Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:5]=1[C:6](OC)=[O:7])(=[O:3])[CH3:2].[CH3:17][NH2:18]>C(O)C>[OH:3][C:1]1([CH3:2])[C:4]2[C:5](=[C:10]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:12][CH:13]=2)[C:6](=[O:7])[N:18]1[CH3:17]
Reactant: COC(=O)c1c(C(C)=O)cccc1[N+](=O)[O-]
Reactant: CN
Solvent: CCO
Product: CN1C(=O)c2c([N+](=O)[O-])cccc2C1(C)O
Yield: 85 %

Procedure:
A mixture of methyl 2-acetyl-6-nitrobenzoate (2 g, 8.96 mmol) and 33% methylamine in ethanol (10 mL) was stirred at reflux for 14 h. The solvents were removed under reduced pressure to afford 1.7 g of the desired product (yield: 85%). 1H NMR (CDCl3, 300 MHz): δ=1.80 (s, 3 H), 3.05 (s, 3 H), 7.78 (m, 2 H), 7.95 (m, 1 H).
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH:24]=O)=[CH:16]1.N1CCCCC1>C(O)C>[OH:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([C:10](=[O:12])/[CH:11]=[CH:24]/[C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:15][CH:16]=2)=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1cc(C(C)=O)cc(OC)c1O
Reactant: O=Cc1c[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cc(C(=O)/C=C/c2c[nH]c3ccccc23)cc(OC)c1O
Yield: 19.2 %

Procedure:
4'-Hydroxy-3',5'-dimethoxyacetophenone (1.96 g) and indole-3-carboxaldehyde (1.45 g) were dissolved in ethanol (20 ml), and piperidine (0.85 g) was added thereto, followed by heating under reflux for 32 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. The obtained crude crystals were recrystallized from ethyl acetate to give Compound 70 (0.62 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH2:24][C:25]1[S:26][C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[S:26]1[C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=[C:25]1[NH:24][C:13](=[O:14])/[C:12](/[C:4]1[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=1)=[N:16]/[O:17][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: Nc1nc2ccccc2s1
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCCC2)C(=O)O)cc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(/C(=N\OC2CCCCC2)C(=O)Nc2nc3ccccc3s2)cc1Cl
Reaction time: 2 h
Yield: 56.4 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclohexyloxyimino-acetic acid (prepared as in Example 9, 112 mg, 0.31 mmol), 2-aminobenzothiazole (47 mg, 0.31 mmol) and N,N-diisopropylethylamine (163 μL, 0.93 mmol) were combined in acetonitrile (1.25 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (118 mg, 0.31 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 60% ethyl acetate/hexanes) to afford (E)-N-benzothiazol-2-yl-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclohexyloxyimino-acetamide (86 mg, 56%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C22H22ClN3O4S2 [M+] 491.07, found 492 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.26-1.64 (m, 6H, 3×CH2), 1.75 (m, 2H, 2×CH of CH2), 2.00 (m, 2H, 2×CH of CH2), 3.32 (s, 3 H, SO2CH3), 4.36 (m, 1 H, OCH), 7.35 (brt, 1 H, Ar), 7.48 (brt, 1 H, Ar), 7.65 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.76 (d, Jm=1.5 Hz, 1 H, Ar), 7.83 (brt, 2H, Ar), 8.23 (d, Jo=8.2 Hz, 1 H, Ar), 10.24 (s, 1 H, NH).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH:4]([C:21]1[CH:26]=[CH:25][C:24]([O:27][Si](C(C)(C)C)(C)C)=[CH:23][CH:22]=1)[N:5]([S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]#[C:19][CH3:20])=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH3:6].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([S:7]([N:5]([CH:4]([C:21]2[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=2)[C:3]([O:2][CH3:1])=[O:35])[CH3:6])(=[O:9])=[O:8])=[CH:11][CH:12]=1)[C:18]#[C:19][CH3:20]
Reactant: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)OC)c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)OC)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55769.2 %

Procedure:
To a solution of 6.0 g (0.012 mmol) of [4-(tert-butyl-dimethyl-silanyloxy)phenyl]-[(4-but-2-ynyloxy-benzenesulfonyl)-methyl-amino]-acetic acid methyl ester in 100 mL of THF was added 11.6 mL of a 1.0M solution of tetrabutylammonium fluoride in THF. The reaction was stirred for 1 h at room temperature and then acidified with 5% HCl solution and extracted with ethyl acetate. The organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:1) to give 2.7 g of methyl [{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino](4-hydroxyphenyl)acetate as a white solid. Electrospray Mass Spec 404.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)[CH:10]=[C:11]([CH2:13]O)[N:12]=2)=[CH:4][CH:3]=1.C(N(S(F)(F)[F:31])CC)C.O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)[CH:10]=[C:11]([CH2:13][F:31])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(-n2cc(CO)nc2-c2ccc(Cl)cc2)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2cc(CF)nc2-c2ccc(Cl)cc2)cc1
Reaction time: 2 h

Procedure:
To a suspension of 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-4-methanol (Example 158) (250 mg, 0.689 mmole) in 5 ml of dichloromethane was added dropwise a solution of diethylamino sulfur trifluoride (DAST) (166 mg, 1.03 mmole) in 1 ml of dichloromethane. As the addition proceeded, the mixture became homogeneous. After stirring for two hours, water was added, the layers separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. Chromatography of the residue over silica gel using 60% ethyl acetate in hexane gave the title compound as a very slightly yellow solid (106 mg): mp (DSC) 165° C. Anal. Calc'd. for C17H14ClFN2O2S.¼H2O (MW 369.33): C, 55.29; H, 3.82; N, 7.59. Found: C, 55.15; H, 3.82; N, 7.42.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH3:12][S:13][CH:14]([S:17][CH3:18])[S:15][CH3:16].[OH:19][C@H:20]1[CH2:42][CH2:41][C@@:40]2([CH3:43])[C:22](=[CH:23][CH2:24][C@@H:25]3[C@@H:39]2[CH2:38][CH2:37][C@@:36]2([CH3:44])[C@H:26]3[CH2:27][CH2:28][C@@H:29]2[C@H:30]([CH3:35])[CH2:31][CH2:32][CH:33]=[O:34])[CH2:21]1>O1CCCC1>[OH:19][C@H:20]1[CH2:42][CH2:41][C@@:40]2([CH3:43])[C:22](=[CH:23][CH2:24][C@@H:25]3[C@@H:39]2[CH2:38][CH2:37][C@@:36]2([CH3:44])[C@H:26]3[CH2:27][CH2:28][C@@H:29]2[C@H:30]([CH3:35])[CH2:31][CH2:32][CH:33]([OH:34])[C:14]([S:17][CH3:18])([S:15][CH3:16])[S:13][CH3:12])[CH2:21]1
Reactant: C[C@H](CCC=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CSC(SC)SC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSC(SC)(SC)C(O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.67 h
Yield: 70.5 %

Procedure:
Under an argon atmosphere at -78° C., 10.4 ml (17.7 mmoles) of a hexane solution of n-butyllithium was added to a solution of 2.4 ml (18.0 mmoles) of tris(methylthio)methane in 40 ml of tetrahydrofuran (THF for short), and the mixture was stirred for 40 minutes at the same temperature. To the mixture was added dropwise 15 ml of a THF solution of 798 mg (1.8 mmoles) of 3β-hydroxychol-5-en-24-al [compound of formula(VI)], and the mixture was stirred at -78° C. for 40 minutes. The mixture was extracted with ether in a customary manner, and the resulting residue was dissolved in a mixture of 10 ml of THF and 5 ml of methanol. Four drops of 2N hydrochloric acid was added, and the mixture was stirred at room temperature for 100 minutes. The mixture was extracted with ether in a customary manner, and the resulting crude product was purified by silica gel column chromatography [31 g; eluted with hexane/ethyl acetate (10:1)] to give 651 mg of the captioned compound having a melting point of141° to 143° C. (recrystallized from methanol).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[Cl:8][CH2:9][CH2:10][CH2:11]/[C:12](=[CH:20]\[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]2)=[C:23]([F:33])[CH:22]=1)/[C:13]([O:15]C(C)(C)C)=[O:14]>C(Cl)(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[Cl:8][CH2:9][CH2:10][CH2:11]/[C:12](=[CH:20]\[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]2)=[C:23]([F:33])[CH:22]=1)/[C:13]([OH:15])=[O:14]
