mmol) was dissolved in methanol (2 mL). A 4 N hydrochloric acid/ethyl acetate solution (4 mL) was added, and the mixture was stirred at 70° C. for 30 minutes. Following concentration under reduced pressure, the residue was dissolved in DMA (5 mL). Fumaric acid monoethyl ester (54.42 mg, 0.38 mmol), WSC hydrochloride (197.41 mg, 1.03 mmol) and DMAP (41.94 mg, 0.34 mmol) were added, and the mixture was stirred at room temperature overnight. Dilute hydrochloric acid was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[Li+].CC([N-]C(C)C)C.[C:21]([O:25][C:26]([N:28]1[CH2:32][CH:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:30][C@@H:29]1[C:41]([OH:43])=[O:42])=[O:27])([CH3:24])([CH3:23])[CH3:22].CI>C1COCC1>[C:21]([O:25][C:26]([N:28]1[CH2:32][CH:31]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:30][C:29]1([CH3:1])[C:41]([OH:43])=[O:42])=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)NC(C)C
Reactant: CC(C)(C)OC(=O)N1CC(OCc2ccccc2)C[C@@H]1C(=O)O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(OCc2ccccc2)CC1(C)C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 21.7 %

Procedure:
To a cooled (−78° C.) solution of diisopropylamine (0.032 mol) in dry THF (15 mL), n-BuLi (0.030 mol) was added dropwise under argon atmosphere, and the reaction was stirred for 30 min at −78° C., then for one hour at −20° C. The resulting LDA solution was transferred to the solution of the known compound (R)-4-benzyloxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (CAS: 54631-81-1, e.g. Tetrahedron, 42(21), 6039-45; 1986) (3.5 g, 0.011 mol) in THF (15 mL) at −78° C., and the mixture was stirred for 30 minutes at −78° C., then at 0° C. for one hour. The reaction mixture was once again cooled to −78° C. and methyl iodide (0.82 mL, 0.013 mol) was added to it over 10 min and stirred the reaction mixture was stirred at 0° C. then at rt for one hour. After completion of the reaction by TLC, the reaction mixture was quenched with 1N HCl (20 mL) and extracted with DCM. The organic layer was concentrated under reduced pressure to give a crude material, which was purified through column chromatography (10-20% ethyl acetate:hexane, basic alumina, diameter of column—2.5 cm, height of alumina—approx. 7 inch) to afford the desired (rac)-4-benzyloxy-2-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 800 mg (22%) as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.Cl[C:12]([CH3:15])([CH3:14])[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-].O>C(Cl)Cl>[C:12]([C:5]1[S:1][C:2]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)=[CH:3][CH:4]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: c1csc(-c2cccs2)c1
Reactant: CC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1ccc(-c2cccs2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
2,2′-bithiophene (10 g, 60.1 mmol) was dissolved in DCM (300 mL) and 2-chloro-2-methylpropane (7.95 g, 72.2 mmol) was added. Aluminum chloride (8.82 g, 66.2 mmol) was added in one portion, and the colourless solution turned a green/brown colour immediately. The reaction mixture was stirred at room temperature for 30 minutes, then was poured into water (500 mL), mixed well and separated. The aqueous portion was extracted with DCM (200 mL) and the combined organics were washed with brine (2×400 mL), dried over MgSO4, filtered and solvent removed by rotary evaporation to afford a clear, green oil (13.3 g, 99%) that was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.17 (dd, J=5.1, 1.1 Hz, 1H), 7.10 (dd, J=3.6, 1.1 Hz, 1H), (dd, J=5.1, 3.6 Hz, 1H), 6.98 (d, J=3.6 Hz, 1H), 6.73 (d, J=3.7 Hz, 1H), 1.40 (s, 9H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].CC(C)=[O:12].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:12])=[O:9]
Reactant: CC(C)=O
Reactant: COCCCCCCO
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: COCCCCCC(=O)O

