Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([N:10]1[C:5]2[C:6](=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:8]=[CH:9]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: Clc1ccc2[nH]ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc2c(ccn2Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-chloro-1H-pyrrolo[3,2-b]pyridine (0.50 g, 3.3 mmol, Adesis) and K2CO3 (1.4 g, 9.8 mmol) in DMF (12 mL) at 0° C. was added benzyl bromide (0.43 mL, 3.6 mmol, Aldrich) dropwise. The mixture was allowed to warm to ambient temperature and stir overnight. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with water (3×), brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-20% EtOAc in hexanes afforded product as a clear oil (0.77 g, 97%).
Reaction SMILES: [N:1]1([C:7]2[N:21]=[C:10]3[N:11]=[CH:12][CH:13]=[C:14]([C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)[N:9]3[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:23][CH2:24][CH2:25][C:26]#[N:27].C(=O)([O-])[O-].[K+].[K+].[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>C(Cl)(Cl)Cl.CN(C)C=O>[N:18]1[CH:19]=[CH:20][C:15]([C:14]2[N:9]3[N:8]=[C:7]([N:1]4[CH2:2][CH2:3][N:4]([CH2:23][CH2:24][CH2:25][C:26]#[N:27])[CH2:5][CH2:6]4)[N:21]=[C:10]3[N:11]=[CH:12][CH:13]=2)=[CH:16][CH:17]=1
Reactant: c1cc(-c2ccnc3nc(N4CCNCC4)nn23)ccn1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: N#CCCCN1CCN(c2nc3nccc(-c4ccncc4)n3n2)CC1
Yield: 30.1 %

Procedure:
A mixture of 5.6 g (0.02 moles) of 2-(1-piperazinyl)-7-(4-pyridyl)[1,2,4]triazolo[1,5-a]pyrimidine (prepared as described in Example 47), 3.0 g (0.02 moles) of 4-bromobutyronitrile, 4.0 g of potassium carbonate and 50 ml of N,N-dimethylformamide was heated at reflux for 16 hours with stirring. The mixture was cooled and filtered. The filter was washed with N,N-dimethylformamide and the combined filtrate and wash was evaporated in vacuo to give a dark syrup. The syrup was dissolved in chloroform and passed through a pad of magnesium silicate washing with chloroform. The filtrate was evaporated to a syrup and crystallized from ethanol/ether. The precipitate was collected by filtration and washed with ether and gave 2.1 g of the desired product as golden crystals, mp 147°-148° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16]([N:18]([CH2:36][CH:37]([CH3:39])[CH3:38])[C@@H:19]1[CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][C@H:21]([C:32]([O:34][CH3:35])=[O:33])[CH2:20]1)=[O:17].C(OCC)(=O)C.Cl>CO>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16]([N:18]([CH2:36][CH:37]([CH3:39])[CH3:38])[C@@H:19]1[CH2:24][NH:23][CH2:22][C@H:21]([C:32]([O:34][CH3:35])=[O:33])[CH2:20]1)=[O:17]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C2)cc2ccccc21
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)OC)C2)cc2ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 39.8 %

