Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][S:5]([N:8]([CH3:23])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:7])=[O:6].[NH2:25][OH:26]>>[OH:26][NH:25][C:3](=[O:2])[CH2:4][S:5]([N:8]([CH3:23])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:7])=[O:6]
Reactant: NO
Reactant: COC(=O)CS(=O)(=O)N(C)Cc1ccc(-c2ccc(Cl)cc2)cc1
Product: CN(Cc1ccc(-c2ccc(Cl)cc2)cc1)S(=O)(=O)CC(=O)NO

Procedure:
In a manner similar to Example 1 (b), methyl-2-({methyl[(4'-chlorobiphenyl-4-yl)methyl]amino}sulfonyl)acetate was reacted with hydroxylamine to give the title compound as a colourless solid.
Reaction SMILES: [CH2:1]([C:3]([CH2:8][OH:9])([CH3:7])[C:4]([OH:6])=[O:5])[OH:2].[OH-].[K+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[CH2:1]([C:3]([CH2:8][OH:9])([CH3:7])[C:4]([O:6][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5])[OH:2]
Reactant: BrCc1ccccc1
Reactant: CC(CO)(CO)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(CO)(CO)C(=O)OCc1ccccc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 64.9 %

Procedure:
A mixture of 2,2-bis(methylol)propionic acid (bisMPA) (18.0 g, 0.134 mol), KOH (85% assay; 8.9 g, 0.135 mol), and DMF (100 mL) was heated to 100° C. for 1 hour (the reaction mixture became a homogenous solution after 0.5 hour reaction). Benzyl bromide (27.6 g, 0.162 mol) was added to the warm solution under stirring, and the reaction was continued at 100° C. for 16 hours. The reaction mixture was cooled down and the solvent was removed under vacuum. Ethyl acetate (120 mL), hexanes (120 mL), and water (80 mL) were added to the residue. The organic layer was retained, washed with water (80 mL), dried over MgSO4 and evaporated. The resulting solid was recrystallized from toluene (30 mL) to give pure benzyl 2,2-bis(methylol)propionate (BnMPA) (19.5 g, 65%). 1H NMR (400 MHz, CDCl3, 22° C.): delta 7.38 (m, 5H, PhH), 5.19 (s, 2H, —OCH2Ph), 3.94 (d, 2H, —CH2OH), 3.73 (d, 2H, —CH2OH), 1.12 (s, 3H, —CH3).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH:7]=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3][CH2:2]1>C(O)C.[C].[Pd]>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C=CC1CCOCC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC1CCOCC1
Yield: 87.3 %

Procedure:
In 200 ml of ethanol is dissolved 17 g of ethyl 3-(3,4,5,6-tetrahydro-2H-pyran -4-yl)acrylate, and a catalytic reduction reaction is carried out at ordinary temperature and at atmospheric pressure using 4 g of 10% palladium-carbon (50% in water) as a catalyst. After absorption of hydrogen stops, the catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is distilled under vacuum to give 15 g (bp 121-123°/16 mmHg)of ethyl 3-(3,4,5,6-tetrahydro-2H-pyran -4-yl)propionate as an oily material.
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[CH:12]=[CH:11][C:10]=2[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:7])=[CH:4][N:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>CCOC(C)=O>[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:2]2[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]3[CH:14]=[C:13]([C:15]4[S:16][CH:17]=[CH:18][CH:19]=4)[CH:12]=[CH:11][C:10]=3[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:7])=[CH:4][N:3]=2)[CH2:33][CH2:32]1
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(Cl)nc1
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(C(=O)Nc3cc(-c4cccs4)ccc3NC(=O)OC(C)(C)C)cn2)CC1
Temperature: 90 °C
Yield: 37.6 %

Procedure:
A mixture of chloride 46 (0.15 g, 0.35 mmol) and N-methylpiperazine (0.5 mL, 4.5 mmol) was heated to 90° C. in a sealed tube for 18 h. The reaction mixture was then diluted with AcOEt, washed with saturated aqueous NaHCO3, brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (eluent: 2:1 AcOEt:hexane) to afford title compound 48 (65 mg, 38% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[OH-].[K+].[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccnc(N)c1
Reactant: OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Product: Cc1ccnc(NCc2ccccc2)c1

