Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:3](=[O:29])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[C:7]([CH:22]=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:6]1.[H][H]>[Pd].C(O)C>[CH3:1][N:2]([CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:3](=[O:29])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[C:7]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:6]1
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1cn(CC(=O)N(C)CCc2ccccc2)c2ccc(OCc3ccccc3)cc12
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1cn(CC(=O)N(C)CCc2ccccc2)c2ccc(OCc3ccccc3)cc12

Procedure:
A mixture of 0.93 g of N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carbethoxyvinyl)indol-1-yl]acetamide, 0.5 g of 10% palladium on activated carbon and 150 ml of ethanol is shaken under 40 psi of hydrogen on a Parr Apparatus for 40 minutes. The mixture is filtered to remove the catalysts and the filtrate is concentrated in vacuo. The residue is purified by dry column chromatography over silica gel eluting with a solvent system of ethyl acetate/hexane (2:1, v/v) to give N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carbethoxyethyl)indol-1-yl]acetamide as white powder (m.p. 81°-83° C.).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH2:29]([N:31]([CH2:37][CH3:38])[CH:32]1[CH2:36][CH2:35][NH:34][CH2:33]1)[CH3:30]>>[CH2:29]([N:31]([CH2:37][CH3:38])[CH:32]1[CH2:36][CH2:35][N:34]([CH2:2][C:3]2[N:4]([CH3:28])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([N:18]2[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]2[CH3:27])[N:6]=3)[CH2:33]1)[CH3:30]
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: CCN(CC)C1CCNC1
Product: CCN(CC)C1CCN(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)C1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with N,N-diethylpyrrolidin-3-amine via General Procedure E to give 27.8 mg of 296 following reverse phase purification. MS (Q1) 504.3 (M)+
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:6]=2[CH:33]=1.[CH3:34][N:35]1[CH:39]=[CH:38][C:37]([Sn](CCCC)(CCCC)CCCC)=[N:36]1.O>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>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([S:20]([N:7]2[C:6]3[CH:33]=[C:2]([C:39]4[N:35]([CH3:34])[N:36]=[CH:37][CH:38]=4)[CH:3]=[CH:4][C:5]=3[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:19])([F:17])[F:18])[CH:14]=[CH:15][C:9]=3[CH2:8]2)(=[O:22])=[O:21])=[CH:28][CH:27]=1)([CH3:30])([CH3:32])[CH3:31]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(Br)cc32)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccn(C)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Cn1nccc1-c1ccc2c(c1)N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Temperature: 25 °C

Procedure:
A mixture of 8-bromo-6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (intermediate 53, 100 mg, 0.185 mmol), 1-methyl-3-(tributylstannyl)-1H-pyrazole (62.4 mg, 0.168 mmol, prepared according to Heterocycles, 1997, 45, 1463), and PdCl2(PPh3)2 (11.8 mg, 0.0168 mmol) in THF (1.0 mL) was refluxed overnight. After cooling to room temperature, water was added, the reaction mixture was extracted with EtOAc, and the organic extracts were washed with water, brine, dried over MgSO4 and concentrated. The residue was purified via reverse phase HPLC to provide the title compound. LC/MS: m/e 542.1 (M+H)+. 1H NMR (500 MHz, CD3OD): δ 7.66 (1H, d), 7.59 (1H, s), 7.50 (1H, s), 7.38 (111, d), 7.18 (2H, d), 7.08-7.13 (2H, m), 6.97 (2H, d), 6.40 (1H, s), 4.60-5.00 (2H, br s), 3.97 (3H, s), 1.26 (9H, s).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=3[CH3:27])[N:13]=[C:12]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=3[CH3:27])[N:13]=2)=[CH:29][CH:30]=1
Reactant: COc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCN(C(=O)OC(C)(C)C)CC3)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)c(C)c1

