Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[N:5]=[C:4]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[N:17]=2)[CH:3]=1.[Cl:29][C:30]1[C:31]([F:39])=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](O)=[O:34].O.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:29][C:30]1[C:31]([F:39])=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33]([N:12]1[CH2:11][CH2:10][CH:9]([CH2:8][C:6]2[N:5]=[C:4]([NH:15][C:16]3[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:28])[CH3:27])[N:17]=3)[CH:3]=[C:2]([CH3:1])[N:7]=2)[CH2:14][CH2:13]1)=[O:34]
Reactant: O=C(O)c1cccc(Cl)c1F
Reactant: Cc1cc(Nc2ccn(COCC[Si](C)(C)C)n2)nc(CC2CCNCC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2ccn(COCC[Si](C)(C)C)n2)nc(CC2CCN(C(=O)c3cccc(Cl)c3F)CC2)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 29.8 mg of 6-methyl-2-(piperidin-4-ylmethyl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrimidin-4-amine in 2 ml of chloroform were added 39.1 mg of 3-chloro-2-fluorobenzoic acid, 0.093 ml of triethylamine, 29.5 mg of hydroxybenzotriazole hydrate and 43.8 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at room temperature, followed by stirring the reaction mixture at room temperature for 1.5 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution, and extracted with chloroform. The resulting chloroform layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=1/1 to ethyl acetate) to give the title compound.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1.Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.BrC1C=CC(C=O)=C(F)C=1.BrC1N=CC=CN=1>>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:2]1[S:6][CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1
Reactant: Brc1ccccn1
Reactant: O=Cc1csc(Br)c1
Agent: Brc1ncccn1
Agent: O=Cc1ccc(Br)cc1F
Product: O=Cc1csc(-c2ccccn2)c1

Procedure:
The title compound is prepared by a procedure analogous to Reference Example 15 by substituting 5-bromo-3-thiophenecarboxaldehyde (prepared as described in Chem. Pharm. Bull. 1999, 47,1393) and 2-bromopyridine, respectively, for the 4-bromo-2-fluorobenzaldehyde and 2-bromopyrimidine of Reference Example 15. MS 190 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[C:5]([C:16]([OH:18])=[O:17])=[C:6]1[S:15][CH2:14][CH2:13][N:7]12.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>N1C=CC=CC=1>[Cl:12][C:11]1[C:2]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:3]2[C:8](=[CH:9][CH:10]=1)[N:7]1[CH2:13][CH2:14][S:15][C:6]1=[C:5]([C:16]([OH:18])=[O:17])[C:4]2=[O:19]
Reactant: C1CNCCN1
Reactant: O=C(O)c1c2n(c3ccc(Cl)c(Cl)c3c1=O)CCS2
Solvent: c1ccncc1
Product: O=C(O)c1c2n(c3ccc(Cl)c(N4CCNCC4)c3c1=O)CCS2

Procedure:
A mixture of 500 mg (1.58 mmol) of 6,7-dichloro-5-oxo-1,2-dihydro-5H-thiazolo(3,2-a)quinoline-4-carboxylic acid, 1.0 gram (11.6 mmol) of piperazine, and 20 ml of pyridine was heated to reflux for ten hours. The content was then concentrated under reduced pressure, water was added to the residue, insoluble matters were taken out by filtration, washed with water, dried, and recrystallized from dimethyl formamide to give the title compound. Yield was 420 mg (72.7 percent). Melting point: 244° to 245° C. (decomposition). Elementary analysis calculated as C16H16ClN3O3S.21/2 H2O: C 46.77, H 5.15, N 10.22; Found: C 46.66, H 4.90, N 9.81.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[C:9]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22]O)[CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Br:1][C:2]1[N:3]=[CH:4][C:5]([O:8][CH2:22][CH:19]2[CH2:20][CH2:21][N:16]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:17][CH2:18]2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(Br)nc2)CC1
Yield: 82.6 %

