Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:26][CH2:25][O:24][C:23]4=[O:27])=[CH:18][CH:17]=3)=[O:15])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH3:30]B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[F-].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCCC1>[CH3:30][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:26][CH2:25][O:24][C:23]4=[O:27])=[CH:18][CH:17]=3)=[O:15])[CH2:12][CH2:13]2)=[O:7])=[CH:28][CH:29]=1
Reactant: O=C(c1ccc(Cl)cc1)C1CCN(C(=O)c2ccc(N3CCOC3=O)cc2)CC1
Reactant: CB(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)C2CCN(C(=O)c3ccc(N4CCOC4=O)cc3)CC2)cc1
Yield: 28.5 %

Procedure:
To a mixture of 3-{4-[4-(4-chlorobenzoyl)piperidine-1-carbonyl]phenyl}oxazolidin-2-one (413 mg) described in Example 40, methylboronic acid (120 mg), palladium (II) acetate (11 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (41 mg) and potassium fluoride (232 mg) was added tetrahydrofuran (3 mL), and the mixture was refluxed for 5 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform:methanol) to give the title compound (112 mg).
Reaction SMILES: [CH2:1]([N:5]1[CH2:11][CH2:10][C:9](=[O:12])[NH:8][C:7]2[CH:13]=[N:14][C:15]([Cl:17])=[N:16][C:6]1=2)[CH2:2][CH2:3][CH3:4].[CH3:18]N(C)C(=O)C.IC.[H-].[Na+]>O>[CH2:1]([N:5]1[CH2:11][CH2:10][C:9](=[O:12])[N:8]([CH3:18])[C:7]2[CH:13]=[N:14][C:15]([Cl:17])=[N:16][C:6]1=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCC(=O)Nc2cnc(Cl)nc21
Reactant: CC(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCCCN1CCC(=O)N(C)c2cnc(Cl)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.102 g (0.0004 mole) of 9-butyl-2-chloro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-44), 1 mL of N,N-dimethylacetamide and 0.037 mL (0.0006 mole) of iodomethane at 0 degrees was added 0.024 g (0.0006 mole) of 60% sodium hydride in oil. The mixture was stirred at ambient temperature for 1 hour, then 20 mL of water was added. The precipitate was collected by filtration to give 0.094 g of 9-butyl-2-chloro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-44) as an yellow solid.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=O)[CH3:2].B.C1COCC1>C1COCC1>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH2:16])(=[O:14])=[O:15])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)[CH3:2]
Reactant: CC(=O)N1CCc2cc(S(N)(=O)=O)ccc21
Agent: B
Solvent: C1CCOC1
Product: CCN1CCc2cc(S(N)(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.6 %

Procedure:
To a suspension of 1-acetylindoline-5-sulfonamide (Intermediate 52A, 120 mg, 0.50 mmol) in THF (2.0 mL) was added BH3.THF (5.0 mL, 5.0 mmol, 1.0M solution in THF). The resulting reaction mixture was stirred at room temperature for 1 h, then quenched carefully with MeOH and concentrated in vacuo to give the title compound (115 mg, 100%) as a white solid. 1H NMR (CD3OD) δ 7.56 (dd, J=8.4, 2.0 Hz, 1H), 7.48 (d, J=1.6 Hz, 1H), 6.46-6.44 (m, 1H), 3.51 (t, J=8.6 Hz, 2H), 3.24-3.20 (m, 2H), 2.99 (t, J=8.5 Hz, 2H), 1.17-1.13 (m, 3H); MS(ESI+) m/z 227.2 (M+H)+.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([O:14][CH2:15][CH3:16])=[O:13].N([O-])=O.[Na+].[ClH:21]>O.[Cu]Cl>[Cl:21][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Cl
Reactant: CCOC(=O)c1cccc2c(N)cccc12
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cccc2c(Cl)cccc12
Temperature: 25 °C

