Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=3)[N:7](C(OC(C)(C)C)=O)[C:6]=2[C:5]([O:23][CH3:24])=[C:4]2[NH:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][C:31]=3[C:3]=12.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+].C(O)(C(F)(F)F)=O>CC([O-])=O.CC([O-])=O.[Pd+2]>[F:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[C:5]([O:23][CH3:24])=[C:4]3[NH:25][C:26]4[CH:27]=[CH:28][C:29]([F:32])=[CH:30][C:31]=4[C:3]3=[C:2]([N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[C:14]2=1
Reactant: COc1c2[nH]c3ccc(F)cc3c2c(Br)c2c3cc(F)ccc3n(C(=O)OC(C)(C)C)c12
Reactant: C1CCNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O=C(O)C(F)(F)F
Product: COc1c2[nH]c3ccc(F)cc3c2c(N2CCCC2)c2c1[nH]c1ccc(F)cc12

Procedure:
The title compound was prepared by the reaction tert-butyl 12-bromo-2,10-difluoro-6-methoxyindolo[2,3-b]carbazole-5(7H)-carboxylate with pyrrolidine in the presence of Pd(OAc)2, BINAP, and NaOtBu at 80° C. for 2 h, followed deprotection with TFA. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.29 (s, 2H), 7.70 (dd, J=10.0, 2.4 Hz, 2H), 7.43 (dd, J=8.8, 4.8 Hz, 2H), 7.19 (td, J=9.2, 2.4 Hz, 2H), 4.05 (s, 3H), 3.43-3.55 (m, 4H), 2.40-2.30 (m, 4H).
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][CH2:7][CH2:8][O:9][CH:10](O)[CH3:11])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([OH:27])[CH2:16][O:17][CH2:18][CH2:19][O:20]CCOCCO.CC([Si](Cl)(C)C)(C)C.N1C=CN=C1>CN(C=O)C>[C:1]([Si:5]([CH3:14])([CH3:13])[O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:27][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCCOCCOCCOCCO
Reactant: CC(O)OCCO[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOCCOCCOCCO

Procedure:
Compound 28b was prepared according to the procedure described hereinabove for Compound 28a, using tetraethylene glycol (6 grams, 30 mmol), TBDMSCl (3 grams, 20 mmol), and imidazole (1.4 grams, 20 mmol) in DMF (24 ml), yielding 3.79 grams of the product (41% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]([CH3:26])([CH3:25])[CH2:6][C:7]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:14]2[C:9](=[N:10][C:11]([OH:24])=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2].Cl[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:1]([O:3][C:4](=[O:27])[C:5]([CH3:26])([CH3:25])[CH2:6][C:7]1[N:15]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[C:14]2[C:9](=[N:10][C:11]([O:24][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2]
Reactant: ClCc1ccccn1
Reactant: CCOC(=O)C(C)(C)Cc1cc2nc(O)ccc2n1Cc1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C(C)(C)Cc1cc2nc(OCc3ccccn3)ccc2n1Cc1ccc(Cl)cc1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
3-[1-(4-Chlorobenzyl)-5-hydroxy-1H-pyrrolo[3,2-b]pyridin-2-yl]-2,2-dimethyl-propionic acid ethyl ester (0.100 g, 0.26 mmol) was dissolved in acetone (2 mL), and 2-chloromethyl-pyridine (0.064 g, 0.39 mmol), tetrabutylammonium iodide (0.095 g, 0.26 mmol) and K2CO3 (0.107 g, 0.77 mol) were added. The mixture was stirred at 65° C. overnight, and two products were observed by TLC analysis. The reaction was cooled to room temperature, diluted with water, and extracted with EtOAc three times. The combined organic layers were washed with water, brine, dried over MgSO4, filtered, and concentrated to give a 1:2 mixture of the O-alkylated and N-alkylated products. The crude material was purified by preparative TLC to obtain the O-alkylated title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[CH2:22][CH:21]3[OH:36])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:38][C:39]1[CH:40]=[CH:41][C:42]2[O:47][CH2:46][C:45](=[O:48])[N:44]([CH2:49][CH2:50][CH2:51][O:52][CH3:53])[C:43]=2[CH:54]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:15]=[CH:16][C:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[CH2:22][CH:21]3[O:36][CH2:38][C:39]3[CH:40]=[CH:41][C:42]4[O:47][CH2:46][C:45](=[O:48])[N:44]([CH2:49][CH2:50][CH2:51][O:52][CH3:53])[C:43]=4[CH:54]=3)=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(C3CCN(C(=O)OCc4ccccc4)CC3O)cc2)C1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(O[C@H]4CCN(C(=O)OC(C)(C)C)C4)cc3)cc21

