Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)Cl>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:4]1[C:3]([O:2][CH3:1])=[N:7][N:6]([CH3:8])[C:5]1=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1nn(C)c(=O)n1-c1ccccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1nn(C)c(=O)n1-c1ccccc1CBr
Yield: 34.2 %

Procedure:
To a solution/suspension of 6.7 g 2,4-dihydro-5-methoxy-2-methyl-4-(2-methylphenyl)-3H-1,2,4-triazol-3-one dissolved in 95 mL carbon tetrachloride under N2 was added N-bromosuccinimide (6.53 g) followed by a catalytic amount of benzoyl peroxide. The solution was heated at reflux for 2 h. Another 1.63 g N-bromosuccinimide and a catalytic amount of benzoyl peroxide were added and the solution was heated at reflux for an hour. After cooling, methylene chloride was added and the organic layer was washed successively with water, the 0.1 N sodium thiosulfate solution, then saturated aqueous NaCl. The combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (3-10% diethylether/methylene chloride as eluent) to afford 3.12 g of the title compound of Step D. 1H NMR (CDCl3) δ 7.5 (m,1H), 7.44 (m,2H), 7.22 (m,1H), 4.60 (d,1H), 4.36 (d,1H), 3.96 (s,3H), 3.47 (s,3H).
Reaction SMILES: [C:1]1([CH:7]([N:14]2[CH2:17][CH:16]([CH2:18][OH:19])[CH2:15]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[C:1]1([CH:7]([N:14]2[CH2:17][CH:16]([CH2:18][O:19][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:15]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Yield: 99 %

Procedure:
The title compound from Step B above (1.7 g, 6.72 mmoles) and triethylamine (1.1 g, 10.87 mmoles) were dissolved in CH2Cl2 (20 mL) and the mixture was stirred under nitrogen at 0° C. Methanesulfonylchloride (1.1 g, 9.6 mmoles) was added and the solution was stirred at room temperature for 2 h. The solution was diluted with CH2Cl2 and washed with saturated aqueous sodium bicarbonate, water and dried (MgSO4), filtered and evaporated to dryness to give the title compound (2.32 g, 99%). FABMS (M+1)=332.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH:19]=4)=[N:15][C:14]=3[C:28](O)=[O:29])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([O:38][C:39](=[O:47])[C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([NH2:46])[CH:41]=1)C1C=CC=CC=1>>[C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH:19]=4)=[N:15][C:14]=3[C:28]([NH:46][C:42]3[CH:41]=[C:40]([CH:45]=[CH:44][CH:43]=3)[C:39]([OH:47])=[O:38])=[O:29])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C(O)c1nc(-c2ccc3ccccc3c2)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Reactant: Nc1cccc(C(=O)OCc2ccccc2)c1
Product: O=C(O)c1cccc(NC(=O)c2nc(-c3ccc4ccccc4c3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-naphthalen-2-yl-1H-imidazole-4-carboxylic acid (Example 44) was reacted with 3-amino-benzoic acid benzyl ester according to the procedure of Example 20, step d. The benzyl ester was deprotected according to the procedure of Example 20, step e to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 12.91 (1H, br s), 9.90 (1H, br s), 8.54 (2H, d), 8.27 (1H, dd), 8.04-7.94 (4H, m), 7.65-7.44 (4H, m), 3.04 (2H, m), 1.98 (3H, br s), 1.66 (6H, m), 1.58 (6H, s), 1.45 (2H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 63.85; H, 7.57; N, 7.80%; C40H50N4O8.1.9 H2O requires: C, 64.12; H, 7.24; N, 7.48%.
Reaction SMILES: Cl[C:2]1[C:3]([C:20]([NH2:22])=[O:21])=[N:4][C:5]([CH2:18][CH3:19])=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:7]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.CS(O)(=O)=O.C(=O)([O-])O.[Na+]>CN1CCCC1=O>[CH2:18]([C:5]1[N:4]=[C:3]([C:20]([NH2:22])=[O:21])[C:2]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([N:27]3[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]3)=[CH:36][CH:35]=2)=[N:7][C:6]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[CH3:19]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CCc1nc(C(N)=O)c(Cl)nc1Oc1cccc([N+](=O)[O-])c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Oc1cccc([N+](=O)[O-])c1
Temperature: 200 °C
Yield: 41.6 %