Procedure:
2-Amino-4-methylpyridine was reacted with potassium hydroxide in benzyl alcohol according to the method of Sprinzak (Org. Syn. Coll. Vol. IV. 91 (1963)) to form the title compound.
Reaction SMILES: Cl[C:2]1[O:11][C:5]2=[C:6]([NH2:10])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1.[CH:12]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17](B(O)O)[C:16]=2[CH:15]=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH:12]1[C:21]2[C:16](=[C:17]([C:2]3[O:11][C:5]4=[C:6]([NH2:10])[N:7]=[CH:8][CH:9]=[C:4]4[CH:3]=3)[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1
Reactant: OB(O)c1cccc2cnccc12
Reactant: Nc1nccc2cc(Cl)oc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1nccc2cc(-c3cccc4cnccc34)oc12
Yield: 90.1 %

Procedure:
A mixture of 2-chlorofuro[2,3-c]pyridin-7-amine (4.0 g, 23.8 mmol) and 5-isoquinoline boronic acid (4.33 g, 25.0 mmol) in 1,4-dioxane (150 mL) and water (50 mL) was sparged with nitrogen for 15 min and then treated with Pd(PPh3)2Cl2 (250 mg). After sparging with nitrogen for another 5 min, K2CO3 (2.2 g, 59.5 mmol) was added and the mixture heated at reflux overnight. The 1,4-dioxane was removed in vacuo and DCM was added. The phases were separated and the organic phase was washed with water, then brine. The solution was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (2% MeOH:DCM) to provide the 5.6 g (90%) of the title compound. 1H NMR (300 MHz, CD3OD): δ 6.99 (d, J=5.4 Hz, 1H), 7.27 (s, 1H), 7.73 (d, J=5.4 Hz, 1H); 7.81 (t, J=8.1 Hz, 1H), 8.22 (d, J=8.1 Hz, 1H), 8.29 (dd, J=7.4 Hz, J=1.0 Hz, 1H), 8.44 (d, J=5.4 Hz, 1H), 8.55 (d, J=6.0 Hz, 1H); 9.32 (s, 1 H).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17]CC[C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][N:22]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[N:23]1.N1C=C(B(O)O)C=NC=1>>[N:13]1([C@H:11]2[CH2:10][C@H:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([C:25]5[CH:24]=[N:23][N:22]([CH3:21])[CH:26]=5)[CH:20]=[CH:19][C:5]=4[N:6]=3)[CH2:12]2)[CH2:14][CH2:18][CH2:17]1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: OB(O)c1cncnc1
Product: Cn1cc(-c2ccc3nc([C@H]4C[C@H](N5CCC5)C4)sc3c2)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, except for substituting the product of Example 61A for the product of Example 1E, and substituting 1-methyl-4-1H-pyrazoleboronic acid pinacol ester for pyrimidine-5-boronic acid. 1H NMR (300 MHz, CDCl3) δ ppm 7.89-7.97 (m, 2H) 7.80 (s, 1H) 7.65 (s, 1H) 7.55 (dd, J=8.31, 1.86 Hz, 1H) 3.97 (s, 3H) 3.92-4.07 (m, 1H) 3.21-3.45 (m, 5H) 2.36-2.62 (m, 4H) 2.06-2.24 (m, 2H). MS: (M+H)+=325.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[N:19]([NH:20][CH:21]([CH3:23])[CH3:22])[C:18]([CH2:24][O:25][CH2:26][CH3:27])=[N:17][C:11]=3[C:12]([NH2:16])=[N:13][C:14]=2[CH:15]=1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl.C(Cl)(Cl)Cl>[NH2:16][C:12]1[C:11]2[N:17]=[C:18]([CH2:24][O:25][CH2:26][CH3:27])[N:19]([NH:20][CH:21]([CH3:22])[CH3:23])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:15][C:14]=2[N:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOCc1nc2c(N)nc3cc(OCCCN)ccc3c2n1NC(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(OCCCNS(C)(=O)=O)ccc3c2n1NC(C)C
Reaction time: 16 h