Procedure:
Analogously to Method D, 0.980 g of benzyl 4-[4-(1-tert-butoxycarbonylpyrrolidin-3(S)-yloxy)phenyl]-3-hydroxypiperidine-1-carboxylate and 0.572 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one are reacted. The title compound is obtained as a yellowish oil. Rf=0.14 (1:1 EtOAc-heptane). Rt=5.63.
Reaction SMILES: COC=CC#[N:6].[F:7][C:8]([F:24])([F:23])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([O:21]C)(OC)[CH2:16][C:17]#[N:18])=[CH:11][CH:10]=1.NO.Cl.C[O-].[Na+]>CO>[F:7][C:8]([F:24])([F:23])[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:21][N:6]=[C:17]([NH2:18])[CH:16]=2)=[CH:11][CH:10]=1
Reactant: COC=CC#N
Reactant: COC(CC#N)(OC)c1ccc(C(F)(F)F)cc1
Agent: C[O-]
Agent: Cl
Agent: NO
Solvent: CO
Product: Nc1cc(-c2ccc(C(F)(F)F)cc2)on1
Temperature: 20 °C

Procedure:
3-(4-Trifluoromethyl)phenyl)-3-methoxyacrylonitrile plus 3-(4-(trifluoromethyl)phenyl)-3,3-dimethoxypropionitrile (1330 grams as a mixture) and hydroxylamine.HCl (1180 grams) were dissolved in methanol and chilled to 20° C. in an ice-bath. Next sodium methylate (1890 grams) was added portionwise over a 11/2 hour period keeping the temperature between 20°-30° C. The reaction mixture was then heated to reflux for about 17 hours and then cooled to 40° C. and filtered. After the filtrate was stripped and poured into ice-water with stirring, a light yellow solid precipitate formed which was filtered and identified by NMR analysis as the desired product, yield 994 grams.
Reaction SMILES: C[C@]12C(C)(C)[C@H](CC1)C[C@H]2NCCN[C@@H]1C[C@@H]2C(C)(C)[C@@]1(C)CC2.[C:25]1([CH2:31][O:32][CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=2)[CH:40]=[O:41])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[N+:45]([CH3:48])([O-:47])=[O:46].C(N(C(C)C)CC)(C)C.Cl>O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.COC(C)(C)C.C(O)C>[N+:45]([CH2:48][C@H:40]([C:39]1[CH:42]=[CH:43][CH:44]=[C:37]([O:36][CH2:35][CH2:34][CH2:33][O:32][CH2:31][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:38]=1)[OH:41])([O-:47])=[O:46]
Reactant: O=Cc1cccc(OCCCOCc2ccccc2)c1
Reactant: C[N+](=O)[O-]
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CC1(C)[C@@H]2CC[C@@]1(C)[C@H](NCCN[C@@H]1C[C@H]3CC[C@]1(C)C3(C)C)C2
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: COC(C)(C)C
Product: O=[N+]([O-])C[C@@H](O)c1cccc(OCCCOCc2ccccc2)c1
Temperature: 55 °C
Reaction time: 0.08 h