Procedure:
1-(4-Methoxybutyl)-1H-indole-2-carboxylic acid (247 mg), 1-tert-butyl 3-methyl (3R,5S)-5-[(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (314 mg) and diisopropylethylamine (862 μl) were dissolved in methylene chloride (5 ml), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (337 mg) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (3:7) was concentrated under reduced pressure to give 1-tert-butyl 3-methyl (3R,5S)-5-[{[1-(4-methoxybutyl)-1H-indol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (40 mg) as an oil. The obtained 1-tert-butyl 3-methyl (3R,5S)-5-[{[1-(4-methoxybutyl)-1H-indol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (40 mg) was dissolved in methanol (2 ml), 4M hydrogen chloride-ethyl acetate (2 ml) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, and the residue was purified by reversed-phase preparative HPLC, and the object fraction was concentrated under reduced pressure. An aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give the object product (13 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]2[CH2:13][C:12]([CH3:15])([CH3:14])[O:11][C:10]2=[O:16])=[N:4][CH:5]=[C:6](I)[CH:7]=1.[C:17]1([C:23]#[CH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[C:3]([N:9]2[CH2:13][C:12]([CH3:15])([CH3:14])[O:11][C:10]2=[O:16])=[N:4][CH:5]=[C:6]([C:24]#[C:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1
Reactant: CC1(C)CN(c2ncc(I)cc2F)C(=O)O1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)CN(c2ncc(C#Cc3ccccc3)cc2F)C(=O)O1
Temperature: 70 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
Bis-(triphenylphosphine)-palladium(II)dichloride (12.5 mg, 17.9 μmol, 0.05 equiv.) was dissolved in 1 ml DMF. (120 mg, 357 μmol) 3-(3-Fluoro-5-iodopyridin-2-yl)-5,5-dimethyloxazolidin-2-one (Example 1, step 2) and phenylacetylene (72.9 mg, 78.4 μl, 714 μmol, 2 equiv.) were added at room temperature. Triethylamine (108 mg, 149 μl, 1.07 mmol, 3 equiv.), triphenylphosphine (2.81 mg, 10.7 μmol, 0.03 equiv.) and copper(I)iodide (2.04 mg, 10.7 μmol, 0.03 equiv.) were added and the mixture was stirred for 3 hours at 70° C. The reaction mixture was cooled and extracted with saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 40:60. The desired 3-(3-fluoro-5-(phenylethynyl)pyridin-2-yl)-5,5-dimethyloxazolidin-2-one (96 mg, 309 μmol, 86.6% yield) was obtained as a yellow solid, MS: m/e=311.2 (M+H+).
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:25]1([NH2:35])[C:34]2[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=2[CH:28]=[CH:27][CH:26]=1>>[C:25]1([NH:35][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([C:15]3[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=3)=[CH:18][CH:19]=2)[C:34]2[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=2[CH:28]=[CH:27][CH:26]=1
Reactant: Nc1cccc2c1CCCC2
Reactant: CCCCCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Product: CCCCCCCCCCCc1noc(-c2ccc(CNc3cccc4c3CCCC4)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 5,6,7,8-tetrahydronaphthalen-1-ylamine gave the title compound as an oil. M+(LC/MS(ESI)): 460.4. HPLC (Condition A), Rt: 6.36 min (HPLC purity: 73.3%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:12](O)[CH3:13]>S(=O)(=O)(O)O>[CH2:12]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([F:11])[CH:10]=[C:2]([Br:1])[CH:3]=1)[CH3:13]
Reactant: CCO
Reactant: O=C(O)c1cc(F)cc(Br)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(F)cc(Br)c1
Temperature: 90 °C
Reaction time: 17 h

Procedure:
Sulphuric acid (5 drops) was added to 3-bromo-5-fluorobenzoic acid (1.194 g, 5.45 mmol) in ethanol (10 ml) and refluxed with stirring at 90° C. for 17 hours. Reaction mixture partitioned between diethyl ether and water, washed with sodium hydrogen carbonate, dried (MgSO4) and evaporated to dryness.
Reaction SMILES: C([O:5][C:6](=[O:31])[CH2:7][CH:8]([N:15]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17])[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:24]([N:15]([CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17])[CH:8]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:7][C:6]([OH:31])=[O:5])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(c1ccccc1)N(Cc1ccccc1)C(CC(=O)OC(C)(C)C)C1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(c1ccccc1)N(Cc1ccccc1)C(CC(=O)O)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[benzyl-(1-phenyl-ethyl)-amino]-3-cyclohexyl-propionic acid tert-butyl ester (13.7 g, 32.5 mmol) in dichloromethane (65 mL) at 0° C., trifluoroacetic acid (65 mL) was slowly added (over 30 min). The reaction mixture was then stirred for 2 hours at room temperature. The solvent was evaporated and the residue azeotroped (3×50 ml, toluene) to yield a residue.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[C:9](/[CH3:13])=[CH:10]/[CH2:11][OH:12])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH2:14]([O:16][C@@H:17]([CH2:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:15]>>[Br:1][C:2]1[CH:3]=[C:4](/[C:9](/[CH3:13])=[CH:10]/[CH2:11][O:12][C:27]2[CH:26]=[CH:25][C:24]([CH2:23][C@H:17]([O:16][CH2:14][CH3:15])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:29][CH:28]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: C/C(=C\CO)c1cc(Br)cc(Br)c1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2cc(Br)cc(Br)c2)cc1)OCC
Yield: 80.9 %

