Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[C:8]([Br:18])[CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.Cl.[CH2:20]([N:27]([CH2:31][CH2:32]Cl)[CH2:28][CH2:29]Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH2:20]([N:27]1[CH2:31][CH2:32][N:1]([C:2]2[CH:14]=[C:13]3[C:5]([C:6]4[CH:7]=[C:8]([Br:18])[CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=4[NH:12]3)=[CH:4][CH:3]=2)[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCCN(CCCl)Cc1ccccc1
Reactant: NC(=O)c1cc(Br)cc2c1[nH]c1cc(N)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Br)cc2c1[nH]c1cc(N3CCN(Cc4ccccc4)CC3)ccc12
Temperature: 80 °C

Procedure:
7-Amino-3-bromo-9H-carbazole-1-carboxamide 470B (400 mg, 1.315 mmol), N-benzyl-2-chloro-N-(2-chloroethyl)ethanamine hydrochloride (707 mg, 2.63 mmol) and sodium carbonate (697 mg, 6.58 mmol) were mixed in DMF (8 mL) in a sealed microwave vial. The vial was degassed and filled with N2. The mixture was heated at 80° C. for 16 hrs in an oil bath. The mixture was then heated in microwave at 200 C for 1 hr. The mixture was purified using preparative HPLC to give titled product. MS (ESI) m/z 463.07 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)=[O:12])[S:10][C:3]=12.[F:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1O.[C:29]([O-])([O-])=O.[K+].[K+]>O(C1C=CC=CC=1)C1C=CC=CC=1>[F:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[CH2:29][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)=[O:12])[S:10][C:3]=12
Reactant: O=C(c1ccco1)c1cc2nccc(Cl)c2s1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=C(c1ccco1)c1cc2nccc(Cc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 180 °C
Yield: 39.3 %

Procedure:
To a suspension of 239 (35 mg, 0.133 mmol) in Ph2O (2 mL) was added 2-fluoro-4-nitrophenol (42 mg, 0.265 mmol) and K2CO3 (73 mg, 0.530 mmol). The reaction mixture was heated at 180° C. in a sealed flask for 60 hrs, cooled down to room temperature, loaded onto a flash chromatography column and eluted with EtOAc/hexane mixture (1:1), to afford title compound 240 (20 mg 39% yield) as a yellow solid. MS (m/z): 385.1 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[O:16][C:17]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][C:18]=2[N:19]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)(=O)C>[C:24]([C:21]1[CH:22]=[CH:23][C:17]2[O:16][C:15]([C:14]3[CH:13]=[CH:12][N:11]=[CH:10][C:9]=3[OH:8])=[N:19][C:18]=2[CH:20]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: [H][H]
Reactant: CC(C)(C)c1ccc2oc(-c3ccncc3OCc3ccccc3)nc2c1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc2oc(-c3ccncc3O)nc2c1
Yield: 82.7 %

Procedure:
A mixture of 2.1 g of 2-(3-benzyloxypyridin-4-yl)-5-tert-butylbenzoxazole, 0.58 g of 5% palladium on carbon and 50 ml of acetic acid was stirred under about one atmosphere of hydrogen at room temperature for six hours. The reaction mixture was filtered through Celite™. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.3 g of 4-(5-tert-butylbenzoxazole-2-yl)pyridin-3-ol (hereinafter, referred to as “active compound 103”).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[O:22]CC2C=CC=CC=2)[NH:15][CH:14]=1)=[O:12].CO.[H][H]>[Pd].C(O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[OH:22])[NH:15][CH:14]=1)=[O:12]
Reactant: COc1ccc(NC(=O)c2c[nH]c3cccc(OCc4ccccc4)c23)c(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: COc1ccc(NC(=O)c2c[nH]c3cccc(O)c23)c(F)c1