Procedure:
A mixture of 3-chloro-6-ethyl-5-(3-nitrophenoxy)pyrazine-2-carboxamide (500 mg), 4-(4-methylpiperazin-1-yl)aniline (300 mg), methanesulfonic acid (201 μl), and N-methylpyrrolidone (2 mL) was heated in a microwave reaction device at 200° C. for 1 hour. To the reaction mixture was added 4-(4-methylpiperazin-1-yl)aniline (150 mg) and the mixture was heated at 200° C. for 30 minutes. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the precipitated solid was collected by filtration and then dried. The obtained solid was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-200:10:1) to obtain 6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(3-nitrophenoxy)pyrazine-2-carboxamide (308 mg) as a yellow solid.
Reaction SMILES: [ClH:1].C[C:3]1C=C2[C:6]([NH:7]C=C2CCN)=[C:5](Br)[CH:4]=1.Cl.[CH3:17][C:18]([C:21]1[CH:26]=[CH:25][C:24]([NH:27]N)=[CH:23][CH:22]=1)([CH3:20])[CH3:19]>>[ClH:1].[CH3:17][C:18]([C:21]1[CH:26]=[C:25]2[C:24]([NH:27][CH:3]=[C:4]2[CH2:5][CH2:6][NH2:7])=[CH:23][CH:22]=1)([CH3:20])[CH3:19]
Reactant: Cc1cc(Br)c2[nH]cc(CCN)c2c1
Reactant: CC(C)(C)c1ccc(NN)cc1
Agent: Cl
Product: CC(C)(C)c1ccc2[nH]cc(CCN)c2c1

Procedure:
5-(1,1-dimethylethyl)-tryptamine hydrochloride was prepared (2.95 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 7, except using 4-(1,1-dimethylethyl) phenylhydrazine hydrochloride (6.00 g) as starting material. ##STR54##
Reaction SMILES: [N:1](C(OCC1C=CC=CC=1)=O)([CH2:3][C:4]([NH:6][C@H:7]([C:14]([NH:16][C@H:17]([C:30]([O:32][CH3:33])=[O:31])[CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:15])[CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)=[O:5])[CH3:2].C(=O)=O>CO>[NH:1]([CH2:3][C:4]([NH:6][C@H:7]([C:14]([NH:16][C@H:17]([C:30]([O:32][CH3:33])=[O:31])[CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:15])[CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)=[O:5])[CH3:2]
Reactant: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)CN(C)C(=O)OCc1ccccc1
Agent: O=C=O
Solvent: CO
Product: CNCC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC

Procedure:
390 mg of Z-Sar-His-Lys(Boc)-OMe are dissolved in 10 ml of 95% strength MeOH and, after the addition of 40 mg of Pd-on-carbon, hydrogenated with CO2 -absorption until saturation. The catalyst is filtered off, the filtrate is concentrated to dryness and the amorphous residue is dried to constant weight in a high vacuum at 40°, yielding H-Sar-His-Lys(Boc)-OMe; Rf (G)=0.1; Rf (E)=0.25.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH:23]=[CH:22][C:21]([CH3:24])=[N:20]1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[CH:23]=[CH:22][C:21]([CH3:24])=[N:20]2)=[O:11])=[N:27][CH:28]=1
Reactant: Cc1ccc(-n2ccc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Clc1ccc(Br)nc1
Product: Cc1ccc(-n2ccc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(Cl)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)methanone and 2-bromo-5-chloropyridine. ESI-MS (m/z): 438 [M+1]+.
Reaction SMILES: [Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.Cl.C[N:14](C)[CH2:15][CH2:16]CN=C=NCC.C(N)C>ClCCl>[Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH:14][CH2:15][CH3:16])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)C(Br)c1ccccc1
Agent: CCN
Agent: Cl
Solvent: ClCCl
Product: CCNC(=O)C(Br)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.4 %

Procedure:
A mixture of 1.0 g (4.65 mmol) alpha-bromophenylacetic acid (Aldrich), 1.16 g (6.05 mmol) (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (Aldrich), 2.80 mL (5.6 mmol) ethyl-amine (Aldrich, 2 M in dichloromethane) in dichloromethane (30 mL) is stirred at room temperature for 18 h. The reaction mixture is washed with NaOH 1 M (15 mL) and the organic phase is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (gradient: cyclohexane/ethyl acetate 90:10 to 50:50) to yield the title compound (0.32 g, content ca. 90%).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([F:36])([F:35])[F:34])=[C:23]([CH3:37])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl.C([O:45]CC)C.CCCCCC>CC(C)=O>[CH3:37][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([OH:45])=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:34])([F:36])[F:35]
Reactant: CCOCC
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Reaction time: 8 h