Reactant: Cc1cn(-c2ccc(/C=C(\CCCCl)C(=O)OC(C)(C)C)cc2F)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1cn(-c2ccc(/C=C(\CCCCl)C(=O)O)cc2F)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
chloroform (5 mL) and TFA (10 mL) were added to tert-butyl(E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}valerate (1.96 g), and the reaction solution was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure. The residue was solidified with methylene chloride, ethyl acetate, and heptane and separated by filtration to obtain 2.19 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: C(C1C=C(NC(=O)[CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([B:25]([OH:27])[OH:26])=[CH:21][CH:20]=2)C=CC=1S(CC)(=O)=O)#N.BrC1C=CC(CC[CH2:38][N:39](C)[C:40]([NH:42][C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([C:49]#[N:50])[CH:44]=2)=[O:41])=CC=1>>[C:49]([C:45]1[CH:44]=[C:43]([NH:42][C:40](=[O:41])[N:39]([CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([B:25]([OH:26])[OH:27])=[CH:23][CH:24]=2)[CH3:38])[CH:48]=[CH:47][CH:46]=1)#[N:50]
Reactant: CN(CCCc1ccc(Br)cc1)C(=O)Nc1cccc(C#N)c1
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Product: CN(CCCc1ccc(B(O)O)cc1)C(=O)Nc1cccc(C#N)c1
Yield: 91 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 22C (210 mg, 0.54 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 22D (146 mg, 91%) as a clear oil. MS (ESI) m/z 338.3 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCN(c4ccc(F)cc4)CC3)cnc12
Reactant: CS(N)(=O)=O
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCN(c4ccc(F)cc4)CC3)cnc12
Yield: 45.3 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-[4-(4-fluorophenyl)piperazine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.04 g, 0.08 mmol) obtained in step 2 and methanesulfonamide (0.038 g, 0.400 mmol), the title compound (0.02 g, 48%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.Br[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: COC(=O)c1cccc(Sc2c(C)n(Cc3ccc4ccccc4c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and 2-(bromomethyl)naphthalene.
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]([O:20][CH3:21])[C@H:17]([O:22][CH2:23][F:24])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([C@:27]1([OH:35])[CH:32]2[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]2)[CH2:28]1)#[CH:26].C(N(CC)CC)C.N>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.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:26]#[C:25][C@:27]2([OH:35])[CH:32]3[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]3)[CH2:28]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]([O:20][CH3:21])[C@H:17]([O:22][CH2:23][F:24])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Reactant: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1OCF
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CO[C@H]1CN(c2ccc(C#C[C@@]3(O)CN4CCC3CC4)c(Cc3ccccc3)n2)C[C@H]1OCF
Temperature: 75 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
A mixture of 43.9 mg of 2-benzyl-6-[(3R,4S)-3-(fluoromethoxy)-4-methoxypyrrolidine-1-yl]-3-iodopyridine, 16.5 mg of (3R)-3-ethynyl-3-quinuclidinol, 11.5 mg of tetrakis(triphenylphosphine)palladium(0), 0.9 mg of cuprous iodide, 42 μl of triethylamine and 3.0 ml of N,N-dimethylformamide was heated under stirring for 1 hours at 75° C. in a nitrogen atmosphere. The reaction solution was poured into an aqueous dilute ammonia, and then the mixture was extracted with ethyl acetate. The organic phase was washed with brine and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (15:1), to give 33 mg of the target compound.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:38]3[CH:39]=[C:34]([CH3:33])[CH:35]=[CH:36][CH:37]=3)[C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:31])(=[O:32])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: Cc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cccc(-n2c(C(=O)N3CCS(=O)(=O)CC3)cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc32)c1
