Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16].[Cl:22][C:23]([CH2:25]Cl)=[CH2:24]>O1CCCC1>[Cl:22][C:23](=[CH2:24])[CH2:25][CH:14]([CH:15]([CH3:17])[CH3:16])[C:13]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CC(C)C
Reactant: C=C(Cl)CCl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=C(Cl)CC(C(=O)OCC)C(C)C
Temperature: -4 °C
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
A 1 liter flask was equipped with a mechanical stirrer, reflux condenser, nitrogen inlet, addition funnel, and thermometer. The flask was charged with 200 ml of tetrahydrofuran (THF) and 31.37 g (0.300 mol) of diisopropylamine and cooled to -4° C. The n-butyllithium solution (265 ml of 1.6M, 0.424 mol) was added dropwise at -4° to -6° C. over 22 minutes. The reaction mixture was then stirred for 30 minutes at -4° C. and then 39.06 g (0.300 mol) of ethyl isovalerate added over 15 minutes. The reaction mixture was cooled to -78° C. and 44.39 g (0.400 mol) of 2,3-dichloro-1-propene added dropwise. During the addition of the halide, the temperature was maintained at -78° C. to -74° C. The reaction mixture was stirred for 2 hrs. at -78° C. to give a clear, tan colored solution. The temperature of the reaction mixture was then allowed to rise to -40° C., and stirred at -40° C. to -30° C. for 2 hours. The reaction mixture was then allowed to stand at room temperature over the weekend. The reaction mixture was quenched with 25 ml of water and then poured into 300 ml of ice water. The aqueous mixture was extracted twice with 250 ml portions of ether. The combined ether extracts were washed with saturated sodium chloride solution, dried (MgSO4), and the ether removed. The residue was vacuum distilled through a vigreux column to give 28.02 g (46% yield) of ethyl 4-chloro-2-isopropyl-4-pentenoate, bp 53°-63° C./0.70 mm.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([CH:11]([C:13]3[N:14]=[C:15]([C:20]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH:23]=[CH:22][CH:21]=4)[N:16]([CH2:18][CH3:19])[CH:17]=3)[OH:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:32]I>CN(C=O)C.CCOC(C)=O>[CH:1]1([N:5]2[CH2:6][CH2:7][CH:8]([CH:11]([C:13]3[N:14]=[C:15]([C:20]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH:23]=[CH:22][CH:21]=4)[N:16]([CH2:18][CH3:19])[CH:17]=3)[O:12][CH3:32])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCn1cc(C(O)C2CCN(C3CCC3)CC2)nc1-c1cccc2ccccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1cc(C(OC)C2CCN(C3CCC3)CC2)nc1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1-cyclobutyl-piperidin-4-yl)-(1-ethyl-2-naphthalen-1-yl-1H-imidazol-4-yl)-methanol (20 mg) in DMF (2 ml) is added NaH (6 mg, 60%), followed by CH3I (15 mg). The resulting mixture is stirred at rt for 30 min, and then diluted with EtOAc, washed with water and brine, dried and solvent removed. The crude product is purified by column (2% Et3N, 3% MeOH in EtOAc) to afford the title compound as an oil. LCMS 404.1 (M+1). 1H NMR (CDCl3) δ ppm 1.25 (t, 3H), 1.40-2.05 (m, 11H), 2.60 (m, 1H), 2.90 (m, 2H), 3.36 (s, 3H), 3.75 (q, 214), 4.05 (d, 1H), 7.02 (s, 1H), 7.42-7.60 (m, 5H), 7.86-7.96 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7]1([CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1)[CH2:6]2.[CH2:19](O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:20]1[O:21][C:8]2([C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[CH2:6][C:7]32[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]3)[O:12][CH2:19]1
Reactant: COc1ccc2c(c1)CC1(CCC(=O)CC1)C2=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COc1ccc2c(c1)CC1(CCC(=O)CC1)C21OCCO1
Yield: 73 %