Procedure:
The title compound (851 mg, 81%) was prepared from (E)-3-(3,5-dibromo-phenyl)-but-2-en-1-ol (612 mg, 2.0 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (500 mg, 2.10 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [CH:1]1([N:5]2[C:9]3[N:10]=[C:11]([CH:19]4[CH2:21][CH2:20]4)[CH:12]=[C:13]([C:14]([O:16]CC)=[O:15])[C:8]=3[C:7]([CH3:22])=[N:6]2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([N:5]2[C:9]3[N:10]=[C:11]([CH:19]4[CH2:20][CH2:21]4)[CH:12]=[C:13]([C:14]([OH:16])=[O:15])[C:8]=3[C:7]([CH3:22])=[N:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C1CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(C2CCC2)c2nc(C3CC3)cc(C(=O)O)c12
Reaction time: 1 h

Procedure:
The title compound was prepared in the same manner as described for intermediate 46 using ethyl 1-cyclobutyl-6-cyclopropyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (550 mg, 1.837 mmol), sodium hydroxide (3 ml, 3.00 mmol), and ethanol (30 mL) wherein the stir time was 1 h. The final product was collected as 0.490 g (98%). LCMS E-S (M+H)=272.5 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.10 (m, 4 H), 1.80-1.91 (m, 2 H), 2.26-2.43 (m, 3 H), 2.58 (s, 3 H), 2.59-2.71 (m, 2 H), 5.35 (dq, J=8.59, 8.42 Hz, 1 H), 7.44 (s, 1 H), 13.73 (br. s., 1 H).
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH2:7][C:8]#[N:9])(=[O:5])[OH:4])[CH3:2].[CH2:10](O)[CH2:11][OH:12]>C1(C)C=CC=CC=1>[CH2:1]([P:3]([CH2:6][CH2:7][C:8]#[N:9])(=[O:4])[O:5][CH2:10][CH2:11][OH:12])[CH3:2]
Reactant: OCCO
Reactant: CCP(=O)(O)CCC#N
Solvent: Cc1ccccc1
Product: CCP(=O)(CCC#N)OCCO
Yield: 88.9 %

Procedure:
441 g (3.0 mol) of ethyl(2-cyanoethyl)phosphinic acid (produced as in Example 5) are at 85° C. dissolved in 400 ml of toluene and admixed with 248 g (4 mol) of ethylene glycol and esterified at about 100° C. in a distillation apparatus equipped with water trap during 4 h. On completion of the esterification the toluene and excess ethyl glycol is removed in vacuo to leave 510 g (89% of theory) of 2-hydroxyethyl ethyl-2-cyanoethylphosphinate as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:23](OC)(OC)(OC)[CH2:24][CH2:25][CH3:26]>C1(C)C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH2:24]([C:23]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:25][CH3:26]
Reactant: CCCC(OC)(OC)OC
Reactant: CCOC(=O)CCCCCNc1c(N)cnc2ccccc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)OCC
Yield: 89.3 %

Procedure:
A solution of ethyl 6-(3-aminoquinolin-4-ylamino)hexanoate (34.3 g, 114 mmol), trimethyl orthobutyrate (19.5 g, 131 mmol), and pyridinium p-toluenesulfonate (1.0 g, 4.0 mmol) in toluene (250 mL) was heated at reflux under a Dean-Stark trap for 5 hours, periodically draining off the distillate and adding fresh toluene to the reaction mixture. The solution was concentrated under reduced pressure, and the residue was taken up in dichloromethane (150 mL), washed successively with a saturated aqueous sodium bicarbonate solution and water (100 mL each), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide ethyl 6-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanoate (36.0 g) as a dark oil that was used directly in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][C:38]([O:40][CH3:41])=[O:39])#[CH:30].CCN(CC)CC>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:9][S:8][C:4]1[N:3]=[C:2]([C:30]#[C:29][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH:7]=[CH:6][N:5]=1
Reactant: CSc1nccc(Cl)n1
Reactant: C#Cc1ccccc1CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccccc1C#Cc1ccnc(SC)n1
Temperature: 100 °C
Yield: 100.2 %

