Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C([O:18][C:19](=[O:51])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([O:38]CC)=[O:37])[CH:31]=2)=[O:29])[CH:25]=[CH:24][C:23]=1[O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]Br)C>CCCCCC.C(OCC)(=O)C>[C:36]([C:32]1[CH:31]=[C:30]([C:28]([C:26]2[CH:25]=[CH:24][C:23]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][O:1][C:2]3[CH:12]=[CH:11][C:5]4[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=4[C:3]=3[CH2:13][CH2:14][CH3:15])=[C:22]([CH2:21][CH2:20][C:19]([OH:51])=[O:18])[CH:27]=2)=[O:29])[CH:35]=[CH:34][CH:33]=1)([OH:38])=[O:37]
Reactant: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1OCCCCCCCCBr
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCCCCCCOc2ccc(C(=O)c3cccc(C(=O)O)c3)cc2CCC(=O)O)ccc2c1OCCC2=O
Yield: 59.3 %

Procedure:
Starting with 0.128 g (0.62 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, and 0.349 g (0.62 mmol) of 2-[(8-bromooctyl)oxy]-5-[[3-(ethoxycarbonyl)phenyl]carbonyl]benzenepropanoic acid ethyl ester, the title compound (0.232 g; 76.3% overall yield) was obtained as a white solid, mp 112°-117° C. (recrystallized from hexane-ethyl acetate), using the procedure of example 22.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH2:16][C:17]([O:19]C)=[O:18])[C:10](=[O:21])[N:9]([CH:22]([CH3:24])[CH3:23])[C:8]=2[N:7]=[C:6]1[N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.O.[Li+].[OH-]>C(O)(=O)C>[Cl:1][C:2]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:10](=[O:21])[N:9]([CH:22]([CH3:24])[CH3:23])[C:8]=2[N:7]=[C:6]1[N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COC(=O)CCn1c(=O)c2c(nc(N3CCCCC3)n2Cc2c(F)cccc2Cl)n(C(C)C)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)n1c(=O)n(CCC(=O)O)c(=O)c2c1nc(N1CCCCC1)n2Cc1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.9 %

Procedure:
A solution of methyl 3-[7-(2-chloro-6-fluorobenzyl)-3-isopropyl-2,6-dioxo-8-piperidin-1-yl-2,3,6,7-tetrahydro-1H-purin-1-yl]propanoate (9 mg, 0.018 mmol) in 150 μTHF and 50 μL H2O was treated with 18 μL 1 N LiOH. The reaction mixture was stirred at room temperature overnight and then treated with 18 μL 1 N acetic acid. The product was extracted into EtOAc and then the solvent was removed by reduced pressure. The crude product was purified by preparative thin layer chromatography (silica gel, 1 mm plate, EM Science 20×20 cm silica gel 60 F264) eluting with 100% EtOAc to give 3 mg (13% yield) of the title compound as a clear oil: 1H NMR (CDCl3, 400 MHz) 7.23-7.17 (m, 1H), 7.15-7.12 (m, 1H), 6.99-6.94 (m, 1H), 5.52 (s, 2H), 5.16-5.07 (m, 1H), 4.21 (t, 2H, J=6.9 Hz), 3.14-3.04 (m, 4H), 2.66 (t, 2H, J=6.9 Hz), 1.56-1.51 (m, 12H); MS (ESP+) m/e 492 (MH+); TLC (EtOAc:hexanes/1:1) Rf=0.61.
Reaction SMILES: [OH:1][C:2]1[C:7](C(C)(C)C)=[CH:6][C:5]([CH3:12])=[CH:4][C:3]=1[N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]2=[N:14]1.CC(C1C=C(N2N=C3C(C=CC([Cl:42])=C3)=N2)C(O)=C(C(C)(C)C)C=1)(C)C>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:12])=[CH:4][C:3]=1[N:13]1[N:14]=[C:15]2[CH:21]=[C:20]([Cl:22])[C:19]([Cl:42])=[CH:18][C:16]2=[N:17]1
Reactant: Cc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Reactant: CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Product: Cc1ccc(O)c(-n2nc3cc(Cl)c(Cl)cc3n2)c1