Procedure:
A mixture of 4.89 g. (0.0196 M) of 6'-methoxyspiro(cyclohexane-1,2'-indan)-1',4-dione [8] (prepared as in Example 15B), 1.21 g. of ethylene glycol and 0.2 g. of p-toluenesulfonic acid in 100 ml. of benzene is heated at reflux under a Dean-Stark trap for about 5 hours. The mixture is allowed to cool, washed with aqueous sodium bicarbonate solution and evaporated to dryness. The residue is recrystallized twice from methylene chloride: Skellysolve B to give 4.13 g. (73% yield) of 5'-methoxyspiro(cyclohexane-1,2'-indan)-1',4-dione 4-ethylene ketal [9 ] having a melting point of 142° to 144° C.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=[CH:4][C:3]1=[O:16].[OH:17]O>C(O)(=O)C>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][C:4](=[O:17])[C:3]1=[O:16]
Reactant: Cn1c(=O)cnc2ccc(C(F)(F)F)cc21
Reactant: OO
Solvent: CC(=O)O
Product: Cn1c(=O)c(=O)[nH]c2ccc(C(F)(F)F)cc21
Reaction time: 24 h

Procedure:
1-Methyl-7-trifluoromethyl-2(1H)-quinoxalinone (2.68 grams) was dissolved in 20 ml. of acetic acid and 20 ml. of 30 percent hydrogen peroxide were added. The reaction mixture was held at room temperature for 24 hours, by which time a solid had separated out. It was collected by filtration. NMR and microanalysis confirmed that the product was 1-methyl-7-trifluoromethyl-2(1H), 3(4H)-quinoxalinedione. The product melted at 283°-287° C.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[C:20]([N:39]1[CH:43]=[C:42]([CH:44]=[O:45])[N:41]=[CH:40]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[F:13][C:14]1[C:19]([CH:44]([C:42]2[N:41]=[CH:40][N:39]([C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:43]=2)[OH:45])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Fc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OC(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccnc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 22.4 %

Procedure:
A 2.5M n-butyl lithium in hexanes solution (6 ml, 15 mmol) was added dropwise to a solution of diisopropylamine (2.12 ml, 15 mmol) in tetrahydrofuran (30 ml), cooled to −78° C. The reaction mixture was allowed to warm up to 0° C. for 30 minutes before being cooled down to −78° C. 2-Fluoropyridine (1.36 g, 14 mmol) in tetrahydrofuran (10 ml) was added dropwise. The reaction mixture was stirred at −78° C. for 1 hour. A solution of 1-trityl-1H-imidazole-4-carbaldehyde (4.5 g, 13.3 mmol) in tetrahydrofuran (10 ml) was added dropwise. The reaction mixture was allowed to warm up to room temperature and was stirred for 18 hours. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate and extracted into ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound (1.3 g, 22% yield).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>C(OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)=[CH:5][CH:4]=1
Reactant: C1=COCCC1
Reactant: OCCc1ccc(CBr)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: BrCc1ccc(CCOC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.5 %

Procedure:
A mixture of 16.9 g (78.5 mmoles) of 4-(bromomethyl)benzeneethanol (prepared according to Plaue S. and Heissler D. Tetrahedron Lett. (1987) 28, 1401-4), 10.6 g (125 mmoles) of 3,4-dihydro-2H-pyrane and 0.16 g of para-toluenesulfonic acid in 160 ml dry ethyl ether, is stirred 16 hours at room temperature. The reaction mixture is thereafter washed with a solution saturated with sodium bicarbonate, then water, dried over Na2SO4 and concentrated, to give 21.5 g (yield=91.5%) of a yellow oil used without other purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:38])[CH2:20][C:21]2[CH:37]=[CH:36][C:24]3[N:25]=[C:26]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])[O:27][C:23]=3[CH:22]=2)=[CH:14][CH:13]=1)[CH2:6][C:7]([O:9]CC)=[O:8].[OH-].[Na+]>C(O)C.O>[OH:1][CH2:2][CH2:3][CH2:4][CH:5]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:38])[CH2:20][C:21]2[CH:37]=[CH:36][C:24]3[N:25]=[C:26]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])[O:27][C:23]=3[CH:22]=2)=[CH:16][CH:17]=1)[CH2:6][C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)CC(CCCO)c1ccc(NC(=O)Cc2ccc3nc(Nc4ccccc4C)oc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)Nc3ccc(C(CCCO)CC(=O)O)cc3)cc2o1
Temperature: 40 °C
Yield: 57.5 %