Procedure:
A solution of 7-(3-aminopropoxy)-2-ethoxymethyl-N1-isopropyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.84 g, 2.26 mmol) in 25 mL of CH2Cl2 was placed under an atmosphere of nitrogen. The solution was treated with triethylamine (0.63 mL, 4.75 mmol) and cooled in an ice water bath. The solution was slowly treated with methanesulfonyl chloride (0.184 mL, 2.37). The reaction was stirred and allowed to slowly come to ambient temperature. After 16 h, the reaction mixture was diluted with CHCl3 (20 mL) and transferred to a separatory funnel. The organic solution was washed with 10% Na2CO3 solution (15 mL), H2O (15 mL) and brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a tan foam. The foam was purified by chromatography (SiO2, 10–50% (80:18:2 CHCl3:MeOH:NH4OH) in CHCl3) to give a light yellow solid. The solid was crystallized from MeCN to yield N-(3-{[4-amino-2-(ethoxymethyl)-1-(isopropylamino)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)methanesulfonamide (0.295 g) as white crystals. mp 181–183° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.46 (d, J=9.0 Hz, 1H), 7.09 (t, J=6.8 Hz, 1H), 7.02 (d, J=2.6 Hz, 1H), 6.90 (d, J=2.1 Hz, 1H), 6.87 (d, J=2.5 Hz, 1H), 6.54 (s, 2H), 4.71 (s, 2H), 4.11 (t, J=6.1 Hz, 2H), 3.64–3.58 (m, 3H), 3.14 (q, J=6.1 Hz, 2H), 2.91 (s, 3H), 1.96 (p, J=6.6 Hz, 2H), 1.15 (t, J=7.0 Hz, 3H), 1.01 (d, J=6.1 Hz, 6H); 13C NMR (75 MHz, DMSO-d6) δ 158.1, 152.6, 149.4, 147.2, 133.7, 122.6, 111.5, 109.1, 107.9, 65.8, 65.0, 63.0, 51.6, 29.7, 20.6, 15.3; MS (APCI) m/z 451 (M+H)+; Anal. Calcd for C20H30N6O4S: C, 53.32; H, 6.71; N, 18.65; S, 7.12; Found: C, 53.44; H, 6.68; N, 18.83; S, 7.09.
Reaction SMILES: CNC(OCC)=O.[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[CH3:18])[NH2:14])[CH3:9]>O1CCOCC1>[CH2:8]([O:10][CH:11]1[CH:17]([CH3:18])[CH2:16][CH2:15][CH:13]([NH2:14])[CH2:12]1)[CH3:9]
Reactant: CCOc1cc(N)ccc1C
Agent: CCOC(=O)NC
Solvent: C1COCCO1
Product: CCOC1CC(N)CCC1C

Procedure:
4 g of N-[4-(β-<2-methoxy-5-methylbenzamido>-ethyl)-benzenesulfonyl]-methyl-urethane (melting point 175° - 177°C) are suspended in 75 ml of dioxane and 1.7 g of 3-ethoxy-4-methyl-cyclohexylamine (boiling at 80°C under a pressure of 10 mm of mercury) obtained by hydrogenation of the nucleus of 3-ethoxy-4-methylaniline at Co2O3 at 260° C and 250 atmospheres H2) are added. The whole is heated for 1 hour to 110°C. Then the N-[4-(β-<2-methoxy-5-methylbenzamido>-ethyl)-benzenesulfonyl]-N'-(3-ethoxy-4-methyl-cyclohexyl)-urea is precipitated by means of water. The cristals melt after recrystallization from methanol at 172°- 174°C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:16]2[NH:15][C:14](=[O:17])[O:13][C:12]([CH3:19])([CH3:18])[C:11]=2[CH:10]=[CH:9][CH:8]=1.[CH:20]1([C:26]2[CH:31]=[CH:30][C:29]([SH:32])=[CH:28][CH:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([C:26]2[CH:27]=[CH:28][C:29]([S:32][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]3[C:16]4[NH:15][C:14](=[O:17])[O:13][C:12]([CH3:19])([CH3:18])[C:11]=4[CH:10]=[CH:9][CH:8]=3)=[CH:30][CH:31]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: Sc1ccc(C2CCCCC2)cc1
Reactant: CC1(C)OC(=O)Nc2c(OCCCCCl)cccc21
Product: CC1(C)OC(=O)Nc2c(OCCCCSc3ccc(C4CCCCC4)cc3)cccc21

Procedure:
Prepared analogously to Example 1 from 8-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-cyclohexyl-thiophenol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[CH3:19])[CH2:6][CH:7](C(OC)=O)[C:8]([O:10]C)=[O:9].[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH:16]=[CH:17][C:18]=1[CH3:19]
Reactant: COC(=O)C(Cc1ccc(C)c(OC)c1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(CCC(=O)O)ccc1C
Yield: 123 %

