Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]Cl.[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH:16][C:17]([NH:19][C:20]1[N:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([CH3:28])[N:21]=1)=[O:18])(=[O:15])=[O:14])[CH:4]=C.[CH2:29]([Cl:31])Cl>>[Cl:1][CH:4]([CH2:29][Cl:31])[CH2:3][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH:16][C:17]([NH:19][C:20]1[N:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([CH3:28])[N:21]=1)=[O:18])(=[O:15])=[O:14]
Reactant: C=CCOc1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1
Reactant: ClCl
Reactant: ClCCl
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2OCC(Cl)CCl)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.13 g of chlorine are introduced within 20 minutes into a solution of 11.37 g of N-(2-allyloxyphenylsulfonyl)-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)urea in 100 ml of methylene chloride at a temperature of 0° C. The reaction mixture is stirred for a further 18 hours at room temperature. After addition of petroleum ether, the product is precipitated. Yield: 12.1 g of N-[2-(2,3-dichloropropyloxy)-phenylsulfonyl]-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)urea with a melting point of 117°-118° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]1([N:29]2[C:33]([NH:34][C:35](=O)[O:36]C3C=CC=CC=3)=[CH:32][C:31]([C:44]3([C:47]([F:50])([F:49])[F:48])[CH2:46][CH2:45]3)=[N:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:35]([NH:34][C:33]2[N:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:30]=[C:31]([C:44]3([C:47]([F:50])([F:48])[F:49])[CH2:46][CH2:45]3)[CH:32]=2)=[O:36])[CH:20]=[CH:21][CH:22]=1.[C:23]1([N:29]2[C:33]([NH:34][C:35](=[O:36])[NH2:7])=[CH:32][C:31]([C:44]3([C:47]([F:49])([F:50])[F:48])[CH2:46][CH2:45]3)=[N:30]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: O=C(Nc1cc(C2(C(F)(F)F)CC2)nn1-c1ccccc1)Oc1ccccc1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C5(C(F)(F)F)CC5)nn4-c4ccccc4)c3)c2cc1OC
Product: NC(=O)Nc1cc(C2(C(F)(F)F)CC2)nn1-c1ccccc1
Yield: 173.3 %

Procedure:
The title compound was prepared from 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg, 0.3 mmol) and the carbamate from Example 137A (116 mg, 0.3 mmol) using the procedure in Example 115C to give 14346,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)urea (160 mg, 0.26 mmol, 88%). 1H NMR (300 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.69 (s, 1H), 8.61 (s, 1H), 7.79 (s, 1H), 7.58-7.50 (m, 4H), 7.49-7.38 (m, 3H), 7.34 (d, 2H), 7.25 (d, 1H), 6.56 (s, 1H), 3.99 (s, 6H), 1.35-1.29 (m, 4H); LC-MS (ESI) m/z 607 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(O)C.[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([N:36]=[C:37]=[S:38])=[O:35]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:37]([NH:36][C:34](=[O:35])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH3:27])=[S:38])=[C:18]([F:23])[CH:17]=1
Reactant: Cc1ccccc1C(=O)N=C=S
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4C)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 2-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (66 mg, yield 85%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[N+:16]([O-])=O.[H][H]>CO.[Pd]>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[NH2:16]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cnccc1Nc1cccc(F)c1F
Agent: [Pd]
Solvent: CO
Product: Nc1cnccc1Nc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 90 %