Procedure:
To a solution of 2,2,2-trichloro-1-(10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)ethanone of Step E (2.3 g, 3.9 mmol) in acetone (20 mL) was added 2.5 N sodium hydroxide (3.1 mL, 7.8 mmol). After stirring overnight, the reaction mixture was acidified with 2 N hydrochloric acid (4.3 mL, 8.6 mmol) and then concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown solid. Trituration with diethyl ether/hexane provided the title compound (1.32 g) as a white solid, m.p. 233-235° C.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]#[CH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N:16]=[N+:17]=[N-:18])(C)C>CN(C=O)C.CO.[Cu]I>[N:16]1[NH:17][N:18]=[C:10]([CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH:11]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: [Cu]I
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cn[nH]n1
Temperature: 100 °C
Yield: 98 %

Procedure:
To a solution of N-Boc-propargyl amine (1.60 g, 10.3 mmol) in a mixture of DMF:MeOH (4:1, 10 mL) was added trimethylsilylazide (2.0 mL, 15.2 mmol) and CuI (95 mg, 0.50 mmol). The resulting mixture was heated to 100° C. for 16 h, whereupon it was concentrated in vacuo and purified via silica gel chromatography, affording the title compound (2.0 g, 99%) as a light yellow oil; LCMS: m/z=196.9 (M−1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=O.C([O:14][C:15]([NH:17][NH2:18])=[S:16])C>C(#N)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[CH2:2][S:16][C:15](=[O:14])[NH:17][N:18]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=S)NN
Reactant: O=C(CBr)c1ccc(Cl)cc1
Solvent: CC#N
Product: O=C1NN=C(c2ccc(Cl)cc2)CS1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-bromo-1-(4-chloro-phenyl)-ethanone (90.71 mmoles) and hydrazine-carbothioic acid O-ethyl ester (90.71 mmoles) in acetonitrile (84 ml) is stirred at ambient temperature for 3 hours. The solid formed is filtered off, washed with acetonitrile and ethyl ether and then dried in vacuo to yield the title product, which is used directly in the next Step.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:5][N:4]=1.[OH-].[NH4+].[CH:19](O)=[O:20]>>[CH:19]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:5][N:4]=1)=[O:20]
Reactant: O=CO
Reactant: COC(=O)CCCCc1ccc(CN)nc1
Agent: [NH4+]
Agent: [OH-]
Product: COC(=O)CCCCc1ccc(CNC=O)nc1

Procedure:
2-Aminomethyl-5-(4-methoxycarbonylbutyl)pyridine (0.20 g) is heated at 90° in 0.6 ml of formic acid for 18 hours. The mixture is cooled to 0°, made basic with saturated ammonium hydroxide solution and extracted with methylene chloride (4×15 ml). Drying, filtration and evaporation of the extracts yields 2-(N-formylaminomethyl)-5-(4-methoxycarbonylbutyl)pyridine as an oil (IR 1720, 1675 cm-1) which is redissolved in 1 ml of toluene and heated at 90° for 18 hours with phosphorus oxychloride (0.166 g). Evaporation of excess phosphorus oxychloride with toluene, basification at 0° with saturated ammonium hydroxide solution, extraction with methylene chloride (4×15 ml) and drying over sodium sulfate yields an oil which is chromatographed (silica gel, ethyl acetate) to yield 6-(4-methoxycarbonylbutyl)-imidazo[1,5-a]pyridine; Rf=0.26; NMR (CDCl3) 3.58 (s, 3H), 6.45 (d, 1H), 7.25 (d, 1H), 7.38 (s, 1H), 7.62 (s, 1H), 7.94 (s, 1H); IR (CH2Cl2) 1730 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]1(Br)[CH2:13][CH2:12][CH2:11][CH2:10]1.[OH-].[Na+].CN(C=O)C>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: BrC1CCCC1
Reactant: Oc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(OC2CCCC2)cc1
Temperature: 100 °C
Reaction time: 13.5 h
Yield: 83.3 %