Procedure:
2-(2'-hydroxy-3'-t-butyl-5'-methylphenyl)-5- chlorobenzotriazole which are commercially available from Ciba-Geigy under the designations Tinuvin 327 and 326 respectively.
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([NH:16][C:17]1[N:22]=[C:21](Cl)[N:20]=[C:19]([O:24][CH3:25])[N:18]=1)=[O:15])(=[O:12])=[O:11].O1CCOCC1.[F:33][C:34]([F:38])([F:37])[CH2:35][OH:36].C(=O)([O-])[O-].[K+].[K+]>O>[F:26][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([NH:16][C:17]1[N:18]=[C:19]([O:24][CH3:25])[N:20]=[C:21]([O:36][CH2:35][C:34]([F:38])([F:37])[F:33])[N:22]=1)=[O:15])(=[O:12])=[O:11]
Reactant: COc1nc(Cl)nc(NC(=O)NS(=O)(=O)c2ccccc2OC(F)F)n1
Reactant: OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1nc(NC(=O)NS(=O)(=O)c2ccccc2OC(F)F)nc(OCC(F)(F)F)n1
Reaction time: 12 h

Procedure:
A mixture of 8.2 g of N-(2-difluoromethoxyphenyl-sulfonyl)-N'-(4-chloro-6-methoxy-1,3,5-triazin-2-yl)-urea, 60 ml of dioxane, 20 ml of 2,2,2-trifluoroethanol and 5.5 g of potassium carbonate is stirred at 55°-60° for 12 hours and then taken up in 300 ml of water and filtered over active charcoal. After the mixture has been acidified with 2N hydrochloric acid, the product precipitates and is separated off by filtration. Yield: 7.7 g of N-(2-difluoromethoxyphenyl-sulfonyl)-N'-[4-methoxy-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl]-urea of melting point 155°-157°.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][N:15]=2)[C:12]=1[CH3:13])=[O:7])[CH3:4].[CH2:22](I)[CH3:23].O>CN(C)C=O>[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][CH2:22][CH3:23])=[CH:16][N:15]=2)[C:12]=1[CH3:13])=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cnn(-c2ccc(CO)cn2)c1C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCc1ccc(-n2ncc(C(=O)OCC)c2C)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (175 mg) was added at room temperature to a solution of 1-[5-(hydroxymethyl)pyridin-2-yl]-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (935 mg) described in Reference Example 41(3) in N,N-dimethylformamide (18 ml), and stirred at the same temperature for 30 minutes. Ethyl iodide (0.6 ml) was added and the mixture was stirred at 80° C. for two hours. Then, Sodium hydride (175 mg) and ethyl iodide (0.6 ml) were added and stirred at 80° C. for two hours. After the reaction, the reaction solution was cooled to room temperature, water was added and extracted with ethyl acetate four times. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated, and the residue was purified with a silica gel column chromatography (n-hexane/ethyl acetate) to give 1-[5-(ethoxymethyl)pyridin-2-yl]-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (223 mg) as a white solid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:20]([OH:22])=O)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CN.C[CH2:34][N:35](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([C:20]([NH:35][CH3:34])=[O:22])[CH2:23][C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)[C@@H](CC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 18 h
Yield: 71 %

Procedure:
Prepared using General Procedure 7. To a stirring solution of (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(tert-butoxy)-4-oxobutanoic acid (308 mg, 0.75 mmol), methylamine (40 wt % in water, 174 μL, 2.25 mmol), and DIEA (415 μl, 2.25 mmol) in DMF (7.5 mL) cooled to 0° C. was added HATU (569 mg, 1.5 mmol). The reaction mixture was allowed to warm slowly and stirring continued for 18 h. The reaction mixture was poured onto ice-water and the solid was filtered. The solid was dissolved in DCM (10 mL), dried over MgSO4 and evaporated. The crude product was purified by column chromatography to afford 226 mg (71%) of tert-butyl (R)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(methylamino)-4-oxobutanoate. LCMS-ESI (m/z) calculated for C24H28N2O5: 424.2. found 447.1 [M+Na]+, tR=3.12 min. (Method 16).
Reaction SMILES: [C:1]([CH:3]([NH:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[NH:28][C:27]2=[O:36])[CH2:22][CH2:21]1)=[O:19])[CH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([CH2:14][CH3:15])[CH:13]=1)[NH:10][N:9]=[C:8]2[CH3:16])#[N:2].[N:37]([Sn](C)(C)C)=[N+:38]=[N-:39]>O1CCCC1>[CH2:14]([C:12]1[CH:13]=[C:5]([CH2:4][CH:3]([NH:17][C:18]([N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[CH2:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[NH:28][C:27]3=[O:36])[CH2:24][CH2:25]2)=[O:19])[C:1]2[NH:39][N:38]=[N:37][N:2]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][N:9]=[C:8]2[CH3:16])[CH3:15]
Reactant: CCc1cc(CC(C#N)NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)cc2c(C)n[nH]c12
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: C1CCOC1
Product: CCc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2nnn[nH]2)cc2c(C)n[nH]c12