Procedure:
6-Methoxy-hexanol (8.16 g) was oxidized with Jones reagent (2.67-M, 53 ml) in acetone (100 ml) at -10° C. to give 6.17 g of 6-methoxy-caproic acid.
Reaction SMILES: [C:1](=[O:8])([O-])[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[Si:9]([O:16][C@H:17]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@@H:18]1[NH:22][CH:21]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=2)[CH2:20][CH2:19]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>>[NH2:30][C:27]1[N:28]=[CH:29][C:24]([CH2:23][C@@H:21]2[CH2:20][CH2:19][C@H:18]([C@H:17]([O:16][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:22]2[C:1]([O:2][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:8])=[CH:25][CH:26]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H](c1ccccc1)[C@H]1CCC(Cc2ccc(N)nc2)N1
Reactant: CC(C)(C)OC(=O)[O-]
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(N)nc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
To a solution of 121 mg (0.30 mmol) of 5-({(5R)-5-[(R)-([tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]pyrrolidin-2-yl}methyl)pyridin-2-amine in 5 mL of anhydrous THF (from Step B above) was added tert-butyl carbonate (66 mg, 0.30 mmol), followed by TEA (42 μL, 0.30 mmol) and the resulting solution stirred at room temperature under nitrogen atmosphere overnight. The reaction mixture was put directly on a preparative plate (1500 μM) and eluted with 60% ethyl acetate in hexane to afford the title compound (40.3 mg, 27%). LC-MS: C28H43N3O3Si calculated 497.23 found m/z (ES) 498.2 (MH)+ and 398.2 (M-Boc)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:30]#[N:31])=[C:4]([CH:27]=[CH:28][CH:29]=1)[O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12][C:13]1[CH:14]=[C:15]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:16]([NH:18][CH:19]([CH3:21])[CH3:20])=[O:17].O=[C:33]([CH3:40])[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[NH2:31][C:30]1[C:3]2[C:2](=[CH:29][CH:28]=[CH:27][C:4]=2[O:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]2[O:12][C:13]2[CH:14]=[C:15]([C:16](=[O:17])[NH:18][CH:19]([CH3:21])[CH3:20])[CH:22]=[CH:23][C:24]=2[O:25][CH3:26])[N:1]=[C:33]([CH3:40])[C:34]=1[C:35]([O:37][CH2:38][CH3:39])=[O:36]
Reactant: COc1ccc(C(=O)NC(C)C)cc1OC1CCCCC1Oc1cccc(N)c1C#N
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OC3CCCCC3Oc3cc(C(=O)NC(C)C)ccc3OC)c2c1N

Procedure:
Prepared as in Example 2a from (±)-3-((2-(3-amino-2-cyanophenoxy)cyclohexyl)oxy)-N-isopropyl-4-methoxybenzamide (Example 129b) and ethyl 3-oxobutanoate as a yellow solid (78%). MS 536 (MH+).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].CN1CCOCC1.Cl[C:28]([O:30][CH:31]([Cl:35])[CH:32]([CH3:34])[CH3:33])=[O:29]>ClCCl>[Cl:35][CH:31]([O:30][C:28]([NH:2][CH2:3][CH:4]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])=[O:29])[CH:32]([CH3:34])[CH3:33]
Reactant: CC(C)C(Cl)OC(=O)Cl
Reactant: CC(C)CC(CN)CC(=O)OCc1ccccc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)CC(CNC(=O)OC(Cl)C(C)C)CC(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
To a stirred solution of (39) (594 mg, 2.38 mmol) in dichloromethane at 0° C. was added N-methylmorpholine (0.523 mL, 4.77 mmol) and 1-chloro-2-methylpropyl chloroformate (0.347 mL, 2.38 mmol). The resulting solution was stirred at 0° C. until the reaction was complete (˜30 min, as monitored by TLC) and then was diluted with dichloromethane, washed successively with cold 1N HCl solution, water and brine, then dried over anhydrous Na2SO4. Filtration and removal of the solvent in vacuo afforded the title compound (42) as a mixture of two diastereomers (840 mg, 92%), which was used without further purification in the following example. 1H-NMR (CDCl3, 400 MHz): δ 0.86 (2 d, 6H), 1.02 (2 d, 6H), 1.15 (m, 2H), 1.63 (m, 1H), 2.14 (m, 2H), 2.34 (m, 2H), 3.10 (m, 1H), 3.28 (m, 1H), 5.11 (br.s, 3H), 6.29 (d, 1H), 7.31 (m, 5H).
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[CH2:9](NCCCC)[CH2:10][CH2:11]C>>[CH3:11][C:10]1[N:8]=[C:4]2[CH:3]=[CH:2][CH:7]=[CH:6][N:5]2[CH:9]=1
Reactant: Cc1ccnc(N)c1
Reactant: CCCCNCCCC
Product: Cc1cn2ccccc2n1