Procedure:
N-(2-Fluoro-4-methoxyphenyl)-4-benzyloxy-1H-indole-3-carboxamide (1.34 g, 3.4 mmol), prepared using the method above, was slurried with 10% Palladium on Carbon (134 mg) in ethanol (35 mL) in a Parr bottle and placed under a Hydrogen atmosphere (50 psi) for 5 h. Methanol (5 ml) was added and the mixture returned to the Hydrogen atmosphere for an additional 18 h. The solution was filtered through Celite, concentrated in vacuo, and the residue purified by flash chromatography to afford N-(2-fluoro-4-methoxyphenyl)-4-hydroxy-1H-indole-3-carboxamide (Compound 2) as a beige solid; mp 259°-261° C. (d).
Reaction SMILES: [N:1]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH2:10][CH2:9][CH:8]([CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[O:7]3)[CH:4]=[CH:3][CH:2]=1.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][NH:40][CH2:41][CH:42]=1>CS(C)=O>[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][N:40]([CH2:15][CH:8]2[CH2:9][CH2:10][C:11]3[C:6](=[C:5]4[C:14](=[CH:13][CH:12]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[O:7]2)[CH2:41][CH:42]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc4ncccc4c3O2)cc1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Solvent: CS(C)=O
Product: Fc1ccc2[nH]cc(C3=CCN(CC4CCc5ccc6ncccc6c5O4)CC3)c2c1
Temperature: 77.5 °C
Yield: 6.2 %

Procedure:
Toluene-4-sulfonic acid 7,8-dihydro-6H-5-oxa-1-aza-phenanthren-6-ylmethyl ester (0.22 g, 1.67 mmole) and 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (4.0 g, 1.8 mmole) were combined in 200 mL of DMSO and heated at 75-80° C. under nitrogen for 13 hours. After cooling to room temperature, the mixture was partitioned between 400 mL each of ethyl acetate and saturated sodium bicarbonate solution. The organic phase was removed, washed with saturated brine, dried over magnesium sulfate and concentrated to an oil in vacuum. This was column chromatographed on silica gel using first methylene chloride to elute impurities and then 5% methanol in methylene chloride to elute the product, 0.19 g of a yellow oil. The oil was recrystallized from isopropanol with the addition of 0.05 g of oxalic acid to give 0.043 g of the title compound as a yellow solid (m.p. 148° C.).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C.[CH3:29][O:30][C:31]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:32]=1[CH2:33][NH2:34]>O>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](=[O:20])(=[O:19])[NH:34][CH2:33][C:32]1[CH:35]=[CH:36][C:37]([O:39][CH3:40])=[CH:38][C:31]=1[O:30][CH3:29]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)Cl)c2)N1C
Agent: Br
Solvent: CCN(CC)CC
Solvent: O
Product: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)NCc3ccc(OC)cc3OC)c2)N1C
Product: Cl

Procedure:
8.8 g of 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol-hydrobromide were reacted as prescribed in Example 76 with 5 g of triethyl amine and 3.5 g of 2,4-dimethoxybenzyl amine and worked up. After treating with water, the amorphous 4-[4-chloro-3-(2,4-dimethoxybenzylsulfamoyl)-phenyl]-3-methyl-2-methylimino-1,3-thiazolidine-4-ol was extracted with 70 ml of ethyl acetate, dried over sodium sulfate and the solvent was acidified with ethanolic hydrochloric acid (15%). The amorphous precipitated end product was crystallized under isopropanol. Melting point: 163° C. (decomposition).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Li]CCCC.Br[CH2:18][CH2:19][C:20]1[O:21][C:22]([CH3:25])=[CH:23][CH:24]=1>C1COCC1>[CH3:25][C:22]1[O:21][C:20]([CH2:19][CH2:18][S:11][C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)=[CH:24][CH:23]=1
Reactant: Cc1ccc(CCBr)o1
Reactant: CC(=O)Nc1ccc(S)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(SCCc2ccc(C)o2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.6 %