Procedure:
A stirred solution of 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1-cyano-2-(7-ethyl-3-methyl-1H-indazol-5-yl)-ethyl]-amide (0.25 g, 0.5 mmol) in tetrahydrofuran (6 mL) was treated with azidotrimethyltin (0.16 g, 0.77 mmol). The resulting suspension was heated at reflux overnight. The solvents were evaporated, dissolved in ethyl acetate and washed with water (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography afforded the desired tetrazole. 1H-NMR (CD3OD) δ 1.3 (t, J=7.6, 3H), 1.45-1.70 (m, 4H), 1.87 (m, 1H), 2.0 (s, 3H), 2.75-2.90 (m, 4H), 3.42 (m, 1H), 3.72 (d, J=6.6, 1H), 4.12 (m, 4H), 4.88 (m, 1H), 5.48 (dd, J=7.0, 7.9, 1H), 6.77 (d, J=7.9, 1H), 6.94 (m, 1H) 6.98 (s, 1H), 7.09 (d, J=7.3, 1H), 7.14 (dd, J=7.9, 7.6, 1H), 7.30 (s, 1H). Mass spec.: 529.26 (MH)+.
Reaction SMILES: [CH2:1]([Si:3]([CH2:35][CH3:36])([CH2:33][CH3:34])[O:4][C@H:5](/[CH:18]=[CH:19]/[Sn](CCCC)(CCCC)CCCC)[CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)[CH3:2].C([Li])CCC.[Cu](C#N)C#N.C[Li].[CH2:49]([C:52]1[C:53](=[O:65])[CH2:54][C@@H:55]([O:57][Si:58]([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:60])[CH3:59])[CH:56]=1)[CH:50]=[CH2:51].[NH4+].[Cl-].[NH4+].[OH-]>O1CCCC1>[CH2:49]([C@@H:52]1[C@@H:56](/[CH:19]=[CH:18]/[C@@H:5]([O:4][Si:3]([CH2:35][CH3:36])([CH2:1][CH3:2])[CH2:33][CH3:34])[CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C@H:55]([O:57][Si:58]([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:59])[CH3:60])[CH2:54][C:53]1=[O:65])[CH:50]=[CH2:51]
Reactant: C=CCC1=C[C@H](O[Si](C)(C)C(C)(C)C)CC1=O
Reactant: CCCC[Sn](/C=C/[C@H](COc1cccc(C(F)(F)F)c1)O[Si](CC)(CC)CC)(CCCC)CCCC
Agent: N#C[Cu]C#N
Agent: [Cl-]
Agent: [Li]C
Solvent: C1CCOC1
Product: C=CC[C@H]1C(=O)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1/C=C/[C@H](COc1cccc(C(F)(F)F)c1)O[Si](CC)(CC)CC
Reaction time: 1 h
Yield: 37.6 %

Procedure:
A 100 ml three-necked flask was flame dried and allowed to be cooled under nitrogen. (R,E)-triethyl(4-(tributylstannyl)-1-(3-(trifluoromethyl)phenoxy)but-3-en-2-yloxy)silane (15.11 g, 23.8 mmol) and 20 ml tetrahydrofuran were added to the reaction flask, followed by dropwise addition of n-butyl lithium (14.9 ml, 1.6 M in hexane) at −70° C. A suspension solution of copper cyanide (2.13 g, 23.8 mmol) in 20 ml tetrahydrofuran was cooled to −20° C., followed by dropwise addition of methyl lithium (11.9 ml, 2 M in ether). The homogenous organo-metallic solution was cooled and added into the reaction flask while stirring for 60 minutes. Then, a solution of (R)-2-allyl-4-(tert-butyldimethylsilyloxy)cyclopent-2-enone (3 g, 11.9 mmol) in 20 ml tetrahydrofuran at −70° C. was added to the reaction mixture for 10 minutes. After being stirred for another 20 minutes, the reaction mixture was poured into a mixture of 9/1 (v/v) saturated aqueous NH4Cl/NH4OH solution to be phase separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over magnesium sulfate. The solid was filtered off and organic solvent was evaporated off under vacuum. The crude product was purified by chromatography and then concentrated under reduced pressure to provide 2.68 g of the title compound (37.7% yield).
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([OH:11])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](Br)#[C:19][CH2:20][CH3:21]>CN(C)C=O>[C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([O:11][C:2]#[C:1][CH2:6][CH3:5])[C:8]([O:10][C:18]#[C:19][CH2:20][CH3:21])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(O)(c1ccccc1)c1ccccc1
Reactant: CCC#CBr
Solvent: CN(C)C=O
Product: CCC#COC(=O)C(OC#CCC)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 122.1 %