Procedure:
Copper (II) acetate monohydrate (3.70 g, 0.05 eq) and bis-camphorethylenediamine (N1,N2-bis[(1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1,2-ethanediamine) (7.38 g, 0.06 eq) were charged to a reactor, followed by ethanol (200 mL, 2 vol). The contents were heated to 50-60° C. for ˜1 h or until all solids dissolved, then cooled to room temperature and stirred, at which time a solution of 3-({3-[(phenylmethyl)oxy]propyl}oxy)benzaldehyde in ethanol (100 g, 1 eq in 50 mL, 0.5 vol) was charged. The reaction mixture was cooled to −10° C. to −20° C., whereupon nitromethane (112.7 g, 5 eq) was added slowly to the reaction, maintaining a temperature below −10° C., followed by diisopropylethylamine (1.94 mL, 1.44 g, 0.03 eq). The reaction temperature was maintained at −10° C. for ˜22-30 h. When the reaction was complete, a room temperature solution of 1 N HCl (250 mL, 2.5 vol) and t-butyl methyl ether (TBME, 500 mL, 5 vol) were charged to the reaction vessel. Following the addition, the contents were stirred for ˜5 minutes and brought to 20° C. (˜room temperature), and then the layers were allowed to separate and the aqueous phase removed. The organic phase was then washed 2× with water (250 mL, 2.5 vol) and each time the aqueous phase removed. TBME was then distilled off and replaced with absolute ethanol.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:12]2[N:13]=[C:14]([CH2:33][CH2:34][CH2:35][CH3:36])[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][S:21]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1>CO.[Pd]>[ClH:1].[NH2:2][C:3]1[C:12]2[N:13]=[C:14]([CH2:33][CH2:34][CH2:35][CH3:36])[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][S:21]([C:24]3[CH:25]=[CH:26][C:27]([NH2:30])=[CH:28][CH:29]=3)(=[O:23])=[O:22])[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)c1ccc(N)cc1
Reaction time: 2 h
Yield: 94.8 %

Procedure:
A solution of N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl) butyl]-4-nitro-1-benzenesulfonamide hydrochloride (0.38 g) in methanol (250 ml) was charged with a catalytic amount of 10% palladium on carbon (0.085 g). The reaction was placed under an atmosphere of hydrogen (50 psi; 3.44×105 Pa)) and shaken on a Parr apparatus for 2 hours. The reaction mixture was filtered and the solvent removed in vacuo. The solid product was recrystallized from 2-propanol to provide 0.34 g of N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-amino-1-benzenesulfonamide hydrochloride as an off white powder, m.p. 203.1-205.0° C. 1H NMR (300 MHz, DMSO-d6) δ 8.65 (very broad s, 2H), 8.21(d, J=8.0 Hz, 1H), 7.82 (m, 1H), 7.71 (t, J=7.7 Hz, 1H), 7.58 (t, J=7.7 Hz, 1H), 7.38 (d, J=8.7 Hz, 2H), 7.13 (t, J=5.9 Hz, 1H), 6.60 (d, J=8.7 Hz, 2H), 5.92 (broad s, 2H), 4.55 (t, J=7.6 Hz, 2H), 2.96 (t, J=7.6 Hz, 2H), 2.70 (q, J=6.4 Hz, 2H), 1.81 (m, 4H), 1.58-1.43 (m, 4H), 0.96 (t, J=7.4 Hz, 3H); IR (KBr) 3430, 3316, 3046, 2955, 2868, 2679, 1671, 1594, 1334, 1157, 1091, 851, 776, 759 cm−1; MS (EI) m/e 466.2145 (466.2151 calcd for C24H30N6O2S). Anal calcd for C24H30N6O2S*HCl: C, 57.30; H, 6.21; N, 16.71. Found: C, 57.36; H, 6.31; N, 16.21.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][C@@H:8]([CH3:11])[CH:9]=O)([CH3:4])([CH3:3])[CH3:2].[CH3:13]OP(C(=[N+]=[N-])C(=O)C)(=O)OC.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C.[Cl-].[Na+]>[CH3:11][C@H:8]([NH:7][C:6](=[O:12])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:9]#[CH:13]
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Reactant: C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#C[C@H](C)NC(=O)OC(C)(C)C
Yield: 52.8 %