Procedure:
To a solution of 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.4 mmol) in toluene (3 mL) was added 4-methoxy-2-methyl-benzyl chloride (0.9 mmol) and cyanomethylene-tri-n-butylphosphorane (1 mmol). The mixture was heated at 110° C. for 16 h. After concentration and purification (SiO2, EtOAc/hexanes), 3-(4-chloro-phenyl)-1-(4-methoxy-2-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester was obtained (54 mg). The other regioisomer, 3-(4-chloro-phenyl)-2-(4-methoxy-2-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester, was also obtained (86 mg). 3-(4-Chloro-phenyl)-1-(4-methoxy-2-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (20 mg) was treated with TFA (1 mL) in CH2Cl2 (10 mL) for 4 h. After concentration of the reaction mixture, the title compound was obtained (0.02 g). MS (ESI): exact mass calculated for C22H24ClN3O, 381.16; found, m/z 382.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.39-7.37 (m, 2H), 7.34-7.32 (m, 2H), 6.68-6.66 (br m, 1H), 6.54-6.52 (br m, 1H), 6.37 (d, J=8.3 Hz, 1H), 5.21 (s, 2H), 2.81-2.79 (m, 4H), 2.71-2.69 (m, 4H).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:9](C1C=CC(O)=CC=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH3:10]>C1(C)C=CC=CC=1>[C:9]([C:1]1[CH:2]=[C:3]([CH3:8])[CH:4]=[CH:5][C:6]=1[OH:7])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH3:10]
Reactant: Cc1ccc(O)cc1
Reactant: CC(C)(c1ccccc1)c1ccc(O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(O)c(C(C)(C)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 44.3 %

Procedure:
Into a 200 ml reactor thoroughly dried and purged with nitrogen, 34.15 g (316.0 mmol) of paracresol, 2.50 g of Umberist-15E (trade name, available from Organo Co.) and 20 ml of toluene were introduced. To the reactor, a solution containing 14.40 g (105.0 mmol) of 4-cumylphenol diluted with 30 ml of a toluene was dropwise added at 80° C., followed by stirring for 17 hours. After the system was cooled to room temperature, the reaction solution was filtered with washing with hexane. The resulting liquid was purified by silica gel column chromatography to obtain 10.52 g (yield: 44%) of 2-cumyl-4-methylphenol.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH:8]([Br:10])[Br:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(C)C=CC=CC=1.[Br:20]Br.[OH-].[Na+]>O>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([Br:20])([Br:9])[Br:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(C(Br)Br)cc1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(C(Br)(Br)Br)cc1
Temperature: 50 °C
Reaction time: 10 h
Yield: 85 %

Procedure:
A solution of 100 parts of p-nitrobenzal bromide in 500 parts of toluene is added to a solution of 80 parts of bromine plus 160 parts of 50% sodium hydroxide in a 1,000 parts of water at 50° C. The mixture is stirred mechanically at 50° C for 10 hours. The toluene layer is separated; the water layer is extracted with 500 parts of toluene. The combined toluene layers are dried and evaporated to give 110 parts (85% yield) of p-nitrobenzotribromide, m.p. 74°-81° C.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[Na].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]#[N:14]>C(OCC)(=O)C>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([C:1](=[O:3])[CH3:2])[C:13]#[N:14]
Reactant: N#CCc1ccccc1Cl
Reactant: CCO
Agent: [Na]
Solvent: CCOC(C)=O
Product: CC(=O)C(C#N)c1ccccc1Cl
Temperature: 100 °C
Reaction time: 1 h

Procedure:
The procedure of P. L. Julian et al (Org. Syn, C. V. II, p, 487) was used. To 25 mL of anhydrous ethanol was added 2.0 g or sodium metal. The mixture was heated to 100° C. with a heating mantle to effect complete reaction. To the warm solution was added 10.0 g 2-chlorophenylacetonitrile followed by 9.7 mL dry ethyl acetate. After one hour, the mixture was cooled to -10° C. and was filtered through a medium fritted funnel. The white precipitate was washed twice with ether and was combined with the first batch. The solid material was dissolved in 75 mL water. To this was added 5 mL acetic acid. The mixture was then extracted three times with ether. The combined organic material was dried over sodium sulfate, stripped of solvent in vacuo, and was restripped from toluene to give the title compound sufficiently pure for the the next reaction. Rf 0.14 in 20% ethyl acetate/hexane.
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[C:25]4=[N:26][NH:27][C:28](=[O:33])[C:29]5[CH:30]=[CH:31][CH:32]=[C:23]([C:24]=54)[NH:22][CH:21]3[C:34]3[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=3)=[CH:16][CH:15]=2)=[O:13])[CH2:8][CH2:7]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:42][NH:43]C.[BH4-].[Na+]>CO>[C:1]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH:20]3[C:25]4=[N:26][NH:27][C:28](=[O:33])[C:29]5[CH:30]=[CH:31][CH:32]=[C:23]([C:24]=54)[NH:22][CH:21]3[C:34]3[CH:41]=[CH:40][C:37]([CH2:38][NH:43][CH3:42])=[CH:36][CH:35]=3)=[CH:18][CH:19]=2)=[O:13])[CH2:10][CH2:11]1)(=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: CNC
Reactant: CC(C)C(=O)N1CCN(C(=O)c2ccc(C3c4n[nH]c(=O)c5cccc(c45)NC3c3ccc(C=O)cc3)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(C(=O)N3CCN(C(=O)C(C)C)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 45.5 %

