Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH:10][S:11]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([N+:21]([O-:23])=[O:22])[C:15]=2Cl)(=[O:13])=[O:12])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].[OH2:27].Cl>O1CCOCC1>[N:1]1([CH2:7][CH2:8][CH2:9][NH:10][S:11]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([N+:21]([O-:23])=[O:22])[C:15]=2[OH:27])(=[O:13])=[O:12])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NCCCN2CCOCC2)c1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NCCCN2CCOCC2)c1O
Yield: 105.9 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, N-[3-(4-morpholinyl)propyl]-2,6-dichloro-3-nitrobenzenesulfonamide (10 g, 2.51 mmol), 60% NaH (301 mg, 7.53 mmol) and water (54 μL, 3.0 mmol) were reacted. The mixture was acidified with 4.ON HCl in 1,4-dioxane and concentrated to give the crude product (1.01 g), which was carried onto the next steps without purification. LC-MS 380.0 (M+).
Reaction SMILES: C([O-])(=O)C.[K+].Cl[C:7]1[C:8]([O:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)=[N:9][CH:10]=[CH:11][N:12]=1.CC1(C)C(C)(C)OB([C:32]2[CH2:33][CH2:34][CH2:35][N:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:37]=2)O1>CC#N>[CH3:21][O:20][C:18]([C:17]1[CH:22]=[CH:23][C:14]([O:13][C:8]2[C:7]([C:34]3[CH2:33][CH2:32][CH2:37][N:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:35]=3)=[N:12][CH:11]=[CH:10][N:9]=2)=[CH:15][CH:16]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1C=C(B2OC(C)(C)C(C)(C)O2)CCC1
Reactant: COC(=O)c1ccc(Oc2nccnc2Cl)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(Oc2nccnc2C2=CN(C(=O)OC(C)(C)C)CCC2)cc1
Temperature: 80 °C

Procedure:
To a mixture of (amphos)2PdCl2 (0.145 g, 0.205 mmol), potassium acetate (1.045 g, 10.65 mmol), methyl 4-(3-chloropyrazin-2-yloxy)benzoate (1.084 g, 4.10 mmol), and tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate (1.900 g, 6.14 mmol) under N2 was added MeCN (7.0 mL) and Ar degassed water (0.70 mL). The reaction mixture was degassed with Ar (10 min) then heated to 80° C. for 20 h. The reaction mixture was diluted with H2O (20 mL) and extracted with Teac (2×10 mL). The combined organic extracts were washed with brine (10 mL), dried (MgSO4), and concentrated. Purification by ISCO (120 g SiO2, 10-100% Teac/hexanes) gave tert-butyl 5-(3-(4-(methoxycarbonyl)phenoxy)pyrazin-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate as a yellow oil.
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[Cl:28][C:29]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>ClCCl>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:31](=[O:32])[C:30]3[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:29]=3[Cl:28])[CH:22]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(N)c2)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CC1
Yield: 98 %