Procedure:
A solution of 25.84 g (0.1072 mol) of dimethyl 2-(3-methoxy-4-methylbenzyl)malonate in 150 mL of MeOH was treated with a solution of 20 g (0.5 mol) of NaOH in 100 mL of H2O and heated at reflux overnight. The solution was concentrated under reduced pressure and the residue taken up in H2O and washed with Et2O. The solution was acidified to Congo Red end point with dilute HCl and the solution extracted with Et2O. The Et2O was washed with saturated NaCl and dried over MgSO4. Removal of the solvent under reduced pressure gave 25.6 g of an oil. This was taken up in 125 mL of dioxane and heated at reflux overnight. Removal of the solvent under reduced pressure gave 20.5 g of the crude product. Chromatography on silica gel, eluting with CHCl3/MeOH (98/2) gave 8.65 g (41.6% yield) of the product as a white solid, mp 80-82° C. The structure was confirmed by NMR and mass spectroscopy. MS m/z 195 (M+H+).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Si:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([NH:30][CH2:31][C@@H:32]([C:34]2[CH:45]=[CH:44][C:37]3[O:38][C:39]([CH3:43])([CH3:42])[O:40][CH2:41][C:36]=3[CH:35]=2)[OH:33])[CH3:29])=[CH:23][CH:22]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C1COCC1>[Si:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][C@@H:28]([N:30]2[CH2:31][C@@H:32]([C:34]3[CH:45]=[CH:44][C:37]4[O:38][C:39]([CH3:43])([CH3:42])[O:40][CH2:41][C:36]=4[CH:35]=3)[O:33][C:1]2=[O:2])[CH3:29])=[CH:25][CH:26]=1)([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15]
Reactant: CC(Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1)NC[C@H](O)c1ccc2c(c1)COC(C)(C)O2
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: C[C@@H](Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1)N1C[C@@H](c2ccc3c(c2)COC(C)(C)O3)OC1=O
Temperature: 20 °C
Reaction time: 18 h
Yield: 36.5 %

Procedure:
1,1′-Carbonyldiimidazole (0.62 g) was added to a solution of (1R)-2-{[2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methylethyl]amino}-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (0.83 g) in THF (8 ml). The mixture was stirred for 18 h at 20° C. and partitioned between Et2O and water. The organic phase was washed with brine, dried (MgSO4) and evaporated to dryness. The residue was purified by chromatography on a Biotage (40 g) eluting with cyclohexane-EtOAc (5:1 then 3:1) to give (5R)-3-[(1S)-2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methylethyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (0.32 g), LCMS RT=4.17 min and (5R)-3-[(1R)-2-(4-{[tent-butyl(dimethyl)silyl]oxy}phenyl)-1-methylethyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (0.36 g) LCMS RT=4.15 min.
Reaction SMILES: [Cl:1][CH:2]([Cl:17])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([F:15])[CH:8]=1)=O.[CH:18]1[C:23]([NH:24][NH2:25])=[CH:22][CH:21]=[C:20]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:19]=1.Cl.O>C(O)C>[Cl:1][CH:2]([Cl:17])[C:3]1[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([F:15])[CH:8]=2)[N:24]([C:23]2[CH:18]=[CH:19][C:20]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:21][CH:22]=2)[N:25]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: COc1ccc(C(=O)CC(=O)C(Cl)Cl)cc1F
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cc(C(Cl)Cl)nn2-c2ccc(S(N)(=O)=O)cc2)cc1F
Yield: 62.7 %

Procedure:
4,4-Dichloro-1-(3-fluoro-4-methoxyphenyl)-butane-1,3-dione from Step 2 (2.8 g, 10 mmol) was dissolved in ethanol (100 mL). To the stirred mixture was added 4-sulfonamidophenylhydrazine hydrochloride (2.46 g, 11 mmol) and heated to reflux for 16 hours. The mixture was cooled and water was added until crystals slowly appeared. Filtration yielded a light tan solid (2.7 g, 63%): mp 190°-193° C.: 1H NMR (DMSO-d6) 7.84 (d, J=8.4Hz, 2H), 7.53 (s, 1H), 7.48 (d, J=8.4Hz, 2H), 7.47 (brs, 2H), 7.3-7.0 (m, 3H), 6.95 (s, 1H), 3.85 (s, 3H). Anal. Calc'd for C17H14N3SO3FCl2: C, 47.45; H, 3.28; N, 9.76. Found: C, 47.68; H, 3.42; N, 10.04.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@@H:7]([CH2:12][NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:6][CH2:5]2.C(N(CC)CC)C.[C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:34])[CH:32]=[CH2:33]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:16]([O:15][C:14]([NH:13][CH2:12][C@H:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2](/[CH:33]=[CH:32]/[C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:3]=2)[O:8]1)=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(NC[C@H]1CCc2cc(I)ccc2O1)OCc1ccccc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)/C=C/c1ccc2c(c1)CC[C@H](CNC(=O)OCc1ccccc1)O2
Temperature: 25 °C
Yield: 94.5 %