Procedure:
A mixture of 4-(9-(4-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (40 mg, 0.07 mmol) and 33% dimethylamine aq solution (17 mg, 0.14 mmol) in methanol (10 mL) was stirred at room temperature for 40 min. Then the mixture was cooled to 0° C. Sodium borohydride (4 mg, 0.11 mmol) was added. After the addition, the mixture was stirred at this temperature for 2 hr. Methanol was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by prep-HPLC to give the compound 9-(4-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8-(4-((methylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (18 mg, yield 49%) as a light yellow solid. 1H-NMR (400 MHz, CD3OD) δ (ppm): 1.10-1.12 (d, J=6.8 Hz, 6H), 2.67 (s, 3H), 2.81 (brs 1H), 3.33-3.70 (m, 8H), 4.12 (s, 2H), 4.43-4.75 (d, J=7.6 Hz, 1H), 4.88 (d, J=7.4 Hz, 1H), 7.22-7.27 (m, 3H), 7.31-7.37 (m, 4H), 7.42-7.44 (d, J=8.0 Hz, 2H), 7.56-7.58 (d, J=7.2 Hz, 1H), 7.64-7.68 (t, J=8.0 Hz, 1H); LC-MS (ESI) m/z: 579 (M+1)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:21][CH2:20][CH:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:17][CH2:18][CH:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:20][CH2:21]3)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(N2CCC(N3CCC(c4ccccc4)CC3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCC(N3CCC(c4ccccc4)CC3)CC2)cc1

Procedure:
0.5 g of palladium carbon (containing 10% by weight palladium) was added to a solution of 1.2 g (2.7 mmol) of 1-(4-nitrophenyl)-4-(4-phenyl-1-piperidinyl)piperidine (cf. Example 8) in 100 ml of methanol. Hydrogenation was continued until hydrogen uptake ceased, then the solids were filtered off and the solvent was removed under reduced pressure.
Reaction SMILES: C([Li])(CC)C.[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]1[O:16][CH2:15][CH2:14][CH2:13][O:12]1.[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20].O>C1COCC1>[O:16]1[CH2:15][CH2:14][CH2:13][O:12][CH:11]1[C:7]1[O:6][C:10]([Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1
Reactant: c1coc(C2OCCCO2)c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCCO2)o1
Temperature: -20 °C
Reaction time: 2.5 h

Procedure:
200 ml of sec-butyllithium (1.3M solution in cyclohexane, 260 mmol) were added dropwise to a solution of 34.4 g of 2-(2-furyl)-1,3-dioxane (224 mmol, obtainable from furfural and propane-1,3-diol) in 320 ml of THF at −70° C. in the course of 20 minutes. The solution was warmed at −20° C. for 30 minutes and then cooled again to −78° C. A solution of 60.8 ml of tributylstannyl chloride in 160 ml of THF was then added dropwise in the course of 30 minutes, after which the mixture was allowed to warm to room temperature. After 2.5 hours, water was added and the mixture was extracted with ethyl acetate. The organic phase was dried with magnesium sulphate and concentrated and the residue was distilled (boiling point0.8 1 80° C.). 93 g were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:12][C:13]=2[Cl:14])=[CH:4][C:3]=1[N+:21]([O-])=O.[Sn]>C(O)C>[NH2:21][C:3]1[CH:4]=[C:5]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:12][C:13]=2[Cl:14])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Cn1c(C(F)(F)F)cc(Cl)c(-c2ccc(Cl)c([N+](=O)[O-])c2)c1=O
Agent: [Sn]
Solvent: CCO
Product: Cn1c(C(F)(F)F)cc(Cl)c(-c2ccc(Cl)c(N)c2)c1=O
Temperature: 25 °C
Yield: 86.6 %