Procedure:
To a solution of 4-acetamidothiophenol (442 mg, 2.64 mmol) in THF (1 mL) at 0° C. under inert atmosphere was added a solution of n-BuLi (2.00 mL, 3.17 mmol, 1.6 M in hexanes) in THF (1 mL). The reaction solution was stirred at room temperature for 10 min then a solution of compound 21B (500 mg, 2.64 mmol) in THF (3 mL) was added. After the starting material was consumed (as determined by TLC), the reaction was quenched with H2O and the mixture was extracted with EtOAc (2×), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with 50% EtOAc/hexanes gave 0.644 g (2.34 mmol, 88%) of compound 21C. MS (ESI): m/z 276.09 [M+H]+.
Reaction SMILES: Br.[C:2]1([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2([C:21]([OH:23])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([N:18]1[CH2:17][CH2:16][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([C:21]([OH:23])=[O:22])[CH2:20][CH2:19]1)(=[O:26])[CH3:25]
Reactant: O=C(O)C1(c2ccccc2Sc2ccccc2)CCNCC1
Reactant: CC(=O)OC(C)=O
Agent: Br
Solvent: c1ccncc1
Product: CC(=O)N1CCC(C(=O)O)(c2ccccc2Sc2ccccc2)CC1

Procedure:
A mixture of 8 g of 4-(2-phenylthiophenyl)piperidine-4-carboxylic acid hydrobromide, Example 14, and 10 ml of acetic anhydride in 50 ml of pyridine is refluxed for 4 hours. Thereafter, the pyridine is removed by distillation in vacuo and the residue is triturated with 100 ml of 1 N hydrochloric acid. The residue is extracted thrice with portions of chloroform and the combined chloroform extracts are successively washed twice with water, dried, and concentrated. The residue is recrystallized from acetone to provide 1-acetyl-4-(2-phenylthiophenyl)piperidine-4-carboxylic acid.
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:14][CH2:15][CH3:16])(=[O:13])/[CH:6]=[CH:7]\[C:8]([O:10]CC)=O.[NH:17]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[NH2:18]>C(O)C>[O:10]=[C:8]1[NH:18][N:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:6]([C:5]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7]1
Reactant: CCOC(=O)/C=C\C(=O)OCC
Reactant: NNc1cccnc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1CC(=O)NN1c1cccnc1

Procedure:
In a preferred reaction, sodium ethoxide in an anhydrous ethanol are introduced into a reaction vessel and 3-hydrazinopyridine•dihydrochloride is added. The mixture is stirred and diethyl maleate is added. The mixture is heated at about 60° C. until most of the 3-hydrazinopyridine has reacted. The mixture is allowed to cool and the excess base is neutralized with acid. The crude ethyl 5-oxo-2-(pyridin-3-yl)pyrazolidine-3-carboxylate (10a) is conveniently isolated and purified by standard techniques.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:20]=[CH:19][C:18]3[N:17]([CH3:21])[C:16]4[CH2:22][CH:23]5[NH:27][CH:26]([C:15]=4[C:14]=3[C:13]=2C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.[Cl:39]CCl>>[ClH:39].[OH:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16]2[CH2:22][CH:23]4[NH:27][CH:26]([C:15]3=2)[CH2:25][CH2:24]4)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: ClCCl
Reactant: COc1cccc(S(=O)(=O)c2ccc3c(c2C(=O)OC(C)(C)C)c2c(n3C)CC3CCC2N3)c1
Agent: BrB(Br)Br
Product: Cl
Product: Cn1c2c(c3cc(S(=O)(=O)c4cccc(O)c4)ccc31)C1CCC(C2)N1
Reaction time: 4 h