Procedure:
A mixture of 4-bromophenol (40 g, 231 mmol), cyclopentylbromide (50 ml, 462 mmol), NaOH (18.5 g, 462 mmol) and DMF (150 mL) was stirred at 100° C. for 13.5 h, poured into water (300 mL) and extracted with t-BuOMe (4×100 mL). The combined organic extracts were washed with water (2×100 mL), brine, dried (Na2SO4), concentrated and distilled in vacuo to yield the sub-title compound (46.4 g, 94%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH3:23])=[N:16][N:15]3[C:24]=2I)=[CH:8][CH:7]=1.[C:26]([Cu])#[N:27]>CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH3:23])=[N:16][N:15]3[C:24]=2[C:26]#[N:27])=[CH:8][CH:7]=1
Reactant: N#C[Cu]
Reactant: CCCOc1ccc2nc(-c3ccc(OCCOC)cc3)c(I)n2n1
Solvent: CN(C)C=O
Product: CCCOc1ccc2nc(-c3ccc(OCCOC)cc3)c(C#N)n2n1

Procedure:
A mixture of 2-[4-(2-methoxyethoxy)phenyl]-3-iodo-6-propoxyimidazo[1,2-b]pyridazine (100 mg, 0.22 mmol), cuprous cyanide (22 mg, 0.24 mmol) and N,N-dimethylformamide (2 mL) was heated at 80° for 22 hours. More CuCN (10 mg) was added and the mixture heated at 100° for 29 hours. Aqueous ferric chloride solution (5%, acidified with HCl) (7 mL) was added and the resulting mixture heated at 60° for 30 minutes. The resulting suspension was filtered and the collected solid washed with saturated, aqueous sodium bicarbonate solution, water (twice) and air-dried overnight. The beige coloured solid was radially chromatographed on silica gel. Elution with 0-1% methanol in dichloromethane provided Compound 110 (50 mg, 64%) as a brilliant white solid. 1H n.m.r. (CDCl3) δ 1.06, t, J=7.4 Hz, 3H; 1.76-1.96, m, 2H; 3.47, s, 3H; 3.74-3.82, m, 2H; 4.15-4.22, m, 2H; 4.37, t, J=6.6 Hz, 2H; 6.88, d, J=9.5 Hz, 1H; 7.04, d, J=8.8 Hz, 2H; 7.82, d, J=9.5 Hz, 1H; 8.09, d, J=8.7 Hz, 2H. Mass spectrum (APCI+) m/z 353 (M+H, 100%). Further elution afforded recovered starting material (21 mg, 21%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:11][S:12](O)(=[O:14])=[O:13]>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([S:12]([Cl:11])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccccc1Br
Reactant: O=S(=O)(O)Cl
Product: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Br
Temperature: 115 °C
Reaction time: 0.25 h

Procedure:
2-Bromobenzoic acid (10.2 g, 50.8 mmol) was added in several portions to chlorosulfonic acid (50 mL) at 0° C. and the resulting solution held at this temperature for 15 minutes. The mixture was then heated at 115° C. for 16 hours. The reaction mixture was cooled to room temperature and was cautiously added drop-wise onto ice. The resulting suspension was allowed to reach room temperature and filtered. The solid was dried under vacuum at 40° C. for 16 hours. The title compound was obtained as a beige solid 85% yield, 12.8 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[SH:12].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[OH:22])[CH:17]=O>CN(C=O)C>[Br:13][C:14]1[CH:15]=[C:16]([CH:17]2[NH:1][C:2]3[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=3[S:12]2)[CH:19]=[CH:20][C:21]=1[OH:22]
Reactant: O=Cc1ccc(O)c(Br)c1
Reactant: Nc1cc(C(F)(F)F)ccc1S
Solvent: CN(C)C=O
Product: Oc1ccc(C2Nc3cc(C(F)(F)F)ccc3S2)cc1Br
Temperature: 100 °C
Yield: 10.5 %

Procedure:
In a DMF (3 mL) solvent, a solution including 2-amino-4-trifluoromethylbenzenethiol (100 mg, 0.44 mmol) and 3-bromo-4-hydroxybenzaldehyde (88.4 mg, 0.44 mmol) was heated at a temperature of 100° C. for 2.5 hours. After DMF was evaporated, the residual was distributed between methylene chloride and water, and an organic layer was evaporated. The produced solid was filtered, and washed with ethyl acetate to obtain a solid Compound 119.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)[Cl:13]>>[CH:1]1([CH2:7][C:8]([Cl:13])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CC1CCCCC1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CC1CCCCC1
Reaction time: 1.5 h