Procedure:
0.5 g (1.37 mmol) of 3-(4-chloro-3-nitrophenyl)-4-chloro-1-methyl-6-trifluoromethyl-2(1H)-pyridone was dissolved in 20 ml of ethanol, and 0.8 g (6.78 mmol) of tin was added thereto with stirring at room temperature, followed by stirring for 1 hour. After completion of the reaction, excess ethanol was distilled off under reduced pressure, and ethyl acetate and a saturated sodium hydrogencarbonate aqueous solution were added. The precipitate was collected by filtration and washed with water and a 10% citric acid aqueous solution. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was distilled off under reduced pressure, and the obtained crude crystals were washed with isopropyl ether to obtain 0.40 g (yield: 87%) of the desired product. 1H-NMR (300 MHz, CDCl3) δ value: 3.74(3H,s), 4.06(2H,s), 6.54(1H,dd), 6.59(1H,s), 6.62(1H,d), 7.27(1H,d)ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1.N1C=CC=CC=1.[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>ClCCl>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH:22][S:37]([C:34]3[CH:35]=[CH:36][C:31]([CH3:30])=[CH:32][CH:33]=3)(=[O:39])=[O:38])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C(F)(F)F)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cccc(C3CC(C)(C)c4cc(C(F)(F)F)ccc4N3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a stirred solution of 3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (100 mg, 0.31 mmol) in pyridine (49 mg, 0.62 mmol) and dichloromethane (1.5 mL) at 0° C. was added dropwise a solution of 4-Methyl-benzenesulfonyl chloride (71 mg, 0.37 mmol) in dichloromethane (0.5 mL). The mixture was stirred at room temperature overnight. The mixture was quenched with water (5 mL) and extracted with dichloromethane (5 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel to afford N-[3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-4-methyl-benzenesulfonamide (122 mg, 77.2%) as a white solid. MS (ESI+APCI) M+1=475.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH2:17])[C:11]3[N:12]([CH:14]=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN1CCOCC1>C1(C)C=CC=CC=1>[NH2:17][C:10]1[C:11]2[N:12]([CH:14]=[CH:15][N:16]=2)[CH:13]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:25]([NH:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:26])=[CH:7][CH:6]=2)[N:9]=1
Reactant: Nc1ccc(-c2cn3ccnc3c(N)n2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: CN1CCOCC1
Solvent: Cc1ccccc1
Product: Nc1nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)cn2ccnc12

Procedure:
(FIG. 1) Procedure: A mixture of 1.00 eq. of 6-(4-Amino-phenyl)-imidazo[1,2-a]pyrazin-8-ylamine, 1.50 eq. of phenylisocyanate, and 2.00 eq. of N-methylmorpholine, in toluene is mixed at room temperature for 2 hr. The mixture is partitioned between 1 N NaOH and ethyl acetate and extracted three times. The organic extracts are combined and dried over MgSO4. The solvent is removed under reduced pressure and the resulting residue is purified by flash chromatography (50% ethyl acetate/hexanes) to yield 8.
Reaction SMILES: [CH:1]([CH:3]([O:6][CH:7]([C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:17])[NH2:16])[N:14]=1)[CH:8]=[O:9])[CH2:4][OH:5])=[O:2].[NH2:18][C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1>O>[OH:9][CH:8]1[C@H:7]([C:10]2[S:11][CH:12]=[C:13]([C:15](=[O:17])[NH2:16])[N:14]=2)[O:6][C@H:3]([CH2:4][OH:5])[CH:1]([OH:2])[N:18]1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: Nc1ncccn1
Reactant: NC(=O)c1csc(C(C=O)OC(C=O)CO)n1
Solvent: O
Product: NC(=O)c1csc([C@@H]2O[C@H](CO)C(O)N(c3ncccn3)C2O)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.7 %