Procedure:
A solution of ethyl 6-hydroxy-3-{4-[2-(2-o-tolylamino-benzoxazol-6-yl)-acetylamino]-phenyl}-hexanoate [460 mg, Reference Example 23 (a)] in a mixture of ethanol (30 mL) and water (10 mL) was treated with sodium hydroxide solution (5mL, 1M) and then heated at 40° C. for 2 hours. The mixture was evaporated and the residue was dissolved in water (50 mL). This solution was washed three times with ethyl acetate, then acidified with dilute hydrochloric acid (a white precipitate was formed) and then extracted three times with ethyl acetate. The combined extracts were washed with brine, then dried and then evaporated. The residual white foam was dissolved in sodium hydroxide solution (50 mL, 0.5M) and the solution was washed twice with ether then acidified with dilute hydrochloric acid. The resulting white precipitate was filtered and then dried to give the title compound (250 mg) as a white solid. LC-MS: RT=2.88 minutes (100% by ELSD); MS (ES+), 488 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH2:19][CH2:20][OH:21])[CH:5]=[CH:4][N:3]=1.[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([OH:33])([C:31]#[CH:32])[CH3:30])=[N:27][CH:28]=1.C(N(CC)CC)C>CS(C)=O.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>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:32]#[C:31][C:29]([C:26]4[CH:25]=[CH:24][C:23]([F:22])=[CH:28][N:27]=4)([OH:33])[CH3:30])[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH2:19][CH2:20][OH:21])[CH:5]=[CH:4][N:3]=1
Reactant: C#CC(C)(O)c1ccc(F)cn1
Reactant: Nc1nccc(-n2c(OCCO)nc3ccc(Br)cc32)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(O)(C#Cc1ccc2nc(OCCO)n(-c3ccnc(N)n3)c2c1)c1ccc(F)cn1
Temperature: 25 °C
Yield: 1.5 %