Procedure:
Into a suspension of 1.5 g of 66% sodium hydride-paraffin in 20 cc of dimethylformamide was added a solution of 4.5 g of α-phenyl-α-hydroxyphenylacetic acid in 10 cc of dimethylformamide under cooling, and the mixture was stirred for 1 hour. Successively, 5.8 g of butynyl bromide was added thereto and the stirring was continued for 1 hour. The reaction mixture was poured in ice-water, and the resultant was subjected to extraction with ether. The ether extract was washed with an aqueous solution saturated with sodium chloride, and dried over sodium sulfate. Thereafter ether was distilled out and paraffin was removed to obtain 4.0 g of oily 1-butynyl α-phenyl-α-(1-butynyloxy)phenylacetate, nD25 1.5581.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:28][CH2:29][CH2:30][CH2:31][S:32]([NH2:35])(=[O:34])=[O:33]>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:35][S:32]([CH2:31][CH2:30][CH2:29][Cl:28])(=[O:34])=[O:33])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Reactant: NS(=O)(=O)CCCCl
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)CCCCl)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 3-chloropropanesulfonamide (Synlett, 1997, 375) in accordance with Procedure 1, Method A described hereinabove. Yield (80%); 1H NMR (d6-DMSO) δ 11.82 (br s, 1H), 7.48 (d, J=15.7 Hz, 1H), 7.40–7.09 (m, 12H), 6.87 (d, J=8.4 Hz, 2H), 6.46 (d, J=15.7 Hz, 1H), 3.71 (t, 2H), 3.52 (t, 2H), 2.37 (q, J=7.3 Hz, 2H), 2.07 (p, 2H), 0.83 (t, J=7.3 Hz, 3H); APcI m/z: 492 (M−H−).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][O:15][C:16]1[CH:31]=[CH:30][C:19]([C:20]([NH:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][C:28]=2[NH2:29])=[O:21])=[CH:18][CH:17]=1>>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:29][C:28]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[NH:22][C:20](=[O:21])[C:19]2[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:31][CH:30]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)Nc2cnccc2N)cc1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)Nc2cnccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 49 %

Procedure:
Using 4-tert-butylbenzoyl chloride and a similar procedure to that described for Example 2, Part C, N3-(4-methoxybenzoyl)-3,4-pyridinediamine (300 mg, 1.23 mmol) yielded 243 mg (49%) of the title compound.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=O)[CH:5]=[CH:4][N:3]=[CH:2]1.[ClH:20].Cl.[NH2:22][CH2:23][CH2:24][O:25][NH2:26].N1C=CC=CC=1.C(O)C>[OH-].[Na+].C(OCC)(=O)C>[ClH:20].[ClH:20].[NH2:22][CH2:23][CH2:24][O:25][N:26]=[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)[CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NCCON
Reactant: O=C(CCn1ccnc1)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCO
Product: NCCON=C(CCn1ccnc1)c1cccc(C(F)(F)F)c1
Yield: 53.5 %