Procedure:
Add pyridine (0.66 mL, 8.21 mmol) to a solution of 4-(3-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (preparation 30, 2.0 g, 6.84 mmol) in dichloromethane (35 mL) at 0° C. Stir and add 2-chloro-4-fluorobenzoyl chloride dropwise (1.45 g, 7.52 mmol). Stir at 0° C. for 30 min and 1 hr. at room temperature. Dilute with dichloromethane (30 mL) and wash with sodium hydroxide (1N, 2×25 mL). Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure. Purification by flash chromatography, eluting with ethyl acetate/hexanes [20-40%] to give the title compound (3.0 g, 98%). Mass spectrum (ion spray): m/z=449.0 (M+1); 1H NMR (CDCl3): 7.87 (bs, N—H), 7.80 (dd, J=6.1 Hz, 8.6 Hz, 1H), 7.48 (s, 1H), 7.28-7.24 (m, 1H), 7.21 (dd, J=2.5 Hz, 8.4 Hz, 1H), 7.11 (td, J=2.2 Hz, 8.4 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.73 (dd, J=2.2 Hz, 8.4 Hz, 1H), 4.52 (septet, J=3.6 Hz, 1H), 3.69 (ddd, J=3.7 Hz, 7.7 Hz, 13.6 Hz, 2H), 3.35 (ddd, J=3.9 Hz, 7.7 Hz, 13.6 Hz, 2H), 1.97-1.89 (m, 2H), 1.81-1.72 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][S:15]([NH:18][CH2:19][CH2:20][NH:21][C:22]1[C:26]([C:27]2[N:31]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([Br:39])[CH:33]=3)[C:30](=[O:40])[O:29][N:28]=2)=[N:25][O:24][N:23]=1)(=[O:17])=[O:16])(C)(C)C>O>[Br:39][C:34]1[CH:33]=[C:32]([N:31]2[C:30](=[O:40])[O:29][N:28]=[C:27]2[C:26]2[C:22]([NH:21][CH2:20][CH2:19][NH:18][S:15]([NH2:14])(=[O:16])=[O:17])=[N:23][O:24][N:25]=2)[CH:37]=[CH:36][C:35]=1[F:38]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a 22 L flask containing 98:2 trifluoroacetic acid:water (8.9 L) was added tert-butyl({[2-({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}amino)ethyl]amino}sulfonyl)carbamate (1931 g, 3.42 mol) in portions over 10 minutes. The resulting mixture was stirred at room temperature for 1.5 h, the solvents removed in vacuo, and chased with dichloromethane (2 L). The resulting solid was treated a second time with fresh 98:2 trifluoroacetic acid:water (8.9 L), heated for 1 h at 40-50° C., the solvents removed in vacuo, and chased with dichloromethane (3×2 L). The resulting white solid was dried in a vacuum drying oven at 50° C. overnight. A total of 5409 g was processed in this manner (4990 g, quant. yield). LCMS for C12H12BrFN7O5S (M+H)+: m/z=463.9, 465.9. 1H NMR (400 MHz, DMSO-d6): δ 8.08 (dd, J=6.2, 2.5 Hz, 1H), 7.72 (m, 1H), 7.59 (t, J=8.7 Hz, 1H), 6.67 (t, J=5.9 Hz, 1H), 6.52 (t, J=6.0 Hz, 1H), 3.38 (dd, J=12.7, 6.3 Hz, 2H), 3.11 (dd, J=12.3, 6.3 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[C:6]([NH:13][C:14](=[O:19])[CH2:15][CH2:16][CH2:17]Cl)[CH:5]=1.[H-].[Na+]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:5]=[C:6]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:19])[CH:7]=[C:8]([O:10][CH2:11][CH3:12])[CH:9]=1
Reactant: CCOc1cc(NC(=O)CCCCl)cc(C(=O)OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1cc(C(=O)OC)cc(N2CCCC2=O)c1
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
3-(4-Chloro-butanoylamino)-5-ethoxy-benzoic acid methyl ester (D51) (7 g, 20 mmol, 1 equiv) in THF (50 ml) was treated portionwise with NaH (60% in mineral oil, 0.88 g, 22 mmol, 1.1 equiv) over 15 min at room temperature. The resulting mixture was stirred for 30 min and then diluted with AcOEt (300 ml). The resulting solution was washed with 2N aqueous HCl solution (200 ml), dried over MgSO4 and concentrated in vacuo. Recrystallisation of the residue from Et2O/hexane gave 3-ethoxy-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (B11) (3.5 g, 66%) as white solid.
Reaction SMILES: C([Li])CCC.CCCCCC.CO[C:14]([C:16]1[CH:17]=[N:18][N:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=12)=[O:15].Cl.[C:26](#[N:28])[CH3:27]>C1(C)C=CC=CC=1>[O:15]=[C:14]([C:16]1[CH:17]=[N:18][N:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=12)[CH2:27][C:26]#[N:28]
Reactant: CC#N
Reactant: COC(=O)c1cnn2ccccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: N#CCC(=O)c1cnn2ccccc12
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of dry acetonitrile in toluene (0.66 mL, 13 mmol, 5 eq) cooled down to −78° C. under nitrogen, a solution of n-butyllithium in n-hexane (5.2 mL, 13 mmol, 5 eq) was added dropwise. The mixture was left stirring at −78° C. for 20 minutes and then a solution of pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (0.46 g, 2.6 mmol, 1 eq, prepared according to the reported procedure (Anderson et al. Journal of Heterocyclic Chemistry 1981, 18, 1149-1152) in toluene was added and the reaction allowed to reach room temperature. Upon reaction completion, after about 20 minutes, the mixture was cooled down to 0° C. and HCl 2N was added to pH 2. The organic phase was recovered, dried over Na2SO4 and concentrated under reduced pressure, affording the title product which was used without further purification in the following step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([NH2:20])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH:22]1([CH2:28][C:29](Cl)=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([NH:20][C:29](=[O:30])[CH2:28][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1nn(N)c(=O)c2ccccc12
Reactant: O=C(Cl)CC1CCCCC1
Product: CC(C)(C)OC(=O)NCc1nn(NC(=O)CC2CCCCC2)c(=O)c2ccccc12