Procedure:
4-Methyl-2-aminopyridine (1.4 g, 12.5 mmol) was reacted with β-bromo-α-keto-(4-chloropropoxy)propiophenone as described in Example 8. The resulting product was reacted with dibutylamine as described in Example 8 to produce 2.9 g (75% yield) of the free base of the title compound which was converted to the HCl salt, mp 210° C. to 212° C. IR(KBr): 3460, 2640, 1650 cm-1. MS: 421 (M+). 1H NMR (CD3OD): δ8.89 (s, 1H), 8.77 (d, J=7.5 Hz, 2H), 8.12 (d, J=8.9 Hz, 2H), 7.77 (s, 1H), 7.48 (d, J=7.5 Hz, 2H), 7.20 (d, J=8.9 Hz, 2H), 4.30 (t, J=5.7 Hz, 2H), 3.38-3.16 (m, 6H), 2.65 (s, 3H), 2.35 (m, 2H), 1.81-1.34 (m, 8H), 1.02 (m, 6H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:26]=[C:27]=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH:29][CH2:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[CH:33][C:32]=1[CH2:41][C:42]([N:44]1[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]1)=[O:43]>ClCCl>[CH2:8]([NH:26][C:27](=[O:28])[O:29][CH2:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[CH:33][C:32]=1[CH2:41][C:42]([N:44]1[CH2:45][CH2:46][N:47]([CH3:50])[CH2:48][CH2:49]1)=[O:43])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: COc1cc(CO)c(CC(=O)N2CCN(C)CC2)cc1OC
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCc1cc(OC)c(OC)cc1CC(=O)N1CCN(C)CC1
Reaction time: 15 h

Procedure:
Triethylamine (0.41 ml) and octadecyl isocyanate (0.91 ml) were added to a solution of 2-[2-(hydroxymethyl)-4,5-dimethoxyphenyl]-1-(4-methylpiperazinyl)-1-ethanone (0.82 g) in dichloromethane (8.5 ml) at room temperature. After being stirred for 15 hours, resulting insoluble materials were filtrated out under a vacuum and washed with chloroform. A mixture of the filtrate and chloroform used for washing was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated. The residue was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=50:1-30:1), thereby yielding 0.83 g of the aimed compound as light brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:15]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:20]=CC=C[CH:16]=1.CC(O)C.C(OC(N=NC(OC(C)C)=O)=O)(C)C>C1COCC1>[CH:15]([O:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])([CH3:20])[CH3:16]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COC(=O)c1cc([N+](=O)[O-])ccc1OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
Methyl 2-hydroxy-5-nitrobenzoate (11.82 g, 60 mmol), triphenylphosphine (17.29 g, 66 mmol) and iPrOH (3.96 g, 5 ml, 66 mmol) were taken up in THF (150 ml) and cooled in ice. Di-isopropyl-azodicarboxylate (8.31 g, 10 ml, 66 mmol) was added carefully, and the reaction was stirred at RT overnight. The volatiles were removed in vacuo and the residue treated with EtOAc (50 ml). The solids that didn't dissolve were removed by filtration, and the filtrate evaporated to dryness in vacuo. The residue was purified by column chromatography to give methyl 2-isopropoxy-5-nitrobenzoate (6.92 g, 48.5%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14]>C1(C)C=CC=C(C)C=1>[OH:12][C:11]1[C:2]([NH:1][C:20](=[O:21])[C:19]2[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:24][CH:23]=2)=[C:3]([CH:8]=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc(O)c1N
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: Cc1cccc(C)c1
Product: COC(=O)c1cccc(O)c1NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Methyl 2-amino-3-hydroxybenzoate (0.5 g; 2.99 mmol) was dissolved in m-xylene (40 ml) with warming to 60° C. 4-Nitrobenzoyl chloride (0.556 ml; 2.99 mmol) was added dropwise, and this was left to stir for 4 hours. The solution was cooled to ambient temperature and the m-xylene removed under reduced pressure. The solid was dissolved in water (100 ml) and the organics extracted into ethyl acetate (3×50 ml). The organic fractions were pooled, dried over magnesium sulphate, filtered and the solvent removed under reduced pressure.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[O:8][N:7]=[C:6]([CH3:9])[CH:5]=1.[Br:10][C:11]1[C:12]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)=[N:13][C:14](Cl)=[N:15][CH:16]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[Br:10][C:11]1[C:12]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)=[N:13][C:14]([NH:2][CH2:3][C:4]2[O:8][N:7]=[C:6]([CH3:9])[CH:5]=2)=[N:15][CH:16]=1
Reactant: Cc1cc(CN)on1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Br)n[nH]1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CNc2ncc(Br)c(Nc3cc(C)[nH]n3)n2)on1
Temperature: 120 °C
Yield: 30.9 %