Procedure:
To a solution of N-(2,3-difluorophenyl)-3-nitropyridin-4-amine in 200 mL of methanol under an atmosphere of nitrogen was added 10% Pd/C (0.75 g). The atmosphere was replaced with hydrogen gas and the reaction mixture stirred under balloon pressure for 14 hours at RT. The reaction mixture was filtered over Celite which was washed with methanol (3×30 mL). The filtrate was concentrated in vacuo to give a brown solid. The crude product was triturated with petroleum ether (3×50 mL) to afford N4-(2,3-difluorophenyl)pyridine-3,4-diamine (4.0 g, 90% yield) as light brown solid; LC-MS: 222.2 (M+H).
Reaction SMILES: C[NH:2][CH2:3][C:4]1[N:11]2[C:7]([S:8][CH:9]=[CH:10]2)=[CH:6][N:5]=1.C(O)=O.C(O[C:19](=[O:21])[CH3:20])(=O)C.C1(C)C=CC=CC=1>C(Cl)Cl>[CH3:20][C:19]([NH:2][CH2:3][C:4]1[N:11]2[C:7]([S:8][CH:9]=[CH:10]2)=[CH:6][N:5]=1)=[O:21]
Reactant: CNCc1ncc2sccn12
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(=O)NCc1ncc2sccn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a solution of 100 mg (0.59 mmol) of the above-obtained 5-(N-methylamino)methylimidazo[5,1-b]thiazole in 3 ml of methylene chloride was added a mixture which had been prepared in advance by reacting 1 ml of formic acid with 0.2 ml of acetic anhydride at 50° C. for 10 minutes. The mixture was stirred at room temperature for one hour, and then refluxed for 3 hours. To this was added a mixture which had been prepared in advance by reacting 5 ml of formic acid with 2 ml of acetic anhydride at 50° C. for 10 minutes, and the mixture was refluxed for an additional 2 hours. To the reaction solution cooled to room temperature was added 3 ml of toluene, and the mixture was concentrated to dryness under reduced pressure. To the residue were added methylene chloride and a 50% aqueous solution of potassium carbonate, and the mixture was stirred for 10 minutes. The organic layer was separated, and the aqueous layer was extracted three times with methylene chloride. The combined organic layers were dried over anhydrous potassium carbonate, concentrated under reduced pressure, and purified by flash column chromatography using silica gel, eluting with a 9:1 mixture of ethyl acetate and methanol to give 89 mg (yield 77%) of the title compound as colorless crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:22])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[CH3:23][C:24]1([CH3:40])[O:29][CH:28]([C:30]([NH:32][CH2:33][CH2:34][C:35](O)=[O:36])=[O:31])[C:27]([CH3:39])([CH3:38])[CH2:26][O:25]1>>[CH3:23][C:24]1([CH3:40])[O:29][CH:28]([C:30]([NH:32][CH2:33][CH2:34][C:35]([O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:22])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:36])=[O:31])[C:27]([CH3:39])([CH3:38])[CH2:26][O:25]1
Reactant: CCCCCCCCCCCCCCCC(=O)NCCCO
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Product: CCCCCCCCCCCCCCCC(=O)NCCCOC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 98.9 %

Procedure:
N-(3-Hydroxypropyl)hexadecanamide (3.13 g) and 2.59 g of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid were reacted in the same manner as in Example 15 to obtain 5.48 g of the title compound (yield: 99%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@H:13]([C@@H:14]([O:16][C:17]3[CH:22]=[CH:21][C:20](Cl)=[C:19](Cl)[CH:18]=3)[CH3:15])[CH2:12][CH2:11][N:10]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][N:34]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:9]2)=[CH:4][CH:3]=1.N1CCCCC1.C(N1CC[C@H]([C@H]([OH:62])C)[C@@H](C2C=CC(Cl)=CC=2)C1)C1C=CC=CC=1.[F:70][C:71]([F:80])([F:79])C1C=CC(O)=CC=1.ClC(OC(Cl)=O)C.CCN(C(C)C)C(C)C>CO>[C:39]([C:36]1[CH:37]=[CH:38][C:33]([N:30]2[CH2:31][CH2:32][CH:27]([C:25]([OH:26])=[O:62])[CH2:28][CH2:29]2)=[N:34][CH:35]=1)#[N:40].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@H:13]([C@@H:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:71]([F:80])([F:79])[F:70])=[CH:19][CH:18]=3)[CH3:15])[CH2:12][CH2:11][N:10]([C:25]([CH:27]3[CH2:28][CH2:29][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][N:34]=4)[CH2:31][CH2:32]3)=[O:26])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: C[C@H](Oc1ccc(Cl)c(Cl)c1)[C@H]1CCN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@@H]1c1ccc(Cl)cc1
Reactant: C[C@@H](O)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNCC1
Product: C[C@H](Oc1ccc(C(F)(F)F)cc1)[C@H]1CCN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@@H]1c1ccc(Cl)cc1
Product: N#Cc1ccc(N2CCC(C(=O)O)CC2)nc1

Procedure:
In analogy to the procedure described for the synthesis of 4-{(3S,4S)-3-(4-Chloro-phenyl)-4-[(S)-1-(3,4-dichloro-phenoxy)-ethyl]-piperidine-1-carbonyl}-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile (example 49) the respective piperidine derivative was prepared from (R)-1-[(3S,4S)-1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethanol and 4-trifluoromethyl-phenol via Mitsunobu reaction and subsequently the benzyl group was cleaved by treatment with 1-chloroethyl-chloroformate, DIPEA and methanol. Coupling with 5′-Cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid (commercially available) yielded the title compound as viscous yellow oil. MS (m/e): 597.4 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][C:10](=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:20].[Na+]>CO>[CH3:1][C:2]1([CH3:13])[CH2:11][CH:10]([NH2:20])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1
Reactant: [BH3-]C#N
Reactant: CC1(C)CC(=O)c2ccccc2O1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC1(C)CC(N)c2ccccc2O1