Procedure:
A suspension of 4-chloro-2-methylthiopyrimidine (200 μL, 1.72 mmol), PdCl2(PPh3)2 (121 mg, 0.172 mmol), CuI (33.0 mg, 0.172 mmol), PPh3 (45.0 mg, 0.172 mmol), methyl 2-(2-ethynyl phenyl)acetate (K1) (359 mg, 1.08 mmol) and Et3N (0.938 mL) in THF (6 mL) was heated at 100° C. under microwave irradiation for 10 minutes. The volatiles were removed in vacuo and the resultant residue adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-40% EtOAc in petroleum benzine 40-60° C., then Biotage Isolera, SiO2 cartridge, 0-40% EtOAc in DCM) to give the title compound A1 as a yellow oil (323 mg, 63%); 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J=5.0 Hz, 1H), 7.63 (dd, J=7.6, 1.1 Hz, 1H), 7.44-7.29 (m, 3H), 7.12 (d, J=5.0 Hz, 1H), 3.92 (s, 2H), 3.71 (s, 3H), 2.59 (s, 3H).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][C:9]1[C:14](Cl)=[N:13][CH:12]=[CH:11][N:10]=1.C[O-].[Na+]>C(O)C>[Cl:8][C:9]1[C:14]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:13][CH:12]=[CH:11][N:10]=1
Reactant: Sc1ccccc1
Reactant: Clc1nccnc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: Clc1nccnc1Sc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
22 g (0.2 mol) of thiophenol and 29.8 g (0.2 mol) of 2,3-dichloropyrazine are successively added dropwise to a solution of 10.8 g (0.2 mol) of sodium methylate in 200 ml of ethanol and the mixture is stirred for 1 hour. The reaction mixture is then cooled to 0° C. and the reaction product which has precipitated is filtered off and washed with ethanol and water. After drying, 2-chloro-3-phenylthio-pyrazine, melting point 100°-111° C., is obtained.
Reaction SMILES: [N:1]([CH:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)=[N+]=[N-].O.O.[Sn](Cl)(Cl)(Cl)Cl>CO.C(OCC)(=O)C>[S:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[CH:4]([NH2:1])[CH2:5][CH2:6]2
Reactant: [N-]=[N+]=NC1CCc2cc(-c3cccs3)ccc21
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: NC1CCc2cc(-c3cccs3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
5-(2-thienyl)-2,3-dihydro-1H-indene-1-yl)amine: To a solution of 2-(1-azido-2,3-dihydro-1H-indene-5-yl)thiophene (0.24 g, 0.99 mmol) in methanol (2mL) was added solid tin chloride dihydrate (0.45 g, 1.99 mmol) at room temperature under nitrogen. The reaction was stirred at room temperature overnight. The crude reaction mixture was poured into a separatory funnel and diluted with ethyl acetate (250 mL). The organic layer was washed with 2.0 N aqueous sodium hydroxide (50 mL), saturated aqueous sodium chloride (brine), and dried over anhydrous magnesium sulfate. Filtration, concentration and column chromatography on silica (9:1 dichloromethane/methanol) gave [5-(2-thienyl)-2,3-dihydro-1H-indene-1-yl]amine (0.15 g, 72% yield) as semi-solid: 1H NMR (400 MHz, CDCl3) 7.54 (m, 1H), 7.40 (d, 2H), 7.29 (m, 2H), 7.08 (m, 1H), 4.40 (t, 1H), 3.05 (m, 1H), 2.90 (m, 1H), 2.56 (m, 1H), 1.80 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]3[O:35][CH2:34][CH2:33][O:32][C:29]=3[CH:30]=2)[N:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)(C)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]5[O:35][CH2:34][CH2:33][O:32][C:29]=5[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ncnc2cc3c(cc12)OCCO3
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ncnc4cc5c(cc34)OCCO5)c2)no1
Temperature: 70 °C