Procedure:
A mixture of 5-aminomethyl-3-methylisoxazole hydrochloride (890 mg, 6.0 mmol), 5-bromo-2-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Method 1; 578 mg, 2.0 mmol) and N,N-diisopropylethylamine (1.4 ml, 8.0 mmol) in 1-butanol (10 ml) was heated at 120° C. for 18 hours. The mixture was allowed to cool to ambient temperature and volatiles removed by evaporation. The residue was triturated with ether and the product collected by filtration to give the titled compound (225 mg, 31%). 1H NMR (DMSO): δ 2.15 (s, 3H), 2.2 (s, 3H), 4.5 (m, 2H), 6.1 (br s, 2H), 7.6 (br s, 1H), 8.0 (br s, 2H), 12.05 (br s, 1H); MS: m/z 366.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][CH:12]1[CH2:20][NH2:21].C([O-])(O)=O.[Na+]>CCO.O>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:21][CH2:20][CH:12]2[CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:11]2)[CH:7]=1
Reactant: NCC1Cc2ccccc2O1
Reactant: COc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1nc(Cl)cc(NCC2Cc3ccccc3O2)n1
Yield: 74.5 %

Procedure:
A mixture of 4,6-dichloro-2-methoxy-pyrimidine (0.41 g, 2.3 mmol), C-(2,3-dihydro-benzofuran-2-yl)-methylamine (0.52 g, 3.47 mmol), and NaHCO3 (0.97 g, 12 mmol) in EtOH (7 mL) is heated to reflux for 3 h. The mixture is diluted with water (8 mL), filtered, washed (water). The solid is dissolved in EtOAc, dried (MgSO4), filtered, and concentrated in vacuo to afford (6-chloro-2-methoxy-pyrimidin-4-yl)-(2,3-dihydro-benzofuran-2-ylmethyl)-amine (0.5 g) as a solid. LCMS: RT=2.59 minutes; MS: 292 (M+H).
Reaction SMILES: [Na][Na].[N:3]([C:15]1[CH:16]=[C:17]([OH:24])[C:18](=[CH:22][CH:23]=1)[C:19]([O-:21])=[O:20])=[N:4][C:5]1[CH:13]=[C:9]([C:10]([O-:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1.C(O)(=O)C>O>[N:3]([C:15]1[CH:16]=[C:17]([OH:24])[C:18](=[CH:22][CH:23]=1)[C:19]([OH:21])=[O:20])=[N:4][C:5]1[CH:13]=[C:9]([C:10]([OH:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1
Reactant: O=C([O-])c1ccc(N=Nc2ccc(O)c(C(=O)[O-])c2)cc1O
Agent: [Na][Na]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc(N=Nc2ccc(O)c(C(=O)O)c2)cc1O