Procedure:
The product of Example 41B and 2-cyclohexylacetyl chloride were treated using a method similar to that described in Example 4C to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 11.24 (s, 1H), 8.32 (dd, J=7.8, 1.4, 1H), 8.11 (d, J=8.0, 1H), 8.03-7.94 (m, 1H), 7.90 (td, J=7.5, 1.2, 1H), 7.45-7.36 (m, 1H), 4.48-4.41 (m, 2H), 2.16 (d, J=6.7, 2H), 1.85-1.58 (m, 6H), 1.39 (s, 9H), 1.28-0.95 (m, 5H); MS (ESI−) M/Z 413 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C([ClH:21]O)(C)(C)C>C(Cl)(Cl)(Cl)Cl>[Cl:21][C:8]1[CH:7]=[C:6]([O:5][C:4]2[CH:3]=[C:2]([F:1])[CH:15]=[C:14]([F:16])[CH:13]=2)[CH:11]=[CH:10][C:9]=1[OH:12]
Reactant: Oc1ccc(Oc2cc(F)cc(F)c2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1ccc(Oc2cc(F)cc(F)c2)cc1Cl
Reaction time: 5 h
Yield: 93.4 %

Procedure:
To a solution of 5.0 g p-(3,5-difluorophenoxy)phenol in 50 mg of carbon tetrachloride, there were added dropwise 2.45 g of tert-butylhypochlorous acid with stirring and ice-cooling, and stirring was continued at room temperature of 5 hours. The reaction mixture was concentrated and extracted with 200 ml of ethyl acetate. The extract was washed with 5% aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 5.31 g of 2-chloro-4-(3,5-difluorophenoxy)phenol. Yield, 92%. nD25 : 1.5639
Reaction SMILES: C(N1CCN([NH:14][C:15](=[O:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)CC1)(OC(C)(C)C)=O.[CH2:24]([C:26]1[S:34][C:33]2[N:32]=[C:31]([CH:35]([CH3:37])[CH3:36])[N:30]=[C:29]([N:38]3[CH2:43][CH2:42]N(C(OC(C)(C)C)=O)[CH2:40][CH2:39]3)[C:28]=2[CH:27]=1)[CH3:25]>>[CH2:24]([C:26]1[S:34][C:33]2[N:32]=[C:31]([CH:35]([CH3:37])[CH3:36])[N:30]=[C:29]([N:38]3[CH2:43][CH2:42][N:14]([C:15](=[O:23])[CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:40][CH2:39]3)[C:28]=2[CH:27]=1)[CH3:25]
Reactant: CCc1cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)nc(C(C)C)nc2s1
Reactant: CC(C)(C)OC(=O)N1CCN(NC(=O)Cc2ccccc2)CC1
Product: CCc1cc2c(N3CCN(C(=O)Cc4ccccc4)CC3)nc(C(C)C)nc2s1
Yield: 21 %

