Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25](=[O:59])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:29][C:28]=2[C:39]2[CH:44]=[C:43]([C:45](=[O:58])[NH:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([C:54]([F:57])([F:56])[F:55])[CH:49]=3)[CH:42]=[CH:41][N:40]=2)[N:20]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1.ClCCl.C(O)(C(F)(F)F)=O.CN(CC1N=C(C(NC2C=CC(N3CCCCC3)=CC=2C2C=C(C(=O)NCC3C=CC=C(C(F)(F)F)C=3)C=CN=2)=O)C=CC=1)CCN1CCNCC1.C(N(CC)CC)C.[CH3:129][S:130](Cl)(=[O:132])=[O:131]>ClCCl>[CH3:1][N:2]([CH2:18][C:19]1[N:20]=[C:21]([C:25]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:29][C:28]=2[C:39]2[CH:44]=[C:43]([C:45](=[O:58])[NH:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([C:54]([F:57])([F:56])[F:55])[CH:49]=3)[CH:42]=[CH:41][N:40]=2)=[O:59])[CH:22]=[CH:23][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([S:130]([CH3:129])(=[O:132])=[O:131])[CH2:7][CH2:6]1
Reactant: CS(=O)(=O)Cl
Reactant: CN(CCN1CCN(C(=O)OC(C)(C)C)CC1)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)n1
Agent: CN(CCN1CCNCC1)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCN1CCN(S(C)(=O)=O)CC1)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)n1
Temperature: 0 °C
Yield: 28 %

Procedure:
The tert-butoxycarbonyl group of tert-butyl 4-(2-(methyl((6-((4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)pyridin-2-yl)methyl)amino)ethyl)piperazine-1-carboxylate 52 was cleaved by stirring for 1 hour in 1:1 dichloromethane/TFA and the resultant amine converted to the free base by partitioning between ethyl acetate and aqueous sodium bicarbonate solution. Into a 50-mL round-bottom flask, was placed a solution of 6-((methyl(2-(piperazin-1-yl)ethyl)amino)methyl)-N-(4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenyl)-picolinamide (110 mg, 0.15 mmol, 1.00 equiv) in dichloromethane (5 mL). To this was added triethylamine (23.3 mg, 0.23 mmol, 1.50 equiv). This was followed by dropwise addition of a solution of methanesulfonyl chloride (21.2 mg, 0.18 mmol, 1.20 equiv) in dichloromethane (2 mL) with stirring at 0° C. The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 58.1 mg (28%) of a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.62 (s, 1H), 9.56 (t, J=6.0 Hz, 1H), 9.05 (d, J=5.4 Hz, 1H), 8.42 (d, J=9.0 Hz, 1H), 8.27 (s, 1H), 8.16 (dd, J=4.8 Hz, 2H), 7.88-7.81 (m, 2H), 7.71 (s, 1H), 7.67-7.54 (m, 4H), 7.30 (d, J=7.8 Hz, 1H), 4.63 (d, J=5.7 Hz, 2H), 4.35 (s, 2H), 3.32 (s, 4H), 3.18 (s, 6H), 2.99 (s, 2H), 2.88-2.84 (m, 7H), 2.68 (s, 3H), 1.73-1.59 (m, 6H). MS (ES, m/z): 793 [M+H]+.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([F:30])[CH:29]=2)[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35].C[O-].[Na+]>>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[C:7]([C:24]3[CH:25]=[N:26][CH:27]=[C:28]([F:30])[CH:29]=3)=[N:6][C:5]([C:3]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2cncc(F)c2)c2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cncc(F)c2)c2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Yield: 46.3 %

Procedure:
A mixture of 7-benzyl-1-(5-fluoro-pyridin-3-yl)-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (17 mg, 0.042 mmol), β-alanine (374 mg, 4.19 mmol) and NaOMe solution (6.3 mL, 3.15 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between water and EtOAc. 1 M HCl was added with vigorous stirring until pH was about 3. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-40% EtOAc/CH2Cl2+1% AcOH) to give 9 mg of the title compound. MS: (+) m/z 463.35 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1.Cl.[Cl-].[NH4+]>CO.O.[Zn]>[NH2:10][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([CH3:8])=[CH:6][C:5]=1[OH:9]
Reactant: Cc1cc(O)c([N+](=O)[O-])cc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Cc1cc(O)c(N)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.3 %