Procedure:
A mixture of 2-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]ethan-1-ol (200 mg, 0.57 mmol), 2-(5-fluoropyridin-2-yl)but-3-yn-2-ol (940 mg, 5.69 mmol), bis(triphenylphosphine)palladium(II) dichloride (200 mg, 0.28 mmol) and triethylamine (0.5 mL) in dimethylsulfoxide (1 mL) was irradiated with microwave radiation under nitrogen for 1 hr at 120° C. The reaction mixture was cooled to room temperature then filtered through a frit filter to remove the catalyst. The filtrate was concentrated under vacuum and the crude product (80 mg) was purified by preparative HPLC to give 3.7 mg (1%) of 4-[1-(2-aminopyrimidin-4-yl)-2-(2-hydroxyethoxy)-1H-1,3-benzodiazol-6-yl]-2-(5-fluoropyridin-2-yl)but-3-yn-2-ol as a light yellow solid: 1H NMR (300 MHz, DMSO) delta 8.54 (d, J=2.7 Hz, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.15 (d, J=1.2, 1H), 7.84 (q, 1H), 7.78-7.72 (m, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.24 (q, 1H), 7.10-7.04 (m, 3H), 6.37 (s, 1H), 5.03 (s, 1H), 4.60 (t, J=4.5 Hz, 2H), 3.81 (d, J=4.5 Hz, 2H), 1.82 (s, 3H); LC-MS: m/z=+435 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][S:22]([CH3:24])=[O:23])[C:17]=3[CH:25]=2)[C:3]1=[O:26].ClC1C=C(C=CC=1)C(OO)=[O:32].C(OCC)C>C(Cl)Cl>[CH3:1][N:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][S:22]([CH3:24])(=[O:32])=[O:23])[C:17]=3[CH:25]=2)[C:3]1=[O:26]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CS(C)=O)c3c2)c1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOCC
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CS(C)(=O)=O)c3c2)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1-methyl-3-{3-[(methylsulfinyl)methyl]-1,2-benzisothiazol-5-yl}-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (0.480 g, 1.24 mmol) and 3-chloroperoxybenzoic acid (0.600 g, 60%, 2.10 mmol) in methylene chloride is stirred at room temperature for four hours, washed with 5% sodium carbonate solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a solid. Flash column chromatography of the solid using silica gel and a 10% diethyl ether in methylene chloride solution gives the title product as a white solid which is identified by NMR spectral analyses.
Reaction SMILES: Cl[P:2]1[N:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[P:4](Cl)[N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[C:15]([C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]=1[OH:30])([CH3:18])([CH3:17])[CH3:16]>C(N(CC)CC)C>[C:26]([C:21]1[CH:22]=[C:23]([CH3:25])[CH:24]=[C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:20]=1[O:30][P:2]1[N:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[P:4]([O:30][C:20]2[C:21]([C:26]([CH3:27])([CH3:28])[CH3:29])=[CH:22][C:23]([CH3:25])=[CH:24][C:19]=2[C:15]([CH3:18])([CH3:17])[CH3:16])[N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)N1P(Cl)N(C(C)(C)C)P1Cl
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Product: Cc1cc(C(C)(C)C)c(OP2N(C(C)(C)C)P(Oc3c(C(C)(C)C)cc(C)cc3C(C)(C)C)N2C(C)(C)C)c(C(C)(C)C)c1

Procedure:
The procedure of Example 1 is repeated using 2,4-dichloro-1,3-di-tert-butyl-1,3,2,4-diazadiphosphetidine, 2,6-di-tert-butyl-4-methylphenol and triethylamine to give the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.[C:17](O)(=[O:20])[CH:18]=[CH2:19].C1CCC(N=C=NC2CCCCC2)CC1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:17]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=1)(=[O:20])[CH:18]=[CH2:19]
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: C=CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CC(=O)N[C@@H](Cc1ccc(OC)cc1)C(=O)OC
Yield: 58 %

Procedure:
The same procedures as in Example 1 were carried out from the compound obtained in Example 33 (3.3 g), acrylic acid (1.1 mL), DCC (3.4 g), triethylamine (9.5 mL, 68.2 mmol), and chloroform (140 mL), to give the captioned compound (2.1 g, 58%) as crystals.
Reaction SMILES: F[C:2]1[N:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]([O:17][CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][N:20]2[CH3:24])[CH:8]=1)=[O:5].C(O)(C(F)(F)F)=O.[NH2:36][C:37]1[CH:45]=[CH:44][CH:43]=[C:42]2[C:38]=1[CH2:39][NH:40][C:41]2=[O:46].Cl.[OH-].[Na+]>C(O)(C)(C)C>[CH3:24][N:20]1[CH2:21][CH2:22][CH2:23][C@@H:19]1[CH2:18][O:17][C:9]1[CH:8]=[C:7]([NH:6][C:4]([C:3]2[C:2]([NH:36][C:37]3[CH:45]=[CH:44][CH:43]=[C:42]4[C:38]=3[CH2:39][NH:40][C:41]4=[O:46])=[N:28][CH:27]=[CH:26][CH:25]=2)=[O:5])[CH:12]=[CH:11][C:10]=1[C:13]([F:16])([F:15])[F:14]
Reactant: CN1CCCC1COc1cc(NC(=O)c2cccnc2F)ccc1C(F)(F)F
Reactant: Nc1cccc2c1CNC2=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC[C@@H]1COc1cc(NC(=O)c2cccnc2Nc2cccc3c2CNC3=O)ccc1C(F)(F)F
Temperature: 150 °C