Procedure:
A solution of (S)-tert-butyl(1-oxopropan-2-yl)carbamate (500 mg, 2.89 mmol), dimethyl(1-diazo-2-oxopropyl)phosphonate (610 mg, 3.18 mmol, 1.1 equiv), and potassium carbonate (638 mg, 4.62 mmol, 1.6 equiv) in methanol (14.4 mL) was stirred at room temperature for 18 hours. The reaction was then diluted with ethyl acetate (30 mL) and saturated aqueous sodium chloride (40 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (30 mL) and the combined organic extracts were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (20% EtOAc in Heptane) provided (S)-tert-butyl but-3-yn-2-ylcarbamate (0.258 g, white solid) in 53% yield. 1H NMR (400 MHz, CDCl3) δ 4.49 (m, 1H), 2.26 (d, J=2.2 Hz, 1H), 1.46 (s, 9H), 1.41 (d, J=6.8 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH2:14][C:13]([C:15]([O:17]C)=[O:16])=[C:12]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:11][C:10]=2[C:27]([O:29]C)=[O:28])=[CH:4][CH:3]=1.[Na].[N+](C1C=C(S(O)(=O)=O)C=CC=1)([O-])=O.[OH-].[Na+].Cl>O.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[CH:11][C:10]=2[C:27]([OH:29])=[O:28])=[CH:6][CH:7]=1
Reactant: COC(=O)C1=C(Nc2ccc(Cl)cc2)CC(C(=O)OC)=C(Nc2ccc(Cl)cc2)C1
Agent: Cl
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)O)c1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(Nc2ccc(Cl)cc2)c(C(=O)O)cc1Nc1ccc(Cl)cc1
Yield: 95.9 %

Procedure:
Dimethyl 2,5-bis{(4-chlorophenyl)amino}cyclohexa-1,4-diene-1,4-dicarboxylate (4.47 gm, 10 mmol), the sodium salt of 3-nitrobenzenesulphonic acid (2.3 gm; 10 mmol), ethanol (70 ml) and 1.0M sodium hydroxide (40 ml) were heated to reflux overnight under a nitrogen atmosphere. The bright yellow solution was allowed to cool and water (120 ml) was added. The mixture was acidified with conc. hydrochloric acid when a red solid precipitated out. This material was filtered off, washed with water and dried under vacuum over phosphorous pentoxide to give 4.0 gm (96%) of 2,5-bis{(4-chlorophenyl)amino}terephthalic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCO[CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[NH:1]([CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccccc1)C(=O)OCC

Procedure:
Freshly distilled aniline (46.5 g) and diethyl ethoxymethylene malonate (108 g) were heated together on a steam bath for two hours. The ethanol formed in the reaction was then evaporated off under vacuum to give the intermediate diethyl (anilinomethylene)malonate, m.p. 48° C.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:11](=[O:12])[C:10]([CH3:13])=[CH:9][N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:7]=1)=[O:5].[CH3:25][Mg]Br>C1COCC1>[C:4]([C:6]1[C:11](=[O:12])[C:10]([CH3:13])=[CH:9][N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=2)[N:7]=1)(=[O:5])[CH3:25]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1nn(-c2cccc(C(F)(F)F)c2)cc(C)c1=O
Solvent: C1CCOC1
Product: CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)cc(C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a solution of N-methoxy-N,5-dimethyl-4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxamide (0.535 g, 1.6 mmol) in THF (10 mL) at −78° C. was added methylmagnesium bromide (1.1 mL, 3.2 mmol, 3 M in diethyl ether). The reaction was stirred at that temperature for 1 h then quenched with saturated ammonium chloride aqueous solution (5 mL) then water (2 mL) with slow warming to room temperature. The reaction mixture was diluted with ethyl acetate (20 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×10 mL) and the combined organic extracts are washed with 1 N HCl aqueous solution (15 mL), brine (15 mL), dried (Na2SO4), filtered and concentrated to provide 3-acetyl-5-methyl-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (0.463 g, 98%) as a light yellow solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:12][C@H:11]([CH3:13])[O:10][C@H:9]([CH3:14])[CH2:8]2)=[N:4][C:3]=1[C:15]#[N:16].[CH3:17][C:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[C:20]([CH3:27])[N:19]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][C@H:9]1[O:10][C@@H:11]([CH3:13])[CH2:12][N:7]([C:5]2[S:6][C:2]([C:22]3[CH:21]=[C:20]([CH3:27])[N:19]=[C:18]([CH3:17])[CH:23]=3)=[C:3]([C:15]#[N:16])[N:4]=2)[CH2:8]1
Reactant: C[C@@H]1CN(c2nc(C#N)c(Br)s2)C[C@H](C)O1
Reactant: Cc1cc(B(O)O)cc(C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1cc(-c2sc(N3C[C@@H](C)O[C@@H](C)C3)nc2C#N)cc(C)n1
Temperature: 130 °C
Yield: 85 %