Procedure:
A mixture of 3-(1-(1H)-imidazolyl)-1-(3-trifluoromethylphenyl)-1-propanone (4.60 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (3.07 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was stirred under reflux, under nitrogen, for three hrs. The reaction mixture was diluted with 10% sodium hydroxide solution and ethyl acetate. The layers were separated. The aqueous phase was extracted with ethyl acetate, the organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was taken up in toluene and evaporated. The residue was flash chromatographed (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and concentrated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added to the solution. The solid was collected and recrystallized twice from absolute ethanol/ether to give 2.2 g (32%) of product, mp 223°-225° C. (dec.)
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:23][C:24]3[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=3[CH3:26])[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: Cc1ccccc1CBr
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccccc1Cn1c(CC(F)(F)F)nc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (583 mg) in DMF (6 mL) was added potassium carbonate powder (900 mg) and 2-methylbenzyl bromide (1.2 g). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40% EtOAc/hexanes), followed by washing solid with hexanes to yield the title compound as a tan solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[N:14]1([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH2:26][NH:25][CH2:24][CH2:23]3)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:25]3[CH2:24][CH2:23][C:22]4[C:27](=[CH:28][CH:29]=[C:20]([N:14]5[CH2:19][CH2:18][O:17][CH2:16][CH2:15]5)[CH:21]=4)[CH2:26]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: c1cc2c(cc1N1CCOCC1)CCNC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2cc(N3CCOCC3)ccc2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:10]([Cl:17])=[N:11][C:12](Cl)=[CH:13][C:14]=1[Cl:15].C([Sn](CCCC)(CCCC)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)CCC>CN(C)C=O.O1CCOCC1.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:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:10]([Cl:17])=[N:11][C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:13][C:14]=1[Cl:15]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Fc1cccc(Cl)c1-c1c(Cl)cc(Cl)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Fc1cccc(Cl)c1-c1c(Cl)cc(-c2ccccn2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
64.8 g (0.26 mol) of 3-(2-chloro-6-fluorophenyl)-2,4,6-trichloropyridine (see Example Ab), 83.6 g (0.29 mol) 2-tri-n-butylstannylpyridine and 4.8 g (5.2 mmol) tetrakistriphenylphosphinepalladium(0), dissolved in 600 ml of dimethylformamide and 400 ml 1,4-dioxane, were boiled under reflux for 8 h and then stirred at room temperature overnight. The volatile components were removed under reduced pressure, and 400 ml of water were then added, the mixture was extracted five times with in each case 150 ml of methyl tert-butyl ether and the combined extracts were washed once with 100 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was chromatographed on silica gel using cyclohexane/ethyl acetate and triturated with n-pentane. Yield 36.0 g of a colorless solid of m.p. 45° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[CH:23]=[CH:22][CH:21]=[N:20][C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[C:1]1([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][NH:20][C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(-c2nc3ncccc3nc2-c2ccccc2)cc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1ccc(-c2nc3c(nc2-c2ccccc2)CCCN3)cc1
Temperature: 25 °C

Procedure:
2-Phenyl-3-p-tolyl-pyrido[2,3-b]pyrazine (1.07 g, 3.60 mmol) under nitrogen in dry MeOH (10 ml) was treated with ammonium formate (2.269 g, 36.0 mmol) and 10% palladium hydroxide on carbon (200 mg, 0.142 mmol). The resulting mixture was heated at reflux for 1 hour. After cooling to RT, the mixture was filtered through Celite® (filter material) and the catalyst was washed with MeOH followed by DCM. The filtrate was concentrated in vacuo to yield a solid which was triturated with MeOH. The resulting solid was dried under vacuum to afford the title compound;
Reaction SMILES: Cl.O[CH2:3][C:4]1[CH:9]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][C:5]=1[N-]C(=O)C(C)(C)C.[NH2:22][C:23]([NH2:25])=[S:24]>O1CCOCC1.C(O)(C)C>[NH2:22][C:23]1[S:24][CH2:3][C:4]2[CH:9]=[C:8]([O:10][C:11]([F:12])([F:14])[F:13])[CH:7]=[CH:6][C:5]=2[N:25]=1
Reactant: NC(N)=S
Reactant: CC(C)(C)C(=O)[N-]c1ccc(OC(F)(F)F)cc1CO
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: NC1=Nc2ccc(OC(F)(F)F)cc2CS1
Temperature: 80 °C
Yield: 84 %

Procedure:
Concentrated HCl (4 ml) is added slowly to a solution of N-[2-hydroxymethyl-4-(trifluoromethoxy)phenyl]-pivaloylamide (0.35 g, 1.2 mmol) in dioxane (3 ml) and the resulting reaction mixture heated at 80° C. for 4 hours, then diluted with isopropanol (20 ml), and thiourea (0.14 g, 1.8 mmol) added and the mixture refluxed for 20 hours. The solvent is then evaporated under vacuum and the residue diluted with H2O, basified with 2 N NaOH, and extracted with CH2Cl2. The combined organic extracts are dried over Na2SO4 and concentrated under vacuum. The residue is purified by chromatography through silica, eluting with AcOEt/petroleum ether (1:1). The product is obtained as a yellow solid, with a yield of 84%. Recrystallisation from EtOH gives a solid with m.p. 115-118° C. 1H-NMR (CDCl3): 3.87 (s, 2H), 5.16 (br s, 2H), 6.97-7.11 (m, 3H). MS (ESI): m/z 249 (M+H+).