Procedure:
1 g of disodium-4,5'-azo-bis-salicylate was dissolved in 20 ml of boiling water, whereupon the solution was acidified with acetic acid down to pH 4. After cooling, the product was filtered off, washed with water and dried. Yield: 0.8 g.
Reaction SMILES: [N:1]1([C:7]([C:9]2([CH2:21][NH2:22])[CH2:14][CH2:13][N:12]([S:15]([CH2:18][CH2:19][CH3:20])(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Cl:32][C:33]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>C(Cl)Cl>[Cl:32][C:33]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:34]=1[C:35]([NH:22][CH2:21][C:9]1([C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:8])[CH2:14][CH2:13][N:12]([S:15]([CH2:18][CH2:19][CH3:20])(=[O:17])=[O:16])[CH2:11][CH2:10]1)=[O:36]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CCCS(=O)(=O)N1CCC(CN)(C(=O)N2CCOCC2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCS(=O)(=O)N1CCC(CNC(=O)c2ccc(Cl)cc2Cl)(C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of {[4-(morpholin-4-ylcarbonyl)-1-(propylsulfonyl)piperidin-4-yl]methyl}amine (I-5) (33 mg, 0.10 mmole), DIEA (35 μL, 0.20 mmole), and 2,4-dichlorobenzoyl chloride (23 mg, 0.11 mmole) in DCM (2 mL) was shaken 1 h at room temperature. After this time, LCMS indicated that the reaction was completion. DCM was removed by nitrogen gas flow and the residue was purified by LCMS to afford the title compound (I-6) as a white solid. Analytical LCMS: single peak (214 nm), 2.867 min. 1H NMR (600 MHz, CD3CN): δ 7.52 (dd, J=0.9, 1.5 Hz, 2H), 7.39 (m, 2H), 6.98 (t, J=5.9 Hz, 1H), 3.63 (m, 10H), 3.49 (m, 2H), 3.05 (m, 2H), 2.89 (t, J=7.8 Hz, 2H), 2.30 (m, 2H), 1.74 (m, 2H), 1.62 (m, 2H), 1.01 (t, J=7.4 Hz, 3H); HRMS: calc'd for C21H29Cl2N3O5S [M+H], 506.1278; found 506.1248.
Reaction SMILES: C([O:8][CH2:9][CH:10]([O:20][CH2:21][N:22]1[CH:29]=[C:28]([I:30])[C:26](=[O:27])[NH:25][C:23]1=[O:24])[CH2:11][O:12]CC1C=CC=CC=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO.[NH4+].[OH-]>C(Cl)Cl>[OH:12][CH2:11][CH:10]([O:20][CH2:21][N:22]1[CH:29]=[C:28]([I:30])[C:26](=[O:27])[NH:25][C:23]1=[O:24])[CH2:9][OH:8]
Reactant: O=c1[nH]c(=O)n(COC(COCc2ccccc2)COCc2ccccc2)cc1I
Agent: ClB(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: O=c1[nH]c(=O)n(COC(CO)CO)cc1I
Temperature: -78 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a solution of 45 (1.90 g, 3.64 mmol) in anhydrous CH2Cl2 (60 mL) at −78° C. was added BCl3 (1 M solution in CH2Cl2, 30 mL, 30 mmol) dropwise. The mixture was stirred at −78° C. under nitrogen for 2 h, then at −60° C. for another 4 h. MeOH (10 mL) was added to quench the reaction, followed by 14% NH4OH solution to adjust the mixture to pH 7. After being stirred at room temperature for 1 h, the mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with CH2Cl2/MeOH (9:1 to 4:1) to give the title compound 46 as a pale yellow solid (810 mg, 65%). 1H NMR (DMSO-d6) δ 11.6 (s, 1H, NH), 8.19 (s, 1H, H-6), 7.20, 6.60 (2br, 2H, 20H), 5.15 (s, 2H, CH2N), 4.60 (m, 2H, CH2O), 3.53 (m, 1H, CHO), 3.41 (m, 2H, 2 CH2O).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][S:7][CH:8]1[CH2:29][CH:11]2[N:12]([N:19]=[CH:20][CH:21]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[OH:22])[C:13](=[O:18])[N:14]([CH2:15][CH2:16][CH3:17])[CH:10]2[CH2:9]1)([OH:3])=[O:2].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:1]([CH2:4][CH2:5][CH2:6][S:7][CH:8]1[CH2:29][CH:11]2[N:12]([NH:19][CH2:20][CH:21]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[OH:22])[C:13](=[O:18])[N:14]([CH2:15][CH2:16][CH3:17])[CH:10]2[CH2:9]1)([OH:3])=[O:2]
Reactant: CCCN1C(=O)N(N=CC(O)C2CCCCC2)C2CC(SCCCC(=O)O)CC21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN1C(=O)N(NCC(O)C2CCCCC2)C2CC(SCCCC(=O)O)CC21
Reaction time: 1 h

Procedure:
The compound (0.5 g) of Example 2 was dissolved in a mixture of methanol (5 ml) and acetic acid (5 ml) at 15° C. and to the stirred solution was added sodium cyanoborohydride (0.15 g). After one hour, the solution was concentrated in vacuo, water (20 ml) and chloroform (20 ml) were added and the organic phase separated and dried over anhy. sodium sulphate. Filtration and concentration of the filtrate in vacuo gave the desired produced (0.49 g).