Procedure:
A solution of 2′-hydroxyacetophenone (5.0 mL), acetone (4.7 mL), and pyrrolidine (5.4 mL) in 150 mL of methanol was stirred for 66 hours. The mixture was concentrated and treated with aqueous HCl (pH<1). The acidic layer was extracted twice with ethyl ether, which was dried and concentrated to provide 2,2-dimethylchroman-4-one. The 2,2-dimethylchroman-4-one was dissolved in 300 mL of methanol and treated with ammonium acetate (65 g) and sodium cyanoborohydride (2.5 g) for 24 hours. The resulting mixture was concentrated to 100 mL and diluted with 300 mL water. Concentrated HCl was carefully added until the pH was less than 1 and the acidic mixture was extracted with ethyl ether. The acidic phase was made basic with KOH and then extracted twice with ethyl ether. The basic extracts were dried and concentrated to provide the title compound.
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[CH:10]([CH3:19])[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14].O.[CH3:21]COC(C)=O>C(O)C>[CH2:10]([C:11]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[NH:7][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:19][CH3:21]
Reactant: NNc1ccccc1
Reactant: CCOC(C)=O
Reactant: CCOC(=O)C(=O)CC(C)C
Solvent: CCO
Solvent: O
Product: CCCc1c(C(=O)OCC)[nH]c2ccccc12
Reaction time: 18 h

Procedure:
A solution of phenylhydrazine (1.0 g, 6.92 mmol) in absolute ethanol (50 mL) was placed in an oil bath at 60° C. and a reflux condenser attached. Ethyl 4-methyl-2-oxopentanoate (1.0 g, 6.33 mmol) (prepared according to Singh, J; Kissick, T. P.; Mueller, R. H. Organic Preparations and Procedures International (1989), 21(4), 501-4.) was added dropwise. The reaction mixture was heated to reflux and stirred for 18 h. Water (25 mL) and EtOAc (25 mL) were added and the layers separated. The aqueous layer was extracted with EtOAc (2×25 mL), the organic layers combined, dried over sodium sulfate, filtered and concentrated. Purification was accomplished by column chromatography (hexanes/EtOAc) and RPHPLC. Neutralization and extraction of the desired fractions with EtOAc afforded ethyl 3-propyl-1H-indole-2-carboxylate (0.250 g) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.39 (s, 1H) 7.82 (d, 1H) 7.42 (d, 1H) 7.22 (t, 1H) 7.01 (t, 1H) 4.33 (q, 2H) 4.01-4.09 (m, 1H) 1.39 (d, 6H) 1.35 (t, 3H). MS: m/z 232.0 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11](I)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[B:17](OC(C)C)([O:22][CH:23](C)C)[O:18][CH:19](C)C.C([Li])[CH2:31][CH2:32][CH3:33].CC(CO)(CO)C>ClCCl.C1(C)C=CC=CC=1.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([B:17]2[O:22][CH2:23][C:32]([CH3:31])([CH3:33])[CH2:19][O:18]2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Li]CCCC
Reactant: Cc1ccc(OCc2ccccc2)cc1I
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)(CO)CO
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1ccc(OCc2ccccc2)cc1B1OCC(C)(C)CO1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 131.8 %