Procedure:
While stirring ethyl 5-amino-1-naphthoate (1.358 g, 6.309 mmol) in conc. hydrochloric acid (10 ml), a solution of sodium nitrite (0.52 g, 7.57 mmol) in water (1 ml) was added dropwise under ice-cooling and the mixture was stirred at said temperature for 0.5 hr. To the reaction solution was added a solution of copper(I) chloride (0.34 g, 3.47 mmol) in conc. hydrochloric acid (2 ml) under ice-cooling, and the mixture. was stirred at 100° C. for 0.5 hr. After cooling to room temperature, the reaction solution was diluted with water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=15/1) to give the objective substance.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH2:12])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21]>O1CCCC1>[C:1]1([C:7]2[CH:11]=[C:10]([NH:12][C:20](=[O:21])[O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1cc(-c2ccccc2)no1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1cc(-c2ccccc2)no1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
To a solution of 3-phenylisoxazole-5-amine (420 mg, 2.62 mmol) and pyridine (0.636 ml, 7.87 mmol) in tetrahydrofuran (5 ml) was added 2,2,2-trichloroethyl chloroformate (0.542 ml, 3.93 mmol) with ice-cooling, the mixture was stirred for 30 minutes with ice-cooling, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain the desired product (750 mg, 85.3%) as a solid.
Reaction SMILES: [Si](O[C@H](CO[Si](C(C)(C)C)(C)C)C[N:11]1[C:19]2[C:14](=[CH:15][C:16]([CH2:20]Br)=[CH:17][CH:18]=2)[CH:13]=[C:12]1[C:22]#[N:23])(C(C)(C)C)(C)C.[NH:33]1[CH2:38][CH2:37][CH:36]([NH:39][C:40]2[C:41]3[CH:48]=[C:47]([CH2:49][C:50]([F:53])([F:52])[F:51])[S:46][C:42]=3[N:43]=[CH:44][N:45]=2)[CH2:35][CH2:34]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:52][C:50]([F:51])([F:53])[CH2:49][C:47]1[S:46][C:42]2[N:43]=[CH:44][N:45]=[C:40]([NH:39][CH:36]3[CH2:35][CH2:34][N:33]([CH2:20][C:16]4[CH:15]=[C:14]5[C:19](=[CH:18][CH:17]=4)[NH:11][C:12]([C:22]#[N:23])=[CH:13]5)[CH2:38][CH2:37]3)[C:41]=2[CH:48]=1
Reactant: FC(F)(F)Cc1cc2c(NC3CCNCC3)ncnc2s1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](Cn1c(C#N)cc2cc(CBr)ccc21)O[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc2cc(CN3CCC(Nc4ncnc5sc(CC(F)(F)F)cc45)CC3)ccc2[nH]1
Yield: 33.8 %