Procedure:
To a solution of 4-chloro-5-methyl-2-nitrophenol (5.0 g) in methanol (100 mL) at 0° C. was added zinc powder (8.71 g), which was activated by hydrochloric acid in advance, and a solution of ammonium chloride (7.1 g) in water (20 mL). The suspension was stirred for 4 h at room temperature. Then the insoluble material was filtered off through celite, and the celite cake was washed with ethyl acetate (100 mL). The filtrate and washings were combined and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using hexane/ethyl acetate (3:2) to yield the title compound (1.4 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)(=[O:17])=[O:16])[C:11]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[C:10]([O:34][CH3:35])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[CH2:39][C:40]([O:42][CH3:43])=[O:41].C(Cl)Cl.CCOC(C)=O>CN(C=O)C>[CH3:43][O:42][C:40](=[O:41])[CH2:39][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:9]=[C:10]([O:34][CH3:35])[C:11]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[C:12]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)(=[O:17])=[O:16])[N:13]=2)[CH:3]=1
Reactant: COC(=O)CCl
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2cccc(O)c2)nc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)COc1cccc(-c2nc(NS(=O)(=O)c3ccc(C)cn3)c(Oc3ccccc3OC)c(OC)n2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.41 g of 5-methyl-pyridine-2-sulfonic acid [2-(3-hydroxy-phenyl)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide, product of example 1, were dissolved in DMF (30 ml) and treated with NaH (0.061 g of a 65% NaH suspension in oil) under ice cooling. The mixture was stirred for 1 h at RT, treated dropwise with 0.11 g of methyl chloroacetate and was stirred at RT for 20 h until the reaction was completed according to TLC analysis (CH2Cl2/EtOAc: 4/1). The mixture was partitioned between brine and EtOAc the organic layer was dried over Na2SO4 and the solvent removed in vacuo. The residue was purified on a silica gel chromatography column (eluted with Me2Cl2/EtOAc: 7/1). Combination of the purified fractions and evacuation in vacuo afforded {3-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-phenoxy}-acetic acid methyl ester as a light yellow crystalline solid. ISP mass spectrum, m/e 567.2 (M+1 calculated for C27H26N4O8S: 567).
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([F:13])[C@H:10]([NH:14][C:15](=[O:22])[CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:9]1)C1C=CC=CC=1>[OH-].[Pd+2].[OH-].CO>[F:13][C@@H:11]1[CH2:12][NH:8][CH2:9][C@H:10]1[NH:14][C:15](=[O:22])[CH2:16][CH2:17][S:18]([CH3:21])(=[O:19])=[O:20]
Reactant: CS(=O)(=O)CCC(=O)N[C@@H]1CN(Cc2ccccc2)C[C@H]1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)CCC(=O)N[C@@H]1CNC[C@H]1F
Temperature: 50 °C
Reaction time: 7 h
Yield: 90 %

Procedure:
To a Parr reactor was added N-((3R,4R)-1-benzyl-4-fluoropyrrolidin-3-yl)-3-(methylsulfonyl)propanamide (86.5 g, 263 mmol, 1.0 eq), palladium hydroxide (20% on carbon, 2.59 g, 3.69 mmol, 3 wt/wt %) and MeOH (430 mL). The reactor was purged three times with nitrogen (50 psi) and then purged three times with hydrogen (20 psi). The reactor was heated at 50° C. and then pressurized to 50 psi while stirring at 1200 rpm. The material was hydrogenated for 7 hr and then cooled to 20° C. and purged with nitrogen. The mixture was filtered to remove the catalyst and the cake was washed with MeOH (173 mL). The combined filtrate and wash were concentrated to about 200 mL followed by addition of MTBE (200 mL) and then concentrated to a low stir volume. Additional MTBE (200 mL) was added and the resulting slurry granulated at 20° C. for 16 hr. The desired product was isolated by filtration, washed with MTBE (300 mL) and then dried in an oven at 40° C. for 12 hr. The title compound was isolated in 90% yield (53.3 g, 224 mmol) as a white crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.15 (br. d., J=6.8 Hz, 1 H) 4.96-4.78 (m, 1 H) 4.14-4.01 (m, 1 H) 3.32 (dd, J=8.0, 7.3 Hz, 2 H) 3.13 (dd, J=11.8, 6.8 Hz, 1 H) 3.01-2.93 (m, 1 H) 2.98 (s, 3 H) 2.88 (d, J=3.0 Hz, 1 H) 2.60 (br. s., 1 H) 2.5 7-2.52 (m, 3 H). m/z (EI+) for C8H15FN2O3S 239.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][C:7]([OH:9])=O.[N+]([O-])(O)=O.[O:18]([CH2:22][CH2:23][NH2:24])[N+:19]([O-:21])=[O:20].C(OC(C)C)(C)C>>[O:18]([CH2:22][CH2:23][NH:24][C:7](=[O:9])[CH2:6][O:5][C:4]1[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=1[O:2][CH3:1])[N+:19]([O-:21])=[O:20]
Reactant: COc1ccccc1OCC(=O)O
Reactant: NCCO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: COc1ccccc1OCC(=O)NCCO[N+](=O)[O-]
Yield: 28.2 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.77 g of 2-methoxyphenoxyacetic acid and 0.60 g of nitroxyethylamine nitrate, 0.27 g of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:33][O:34][CH2:35][C:36]#[CH:37]>>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15]([C:37]#[C:36][CH2:35][O:34][CH3:33])[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C#CCOC
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Product: CCCCCCc1cccc(-c2nc(C#CCOC)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1