Procedure:
The crude product containing 4-benzyloxy-2-iodo-1-methybenzene (32.9 g, 101.5 mmol) obtained in Step 1 above and triisopropyl borate (28.1 ml, 121.8 mmol) were placed in a reaction vessel, and then tetrahydrofuran (43 ml) and toluene (170 ml) were added thereto. The resulting mixture was cooled to −78° C., and n-butyllithium (1.6N; n-hexane solution, 76.2 ml, 121.9 mmol) was added dropwise thereto over 30 minutes. The resulting reaction solution was stirred at −78° C. for 30 minutes. After the solution was warmed to 0° C., neopentylglycol (12.7 g, 121.9 mmol) was added thereto and stirred at room temperature for 16 hours. The reaction solution was diluted with dichloromethane (1200 ml), and sequentially washed with a saturated aqueous ammonium chloride solution (1200 ml) and water (1200 ml). The solution was then dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to yield 2-(5-benzyloxy-2-methylphenyl)-5,5-dimethyl-[1,3,2]dioxaborinane (41.5 g) as a crude product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:11][C@@H:10]2[CH2:12][O:13][C:14]2[C:19]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:18][N:17]=[C:16]([CH3:25])[N:15]=2)=[N:7][CH:8]=1.Cl[C@@H:27]([CH3:30])[CH2:28][OH:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:11][C@@H:10]2[CH2:12][O:13][C:14]2[C:19]([C:20]3[CH:24]=[N:23][N:22]([C@@H:27]([CH3:30])[CH2:28][OH:29])[CH:21]=3)=[CH:18][N:17]=[C:16]([CH3:25])[N:15]=2)=[N:7][CH:8]=1
Reactant: C[C@H](Cl)CO
Reactant: COc1ccc([C@H]2C[C@@H]2COc2nc(C)ncc2-c2cn[nH]c2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc([C@H]2C[C@@H]2COc2nc(C)ncc2-c2cnn([C@@H](C)CO)c2)nc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 4-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]methoxy}-2-methyl-5-(1H-pyrazol-4-yl)pyrimidine (NN1) (15 mg, 0.04 mmol) in DMF (0.4 mL) was added and (2S)-2-chloropropan-1-ol (9.0 mg, 0.09 mmol) and potassium carbonate (18.4 mg, 0.13 mmol). The reaction mixture was stirred at ambient temperature for 14 hours. The mixture was filtered and purified by reverse phase chromatography (Waters Sunfire Prep C18 OBD, 5-45% acetonitrile in water with 0.1% TFA modifier) to afford the title compound as a white solid. 1H NMR (500 MHz, DMSO): δ 8.74 (s, 1 H), 8.13 (d, J=11.7 Hz, 2 H), 8.00 (s, 1 H), 7.27 (d, J=7.1 Hz, 2 H), 4.55-4.50 (m, 1 H), 4.37-4.30 (m, 1 H), 3.96 (s, 3 H), 3.78 (s, 3 H), 2.50 (s, 3 H), 2.22 (d, J=7.1 Hz, 1 H), 1.80 (s, 1 H), 1.25-1.16 (m, 2 H), 1.07 (m, 1 H), 1.01 (d, J=5.3 Hz, 3 H); HRMS m/z (M+H) 396.2019 found, 396.2030 required.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[C:11]1([CH3:19])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Mg]Cl.C(O)(=O)C>C1COCC1.O.O.C([O-])(=O)C.[Mn+3].C([O-])(=O)C.C([O-])(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH3:19])[C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: Cc1ccccc1[Mg]Cl
Agent: [Mn+3]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cc(Cl)ncc1C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
13.0 g (82.5 mMol) 6-Chloro-nicotinic acid in 65 ml THF were cooled to 0° C. and 206.3 ml (206.3 mMol) o-tolylmagnesium chloride solution (1M in THF) were added over 45 minutes. The solution obtained was further stirred 3 hours at 0° C. and overnight at room temperature. It was cooled to −60° C. and 103.8 ml (1.8 Mol) acetic acid were added, followed by 35 ml THF and 44.24 g (165 mMol) manganese(III) acetate dihydrate. After 30 minutes at −60° C. and one hour at room temperature, the reaction mixture was filtered and THF removed under reduced pressure. The residue was partitioned between water and dichloromethane and extracted. The crude product was filtered on silica gel (eluent: ethyl acetate/toluene/formic acid 20:75:5) then partitioned between 200 ml aqueous half-saturated sodium carbonate solution and 100 ml dichloromethane. The organic phase was washed with 50 ml aqueous half-saturated sodium carbonate solution, The combined aqueous phases were acidified with 25 ml aqueous HCl 25% and extracted with dichloromethane. The organic extracts were dried (Na2SO4) and concentrated under reduced pressure to yield 10.4 g (51%) of 6-chloro-4-o-tolyl-nicotinic acid as a yellow foam. MS (ISN): 246 (M−H, 100), 202 (M-CO2H, 85), 166 (36).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)(O)[CH3:21])=[C:16]([F:30])[CH:15]=1.FC1C=CC(C(C2C=CC(F)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=CC=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:9]2[C:8]3[C:12](=[C:4]([CH2:3][S:2][CH3:1])[CH:5]=[CH:6][CH:7]=3)[NH:11][CH:10]=2)([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:21])=[C:16]([F:30])[CH:15]=1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: CC(O)(c1ccc(F)cc1)c1ccc(Cl)cc1F
Agent: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3)c[nH]c12
Product: CSCc1cccc2c(C(C)(c3ccc(F)cc3)c3ccc(Cl)cc3F)c[nH]c12