Procedure:
Phenylacetamidopiperazine hydrochloride (Example 141) was reacted 2-isopropyl-4-chloro-6-ethylthienopyrimidine (Example 162) according to Example 87. Yield=21%, ES-MS: (M+H)+ 409.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Br:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:16])[C@:4]1([CH2:32][C:31]2[CH:34]=[CH:35][C:28]([Br:27])=[CH:29][CH:30]=2)[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10]
Reactant: BrCc1ccc(Br)cc1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@]1(Cc2ccc(Br)cc2)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 21 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)proline methyl ester (1.30 g) in THF (20 mL) at −78° C. was added a solution of KHMDS (1.25 g) in THF (20 mL). After 45 minutes, a solution of 4-bromobenzyl bromide (1.59 g) in THF (20 mL) was added at −78° C. The reaction mixture was warmed to room temperature over 3 hours and stirred for an additional 3 hours. The mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4), filtered and concentrated. Purification by flash column chromatography (silica gel; EtOAc/hexane 1:2) afforded N-(tert-butoxycarbonyl)-2-(4-bromobenzyl)proline methyl ester (0.474 g). MS (m/z) 398 (MH+). (2) To a solution of the compound obtained above (0.474 g) in CH2Cl2 (5 mL) was added TFA (1.5 mL). After 1 hour, the reaction mixture was diluted with CH2Cl2, washed with aqueous NaHCO3 and brine, dried (Na2SO4) and concentrated to give 2-(4-bromobenzyl)proline methyl ester. MS (m/z) 298 (MH+). (3) 3,5-Dichlorophenylisocyanate (0.50 g) was added to a solution of the compound obtained above in THF (10 mL) and DIEA (2.0 mL). After 4 hours stirring at room temperature, the reaction mixture was concentrated. The residue was redissolved in EtOAc, washed with aqueous NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. Purification by chromatography (silica gel: EtOAc/hexane: 1/4, Chromatotron (Harrison Research)) afforded 0.33 g of N-[(3,5-dichlorophenyl)carbamoyl]-2-(4-bromobenzyl)proline methyl ester. MS (m/z) 485 (MH+). mp 170.9° C. (4) The compound obtained above (0.153 g) was dissolved in hot EtOH (10 mL) and cooled to 0° C. To the solution at 0° C. was added NaOEt (0.010 g). After 45 minutes of stirring, the mixture was concentrated. Purification by chromatography (silica gel: 15% EtOAc/hexane, Chromatotron) afforded the titled compound (0.129 g). MS (m/z) 453 (MH+). mp 69.4° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1=Cc2cc(OCc3ccc(F)cc3)ccc2S(=O)(=O)CC1
Temperature: 55 °C
Reaction time: 7 h

Procedure:
A mixture of methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (200 mg), 4-fluorobenzyl chloride (0.090 ml), potassium carbonate (134 mg) and DMF (5 ml) was stirred at 55° C. for 7 hours. The reaction mixture was mixed with water and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the residue was subjected to separation and purification using column chromatography (ethyl acetate/hexane 1:1) to obtain methyl 7-[(4-fluorobenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (162 mg) as colorless crystals.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([OH:13])(=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15]>O>[CH2:14]([N:16]([CH2:17][CH3:18])[C:5](=[O:13])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH3:15]
Reactant: CCNCC
Reactant: O=C(O)c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCN(CC)C(=O)c1ccccc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A mixture of thionyl chloride (6 mL) and the benzoic acid was heated at reflux until the starting benzoic acid dissolved. Excess thionyl chloride was removed under reduced pressure leaving the crude acid chloride as a low melting solid which was used without further purification. The crude acid chloride was dissolved in CH2Cl2 (20 mL) and cooled to −10° C. To this stirred solution was added triethylamine (4 mL), followed by the dropwise addition of diethylamine (1.4 equivalents). The heterogeneous reaction mixture was allowed to warm to room temperature and was stirred for 30 minutes. The reaction mixture was transferred to a separatory funnel containing H2O (20 mL). The organic layer was separated and washed with 5% HCl (2×25 mL), H2O (25 ml), and dried over Na2SO4. The solvent was removed under reduced pressure to afford the product N,N-diethyl benzamide.
Reaction SMILES: C[SiH](C)CCOC[N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]1[C:17](=[O:35])[N:18](COCC[Si](C)(C)C)[N:19]=[C:20]([N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)[CH:21]=1>ClCCl.FC(F)(F)C(O)=O>[NH:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]=[C:8]1[C:16]1[C:17](=[O:35])[NH:18][N:19]=[C:20]([N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)[CH:21]=1
Reactant: C[SiH](C)CCOCn1c(-c2cc(-n3ccnc3)nn(COCC[Si](C)(C)C)c2=O)nc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]nc(-n2ccnc2)cc1-c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
40 mg of 4-[1-(2-dimethylsilanylethoxymethyl)-1H-benzimidazol-2-yl]-6-imidazol-1-yl-2-(2-trimethylsilanylethoxymethyl)-2H-pyridazin-3-one are dissolved in 2 ml of a 1:1 mixture of dichloromethane and trifluoroacetic acid, and the mixture is stirred at room temperature for 2 hours. The volatile components are then distilled off, the residue is dissolved in 1 ml of methanol, and 1 ml of a two molar aqueous sodium hydroxide solution is added. The solution is stirred at room temperature for 12 hours and then put directly onto the preparative RP-HPLC (0-100% acetonitrile (+0.05% formic acid) in water (+0.05% formic acid)) to isolate the product.
Reaction SMILES: [Li][C:2]([CH3:5])([CH3:4])[CH3:3].CCCCC.F[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[O:19][CH2:20][C:21]([CH3:24])([CH3:23])[N:22]=1>C1COCC1>[C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[O:19][CH2:20][C:21]([CH3:24])([CH3:23])[N:22]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC1(C)COC(c2ccccc2F)=N1
Reactant: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccccc2C(C)(C)C)=N1
Reaction time: 0.33 h
Yield: 93 %