Procedure:
Palladium acetate (224 mg, 1 mmol) was added to a mixture of the carbamate of Example 11 (4.2 g, 10 mmol), triethylamine (2.1 mL, 15 mmol), and t-butyl acrylate (1.76 mL, 12 mmol) in acetonitrile (50 mL) previously degassed with argon for 20 minutes. The resulting mixture was heated at gentle reflux for 26 hours. It was cooled to room temperature. The catalyst was removed by filtration. The filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL), washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, and filtered over a pad of silica gel. Removal of solvent in vacuo afforded the product as an oil (4.0 g, 95%): 1H NMR (CDCl3) δ1.50 (s, 9H), 1.70 1.85 (m, 1H), 200 (m, 1H), 2.80 (m, 2H), 3.40(m, 1H), 3.65 (m, 1H), 5.12 (s, 2H), 5.25 (m, 1H), 6.21 (d, J=15.3 Hz,1H), 6.76 (d, J=8.4 Hz, 1H), 7.20-7.40 (m, 7H), 7.49 (d, J=15.9 Hz, 1H); CI-MS m/z 424 (M+H+).
Reaction SMILES: C(OC([NH:8][CH2:9][C@H:10]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:17][CH2:16]1)[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.[ClH:31].CO>C(O)(C)C>[ClH:31].[ClH:31].[NH2:8][CH2:9][CH:10]([N:15]1[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:19][CH2:20]1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: COC(=O)C(CN)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 40 °C
Yield: 90 %

Procedure:
A solution of 1.45 g (3.4 mmol) of benzyl 4-((S)-2-tert-butoxycarbonylamino-1-methoxycarbonylethyl)piperazine-1-carboxylate in 3.5 ml of a solution of hydrochloric acid in isopropanol, having a concentration 5-6N, and 10 ml of methanol is heated at 40° C. for 3 h and then evaporated. The residue is taken up in diethyl ether and filtered. 1.2 g (90%) of benzyl 4-(2-amino-1-methoxycarbonylethyl)piperazine-1-carboxylate dihydrochloride are obtained in the form of a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[CH3:23].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[CH2:43]([N:45]([CH2:49][CH3:50])[CH2:46][CH2:47][NH2:48])[CH3:44]>C(Cl)(Cl)Cl.O>[CH2:43]([N:45]([CH2:49][CH3:50])[CH2:46][CH2:47][NH:48][C:35]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[C:17]([CH3:23])[CH:18]=1)=[O:41])[CH3:44]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN(CC)CCN
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN(CC)CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methylaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (142 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1,N1-diethyl-1,2-ethanediamine (56 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (48 mg, yield 33%).
Reaction SMILES: [N].N1C=CC=C1.[C:7]([C:9]1[C:10]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[S:27][CH:28]=[CH:29][C:30]=3[N+:31]([O-:33])=[O:32])=[CH:22][CH:21]=2)=[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:12]([CH3:14])[CH:13]=1)#[N:8].[Br:34]NC(=O)CCC(N)=O>C(Cl)Cl>[Br:34][C:13]1[N:12]([CH3:14])[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:10]([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[S:27][CH:28]=[CH:29][C:30]=3[N+:31]([O-:33])=[O:32])=[CH:24][CH:25]=2)[C:9]=1[C:7]#[N:8]
Reactant: NC(=O)CCC(=O)NBr
Reactant: CCOC(=O)c1c(-c2ccc(-c3sccc3[N+](=O)[O-])cc2)c(C#N)cn1C
Agent: [N]
Solvent: ClCCl
Solvent: c1cc[nH]c1
Product: CCOC(=O)c1c(-c2ccc(-c3sccc3[N+](=O)[O-])cc2)c(C#N)c(Br)n1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The title compound is prepared in a manner analogous to the procedure set forth in Scheme XXIII, step A wherein the starting pyrrole nitrogen is already methylated. For example, to a solution of ethyl 4-cyano-1-methyl-3-[4-(3-nitro(2-thienyl))phenyl]pyrrole-2-carboxylate, prepared directly above (1.0 mmol) in methylene chloride in an ice bath add N-bromo-succinamide (1.5 mmol). Allow the reaction to warm to room temperature and stir for 18 hours. After this time, wash reaction with water while extracting with ethyl acetate. Dry organic layer with sodium sulfate, filter and concentrate in vacuo to provide the title compound. Use as crude in the next step.
Reaction SMILES: Br[CH:2]([CH3:9])[CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1.Cl[C:11]1[N:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=1>O1CCCC1.[Zn]>[O:5]1[CH2:6][CH2:7][O:8][CH:4]1[CH2:3][CH:2]([C:11]1[N:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=1)[CH3:9]
Reactant: CC(Br)CC1OCCO1
Reactant: Fc1cnc(Cl)nc1
Agent: [Zn]
Solvent: C1CCOC1
Product: CC(CC1OCCO1)c1ncc(F)cn1
Temperature: 40 °C
Reaction time: 4 h
Yield: 22.9 %