Procedure:
The title compound was prepared starting from 1.00 g (5.64 mmol) of the compound from Example 8A and 1.52 g (5.64 mmol) of the compound from Example 183A in analogy to the synthesis of the compound from Example 278. 0.95 g (39% of theory) of the target compound were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]([NH:33][C:34](=[O:37])[CH:35]=[CH2:36])([CH3:32])[CH3:31].C(N(CC)CC)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:36]=[CH:35]/[C:34]([NH:33][CH:30]([CH3:32])[CH3:31])=[O:37])[CH:12]=[CH:11][C:10]=1[N:16]1[CH2:17][C:18](=[O:29])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[S:20]1(=[O:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: C=CC(=O)NC(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)NC(=O)/C=C/c1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Temperature: 100 °C

Procedure:
To a mixture of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (240 mg, 0.44 mmol), N-isopropylacrylamide (60 mg, 0.53 mmol) and triethylamine (445 mg, 0.44 mmol) in MeCN (5 mL) in a pressure vessel is added Pd(OAc)2 (5 mg) and the mixture is heated at 100° C. for 8 h. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using hexane/EtOAc (86:15) as eluent to give the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]2[N:5]([CH:6]=[CH:7][N:8]=2)[C:4]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:3]1=2.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:37])=[CH:21][N:20]=1>>[Cl:37][C:22]1[C:23]([NH:25][C:26]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:24][C:19]([NH:16][C:13]2[CH:14]=[CH:15][C:3]3[C:2]([CH3:17])([CH3:1])[CH2:11][CH2:10][C:9]4[N:5]([CH:6]=[CH:7][N:8]=4)[C:4]=3[CH:12]=2)=[N:20][CH:21]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCc2nccn2-c2cc(N)ccc21
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)-n2ccnc2CCC3(C)C)ncc1Cl

Procedure:
2-[5-Chloro-2-(6,6-dimethyl-5,6-dihydro-4H-3,10b-diaza-benz[e]azulen-9-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide was prepared from 6,6-Dimethyl-5,6-dihydro-4H-3,10b-diaza-benz[e]azulen-9-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1223c. Title compound was isolated as a white solid (64 mg, 42%) LCMS 506.22 (M+H), HPLC purity 99%, 1H-NMR (DMSO-d6, 400 MHz) δ 9.69 (s, 1H), 9.38 (s, 1H), 8.47 (m, 1H), 8.23 (s, 1H), 7.80 (d, J=6.3 Hz, 1H), 7.72 (s, 1H), 7.55 (s, 1H), 7.40 (d, J=7.5 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.28-7.23 (m, 2H), 2.92 (m, 2H), 2.74 (d, J=4.4 Hz, 3H), 2.15 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15]([OH:17])=O)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:22]([N:24]([CH2:31][CH3:32])[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[CH3:23]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15]([N:28]3[CH2:29][CH2:30][CH:25]([N:24]([CH2:31][CH3:32])[CH2:22][CH3:23])[CH2:26][CH2:27]3)=[O:17])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1Nc1ccnc2cc(Br)ccc12
Reactant: CCN(CC)C1CCNCC1
Product: CCN(CC)C1CCN(C(=O)c2ccccc2Nc2ccnc3cc(Br)ccc23)CC1

Procedure:
2-(7-Bromo-4-quinolylamino)benzoic acid is converted to the acid chloride which is reacted with 4-diethylamino piperidine as in Example 1 to give the title compound.
Reaction SMILES: C(OC([N:8]([C:25]1[C:34]([N+:35]([O-:37])=[O:36])=[CH:33][CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22](=[O:24])[NH2:23])=[CH:12][CH:11]=1)=O)(C)(C)C.Cl>CO>[C:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:25]2[C:34]([N+:35]([O-:37])=[O:36])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([O:29][CH3:30])=[O:28])=[CH:15][CH:14]=1)(=[O:24])[NH2:23]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N(Cc1ccc(-c2ccccc2C(N)=O)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1NCc1ccc(-c2ccccc2C(N)=O)cc1
Yield: 71.3 %

Procedure:
A mixture of the compound (2.8 g) obtained in Example (54b) in methanol (15 ml) and 1N-HCl (6 ml) was heated for 2 hours under reflux. After removal of the solvent, the residue was made alkaline with an aqueous solution of NaHCO3, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over MgSO4 and concentrated to dryness. The residue was purified by column chromatography on silica gel, and the product was recrystallized from ethyl acetate-hexane to afford yellow needles (1.6 g, 73%).