Procedure:
A mixture of Intermediate 3 (20 g, 66.18 mmol), 2,6-dimethylpyridine-4-boronic acid, pinacol ester ([325142-95-8], 20 g, 85.79 mmol), tetrakis(triphenylphosphine)palladium (4.59 g, 3.97 mmol), 1,4-dioxane (120 mL), sodium carbonate (21.04 g, 198.55 mmol) in ethanol/water 1/1 (120 mL) was stirred and heated under nitrogen atmosphere at 130° C. for 6 h. The solvent was evaporated. The residue was taken up in DCM and washed twice with water. The organic layer was separated, dried with MgSO4 and evaporated. The residue was purified by column chromatography on silica gel (eluent gradient from 100% DCM to 98/2 DCM/MeOH). The desired fractions were collected and evaporated. The resulting residue was recrystallized from DIPE/CH3CN, yielding 18.5 g (85%) of Intermediate 4, after drying overnight under vacuum at 50° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)[C:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(O)(=O)C>[Fe].CO>[CH2:1]([C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[C:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CC(=O)OC)n1Cc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCc1nc(Cl)c(CC(=O)OC)n1Cc1ccc(N)cc1
Yield: 98.5 %

Procedure:
A mixture of methyl 2-butyl-4-chloro-1-(4-nitrobenzyl)imidazole-5-acetate (5.00 g, 13.7 mmol, 1 eq), iron (2.67 g, 47.8 mmol, 3.5 eq), glacial acetic acid (5.47 mL, 95.3 mmol, 7 eq), and methanol (250 mL) was refluxed for 5.5 hours. The solvent was removed by rotary evaporation. The residue was diluted with water (300 mL) and extracted five times with 300 mL portions of ethyl acetate. The organic layers were dried and concentrated. The residue was flash chromatographed in 75:25 hexane/ethyl acetate over silica gel to give 4.53 g of a golden yellow oil which crystallized after standing for several days. NMR (200 MHz, CDCl3) δ 6.72 (d, 2H, J=7 Hz); 6.60 (d, 2H, J=7 Hz); 4.99 (s, 2H); 3.61 (s, 3H); 3.47 (s, 2H); 2.60 (t, 2H, J=7 Hz); 1.68 (m, 2H); 1.35 (m, 2H); 0.86 (t, 3H, J=7 Hz). Mass spectrum shows M+=355/337. Mass Calcd. for C17H22N3O2Cl: 335.1400. Found: 335.1407.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([S:11]([OH:14])(=O)=[O:12])[CH:7]=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2].C(N(CC)CC)C.CN(C)C(=O)C.O=P(Cl)(Cl)[Cl:30]>C1S(=O)(=O)CCC1.C(#N)C>[C:1]([C:4]1[CH:5]=[C:6]([S:11]([Cl:30])(=[O:14])=[O:12])[CH:7]=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)c1cc(S(=O)(=O)O)ccc1O
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: CC(=O)c1cc(S(=O)(=O)Cl)ccc1O
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A mixture of 3-acetyl-4-hydroxy-benzenesulfonic acid (3.0 g) (prepared according to T. Pfliegel et. al., Acta Chim. Acad. Sci. Hung., 98(2) 231-240(1978)) in tetramethylenesulfone (6 mL) and acetonitrile (6 mL) under argon was treated with triethylamine (1.94 mL) and N,N-dimethylacetamide (0.32 mL). This was stirred for 30 min and POCl3 was added dropwise maintaining the temperature below. 25° C. The reaction was stirred for 24 hr, cooled to 10° C. and quenched with water (15 mL). This mixture was warmed to 60° C. and stirred for 1 hr, at which point a precipitate formed which was then filtered and dried to give 2.34 g (72%) of 3-acetyl-4-hydroxybenzenesulfonylchloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH3:22][CH:23]([C:25]1[O:29][N:28]=[C:27]([CH2:30][NH2:31])[CH:26]=1)[CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:31][CH2:30][C:27]2[CH:26]=[C:25]([CH:23]([CH3:24])[CH3:22])[O:29][N:28]=2)=[O:15])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Reactant: CC(C)c1cc(CN)no1
Product: CC(C)c1cc(CNC(=O)c2cnc(OCC3CC3)c(-c3ccc(Cl)cc3)c2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-cyclopropylmethoxy-nicotinic acid (CAS Registry No. 1018782-76-7) and 5-(1-methylethyl)-3-isoxazolemethanamine (CAS Registry No. 154016-49-6) as starting materials, 426.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[N+:9]([O-])([OH:11])=[O:10].ClC1C=C(O)C([N+]([O-])=O)=CC=1Cl>>[Cl:1][C:2]1[C:3]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccccc1Cl
Agent: O=[N+]([O-])c1cc(Cl)c(Cl)cc1O
Product: O=[N+]([O-])c1cccc(Cl)c1O