Procedure:
1,1-Dimethylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (0.88 g, 83%) was prepared as a light yellow solid from 2-bromo-5-hydroxypyridine (0.50 g, 2.87 mmol), N-Boc-4-piperidinemethanol (0.64 g, 2.87 mmol) and Ph3P (0.77 g, 2.87 mmol) in THF (15 mL) followed by diisopropyl azodicarboxylate (0.62 g, 94%, 2.87 mmol) in THF (5 mL) in a manner similar to Example 1, Step 2. The material was purified by chromatography on a silica gel column eluted with 5 to 20% EtOAc/hexanes. 1H NMR (400 MHz, CDCl3): δ 8.04 (bs, 1H), 7.36 (d, 1H, J=8.8 Hz), 7.15-7.05 (m, 1H), 4.25-4.10 (m, 2H), 3.82 (d, 2H, J=6.1 Hz), 2.80-2.70 (m, 2H), 2.05-1.90 (m, 1H), 1.85-1.75 (m, 2H), 1.46 (s, 9H), 1.35-1.20 (m, 2H); LRMS (ESI), m/z 393/395 (M+Na).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]([NH2:29])([CH3:28])[CH3:27].[C:30]([C:33]1[C:41]2[C:36](=[N:37][CH:38]=[C:39]([C:42]3[C:50]4[CH2:49][CH2:48][CH2:47][CH2:46][C:45]=4[N:44]([CH3:51])[N+:43]=3[O-:52])[N:40]=2)[N:35]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:60])([CH3:59])[CH3:58])[CH:34]=1)(O)=[O:31]>CN(C=O)C>[C:26]([NH:29][C:30]([C:33]1[C:41]2[C:36](=[N:37][CH:38]=[C:39]([C:42]3[C:50]4[CH2:49][CH2:48][CH2:47][CH2:46][C:45]=4[N:44]([CH3:51])[N+:43]=3[O-:52])[N:40]=2)[N:35]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:60])([CH3:59])[CH3:58])[CH:34]=1)=[O:31])([CH3:28])([CH3:27])[CH3:25]
Reactant: CC(C)(C)N
Reactant: Cn1c2c(c(-c3cnc4c(n3)c(C(=O)O)cn4COCC[Si](C)(C)C)[n+]1[O-])CCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cn1c2c(c(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4COCC[Si](C)(C)C)[n+]1[O-])CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
In a 16×100 mm screw cap test tube were added HATU (46.3 mg, 122 μmol.20) and 2-methylpropan-2-amine (29.7 mg, 406 μmol) then 3-(7-carboxy-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazole 2-oxide (45 mg, 101 μmol) dissolved in DMF (2.00 mL) was added to give a light yellow solution which immediately formed a white precipitated. The reaction mixture stirred at 25° C. overnight, solvents evaporated and residue purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 50% EtOAc in hexanes over 30 min to yield 3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazole 2-oxide (43 mg, 86.2 μmol, 85.0%) as a clear foam. MS (M+H)+=499 (>90% purity); 1H NMR (CDCl3) δ: 7.82 (s, 1H), 6.21 (s, 1H), 4.52 (s, 2H), 2.36-2.45 (m, 2H), 2.30 (s, 3H), 1.23-1.37 (m, 2H), 0.95-1.12 (m, 2H), 0.89 (dd, J=10.9, 5.6 Hz, 2H), 0.72-0.85 (m, 2H), 0.37 (s, 9H), −0.29-−0.17 (m, 2H), −1.20 (s, 9H).
Reaction SMILES: COC1C=C(OC)C=CC=1C(Cl)=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][N:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.[CH3:36][O:37][C:38]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:39]=1[C:46]([N:48]=[C:49]=[S:50])=[O:47]>C1(C)C=CC=CC=1.C(O)C>[CH3:36][O:37][C:38]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:39]=1[C:46]([N:48]=[C:49]=[S:50])=[O:47].[CH3:36][O:37][C:38]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:39]=1[C:46]([NH:48][C:49]([NH:33][C:32]1[CH:34]=[CH:35][C:29]([O:28][C:19]2[C:18]3[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=3)[N:22]=[CH:21][N:20]=2)=[CH:30][CH:31]=1)=[S:50])=[O:47]
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: COc1ccc(C(=O)Cl)c(OC)c1
Agent: COc1ccc(C(=O)N=C=S)c(OC)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ncnc4cc(OC)c(OC)cc34)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
2,4-Dimethoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-dimethoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2,4-dimethoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) 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 (51 mg, yield 58%).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH3:8][C:9]1([CH3:41])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19](O)=[O:20])[CH:16]=2)[NH:11][CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])[CH2:30][CH2:29]2)[CH:23]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH3:8][C:9]1([CH3:41])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:20])[CH:16]=2)[NH:11][CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:29][CH2:30][N:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])[CH2:32][CH2:33]2)[CH:23]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1ccccc1N1CCN(c2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1N1CCN(c2cccc(C3Nc4ccc(C(=O)NS(C)(=O)=O)cc4CC3(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.6 %