Procedure:
A 1.7M solution of t-BuLi in pentane (161 mL, 274 mmol) was added dropwise to a solution of 2-(2-fluorophenyl)-4,4-dimethyl-2-oxazoline [cf. Meyers A. I. and Williams B. E., Tetrahedron Letters, 223-226(1978)] (48.0 g., 249 mmol) in THF (320 mL), maintaining the reaction temperature between -45° and -40° C. with a dry-ice/acetone cooling bath. The resulting reaction mixture was maintained at ≤-40° C. with a dry-ice/acetonitrile bath, and monitored to completion by GLC over 20 min. This mixture was poured onto ice and extracted three times with ether. These extracts were combined, dried (MgSO4), concentrated and distilled under vacuum to afford 56.87 g of 2-(2-tert-butylphenyl)-4,4-dimethyl-2-oxazoline, a 93% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[NH:33]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]([NH:40][CH3:41])[CH2:34]1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:33]5[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]([NH:40][CH3:41])[CH2:34]5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:30])([F:32])[F:31])[CH:3]=1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CNC1CCCCNC1
Product: CNC1CCCCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-methylamino-azepan-1-yl)-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and Azepan-3-yl-methyl-amine following General Procedure B.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:13])[CH2:11][Cl:12].[C:14](O)(=[O:16])[CH3:15]>>[Cl:12][CH2:11][C:10]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[NH:1][C:14](=[O:16])[CH3:15])=[O:13]
Reactant: COc1ccc(C(=O)CCl)c(N)c1
Reactant: CC(=O)O
Product: COc1ccc(C(=O)CCl)c(NC(C)=O)c1
Yield: 100 %

Procedure:
A solution of 1-(2-amino-4-methoxyphenyl)-2-chloroethanone (9.93 g, 49.74 mmol) (Example 10) in acetic acid (100 mL) was heated at 85° C. for 4 h. The solvent was evaporated under reduced pressure to yield a yellow solid (12.00 g, 100%). LC/MS m/z 242 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 8.45 (d, 1H), 7.73 (d, 1H), 6.63 (dd, 1H), 4.71 (s, 2H), 3.89 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[Br:12][C:13]1[C:18]([C:19]2[C:30]([CH3:31])=[N:29][C:22]3[N:23]=[C:24](SC)[N:25]=[CH:26][C:21]=3[CH:20]=2)=[CH:17][C:16]([NH:32][C:33]([NH:35][CH2:36][CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:34])=[C:15]([F:42])[CH:14]=1.[CH3:43][NH2:44].C1COCC1>C(Cl)Cl>[Br:12][C:13]1[C:18]([C:19]2[C:30]([CH3:31])=[N:29][C:22]3[N:23]=[C:24]([NH:44][CH3:43])[N:25]=[CH:26][C:21]=3[CH:20]=2)=[CH:17][C:16]([NH:32][C:33]([NH:35][CH2:36][CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:34])=[C:15]([F:42])[CH:14]=1
Reactant: CSc1ncc2cc(-c3cc(NC(=O)NCCC(C)(C)C)c(F)cc3Br)c(C)nc2n1
Reactant: CN
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)NCCC(C)(C)C)c(F)cc3Br)c(C)nc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13 %

Procedure:
Add mCPBA (0.152 g, 0.616 mmol) portion wise to a solution of 1-(4-bromo-2-fluoro-5-(7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3,3-dimethylbutyl)urea (0.26 g, 0.513 mmol) in DCM (10 mL) and stir at RT for 2 h. Add methylamine in THF (2.0M, 1.027 mL, 2.054 mmol) and stir at RT overnight. Add water, extract with DCM (3×), wash the combined organics with saturated. NaHCO3, then brine, dry over MgSO4, concentrate to dryness and purify via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). Combine fractions, remove the organics under reduced pressure and neutralize the resulting aqueous residue with NaHCO3. Extract the mixture with EtOAc (2×), wash the combined organics with saturated. NaHCO3, then brine, dry over Na2SO4, concentrate to dryness, treat with 1:1 MeCN/H2O, freeze and lyophilize to afford the title compound as a pale yellow solid (34 mg, 13% yield). MS (m/z): 489.1 (M+1)/491.1 (M+3).