Procedure:
58 mg of (S)-1-(2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-5-(bromomethyl)-1H-indole-2-carbonitrile (0.1 mmol) and 31 mg of N-(piperidin-4-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-amine (0.12 mmol) were dissolved in 0.2 mL of DCM. 26 mg of DIPEA (0.2 mmol) was added to that solution and reaction mixture was stirred for 18 hs. Then reaction mixture was directly loaded on silica gel column and the product was eluted with DCM-MeOH 30:1. After evaporation of solvent TBDMS-protected intermediate was dissolved in 0.2 mL of MeOH and 0.02 mL of 12M HCl was added. The homogenous reaction mixture was stirred overnight and then all volatiles were removed in vacuo. The residue was quenched ammonia and extracted with ethyl acetate. Combined organic fractions were dried over MgSO4 and concentrated. The residue was purified on silica gel column using DCM-MeOH 20:1 to afford 15.9 mg of 5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile (Compound 188). Its monohydrochloride salt was obtained by adding 1 equivalent of 1N HCl solution in diethyl ether to a solution of compound in ethanol. Monohydrochloride salt exists as a mixture of rotomers in approximate ratio 10:1, NMR is described for the major one: 1H NMR (600 MHz, MeOD-d4): 8.63 (s, 1H), 7.95 (s, 1H), 7.78 (s, 1H), 7.77 (d, 1H, J=8.6 Hz), 7.63 (d, 1H, J=8.6 Hz), 7.37 (s, 1H), 4.57 (m, 1H), 4.56 (m, 1H), 4.50 (s, 2H) 4.37 (m, 1H), 4.04 (m, 1H), 3.99 (q, 2H, J=10.3 Hz), 3.65 (m, 2H), 3.60 (d, 2H, J=5.5 Hz), 3.29 (m, 2H), 2.37 (m, 2H), 2.12 (m, 2H). 13C NMR (150 MHz, MeOD-d4): δC 157.45, 150.99, 139.90, 132.27, 129.16127.89, 127.37, 127.00, 125.54, 123.11, 122.50, 118.58, 114.32, 114.25, 113.35, 113.31, 72.35, 64.85, 61.99, 52.44, 49.82, 48.12, 35.32 (q, J=33 Hz), 29.64. ESI MS [MH+]: 545.1941.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]=[O:13])=[N:9][C:8]([O:14][CH3:15])=[CH:7][CH:6]=2.[BH4-].[Na+].O>CO>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][OH:13])=[N:9][C:8]([O:14][CH3:15])=[CH:7][CH:6]=2
Reactant: COc1ccc2ncc(F)c(C=O)c2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2ncc(F)c(CO)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To an ice-chilled suspension of 3-fluoro-6-methoxy-[1.5]naphthyridine-4-carbaldehyde (5 g, 24.25 mmol; prepared as in WO 2006/032466) in MeOH (180 mL) was added NaBH4 (1.03 g, 26.68 mmol, 1.1 eq.) in one portion. After 30 min, the reaction mixture was warmed to rt. Water (180 mL) was added and the volatiles were removed under reduced pressure. The residue was filtered off and washed with water. The aq. filtrate was extracted twice with EA (2×100 mL). The combined org. layers were washed with brine (120 mL), dried over Na2SO4, filtered and evaporated under reduced pressure to afford a yellow solid. The residue was purified by CC (Hept-EA 1:1) to give the title intermediate as a pale yellow solid (4.01 g, 79% yield).
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[C:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])[NH2:22].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([C:24]1[CH:29]=[CH:28][C:27]([C:2]2[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=3)[N:3]=2)=[CH:26][CH:25]=1)(=[O:23])[NH2:22]
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: NC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc(C(N)=O)cc3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
To a solution of methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (120 mg, 0.49 mmol) in dioxane (5 mL) was added 4-carbamoylphenylboronic acid (169 mg, 1.02 mmol), K3PO4 (217 mg, 1.02 mmol), Pd(PPh3)4 (30 mg, 0.03 mmol) and water (5 drops). The resulting solution was stirred for 1 hour at 90° C. and then concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (9% ethyl acetate in petroleum ether) to afford methyl 2-(4-carbamoylphenyl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a yellow solid (103 mg, 66%).
Reaction SMILES: [NH:1]1[C:10](=[O:11])[CH2:9][CH2:8][C:7]2[N:6]=[CH:5][C:4]3[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=3[C:2]1=2.[OH-].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CS(C)=O.O>[C:19]1([CH2:18][N:1]2[C:10](=[O:11])[CH2:9][CH2:8][C:7]3[N:6]=[CH:5][C:4]4[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=4[C:2]2=3)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CCc2ncc3ccccc3c2N1
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C1CCc2ncc3ccccc3c2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.8 %

Procedure:
A stirred solution of 1,4-dihydrobenzo[c]-1,5-naphthyridin-2(3H)-one (3.97 g) in dimethylsulfoxide (sieve dried, 80 ml) was treated sequentially with powdered potassium hydroxide (2.64 g of 85% KOH) and benzyl bromide (3.76 g). The solution was stirred for 1.5 hours at ambient temperature, transferred to a separatory funnel, diluted with water (400 ml) and extracted with ethyl acetate (2×250 ml). The organic phase was washed with water (2×200 ml), dried (Na2SO4), filtered and evaporated to give a solid (4.9 g). Recrystallization from 95% ethanol (32 ml) gave 3.35 g of crystals, m.p. 153.5°-155.5° C.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:21])[C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[C:7]([NH:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:6]=1.C([O-])=O.[NH4+]>C(O)C>[CH3:1][O:2][N:3]([CH3:21])[C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[CH:6]=1
Reactant: CON(C)C(=O)c1ccc([N+](=O)[O-])c(NC2CCCC2)c1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CON(C)C(=O)c1ccc(N)c(NC2CCCC2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
Combine N-[methoxy]-N-[methyl]3-cyclopentylamino-4-nitrobenzamide (2.0 g, 6.82 mmol), ammonium formate (2.1 g, 34.1 mmol), and 0.36 g (3.41 mmol) Pd(C) in ethanol (25 mL). Heat the mixture to 60° C. and stir for two hours. Cool to room temperature and filter through a pad of celite. Concentrate the filtrate under reduced pressure to provide the desired compound (1.79 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C(#N)C.CN(C=O)C>[CH3:9][O:8][C:6]1[N:7]=[C:2]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: C1COCCN1
Reactant: COc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1nc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
To a solution of 6-chloro-2-methoxy-3-nitropyridine (283 mg, 1.5 mmol) in acetonitrile/DMF (2:1, 3 mL) was added morpholine (0.13 mL, 1.5 mmol) and triethylamine (0.21 mL, 1.5 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between water (30 mL) and EtOAc (30 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 20% cyclohexane in EtOAc to give the title compound (280 mg, 78%). 1H NMR (500 MHz, CDCl3): δ 8.28 (d, J=9.0 Hz, 1H), 6.16 (d, J=9.0 Hz, 1H), 4.04 (s, 3H), 3.82 (t, J=4.5 Hz, 4H), 3.71 (t, J=4.5 Hz, 4H).
Reaction SMILES: Br[C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[N:6][CH:7]=1.[C:9]([O:13][C:14](=[O:37])[NH:15][C:16]([C:18]1[S:19][C:20]([S:35][CH3:36])=[C:21]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=2)(=[O:25])=[O:24])[CH:22]=1)=[NH:17])([CH3:12])([CH3:11])[CH3:10].C([O-])([O-])=O.[Na+].[Na+].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.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.CCOC(C)=O.O1CCOCC1.C1(C)C=CC=CC=1.C(O)C>[C:9]([O:13][C:14](=[O:37])[NH:15][C:16](=[NH:17])[C:18]1[S:19][C:20]([S:35][CH3:36])=[C:21]([S:23]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]([C:2]3[C:3]([CH3:8])=[N:4][CH:5]=[N:6][CH:7]=3)[CH:31]=2)(=[O:25])=[O:24])[CH:22]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: Cc1ncncc1Br
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: C1COCCO1
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2cncnc2C)c1
Temperature: 25 °C
Yield: 87 %