Procedure:
To a suspension of 60% sodium hydride (172 mg, 4.3 mmol) in N,N-dimethylformamide (1.5 mL) was added methanesulfonamide (418 mg, 4.4 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 3,3-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (200 mg, 0.44 mmol), and 1,1′-carbonyldiimidazole (170 mg, 1.04 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-{3,3-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carbonyl}methanesulfonamide (46 mg, 20%) as a white solid: LC/MS m/e calcd for C30H36N4O3S (M+H)+: 533.71, observed: 533.2.
Reaction SMILES: C([Li])CCC.[Br-].[CH2:7]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[C:33]([O:36][C:37]1[C:38]([C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:39][C:40]2[O:44][C:43]([CH:45]=O)=[CH:42][C:41]=2[C:47]=1[C:48]([CH3:51])([CH3:50])[CH3:49])(=[O:35])[CH3:34].[Cl-].[NH4+]>O1CCCC1.CCCCC>[C:33]([O:36][C:37]1[C:38]([C:52]([CH3:54])([CH3:53])[CH3:55])=[CH:39][C:40]2[O:44][C:43]([CH:45]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:42][C:41]=2[C:47]=1[C:48]([CH3:49])([CH3:50])[CH3:51])(=[O:35])[CH3:34]
Reactant: CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2oc(C=O)cc2c1C(C)(C)C
Agent: [Br-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCCCCC=Cc1cc2c(C(C)(C)C)c(OC(C)=O)c(C(C)(C)C)cc2o1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.9 %

Procedure:
A pentane solution (6.0 ml) of 1.6M n-butyllithium was added dropwise to a solution of n-heptyltriphenylphosphonium bromide (4.2 g) in tetrahydrofuran (30 ml) under a nitrogen atmosphere. After stirring the mixture at room temperature for 90 min, a solution of 5-acetoxy-4,6-di-tert-butyl-2-formylbenzofuran (2.54 g) in tetrahydrofuran (20 ml) was added dropwise. Subsequently, the mixture was heated under reflux for 1 h and, after cooling, a saturated aqueous solution of ammonium chloride was added and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 5-acetoxy-4,6-di-tert-butyl-2-(1-octenyl)benzofuran [3.1 g (yield, 97%)] as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].Cl[C:20]1[N:21]=[N:22][CH:23]=[C:24]([O:26][CH3:27])[CH:25]=1>>[Cl:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[N:21]=[N:22][CH:23]=[C:24]([O:26][CH3:27])[CH:25]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: COc1cnnc(Cl)c1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Cl
Product: COc1cnnc(-c2cc(C)c(Cl)c(C)c2)c1