Procedure:
In analogy to the procedure described for example 12, [2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 2) was reacted with 3-methoxy-propyne to give the title compound as yellow oil. MS: 491.4 (MH+).
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[C:11]([CH3:12])=[CH:10][CH:9]=[N:8]1.[C:13]1(=[O:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>O1CCCC1>[CH3:12][C:11]1[N:7]([CH2:6][C:13]2([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:8]=[CH:9][CH:10]=1
Reactant: O=C1CCCCC1
Reactant: Cc1ccnn1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccnn1CC1(O)CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of n-butyllithium (25 mL, 2.5M) in tetrahydrofuran (30 mL) was added 1,5-dimethyl-1H-pyrazole (5.0 g) in tetrahydrofuran (20 mL) dropwise via syringe. After 1 hour, cyclohexanone (5.1 g) in tetrahydrofuran (20 mL) was added dropwise and the reaction mixture was allowed to warm to room temperature. The mixture was quenched by the addition of saturated ammonium chloride solution and ethyl acetate. The layers were separated and the aqueous layer was extracted with additional ethyl acetate (twice). The combined organics were dried over Na2SO4, filtered, and concentrated to provide the crude title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[NH:8][C:7](=[O:13])[CH2:6][CH2:5]2.[OH-].[Na+].[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:16][CH:18]1[O:20][CH2:19]1)[NH:8][C:7](=[O:13])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Cl)c(O)cc2N1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CCc2cc(Cl)c(OCC3CO3)cc2N1
Reaction time: 3 h

Procedure:
20.0 grams of 6-chloro-7-hydroxy-3,4-dihydrocarbostyril and 3.7 g of sodium hydroxide are mixed with 100 ml of methanol and stirred for 3 hours, then 150 ml of epichlorohydrin is added thereto and heated for 5 hours under refluxing conditions. After the reaction is completed, the reaction mixture is concentrated under reduced pressure to dryness. The residue thus obtained is mixed with 100 ml of 2N-sodium hydroxide and stirred well. The insoluble matter is separated by filtration, washed with water and dried. The crude crystals thus obtained are recrystallized from methanol-ethanol to obtain 19.7 g of 6-chloro-7-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril in the form of colorless crystals with a melting point of 190°-192° C.
Reaction SMILES: CCCC.[C:5]1([S:11]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([NH:23][C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[C:31](I)[CH:32]=5)[N:27]=[CH:26][N:25]=4)=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:35]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)=[O:36].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.C1(C)C=CC=CC=1>[C:5]1([S:11]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([NH:23][C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[C:31]([C:40]6[CH:41]=[CH:42][C:37]([CH:35]=[O:36])=[CH:38][CH:39]=6)[CH:32]=5)[N:27]=[CH:26][N:25]=4)=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(Nc3ncnc4ccc(I)cc34)ccc21
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCC
Solvent: N#Cc1ccccc1
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc5c(ccn5S(=O)(=O)c5ccccc5)c4)c3c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
To a solution of toluene (100 mL) in a 500 mL round-bottom flask equipped with a reflux condenser was added 1,4-bis(diphenyl)phosphino)-butane (4.25 mg, 0.997 mmol) and bis(benzonitrile)dichloro-palladium (385 g, 0.997 mmol). Nitrogen was bubbled through the reaction mixture for 1 minute and the resulting suspension was stirred at room temperature for 30 minutes. THF (125 mL) and EtOH (50 mL) were then added. To the resulting mixture was added (1-benzenesulfonyl-1H-indol-5-yl)-(6-iodo-quinazolin-4-yl)-amine 20 (3.5 g, 6.6 mmol), 4-formylphenylboronic acid (1.99 g, 13.3 mmol) and 2M aq Na2CO3 (6.7 mL). The mixture was heated at reflux under an atmosphere of N2 for 15 hours. The solvent was removed under reduced pressure and the residue was purified using flash chromatography (silica gel, EtOAc/hexanes 1:1) to provide 3.1 g of 4-[4-(1-benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-benzaldehyde 22 in 92% yield. 1H NMR (DMSO-d6; 400 MHz): δ: 9.24 (s, 1H, NH), 8.84 (s, 1H), 8.33 (dd, 1H, J=8.9 Hz and1.7 Hz), 8.01 (m, 4H), 7.90 (m, 2H), 7.70 (m, 2H), 7.60 (m, 3H), 6.92 (dd, 1H, J=3.7 Hz and 0.6 Hz); MS (Cl) m/e 505.1 (M++1, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:17]=[C:18]4/[C:19](=[O:24])[NH:20][C:21](=[O:23])[S:22]/4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:27]([F:30])([F:29])[F:28])[CH:4]=1.Cl.Cl[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:17]=[C:18]4/[C:19](=[O:24])[N:20]([CH2:33][CH2:34][N:35]5[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)[C:21](=[O:23])[S:22]/4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:27]([F:30])([F:29])[F:28])[CH:4]=1
Reactant: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)NC4=O)ccc32)c(C(F)(F)F)c1
Reactant: ClCCN1CCCCC1
Agent: Cl
Product: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)N(CCN5CCCCC5)C4=O)ccc32)c(C(F)(F)F)c1