Procedure:
A solution of the product of Example 41, step A (86 mg, 0.21 mmol) in dichloromethane (2.5 mL) at 0° C. was treated with boron tribromide (2.5 mL, 2.1 mmol). The reaction was stirred for 4 h then quenched with methanol followed by saturated sodium bicarbonate. The mixture was extracted with dichloromethane and the organic extract concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 95:5 dichloromethane/methanol) and the residue dissolved in a minimum of methanol. The solution was treated with 1.25 M HCl in methanol (2 mL) then concentrated in vacuo to give 2-(3-hydroxyphenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole hydrochloride (21 mg, 23%, AUC HPLC >99%) as an off-white solid: mp 208-212° C.; 1H NMR (DMSO-d6, 300 MHz) δ 10.20 (s, 1H), 8.90-9.40 (m, 2H), 8.32 (s, 1H), 7.60-7.67 (m, 2H), 7.29-7.39 (m, 2H), 7.25 (s, 1H), 6.98 (s, 1H), 5.32-5.39 (br s, 1H), 4.46 (br s, 1H), 3.70 (s, 3H), 3.37-3.39 (m, 1H), 3.01 (d, J=17.0 Hz, 1H), 2.26 (br s, 2H), 2.06-2.12 (m, 1H), 1.72-1.86 (m, 1H). ESI MS m/z 369 [M+H]+
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH:21]([C:22]([NH:24][OH:25])=[O:23])[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].Cl>O1CCOCC1>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([N:15]2[CH:21]([C:22]([NH:24][OH:25])=[O:23])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)(=[O:13])=[O:14])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CCC2C(=O)NO)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC#CCOc1ccc(S(=O)(=O)N2CCNCCC2C(=O)NO)cc1

Procedure:
To the product of Example 291, tert-butyl 4-{[4-(2-butynyloxy)phenyl]-sulfonyl}-5-[(hydroxyamino)carbonyl]-1,4-diazepane-1-carboxylate (0.32 g, 0.68 mmol), was added 4N hydrochloric acid in dioxane (9 mL) After 10 min the reaction mixture was concentrated in vacuo. Trituration of the residue with diethyl ether gave 4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-1,4-diazepane-5-carboxamide as an off-white powder (0.27 g). Electrospray Mass Spec 368.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([N:9]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)=[CH:5][CH:4]=1.[BH4-].[Na+]>O=P(Cl)(Cl)Cl.C(Cl)Cl>[CH3:25][O:24][C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[CH:7]([C:6]1[CH:26]=[CH:27][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[N:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:16][CH2:17]2
Reactant: COc1ccc(C(=O)N(CCc2cccc(OC)c2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(C2c3ccc(OC)cc3CCN2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
A stirred solution of 4-methoxy-N-[2-(3-methoxy-phenyl)-ethyl]-N-phenyl-benzamide in POCl3 under an atmosphere of N2 was heated at reflux for 14 hours. The solution was allowed to cool to rt and concentrated in vacuo. The residue was taken up in CH2Cl2 (30 ml) and washed with sat. NaHCO3 until CO2 evolution ceased. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in MeOH (20 ml), cooled to 0° C., and NaBH4 (0.105 g, 2.77 mmol) was added in a portionwise manner. The reaction was stirred for 2 hours at 0° C., then additional NaBH4 (0.105 g, 2.77 mmol) was added. The reaction was stirred at rt overnight, diluted with CH2Cl2 (50 ml), and washed with sat. NaHCO3 solution (1×50 ml). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was subjected to flash chromatography (SiO2, hexanes:EtOAc 10:1) to give the desired compound as a colorless oil (0.550 g, 1.59 mmol, 58% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1/[CH:29]=[CH:30]/B(O)O>>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1/[CH:29]=[CH:30]/[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)c1ccc(Br)cc1
Reactant: OB(O)/C=C/c1ccc(F)cc1F
Product: COC(=O)c1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2F)cc1