Procedure:
The title compound is prepared from 2-chloro-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 3-chloro-5-methoxy-pyridazine following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 11): tR=0.93 min; Mass spectrum (ESI+): m/z=249/251 (Cl) [M+H]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.[C-:16]#[N:17].[Na+]>CN(C=O)C>[F:15][C:2]([F:14])([F:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[C:12]([C:16]#[N:17])[N:11]=[CH:10]1
Reactant: FC(F)(F)c1ccccc1-n1ccnc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cn(-c2ccccc2C(F)(F)F)cn1
Temperature: 100 °C
Reaction time: 12 h
Yield: 59.4 %

Procedure:
A mixture of 4-(chloromethyl)-1-(3′-methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl-1H-imidazole (1.1 g), NaCN (1.2 g, 24.5 mmol), and dry DMF was stirred at 100° C. for 12 h. The solvent was removed in vacuo, and the residue was partitioned between water and EtOAc, the phases were separated, and the aqueous phase was extracted with EtOAc. The combined extracts were washed with water, brine, dried over sodium sulfate, and evaporated in vacuo. The crude product was purified by flash chromatography (SiO2, 80% EtOAc/hexanes) to give 1-(1-(3′-methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl-1H-imidazole-4-carbonitrile (730 mg, 74%) as a white solid. MS (ESI) 482 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]([CH3:12])=[CH:9][CH2:10]Br.[CH3:13][C:14]1[C:19](=[S:20])[CH2:18][CH:17]=[CH:16][C:15]=1[C:21]([O:23][CH3:24])=[O:22]>CC(C)=O>[CH3:7][C:8]([CH3:12])=[CH:9][CH2:10][S:20][C:19]1[C:14]([CH3:13])=[C:15]([CH:16]=[CH:17][CH:18]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)C1=C(C)C(=S)CC=C1
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(SCC=C(C)C)c1C
Temperature: 25 °C
Reaction time: 10 h

Procedure:
37.9 g (0.275 mol) of potassium carbonate and 43.5 g (0.275 mol) of 3-methyl-2-butenyl bromide were added dropwise to 50 g (0.275 mol) of methyl 3-thio-2-methylbenzoate in 250 ml of acetone, and the mixture was stirred at room temperature for 10 hours. The solvent was distilled off, the residue was taken up in water/ethyl acetate and the organic phase was dried, filtered off and concentrated.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[N:5]=1)([O-])=O>O1CCCC1.NN.[Ni]>[NH2:1][C:4]1[CH:8]=[CH:7][N:6]([CH2:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[N:5]=1
Reactant: N#Cc1ccc(Cn2ccc([N+](=O)[O-])n2)cc1
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Product: N#Cc1ccc(Cn2ccc(N)n2)cc1
Reaction time: 0.08 h

Procedure:
To a solution containing 4-(3-nitro-pyrazol-1-ylmethyl)-benzonitrile (97 mg, 0.42 mmol) in tetrahydrofuran (2 mL), anhydrous hydrazine (100 μL) was added to the clear solution. Raney nickel (˜100 mg washed 3 times with 5 mL of anhydrous tetrahydrofuran) was then added in tetrahydrofuran (300 μL). Gas evolved from the mixture and the reaction was allowed to proceed for 5 min, after which time the raney nickel was removed by filtration through a celite plug. The solvent was removed in vacuo to afford 4-(3-amino-pyrazol-1-ylmethyl)-benzonitrile as a yellow oil, which was used in the following step with no further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:16]([C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH:21]=[CH:22][CH:23]=1)#[CH:17]>C1COCC1.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]([C:17]#[C:16][C:18]2[CH:19]=[C:20]([NH:24][C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])[CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C#Cc1cccc(NC(=O)C(F)(F)F)c1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(C#Cc2ccnc(Cl)n2)c1)C(F)(F)F
Temperature: 50 °C