Procedure:
To a stirring suspension of activated “Rieke” zinc in tetrahydrofuran (21 ml, 1.53 M) was added 2-(2-bromopropyl)-1,3-dioxolane (6.6 g) in tetrahydrofuran (50 ml), a rise in temperature from 21° C. to 40° C. was observed, heated at 40° C. for 1 hour then allowed to cool to ambient temperature before adding 2-chloro-5-fluoropyrimidine (3 g) and [1,2-Bis(diphenylphosphino)-propane]dichloronickel(II) chloride (368 mg). The mixture was stirred at ambient temperature for 4 hours then filtered through a pad of celite and the filtrate evaporated under reduced pressure. Flash chromatography (silica gel, haxane-25% ethyl acetate in hexanes) then gave the product as a pale yellow oil (1.1 g); 1H NMR (d6-DMSO): 8.81 (s, 2H), 4.73 (dd, 1H), 3.66-3.87 (m, 4H), 3.21-3.30 (m, 1H), 2.19 (ddd, 1H), 1.83 (ddd, 1H), 1.27 (d, 3H); m/z 213 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][N:5]=1)(=[O:3])[CH3:2].[Br:11]Br>Br>[BrH:11].[Br:11][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][N:5]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccc(Cl)cn1
Agent: Br
Product: O=C(CBr)c1ccc(Cl)cn1

Procedure:
To a solution of 10 g of 2-acetyl-5-chloropyridine in 150 ml of 48% aqueous hydrobromic acid are added 4 ml of bromine dissolved in 40 ml of hydrobromic acid, with stirring, drop by drop, at 80°. The mixture is stirred for additionally 3 hours at 80°. Afterwards the solution is evaporated in vacuo. The residue is triturated with acetone, filtered by suction, washed with acetone and dried in vacuo to yield yellow crystals of the compound, which is used for the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:15]3[CH:16]=[CH:17][C:18]([O:20][C:21]4[CH:26]=[C:25](Cl)[N:24]=[C:23]([NH2:28])[N:22]=4)=[CH:19][C:14]=3[S:13][N:12]=2)=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].CCN(CC)CC>C1COCC1.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:15]3[CH:16]=[CH:17][C:18]([O:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([NH2:28])[N:22]=4)=[CH:19][C:14]=3[S:13][N:12]=2)=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:30])[F:31]
Reactant: Nc1nc(Cl)cc(Oc2ccc3c(C(=O)Nc4ccc(F)c(C(F)(F)F)c4)nsc3c2)n1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1nccc(Oc2ccc3c(C(=O)Nc4ccc(F)c(C(F)(F)F)c4)nsc3c2)n1

Procedure:
Hydrogenation of 51 mg (0.11 mMol) of 6-(2-amino-6-chloro-pyrimidin-4-yloxy)-benzo[d]isothiazole-3-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide (Step 6.3) in 10 ml THF and 46 μl (0.33 mMol) Et3N in presence of two portions of 0.1 g Pd/C (10%; Engelhard 4505) during 36 h, filtration, concentration of the filtrate and chromatography (Combi Flash; CH2Cl2/hexane 2:3→CH2Cl2→CH2Cl2/ether 7:3) gives the title compound: m.p.: 237-239° C.; MS: [M+1]+=450.