Procedure:
(5Z)-5-[(1-{[4-(Methyloxy)-2-(trifluoromethyl)phenyl]methyl}-1H-indazol-5-yl)methylidene]-3-(2-piperidin-1-ylethyl)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 8) and 1-(2-chloroethyl)piperidine hydrochloride following General Procedure H.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]3[N:25]([C:33]4[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=4)[N:26]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:28]=3)=[O:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C1COCC1>[C:29]([C:27]1[CH:28]=[C:24]([NH:23][C:21]([NH:20][C:17]2[CH:16]=[N:15][C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:19][CH:18]=2)=[O:22])[N:25]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)[N:26]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(N3CCNCC3)nc2)cc1
Temperature: 60 °C

Procedure:
Place 4-{5-[3-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-ureido]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester (565 mg, 1.06 mmol) in THF (10 mL). Add 4 M HCl in dioxane (2.65 mL, 10.6 mmol) and heat to 60° C. for 3 hours. Cool the reaction to room temperature and load onto a Varian™ SCX column. Wash the column with MeOH and then flush off the product with 2 M NH3 in MeOH.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:11][C:12]2[C:19]([CH3:20])=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[CH3:21])[C:5]2[CH:10]=[CH:9][S:8][C:6]=2[N:7]=1.C(O)(C(F)(F)F)=O.[NH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1>C(OCC)(=O)C>[C:34]([C:33]1[CH:36]=[CH:37][C:30]([NH:29][C:2]2[N:3]=[C:4]([O:11][C:12]3[C:19]([CH3:20])=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=3[CH3:21])[C:5]3[CH:10]=[CH:9][S:8][C:6]=3[N:7]=2)=[CH:31][CH:32]=1)#[N:35]
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(Cl)nc2sccc12
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2sccc12
Temperature: 90 °C
Reaction time: 48 h
Yield: 14.5 %

Procedure:
To a solution of 4-(2-chlorothieno[2,3-d]pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (188 mg, 0.59 mmol), TFA (0.37 mL, 4.75 mmol) in TFE (2.5 mL) was added 4-aminobenzonitrile (280 mg, 2.37 mmol) in a sealed tube. The reaction was stirred at 90° C. for 2 d. Reaction mixture was diluted with ethyl acetate (5 mL) and washed with saturated NaHCO3 (3×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by HPLC afforded the product as white solid (34 mg, 14%):
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[CH2:26][NH:27][C:28](=[O:31])[CH2:29][SH:30].C(N(C(C)C)C(C)C)C.[CH3:41][O:42][CH2:43]Cl.O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH2:12][C:11]([C:17]3[CH:18]=[C:19]([Cl:25])[C:20]([Cl:24])=[C:21]([Cl:23])[CH:22]=3)([C:13]([F:16])([F:14])[F:15])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[CH2:26][NH:27][C:28](=[O:31])[CH2:29][S:30][CH2:41][O:42][CH3:43]
Reactant: O=C(CS)NCc1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1Cl
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COCSCC(=O)NCc1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 0 °C