Procedure:
To a flask with a reflux condenser under argon was added 5-Bromo-4-methyl-pyrimidine (9 mg, 0.044 mmol), prepared according to the procedure of Yamanaka, Sakamoto, Nishimura, and Sagi, Chem. Pharm. Bull. 35(8), 3119–3126 (1987). {[4-(3-dihydroxyboranyl-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (20 mg, 0.044 mmol, Example 140: step a), Na2CO3 (2M, 0.220 mL, 0.44 mmol), Pd(PPh3)4 (8 mg, 0.007 mmol), ethanol (0.220 mL) and toluene (0.440 mL). PdCl2(PPh3)2 (42 mg, 0.06 mmol), dioxane (4 mL), and triethylamine (420 μL, 3 mmol) and the mixture was stirred for 2 h 15 min at 90° C. After cooling to rt, EtOAc (2 mL) and NaHCO3 (saturated, 2 mL) were added and the layers were separated. The organic layer concentrated in vacuo followed by purification of the crude material by preparative TLC (5% methanol in dichloromethane) to yield the title compound (19 mg, 87%) as a white solid. 1H-NMR (CDCl3): δ 9.12 (s, 1H), 8.54 (s, 1H), 8.10–7.29 (m, 7H), 2.59 (s, 3H), 2.50 (s, 3H), 1.51 (s, 9H). ESI-MS (m/z): Calcd. for C22H24N4O4S3: 504.1 (M−BOC)+H; found: 405.1.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=[O:9])=O>C(O)CO>[F:1][C:2]([F:16])([F:15])[C:3]1[NH:10][C:8](=[O:9])[C:7]2[C:6](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=1
Reactant: NC(=O)c1ccccc1NC(=O)C(F)(F)F
Solvent: OCCO
Product: O=c1[nH]c(C(F)(F)F)nc2ccccc12
Reaction time: 1 h

Procedure:
2-(Trifluoroacetamido)benzamide (73.0 g, 0.31 mole) was heated in ethylene glycol (150ml) in an oil bath with stirring. The amide dissolved at around 130° and product began to precipitate out at 150°. The temperature was held at 150° for a further 1 hour before cooling. The solid was filtered off washing well with cold water to give the product, 55.7 g (84%).
Reaction SMILES: [CH:1]1([N:4]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:5]([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:13]=3[F:20])[O:9][N:8]=2)=[O:6])[CH2:3][CH2:2]1.[F:27][C:28]([F:39])([F:38])[C:29]1([CH2:32]OS(C)(=O)=O)[CH2:31][CH2:30]1>>[CH:1]1([N:4]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:32][C:29]3([C:28]([F:39])([F:38])[F:27])[CH2:31][CH2:30]3)[CH2:23][CH2:22]2)[C:5]([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:13]=3[F:20])[O:9][N:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)OCC1(C(F)(F)F)CC1
Reactant: N#Cc1ccc(-c2cc(C(=O)N(C3CCNCC3)C3CC3)no2)c(F)c1
Product: N#Cc1ccc(-c2cc(C(=O)N(C3CC3)C3CCN(CC4(C(F)(F)F)CC4)CC3)no2)c(F)c1