Procedure:
6-chloro-2-nitrophenol (12A) was prepared by treating 2-chlorophenol with nitric acid according to the procedure described for preparing 9A, in Example 9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[C:10]([CH2:17][N:18]2[C:22](=[O:23])[N:21]([CH2:24][CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[C:20]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)=[N:19]2)[CH:9]=1.C1C=CC2N(O)N=[N:44]C=2C=1.C(Cl)CCl.N>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([NH2:44])=[O:16])=[C:10]([CH2:17][N:18]2[C:22](=[O:23])[N:21]([CH2:24][CH:25]([OH:30])[C:26]([F:28])([F:29])[F:27])[C:20]([C:31]3[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=3)=[N:19]2)[CH:9]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc(-c2ccccc2Cl)cc1Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O
Agent: N
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: NC(=O)c1ccc(-c2ccccc2Cl)cc1Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
43 mg (0.08 mmol) of the compound from Example 132 were initially charged in 1 ml of DMF, and 14 mg (0.10 mmol) of HOBt and 19 mg (0.10 mmol) of EDC were added. After 10 min of stirring at RT, 0.41 ml (0.20 mmol) of ammonia solution (35% strength in water) was added, and the mixture was stirred at RT for 16 h. Under reduced pressure, the reaction solution was then freed of excess ammonia, about 3 ml of water were added and the mixture was extracted three times with in each case 5 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 1:3→1:5). This gave 19 mg (42% of theory) of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5](Cl)=[N:6][CH:7]=1.[O-:20][CH2:21][CH3:22].[Na+].C(=O)(O)[O-].[Na+].Cl>>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5]([O:20][CH2:21][CH3:22])=[N:6][CH:7]=1
Reactant: CC[O-]
Reactant: O=S(=O)(Nc1cc(Br)cnc1Cl)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOc1ncc(Br)cc1NS(=O)(=O)c1ccc(O)cc1
Yield: 94 %

Procedure:
N-(5-Bromo-2-chloropyridin-3-yl)-4-hydroxybenzenesulfonamide (264 mg, 0.55 mmol) and sodium ethoxide (21% in ethanol, 10 ml, 27 mmol) were stirred at 120° C. for 90 min under microwave conditions. The reaction mixture was poured into sodium bicarbonate saturated solution, neutralized with concentrated chlorhydric acid and extracted with ethyl acetate (×3). The organic phase was dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure to obtain 211 mg (94% yield, 91% purity) of the title compound, which was used in the next synthetic step without further purification.