Procedure:
To a solution of 0.090 g of N-[2-chloro-4-[5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]phenyl]methyl-2-mercaptoacetamide and 0.0446 g of ethyldiisopropylamine in 2 mL of dichloromethane, 0.0278 g of methoxymethyl chloride was added while stirring the solution at 0° C., and the resultant mixture was stirred at room temperature for 1 hour. After the completion of the reaction, 3 mL of water was added to the reaction mixture and the resultant mixture was extracted with chloroform (3 mL×2). The organic phase was dehydrated and dried over saturated saline and anhydrous sodium sulfate in this order and the solvent was distilled off under reduced pressure. The resultant residue was purified by preparative medium pressure liquid chromatography eluting with ethyl acetate-hexane (a gradient from 1:9 to 1:3) using a medium pressure preparative apparatus (trade name: YFLC-Wprep; manufactured by Yamazen Corporation) to obtain 0.0406 g of the objective substance as a colorless resinoid.
Reaction SMILES: [Na].[CH3:2][NH:3][C:4](=[O:6])[CH3:5].[CH3:7][CH:8]=[CH:9][SiH:10](Cl)Cl>C1(C)C=CC=CC=1>[CH3:7][CH:8]=[CH:9][SiH:10]([N:3]([CH3:2])[C:4](=[O:6])[CH3:5])[N:3]([CH3:2])[C:4](=[O:6])[CH3:5]
Reactant: CC=C[SiH](Cl)Cl
Reactant: CNC(C)=O
Agent: [Na]
Solvent: Cc1ccccc1
Product: CC=C[SiH](N(C)C(C)=O)N(C)C(C)=O

Procedure:
The amidosilanes can be prepared as by the following illustration: mixing a sodium salt of N-methylacetamide with methylvinyldichlorosilane in an inert organic solvent such as toluene, filtering the by-produced sodium chloride from the toluene-product solution, and thereafter removing the toluene by vacuum distillation to obtain the product, methylvinyldi(N-methylacetamido)silane.
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([O:7][CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1)#[CH:2].Br[C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][N:19]=1.C(NC(C)C)(C)C>C1COCC1.Cl[Cu]>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([C:2]#[C:1][C:3]2[CH:16]=[CH:15][C:6]([O:7][CH2:8][CH2:9][N:10]3[CH2:11][CH2:12][CH2:13][CH2:14]3)=[CH:5][CH:4]=2)=[N:19][CH:20]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C#Cc1ccc(OCCN2CCCC2)cc1
Agent: Cl[Cu]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Brc1ccc(C#Cc2ccc(OCCN3CCCC3)cc2)nc1
Temperature: 40 °C

Procedure:
A mixture of 9.6 g (44.6 mmol) 1-[2-(4-ethynyl-phenoxy)-ethyl]-pyrrolidine, 10.6 g (44.6 mmol) 2,5-dibromopyridine, 626 mg (0.9 mmol) tetrakis-triphenylphosphane-palladium, 170 mg (0.9 mmol) CuCl and 12.6 mL diisopropylamine in 500 mL THF is heated for 3 h at 40° C. under an argon atmosphere. The solvent is distilled off i.vac., the residue is taken up in EtOAc, the organic phase is washed with water and saturated, aqueous NaCl solution and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified on silica gel (EtOAc/MeOH/NH3 90:10:1).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:7]([CH3:18])=[N:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)C.[NH2:20][NH2:21]>CCO.[Cl-].[Na+].O>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[O:9][N:8]=[C:7]([CH3:18])[C:6]=2[CH2:5][C:4]([NH:20][NH2:21])=[O:3])=[CH:12][CH:13]=1
Reactant: NN
Reactant: CCOC(=O)Cc1c(C)noc1-c1ccc(Br)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1noc(-c2ccc(Br)cc2)c1CC(=O)NN
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-acetic acid ethyl ester (0.114 g, 0.37 mmol) in EtOH (4 mL) was added hydrazine (1M in THF; 2 mL), and the reaction was sealed and stirred at 80° C. overnight. The mixture was poured into brine and extracted with EtOAc. The combined organic layers were washed with H2O and brine, and then dried over MgSO4, filtered, and concentrated to give the title compound.