Procedure:
[R-(R*, R*)]-α-(1-Formyl-2-hydroxyethoxy)-4-carbamoyl-2-1,3-thiazoleacetaldehyde (1.10 g) was dissolved in water (30 ml). To the solution was added 2-aminopyrimidine (0.41 g). The mixture was stirred at ambient temperature for five hours to give a clear solution. The solution was lyophilized to give 2-[(2R, 6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-pyrimidinyl)morpholin-2-yl]-4-carbamoylthiazole (1.50 g).
Reaction SMILES: [C:1]1([C:7]2[C:8]3[C:9](=[N:14][O:15][CH:16]=3)[C:10](=[O:13])[NH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][OH:18]>N1CCCCC1>[CH3:17][O:18][C:16]([C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:12][NH:11][C:10](=[O:13])[C:9]=1[NH2:14])=[O:15]
Reactant: O=c1[nH]nc(-c2ccccc2)c2conc12
Reactant: CO
Solvent: C1CCNCC1
Product: COC(=O)c1c(-c2ccccc2)n[nH]c(=O)c1N
Yield: 70 %

Procedure:
To a stirred solution of 4-phenyl-6H-isoxazolo[3,4-d]pyridazin-7-one (330 mg, 1.55 mmol) (V. Dal Piaz et al., Heterocycles, 1991, 32(6), 1173) in methanol (15 mL), piperidine was added (0.4 mL) and the mixture was refluxed for 1 h. Solvent was removed under reduced pressure and the residue was treated with water. The solid thus formed was isolated by filtration and dried to yield the title product (70% yield).
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][NH2:29])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>>[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][NH:29][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)=[CH:23][CH:22]=1
Reactant: NCCc1ccc(N)cc1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(CCNC2=NC(=O)/C(=C/c3ccc4ncccc4c3)S2)cc1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-(4-amino-phenyl)-ethylamine and DIEA to give 2-[2-(4-amino-phenyl)-ethylamino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 375 (MH+).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:32])[CH2:15][C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30]Br)=[CH:24][CH:23]=1)[C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:39][C:40]([F:49])([F:48])[C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=1>CN(C=O)C.O>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:32])[CH2:15][C@H:16]([C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][O:47][C:44]2[CH:45]=[CH:46][C:41]([C:40]([F:39])([F:48])[F:49])=[CH:42][CH:43]=2)=[CH:24][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: O=C(C[C@@H](c1ccc(OCCBr)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(C[C@@H](c1ccc(OCCOc2ccc(C(F)(F)F)cc2)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
The bromide 47.1 (100 mg, 0.2 mmol) was dissolved in DMF (2.0 mL). Cesium carbonate (260 mg, 0.8 mmol) and 4-trifluoromethylphenol (130 mg, 0.8 mmol) were added to the solution and the mixture was then heated with stirring for three hours. The reaction mixture was then cooled to room temperature and diluted with water. The mixture was extracted with EtOAc (2×50 mL). The combined organic layers were washed with 1M lithium chloride solution (1×25 mL), water (1×25 mL) and brine (1×25 mL) and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure and the residue purified by medium pressure chromatography (silica, 0 to 60% EtOAc: hexanes) to obtain 47.2 (58 mg). MS ESI (pos.): m/e 581.2 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=1)[Si:8]([CH3:11])([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[Br:24]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[N:7]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][Br:24])=[C:14]([Si:19]([CH3:21])([CH3:20])[CH3:22])[CH:13]=1)[Si:8]([CH3:11])([CH3:9])[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N(C(=O)OC(C)(C)C)[Si](C)(C)C)cc1[Si](C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N(c1ccc(CBr)c([Si](C)(C)C)c1)[Si](C)(C)C

Procedure:
A suspension of tert-butyl[4-methyl-3-(trimethylsilyl)phenyl](trimethylsilyl)carbamate (3.00 g, 8.55 mmol), N-bromosuccinimide (NBS, 1.59 g, 8.97 mmol), 2,2′-azobis(2-methylpropionitrile) (AIBN, 42 mg, 0.26 mmol) in CCl4 (40 mL) was refluxed under N2 for 16 h. The reaction mixture was cooled down; hexanes (100 mL) were added and the solid was filtered off and washed with EtOAc. The combined filtrate was washed with aq. NaHCO3, dried over Na2SO4, filtered, concentrated on rotavap and further dried under vacuum. This material was not purified but used directly in the next step (˜80%).