Procedure:
According to the procedure described in Example 13B Step 1, a mixture of 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A (0.138 g, 0.5 mmol), 4-chloro-7,8-dihydro-[1,4]dioxino[2,3-g]quinazoline from the previous step (0.111 g, 0.5 mmol), and Cs2CO3 (0.326 g, 1 mmol) in isopropanol (7 mL) was heated at 70° C. for 13 hours, to afford 1-(5-tert-butylisoxazol-3-yl)-3-[3-(7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4-yloxy]phenyl)urea as a solid. 1H NMR (300 MHz, CDCl3) δ 9.3 (br, 1H), 9.10 (s, 1H), 8.59 (s, 1H), 7.72 (s, 1H), 7.60 (m, 1H), 7.42 (s, 1H), 7.31 (m, 2H), 6.95 (d, 1H), 6.02 (s, 1H), 4.41 (m 4H), 1.30 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]([O:13]C)=[O:12])[S:8][C:7]=2[CH:15]=1.O.[OH-].[Li+].O>CO>[F:16][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[S:8][C:7]=2[CH:15]=1
Reactant: COC(=O)c1cc2ccc(C(F)(F)F)cc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2ccc(C(F)(F)F)cc2s1
Temperature: 75 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
A mixture of 400 mg of methyl 6-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, 105 mg of lithium hydroxide monohydrate, 3 ml of water and 9 ml of methanol was stirred at 75° C. for 2 hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. To the residue was added water, and then washed with tert-butyl methyl ether 3 times. To the aqueous layer was added concentrated hydrochloric acid, and then extracted with chloroform 3 times. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain 355 mg of 6-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid (the present compound 2).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][S:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:31])=[O:30])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: O=S(=O)(Cl)c1ccccc1
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNS(=O)(=O)c1ccccc1
Yield: 61 %

Procedure:
Using the general method of Example 242, 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.53 g, 5.11 mmol) was reacted with benzenesulfonyl chloride (993 mg, 5.62 mmol) to provide 1.37 g of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}benzenesulfonamide as a white powder, m.p. 149-151° C. Analysis: Calculated for C22H25N5O3S: %C, 60.12; %H, 5.73; %N, 15.93; Found: %C, 60.40; %H, 5.82; %N, 15.85.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1N)([CH3:3])[CH3:2].N([O-])=[O:15].[Na+].O>S(=O)(=O)(O)O>[CH:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:15])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc([N+](=O)[O-])ccc1N
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)c1cc([N+](=O)[O-])ccc1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.4 %

Procedure:
2-Isopropyl-4-nitro-phenylamine (2.5 g, 13.9 mmol) was dissolved in 10% sulfuric acid (25 mL) and to this was added sodium nitrite (1.64 g, 23.8 mmol) in portions over 15 min at 0° C. The diazotized solution was added to boiling water and stirred for 15 min. the mixture was cooled to r.t. and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to afford 2-isopropyl-4-nitro phenol (2 g, 80%) as a solid.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:15]=[C:16]1[NH:21][C:20]2[CH:22]=[C:23]([CH:26]=O)[CH:24]=[CH:25][C:19]=2[O:18][CH2:17]1.[N:28]1([C:34]2[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C1COCC1>[O:15]=[C:16]1[NH:21][C:20]2[CH:22]=[C:23]([CH2:26][N:31]3[CH2:32][CH2:33][N:28]([C:34]4[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=4)[CH2:29][CH2:30]3)[CH:24]=[CH:25][C:19]=2[O:18][CH2:17]1
Reactant: O=Cc1ccc2c(c1)NC(=O)CO2
Reactant: NS(=O)(=O)c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(N2CCN(Cc3ccc4c(c3)NC(=O)CO4)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.4 %

Procedure:
Sodium triacetoxyborohydride (1.2 g, 5.9 mmol) is added to a solution of 3-oxo-3,4-dihydro-2H-benzo[1,4]-oxazine-6-carbaldehyde (0.5 g, 2.8 mmol) and 4-(piperazin-1-yl)-benzenesulfonamide (0.17 g, 3.1 mmol) in 20 mL of THF. The mixture is stirred at room temperature overnight. The reaction is quenched by addition of 50 mL of water, and the THF is removed under reduced pressure. The precipitate is collected by filtration and recrystallized from methanol to give 0.05 g (4% yield) of 4-[4-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-piperazin-1-yl]-benzenesulfonamide; mp 150-153° C.
Reaction SMILES: [OH:1][C:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[F:34][C:35]1([F:40])[CH2:39][CH2:38][NH:37][CH2:36]1>>[OH:1][C:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:37]4[CH2:38][CH2:39][C:35]([F:40])([F:34])[CH2:36]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH2:3]1
Reactant: FC1(F)CCNC1
Reactant: CC1CCCC(O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCCC(O)(CNC(=O)c2c(Cl)ccc3nc(N4CCC(F)(F)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and 3,3-difluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.16 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 1H), 0.83 (d, 3H). m/z: 438 [M+H]