Procedure:
To a mixture of 2,4-dichloropyrimidine (14.5 g, 97.5 mmol), dichlorobis(triphenyl-phosphine)palladium(II) (1.3 g, 2.6 mmol), and copper(I) iodide (25 mg, 0.13 mmol) in degassed THF was added triethylamine (34 mL, 263 mmol), and the mixture was heated to 50° C. A solution of N-(3-ethynyl-phenyl)-2,2,2-trifluoro-acetamide (14 g, 65 mmol) in THF was added to the mixture over 45 min. After several h, the reaction was cooled to rt and diluted with DCM. The organic mixture was washed with water and brine, dried over MgSO4 and concentrated. The crude material was purified through silica to give the title compound as an off-white solid. 1H NMR (400 MHz, d6-DMSO): δ 11.43 (s, 1H), 8.83 (d, J=4.8 Hz, 1H), 8.00 (s, 1H), 7.80 (d, J=4.8 Hz, 1H), 7.76 (m, 1H), 7.54-7.52 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[C:14]=3[NH:13][C:12](=O)[C:11]=2[CH2:10][CH2:9]1>C1(OC2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:25])[F:26])[C:14]=3[N:13]=[C:12]([NH:13][CH2:14][CH2:15][OH:21])[C:11]=2[CH:10]=[CH:9]1
Reactant: Cc1ccccc1N1CCc2c1c1cccc(OCC(F)(F)C(F)(F)F)c1[nH]c2=O
Agent: [Pd]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1ccccc1-n1ccc2c(NCCO)nc3c(OCC(F)(F)C(F)(F)F)cccc3c21
Temperature: 25 °C
Yield: 147.9 %

Procedure:
1-(2-Methylphenyl)-4-oxo-6-β,β,γ,γ,γ-pentafluoropropyloxy-2,3,4,5-tetrahydropyrrolo[3,2-c]quinoline (2.6 g, 6.1 mmol), prepared by the procedure of Step 4 in the Example 57, was dissolved in diphenyl ether(20 ml) and 5%-Pd/C(400 mg) was added. The reaction mixture was refluxed for 4 hours, cooled to room temperature, and purified by silica gel chromatography to obtain 2.1 g of desired compound as solid in 58% of yield.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:25])=[C:4]([C:21]([CH3:24])=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](Cl)=[O:32]>CN1CCCC1=O>[Cl:25][C:3]1[C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:19][CH2:20]4)=[O:17])[N:14]=3)[N:11]=2)=[C:21]([CH3:24])[CH:22]=[CH:23][C:2]=1[NH:1][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][CH:36]=[C:28]([C:27]([F:26])([F:37])[F:38])[CH:29]=1
Reactant: Cc1ccc(N)c(Cl)c1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CN1CCCC1=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)c(Cl)c1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 58.4 %

Procedure:
Using N-[6-(3-amino-2-chloro-6-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.42 mmol), 3-(trifluoromethyl)benzoyl chloride (92 mg, 0.44 mmol) and N-methylpyrrolidone (5.0 mL) as starting materials and in the same manner as in Example 344, the title compound (130 mg, 60%) was obtained as a white powder.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)=[O:7].[CH2:13]1[O:22][C:16]2(CCNC[CH2:17]2)[O:15][CH2:14]1>C1COCC1>[CH2:13]1[O:22][C:16]2([CH2:17][CH2:9][N:8]([C:6]([C:2]3[NH:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH2:12][CH2:11]2)[O:15][CH2:14]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=C(c1ccc[nH]1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(c1ccc[nH]1)N1CCC2(CC1)OCCO2
Yield: 70.7 %