Procedure:
2-Fluoro-N-[3-(1-methyl-pyrrolidin-2-ylmethoxy)-4-trifluoromethyl-phenyl]-nicotinamide (402 mg, 1.0116 mmol) was dissolved in tert-butanol (1 mL). To this mix was added TFA (115 mg, 1.0116 mmol) and 4-amino-2,3-dihydro-isoindol-1-one (450 mg, 3.035 mmol). The mix was heated for 6 h at 150° C., allowing the solvent to boil off. The reaction was cooled to RT, dissolved into 1N aqueous HCl, basified to pH 10 with solid NaOH, extracted twice with EtOAc, and dried over Na2SO4. The product precipitated out of solution along with a minor by-product. The EtOAc was filtered off. The crude product was dissolved in MeOH and filtered. The MeOH solution was concentrated down and eluted on silica gel column to yield the titled compound as a light yellow solid. MS: C27H26F3N5O3—525.528; M+H 526.1
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.[C:12]([O:16][C:17](=[O:28])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22][N:21]=1)([CH3:15])([CH3:14])[CH3:13].[OH-].[K+]>CCO>[C:12]([O:16][C:17](=[O:28])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:10]/[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=2)=[O:11])=[CH:22][N:21]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C=O)cn1
Reactant: CC(=O)c1ccc(CO)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)/C=C/c1ccc(/C=C/C(=O)c2ccc(CO)cc2)cn1
Temperature: 0 °C
Reaction time: 5 h
Yield: 34.5 %

Procedure:
A solution of 1-(4-hydroxymethyl-phenyl)-ethanone (750 mg, 5 mmol) in EtOH (15 ml) was added dropwise at 0° C. to a stirred solution of (E)-3-(5-formyl-pyridin-2-yl)-acrylic acid tert-butyl ester (described in Example 11 STEP A-D, 1.16 g, 5 mmol) and 1.7 M KOH (4.4 ml) in EtOH (10 ml). The mixture was stirred at 0° C. for 5 h and the resulting precipitate was filtered and triturated with di-isopropylether to give 630 mg of desired (E)-3-{5-[(E)-3-(4-hydroxymethyl-phenyl)-3-oxo-propenyl]-pyridin-2-yl}-acrylic acid tert-butyl ester. The mother liquors were diluted with water and extracted with AcOEt. The organic layer was dried over Na2SO4 and evaporated in vacuo. The residue was triturated with EtOH to give additional 70 mg of (E)-3-{5-[(E)-3-(4-hydroxymethyl-phenyl)-3-oxo-propenyl]-pyridin-2-yl}-acrylic acid tert-butyl ester.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH2:20]([NH2:23])[CH:21]=[CH2:22].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:20]([NH:23][S:16]([C:14]1[S:15][C:11]([C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17])[CH:21]=[CH2:22]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Reactant: C=CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCNS(=O)(=O)c1ccc(-c2sc(NC(C)=O)nc2C)s1
Reaction time: 1 h