Yield: 76 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone (example 34), 3-methylphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light yellow solid (76%).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].Br[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18]>CN(C=O)C>[CH2:15]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])[CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)CCBr
Reactant: O=C1Nc2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CCN1C(=O)C(=O)c2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of isatin (4.41 g, 30 mmol) in DMF (60 mL) at 0° C. was added 60% NaH (1.50 g, 37.5 mmol) portionwise. After addition, the resulting mixture was stirred for 15 min at 0° C. and 1-bromo-3-methylbutane (4.7 mL, 37.5 mmol) was added dropwise over 2 min. The resulting mixture was stirred for 1 h at 0° C. followed by 6 h at rt. The reaction was cooled to 0° C., quenched with sat. NH4Cl, ice, H2O, extracted with EtOAc (200 mL×2), dried over Na2SO4 and concentrated to give crude 1-isopentylisatin as a dark orange red liquid which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.66 (t, J=7.6 Hz, 1H), 7.54 (d, J=7.2 Hz, 1H), 7.15 (d, J=8.8 Hz, 1H, partially overlapping with the peak at 7.12 ppm), 7.12 (t, J=7.6 Hz, 1H, partially overlapping with the peak at 7.15 ppm), 3.66 (t, J=7.6 Hz, 2H), 1.67-1.57 (m, 1H), 1.48 (q, J=7.2 Hz, 1H), 0.92 (d, J=6.4 Hz, 6H); MS ESI 217.9 [M+H]+, calcd for [C13H15NO2+H]+ 218.1.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5](=[O:34])[CH:6]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:33])[C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[Br:35][CH2:36][CH2:37]Br>C(O)C>[CH3:3][O:4][C:5](=[O:34])[CH:6]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:33])[C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH3:30])([CH3:31])[CH3:32])=[CH:25][CH:24]=1)[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:37][CH2:36][Br:35])=[CH:12][CH:13]=1
Reactant: COC(=O)C(Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccc(C(C)(C)C)cc1
Reactant: BrCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)C(Cc1ccc(OCCBr)cc1)Nc1ccccc1C(=O)c1ccc(C(C)(C)C)cc1
Yield: 42.2 %

Procedure:
To a solution of potassium hydroxide (0.17 g, 2.95 mmol) in ethanol (20 ml) is added 2-[(2-(4-tert-butylbenzoyl)phenyl)amino]-3-(4-hydroxyphenyl)-propionic acid methyl ester (1.27 g, 2.95 mmol) and 1,2-dibromoethane (5.54 g, 29.50 mmol). Then the mixture is heated to reflux for 8 hours. After cooled, the reaction mixture is filtered to remove the solid formed, and then the filtrate is evaporated under a vacuum. The crude product is purified by silica gel chromatography using hexane/EtOAc (4:1) as eluent to give the title compound (0.67 g, 42%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1.[C:29]([CH2:31][C:32]1[N:33]=[CH:34][NH:35][CH:36]=1)#[N:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[O:26]1[CH2:27][CH2:28][N:23]([C:20]2[CH:21]=[CH:22][C:17]([NH:16][C:12]3[N:11]=[C:10]([S:9][C:5]4[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=4)[CH2:2][N:35]4[CH:36]=[C:32]([CH2:31][C:29]#[N:30])[N:33]=[CH:34]4)[CH:15]=[CH:14][N:13]=3)=[CH:18][CH:19]=2)[CH2:24][CH2:25]1
Reactant: BrCc1cccc(Sc2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)c1
Reactant: N#CCc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#CCc1cn(Cc2cccc(Sc3ccnc(Nc4ccc(N5CCOCC5)cc4)n3)c2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
To a stirred mixture of 4-(3-(bromomethyl)phenylthio)-N-(4-morpholinophenyl)pyrimidin-2-amine (100 mg, 0.22 mmol) and 4-cyanomethyl imidazole (47 mg, 0.44 mmol) in dimethyl formamide (2 mL), was added cesium carbonate (154 mg, 0.44 mmol) in one portion. The mixture was stirred at room temperature for 16 hours. It was filtered to remove any inorganic material, and the dimethyl formamide solution was concentrated in vacuo. The residue was column chromatographed on the silica gel using methanol:dichloromethane (4:96) as eluant to give the product (50 mg, 47%).