Procedure:
The title compound was prepared according to the method described in Example 138, Step 3 using methyl 2-[(4-bromophenyl)sulfonyl]benzoate (Step 1) in place of (1S)-1-[2-({4-bromo-3-methylphenyl}sulfonyl)phenyl]ethanol and [(E)-2-(2,4-difluorophenyl)vinyl]boronic acid (Step 2) in place of [(E)-2-(4-fluorophenyl)vinyl]boronic acid. δH (500 MHz, d6 DMSO): 8.22–8.20 (1H, m), 7.94–7.80 (7H, m), 7.69–7.63 (1H, m), 7.44 (1H, d, J 16.4), 7.39 (1H, d, J 16.4), 7.35–7.30 (1H, m), 7.19–7.15 (1H, m), 3.87 (3H, s). m/z (ES+) 383 [(M−MeO)+].
Reaction SMILES: [OH:1][C:2]([C:15]([F:18])([F:17])[F:16])([CH2:5][C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[CH:3]=O.[NH2:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24]([O:30][CH3:31])=[N:25]2>>[F:18][C:15]([F:16])([F:17])[C:2]([CH:3]=[N:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24]([O:30][CH3:31])=[N:25]2)([OH:1])[CH2:5][C:6]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:7])[CH3:14]
Reactant: COc1ccc2c(N)cccc2n1
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1ccccc1
Product: COc1ccc2c(N=CC(O)(CC(C)(C)c3ccccc3)C(F)(F)F)cccc2n1

Procedure:
Analogously to Example 13, 200 mg of 2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentanal and 122 mg of 5-amino-2-methoxyquinoline are converted into 190 mg of product.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]([Si](C)(C)C)([F:22])[F:21].[O:27]=[C:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1>O1CCCC1>[OH:27][C:28]1([C:20]([F:22])([F:21])[F:19])[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Tetrabutylammonium fluoride (50 mg, 1M solution in tetrahydrofuran) was added to an ice-cooled solution of (trifluoromethyl)trimethylsilane (2.1 g, 15 mmol) and tert-butyl 4-oxo-1-piperidinecarboxylate (2 g, 10 mmol) in tetrahydrofuran (20 ml), and the reaction stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure, the residue suspended in ethyl acetate, hydrochloric acid (20 ml, 1N) was added, the mixture stirred for an hour, and then neutralised using sodium bicarbonate. The solution was washed with water, then brine, dried (MgSO4) and evaporated under reduced pressure to give a gum. This was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol (100:0 to 98:2) to afford the title compound, 1.94 g.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][C:7](Cl)=[O:8])[S:3][C:2]1=[O:10].[NH2:11][CH:12]1[C:19](=[O:20])[N:18]2[CH:13]1[S:14][CH2:15][C:16]([CH3:29])=[C:17]2[C:21]([O:23]CC(Cl)(Cl)Cl)=[O:22].C(N(CC)CC)C>C(Cl)(Cl)Cl.C(OCC)(=O)C>[C:21]([C:17]1[N:18]2[CH:13]([S:14][CH2:15][C:16]=1[CH3:29])[CH:12]([NH:11][C:7](=[O:8])[CH2:6][C:4]1[S:3][C:2](=[O:10])[S:1][CH:5]=1)[C:19]2=[O:20])([OH:23])=[O:22]
Reactant: O=C(Cl)Cc1csc(=O)s1
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)C2SC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(=O)s3)C2SC1
Temperature: -10 °C
Reaction time: 24 h
Yield: 14.1 %