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step 1 of Example 9 (110 mg; 0.33 mmol; 1 eq.), is dissolved in DCM (10 ml). Allylamine (0.034 ml; 0.46 mmol; 1.40 eq.) and DIEA (0.17 ml; 0.98 mmol; 3 eq.) are added. After one hour, the solvents are evaporated. The crude product is purified by preparative HPLC, affording Compound (12) is obtained as white-off solid (75 mg; 50%). 1H NMR (DMSO-d6) δ 2.22 (s, 3H), 2.51 (s, 3H), 3.61 (m, 2H), 5.14 (m, 1H), 5.26 (m, 1H), 5.80 (m, 1H), 7.28 (d, J=3.8 Hz, 1H), 7.62 (d, J=3.8 Hz, 1H), 8.17 (t, J=6 Hz, 1H), 12.39 (s, 1H). M−(ESI): 356.12; M+(ESI): 358.12. HPLC, Rt: 3.06 min (purity: 100%).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:27][CH:28]2C[CH2:31][CH2:30][CH2:29]2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.[CH:34]1(CN(C2C=CC(F)=C(F)C=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.NC1C=C(NS(C)(=O)=O)C=CC=1.C1(C=O)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:27]1([N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][S:23]([CH3:26])(=[O:24])=[O:25])[CH:17]=2)[C:13](=[O:14])[N:12]([CH3:34])[C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:3])=[O:33])=[CH:8][N:9]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(NS(C)(=O)=O)c2)s1
Reactant: O=C(O)Cc1csc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2)n1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)Nc1cccc(N)c1
Agent: O=CC1CCCC1
Product: CN(C(=O)N(c1cccc(NS(C)(=O)=O)c1)C1CCCC1)c1ncc(SCC(=O)O)s1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-methanesulfonylaminophenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using N-(3-Amino-phenyl)-methanesulfonamide, cyclopentanecarbaldehyde and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)=[N:4][C:5]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:25])[CH:23]=[CH2:24])[CH2:18][CH2:17]3)=[C:11]([CH3:26])[CH:10]=2)=[N:6][CH:7]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)=[N:4][C:5]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([C:22](=[O:25])[CH2:23][CH2:24][N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH2:20][CH2:21]3)=[C:11]([CH3:26])[CH:10]=2)=[N:6][CH:7]=1
Reactant: C1COCCN1
Reactant: C=CC(=O)N1CCC(c2cc(C)c(Nc3ncc(Cl)c(Nc4cc(C)[nH]n4)n3)cc2C)CC1
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(C(=O)CCN5CCOCC5)CC4)cc3C)ncc2Cl)n[nH]1

Procedure:
A solution of 1-(4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)piperidin-1-yl)prop-2-en-1-one (41 mg, 0.88 mmol) and morpholine (0.1 mL) in DMF (1 mL) was stirred at rt overnight. The crude product was purified by RP-HPLC to give 1-(4-(4-(5-Chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)piperidin-1-yl)-3-morpholinopropan-1-one as a white powder; ESMS m/z 553.2 (M+H+).
Reaction SMILES: [OH:1][CH:2]([CH2:5][CH2:6][CH2:7][CH:8](O)[CH:9]=[CH2:10])[CH:3]=[CH2:4].Cl.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16]Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][CH:8]([CH2:7][CH2:6][CH2:5][CH:2]([OH:1])[CH:3]=[CH2:4])[CH:9]=[CH2:10]
Reactant: C=CC(O)CCCC(O)C=C
Reactant: CN(C)CCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C=CC(O)CCCC(C=C)CCN(C)C
Yield: 57.8 %

Procedure:
A stirred mixture of 3,7-dihydroxy-nona-1,8-diene (181.5 g; 1.16 M), 2-dimethylaminoethylchloride hydrochloride (201 g; 1.4 M), powdered NaOH (163 g; 4.07 M) and toluene (2.4 l) was refluxed during 4.5 h. The reaction mixture was cooled and washed successively with H2O and sat. brine. Work-up and fractional distillation in vacuo (spinning band) gave the title compound as a colourless oil (142 g) (54%) bp. 85°-90°/0.05 Torr, GC (5% Carbowax®) 240°/4.8 min., RF 0.38 [methanol/EtOAc (9:1]; NMR (δ) 1.5 (c, 6H; aliphatic CH2), 2.21 [s, 6H; (CH3)2N], 2.49 (t, J 7 Hz, 2H; CH2N), 3.16* (bs, 1H, OH), 3.15-4.2 [c, 4H, CH2 (O) and CH(O)] and 4.9-6.2 (c, 6H; olefinic H) (*D2O exchange removes this signal); IR (cm-1) 3400 (b), 3080, 1645, 1460, 995 and 920.