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][CH:27]=[C:6]2[C:7]([N:9]([CH:12]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH3:26])[CH:17]=3)[CH2:13][C:14]#[N:15])[C:10](=[O:11])[C:5]=12)=[O:8])([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:29]=[CH:28][CH:27]=[C:6]2[C:7]([N:9]([CH:12]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH3:26])[CH:17]=3)[CH2:13][C:14]#[N:15])[C:10](=[O:11])[C:5]=12)=[O:8]
Reactant: [H][H]
Reactant: CCOc1cc(C(CC#N)N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1cc(C(CC#N)N2C(=O)c3cccc(N)c3C2=O)ccc1OC
Yield: 49.3 %

Procedure:
To a solution of 3-(3-nitrophthalimido)-3-(3-ethoxy-4-methoxyphenyl)propanenitrile (0.2 g, 0.5 mmol) in 30 mL of ethyl acetate was added 0.05 g of 10%, palladium on carbon catalyst. The mixture was hydrogenated in a Parr-Shaker apparatus at 55-60 psi of hydrogen overnight. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford a yellow oil. The crude product was purified by flash column chromatography (silica gel, 3% ethyl acetate/methylene chloride). The resulting yellow solid was then dried in vacuo (60° C.,<1 mm) to afford 0.09 g (50%) of 3-(3-aminophthalimido)-3-(3-ethoxy-4-methoxyphenyl)propanenitrile: mp 171-172.5° C.; 1H NMR (CDCl3)δ 7.47-7.356 (m, 1H); 7.19-7.00 (m, 3H), 6.90-6.29 (m, 2H), 5.56 (dd, J=6.6, 10 Hz, 1H), 5.24 (s, 2H), 4.09 (q, J=7 Hz, 2H), 3.84 (s, 3H), 3.77 (dd, J=10, 16.8 Hz, 1H), 3.27 (dd, J=6.6, 16.8 Hz, 1H), 1.45 (t, J=7 Hz, 3H); 13C NMR (CDCl3)δ 169.4, 167.9, 149.6, 148.5, 145.5, 135.5, 132.1, 129.4, 121.3, 120.0, 117.1, 113.0, 112.2, 111.4, 110.6, 64.5, 55.9, 50.7, 21.1, 14.7; HPLC (Waters Nova-Pak C18 column, 3.9×150 mm, 4 micron, 1 mL/min, 240 nm, 40/60, acetonitrile/0.1% aqueous phosphoric acid) 4.5 min, 100%; Anal. Calcd. for C20H19N3O4. Theoretical: C, 65.74, H, 5.24, N, 11.50. Found: C, 65.54; H, 5.23; N, 11.23.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.CN1CCN([C:41]2[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=2)[NH2:44])CC1>>[CH2:2]1[C:41]2[C:47](=[CH:46][CH:45]=[C:43]([NH:44][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:42]=2)[CH2:5][CH2:4][NH:3]1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 3-(4-methyl-1-piperazinyl)aniline in a manner analogous to Example 64. 1H NMR (400 MHz, DMSO-d6) δ 2.25 (s, 3H), 2.46 (s, 4H), 3.11 (s, 4H), 6.53 (d, 1H, J=5.2 Hz), 6.58 (d, 1H, J=8.2 Hz), 7.09-7.19 (m, 2H), 7.24-7.31 (m, 3H), 7.239-7.65 (m, 5H), 7.86 (d, 1H, J=8.2 Hz), 8.05 (s, 1H), 8.29 (d, 1H, J=5.4 Hz), 8.53 (d, 1H, J=9.0 Hz), 8.88 (d, 1H, J=6.9 Hz), 9.42 (s, 1H), 10.98 (s, 1H); ESIMS (M+H)+=617.