Procedure:
The title compound is prepared from 5-(4-cyano-2-fluoro-phenyl)-isoxazole-3-carboxylic acid cyclopropyl-piperidin-4-yl-amide and methanesulfonic acid (1-trifluoromethyl-cyclopropyl)methyl ester following a procedure analogous to that described for Example 3. LC (method 3): tR=1.35 min; Mass spectrum (ESI+): m/z=477 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:5]=1)[CH3:2].N[C:19](N)=[O:20].CCOC(C)=O>CC1C=CC(C)=C(C)C=1C>[CH:12]1([N:11]2[C:6]3[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=[CH:8][C:7]=3[NH:10][C:19]2=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCOc1ccc(N)c(NC2CCCCC2)c1
Reactant: NC(N)=O
Solvent: Cc1ccc(C)c(C)c1C
Solvent: CCOC(C)=O
Product: CCOc1ccc2[nH]c(=O)n(C3CCCCC3)c2c1
Yield: 39.3 %

Procedure:
A mixture of 3.05 g of the oil obtained in step B) and 1.6 g of urea in 8 ml of 1,2,3,4-tetramethylbenzene is heated at 170°-180° C. for 1 hour 30 minutes. After cooling, it is taken up with AcOEt, washed with water and dried over sodium sulfate and the solvent is evaporated off under vacuum. The residue is taken up with hexane and the brown precipitate formed is filtered off. The precipitate is chromatographed on silica using a DCM/AcOEt mixture (50/50; v/v) as the eluent to give 1.33 g of the expected product, which was precipitated with isopropyl ether. M.p.=203° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH2:15][CH2:14][CH2:13]2)(=[O:9])=[O:8].CCN(CC)CC.[Cl:27][CH2:28][C:29](Cl)=[O:30]>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:29](=[O:30])[CH2:28][Cl:27])[CH2:15][CH2:14][CH2:13]2)(=[O:9])=[O:8]
Reactant: O=S(=O)(Nc1nccs1)c1ccc2c(c1)CCCN2
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1CCCc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
Under N2, a solution of 1,2,3,4-Tetrahydro-quinoline-6-sulfonic acid thiazol-2-ylamide (50 mg, 0.17 mmol), Et3N (17 mg, 24 μl, 0.17 mmol) and CH2Cl2 (0.5 mL) was cooled to 0° C. Chloroacetyl chloride (77 mg, 56 μl, 0.68 mmol) was added dropwise, over a period of 10 minutes. This reaction mixture was stirred at 0° C. for 2 hours. The mixture was purified via silica gel chromatography using 2% MeOH in CH2Cl2 to obtain the amide (30 mg, 0.08 mmol, 47% yield). LC/MS (10-99%) M/Z: M+1 obs=372.1; tR=2.51 min.
Reaction SMILES: S([N:11]=[N+:12]=[N-])(C1C=CC(C)=CC=1)(=O)=O.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=[O:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[N+:11](=[C:24]([C:23](=[O:30])[CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N-:12]
Reactant: CCOC(=O)CC(=O)Cc1ccc(OC)cc1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=[N+]=[N-])C(=O)Cc1ccc(OC)cc1
Temperature: 25 °C
Yield: 65 %

Procedure:
Synthesis of B can be performed in analogy to the protocol in J. Org. Chem. 2001, 66, 2509-2511. At 0° C. a solution of sodium azide (2.287 g, 35.2 mmol) in a minimum amount of water was added to a solution of tosylchloride (6.71 g, 35.2 mmol) in acetone (40 ml). The reaction mixture was stirred at 0° C. for 2 h. Acetone was evaporated and the remaining aqueous residue was extracted three times with Et2O, dried over MgSO4, filtrated and evaporated to provide the tosyl azide as a clear oil. The freshly prepared tosyl azide was dissolved in DCM (40.0 ml), a mixture of commercially available ethyl 4-(4-methoxy-phenyl)-3-oxobutanoate (5.54 g, 23.45 mmol) and triethylamine (4.90 ml, 35.2 mmol) in DCM (dichloromethane) was added, and stirred at room temperature over night. The product as evaporated and purified by flash chromatography on 80 g SiO2 using 20% EtOAc in cyclohexane to obtain 4.03 g of the desired product (15.36 mM; yield: 65%).