Procedure:
Cyclohexyl acetic acid (2.5 g; 0.02 moles) was mixed with SOCl2 (3.7 cc; 0.05 moles) and the resulting solution was kept at 80° C. for 1.5 hours. The mixture was concentrated under vacuum and some washings were carried out with anhydrous toluene to remove SOCl2. The mixture was then dried under vacuum and the title product was obtained as a raw material which was used as such in the next step (b).
Reaction SMILES: C1C[O:4][CH2:3]C1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:18][C:19]1[C:28]([NH2:29])=[C:27]([NH:30][CH2:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.O>N1C=CC=CC=1>[Cl:18][C:19]1[C:28]2[N:29]=[C:3]([OH:4])[N:30]([CH2:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: Nc1c(Cl)nc2ccccc2c1NCC1CCOCC1
Reactant: C1CCOC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: O
Product: Oc1nc2c(Cl)nc3ccccc3c2n1CC1CCOCC1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
THF (50 mL) and 1,1′-carbonyldiimidazole (4.2 g, 26 mmol) were sequentially added to a solution of 2-chloro-N4-(tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine (5 g, 17 mmol) in pyridine (50 mL), and the reaction was heated at 90° C. overnight. The reaction was cooled to approximately 0° C., and water (400 mL) was added. The mixture was stirred for 30 minutes. A precipitate was present and was isolated by filtration and washed with water and diethyl ether to provide 4 g of 4-chloro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-2-ol. A small portion of the product was triturated with hot acetonitrile, isolated by filtration, and washed with cold acetonitrile and diethyl ether to provide beige needles with the following analytical data, mp greater than 275° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.Br[CH2:25][CH2:26][CH2:27][O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]=1[C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:25][CH2:26][CH2:27][O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)=[CH:21][CH:22]=1
Reactant: COC(=O)c1cc(-c2ccc(O)cc2)c(-c2ccccc2Cl)s1
Reactant: BrCCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ccc(OCCCOC3CCCCO3)cc2)c(-c2ccccc2Cl)s1
Temperature: 60 °C
Yield: 95.4 %

Procedure:
2.3 g of the compound obtained in stage 23E), 1.95 g of 2-(3-bromopropoxy)tetrahydro-2H-pyran and 1.2 g of potassium carbonate are added to 15 ml of DMF and then the mixture is heated at 60° C. for 7 hours. It is poured onto ice-cold water, extraction is carried out with ether and the extract is dried and concentrated to dryness. After purifying by chromatography on silica (heptane and then heptane/AcOEt 80/20), 3.1 g of the expected compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:24][CH2:23]3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=3)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:22]3[CH2:23][CH2:24][N:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:26][CH2:27]3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=3)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(N3CCN(c4ccccn4)CC3)c(-c3ccc(F)cc3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(N3CCN(c4ccccn4)CC3)c(-c3ccc(F)cc3)nc2c1

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(4-fluorophenyl)-2-(4-(pyridin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylate (157.4 mg, 0.36 mmol, 1.00 equiv) in methanol (15 mL). This was followed by the addition of a solution of sodium hydroxide (71.1 mg, 1.78 mmol, 5.00 equiv) in water (2 mL) dropwise with stirring. The resulting solution was stirred overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrochloric acid. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with methanol. This resulted in 36 mg (23%) of 3-(4-fluorophenyl)-2-(4-(pyridin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].Br[CH2:13]/[CH:14]=[CH:15]/[Sn:16]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20]>CN(C=O)C>[CH2:25]([Sn:16]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:15]/[CH:14]=[CH:13]/[CH:4]([C:3]([O:10][CH3:11])=[O:9])[C:5]([O:7][CH3:8])=[O:6])[CH2:26][CH2:27][CH3:28]
Reactant: CCCC[Sn](/C=C/CBr)(CCCC)CCCC
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC[Sn](C/C=C/C(C(=O)OC)C(=O)OC)(CCCC)CCCC
Temperature: 20 °C
Reaction time: 3 h

Procedure:
Sodium hydride (75 mg) was added to a solution of dimethyl malonate (387 mg) in dry DMF (5 mL) at 0° C. [(1E)-3-bromoprop-1-enyl](tributyl)stannane (600 mg) was added to the reaction mixture after 10 min. The reaction mixture was stirred for 3 h at 20° C. and then quenched with saturated NH4Cl(aq.). Extraction with EtOAc and drying (MgSO4) of the organic phase gave, after concentration in vacuo, the crude product. Purification was done by chromatography eluting with petroleum ether/Et2O 12:1 to afford the title compound as a liquid.