Procedure:
A solution of (1,3-dithiol-2-on-4-yl)-acetyl chloride (13.2 g.) in chloroform (110 cc.) is added to a solution of 7-amino-3-methyl-8-oxo-2-(2,2,2-trichloroethoxycarbonyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (23 g.) and triethylamine (9.5 cc.) in chloroform (300 cc.), maintained at -10° C., over the course of one hour. The reagents are left in contact for 24 hours at a temperature of between 0° and 10° C., and the chloroform is then driven off under reduced pressure (20 mm.Hg). The residue is taken up in ethyl acetate (one liter) and the solution is washed first with an 0.1 N hydrochloric acid solution (250 cc.), then with a saturated aqueous sodium bicarbonate solution (250 cc.) and finally twice with water (250 cc.). The organic phase is dried over magnesium sulphate, treated with decolourising charcoal and filtered. The filtrate is concentrated under reduced pressure (20 mm.Hg) to a volume of 100 cc. and then added to isopropyl ether (one liter). The product, 3-methyl-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-2-(2,2,2-trichloroethoxycarbonyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (27 g.) precipitates and is filtered off. This product (17 g.) is dissolved in dimethylformamide (120 cc.) and acetic acid (35 cc.). The mixture is cooled in an ice bath, zinc powder (20.8 g.) is added and the mixture is stirred for 31/2 hours. The reaction mixture is then filtered; ethyl acetate (400 cc.) is added to the filtrate and the mixture is washed twice with water (a total of 400 cc.). The organic phase is extracted three times with a saturated sodium bicarbonate solution (200 cc.). The alkaline solution is acidified to pH 2.5 by adding 4 N hydrochloric acid in the presence of ethyl acetate (400 cc.). After decanting the organic phase, the aqueous phase is extracted twice with ethyl acetate (a total of 200 cc.); the organic extracts are combined, washed twice with water (a total of 200 cc.), dried over magnesium sulphate, treated with decolourising charcoal and filtered. The filtrate is concentrated to dryness under reduced pressure (20 mm.Hg). The residue obtained is recrystallised from a mixture of acetone and petroleum ether (100 cc.) to give 2-carboxy-3-methyl-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene (3.5 g.).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br)([O-:3])=[O:2].Cl.[CH3:13][O:14][C:15](=[O:18])[CH2:16][NH2:17].CCN(C(C)C)C(C)C.O>CN(C=O)C>[CH3:13][O:14][C:15](=[O:18])[CH2:16][NH:17][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: COC(=O)CN
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)CNCc1ccccc1[N+](=O)[O-]
Yield: 73.7 %

Procedure:
To a solution of 2-nitrobenzyl bromide (1.0 g, 4.63 mmol) and glycine methyl ester hydrochloride (868 mg, 6.94 mmol) in dry DMF (10 mL), was added DIPEA (2.42 mL, 13.89 mmol) under nitrogen atmosphere. The reaction mixture was stirred at. r.t. overnight. After completion of the reaction as confirmed by TLC, water (50 mL) was added to the reaction mixture. The crude product was extracted with ethyl acetate (20 mL). The aqueous layer was washed with ethyl acetate (2×10 mL), The combined organic extract was dried over Na2SO4 and the solvents were removed in vacuo to afford the crude compound, which was purified by column chromatography (silica gel, 1:9 EtOAc:Pet Ether) to afford pure (2-nitro-benzylamino)-acetic acid methyl ester (765 mg 73%) as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:38][C:11]3[C:12](=[O:37])[N:13]([CH2:16][C:17]4[N:22]=[C:21]([O:23][CH:24]5[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]5)[CH:20]=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1>C(Cl)Cl.C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:38][C:11]3[C:12](=[O:37])[N:13]([CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([O:23][CH:24]5[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]5)[N:22]=4)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(Cn3ncc4cc(-c5ccc(Cl)cc5)sc4c3=O)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=c1c2sc(-c3ccc(Cl)cc3)cc2cnn1Cc1cccc(OC2CCNCC2)n1
Reaction time: 1 h

Procedure:
tert-butyl 4-[(6-{[2-(4-chlorophenyl)-7-oxothieno[2,3-d]pyridazin-6(7H)-yl]methyl}pyridin-2-yl)oxy]piperidine-1-carboxylate (0.22 g, 0.39 mmol) was dissolved in DCM/TFA 5:1 (6 mL) and stirred for 1 hour. The reaction mixture was co-evaporated with toluene, dissolved in DCM (20 mL) and washed with sat. NaHCO3(aq.)/water 1:1 (30 mL). The resulting water phase was extracted with DCM (3×20 mL). The combined organics were dried over a phase separator and concentrated in vacuo to give the product. Yield: 0.16 g (89%). MS (ESI+) 453.06 (M+1H+).