Procedure:
A solution of 1-(1H-pyrrole-2-carbonyl)imidazole (0.54 g, 3.4 mnmol) and 4-piperidone ethylene ketal (0.43 ml, 3.4 mmol) in THF (10 ml) was heated at reflux for 1 h. The mixture was cooled and evaporated, diluted with ethyl acetate, washed with dilute HCl, dried over sodium sulphate and evaporated to afford a beige solid (0.56 g), MS (+CI) 237 ([M+H]+), 1H NMR (CDCl3) 9.47 (1H, br. s), 6.92 (1H, m), 6.53 (1H, m), 6.25 (1H, m), 4.00 (4H, s), 3.91 (4H, t, J 5.4 Hz), 1.78 (4H, t, J 5.8 Hz).
Reaction SMILES: C(OO)(=[O:3])C.[OH:6][N:7]([CH3:19])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=1)=[O:9]>C(Cl)Cl.CO.C(OCC)(=O)C.C(O)C>[OH:6][N:7]([CH3:19])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:18])=[O:3])=[CH:13][CH:12]=1)=[O:9]
Reactant: CC(=O)OO
Reactant: CSc1ccc(NC(=O)N(C)O)cc1
Solvent: CO
Solvent: ClCCl
Solvent: CCO
Product: CN(O)C(=O)Nc1ccc(S(C)=O)cc1
Temperature: 0 °C
Yield: 53.1 %

Procedure:
Peracetic acid (1.7 g of 30%, 6.6 mmol) was added dropwise to a cooled (ice/water bath) solution of 1-hydroxy-1-methyl-3-[4-(methylthio)phenyl]urea (Compound 1, 1.4 g, 6.6 mmol) in a mixture of methylene chloride (25 mL) and methanol (10 mL). The solution was stirred with cooling for 15 minutes. The solvent was removed under reduced pressure at 50° C. to provide a white solid. The solid was dissolved in hot ethyl acetate/ethanol, filtered to remove particulates then diluted with ether to provide 0.8 g of the desired product as a white crystalline solid, m.p. 197.8°-198.2° C. Analysis: Calculated for C9H12N2O3S: %C, 47.36; %H, 5.3; %N, 12.27; Found: %C, 47.27; %H, 4.97; %N, 12.26.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:22][CH:23]([O:25][C:26]1[N:31]=[CH:30][C:29]([C:32]([OH:34])=O)=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36])[CH3:24].O[NH:40]/[C:41](=[N:58]\[H])/[C:42]1[CH:43]=[CH:44][CH:45]=[C:46]2[C:50]=1[NH:49][CH:48]=[C:47]2[CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:24][CH:23]([O:25][C:26]1[N:31]=[CH:30][C:29]([C:32]2[O:34][N:58]=[C:41]([C:42]3[CH:43]=[CH:44][CH:45]=[C:46]4[C:50]=3[NH:49][CH:48]=[C:47]4[CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[N:40]=2)=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36])[CH3:22]
Reactant: [H]/N=C(\NO)c1cccc2c(CCC(=O)OCC)c[nH]c12
Reactant: CC(C)Oc1ncc(C(=O)O)cc1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4cnc(OC(C)C)c(C(F)(F)F)c4)n3)cccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
EDCI (153 mg) and HOBT (132 mg) were added to a solution of 6-[(1-methylethyl)oxy]-5-(trifluoromethyl)-3-pyridinecarboxylic acid (100 mg) in THF (2.5 mL). The mixture was stirred at room temperature for 0.5 hour, followed by addition of ethyl 3-{7-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D35) (165 mg) in THF (2.5 mL). The resulting mixture was stirred at room temperature for 1 hour, followed by addition of TBAF (418 mg). The reaction vessel was sealed and the reaction mixture was stirred at 120° C. in the microwave for 1.5 h. THF was removed. The residue was dissolved in EtOAc. The organic solution was washed with saturated aqueous sodium bicarbonate solution. The organic solution was dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography to afford ethyl 3-(7-{5-[6-[(1-methylethyl)oxy]-5-(trifluoromethyl)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoate (D37) (83 mg) as a white solid. δH (CDCl3, 400 MHz): 1.24 (3H, t), 1.45 (6H, d), 2.74 (2H, t), 3.17 (2H, t), 4.15 (2H, q), 5.58 (1H, m), 7.19 (1H, d), 7.29 (1H, d), 7.82 (1H, d), 8.12 (1H, dd), 8.64 (1H, d), 9.17 (1H, d), 9.55 (1H, s); MS (ES): C24H23F3N4O4 requires 488; found 489.2 (M+H+).