Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C([Li])CCC.CN([CH:27]=[O:28])C1C=CC=CC=1>CCOCC>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:27]=[O:28])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CN(C=O)c1ccccc1
Reactant: Brc1ccc(C2=CCCCC2)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1ccc(C2=CCCCC2)cc1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7 g of p-(1-cyclohexenyl)-phenylbromide in 100 ml of absolute ether there is added at 5° C, while stirring and in an atmosphere of nitrogen, 50 ml of a solution of 4.3 g of n-butyl-lithium in absolute ether. The mixture is allowed to reach room temperature, stirred for 30 minutes at 30° C, then cooled to 20° C and a solution of 4 g of N-methyl-N-formyl-aniline in 50 ml of absolute ether is added dropwise, when the internal temperature rises to 30° C. After the reaction mixture has been allowed to continue to react for 30 minutes at room temperature, it is poured into 100 ml of ice cold 2N hydrochloric acid and extracted with ether. The ether layers are washed with water, dried over sodium sulphate and evaporated in vacuo. The residue is distilled under a high vacuum and yields the p-(1-cyclohexenyl)-benzaldehyde having a boiling point of 110°-120° C (0.2 mm Hg).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]12)=[O:4].C(N(CC)CC)C.[SH:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1>C(Cl)Cl>[N:32]1[CH:33]=[CH:34][C:29]([S:28][CH2:2][C:3]([NH:5][CH:6]2[C:19](=[O:20])[N:8]3[CH:9]([C:14]4[NH:18][N:17]=[N:16][N:15]=4)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]23)=[O:4])=[CH:30][CH:31]=1
Reactant: CC1(C)S[C@@H]2C(NC(=O)CBr)C(=O)N2C1c1nnn[nH]1
Reactant: Sc1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)S[C@@H]2C(NC(=O)CSc3ccncc3)C(=O)N2C1c1nnn[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
To a stirred suspension of 1.0 g (0.0028 mole) of 6-(2-bromoacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam in 25 ml of methylene chloride is added 0.28 g (0.0028 mole) of triethylamine. The mixture is stirred at ambient temperature until a clear solution is obtained, and then 0.39 g of 4-mercaptopyridine is added. Stirring is continued for a further 4 hours at ambient temperature, and then the solid which has precipitated is filtered off. It is washed with methylene chloride, followed by ether, to give 0.68 g (78% yield) of 6(2-[4-pyridylthio]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam, m.p. 120° C. (dec.). The infrared spectrum of the product (KBr disc) shows absorption bands at 1790 cm-1 (β-lactam), 1670 cm-1 (amide II). The NMR spectrum (DMSO-d6) show absorption bands at 9.0-7.0 ppm (multiplet, pyridine hydrogens), 5.9-5.5 ppm (multiplet, C-5 and C-6 hydrogen), 4.0 ppm (singlet, methylene hydrogens), 1.7 ppm (singlet, C-2 methyl hydrogens) and 1.1 (singlet, C-2 methyl hydrogens).
Reaction SMILES: [C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][C:11]([CH2:19][CH2:20][OH:21])([CH2:15][C:16]([CH3:18])=[CH2:17])[C:12](=[O:14])[N:13]=1.OS(O)(=O)=O>C(Cl)Cl>[C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][C:11]2([CH2:19][CH2:20][O:21][C:16]([CH3:18])([CH3:17])[CH2:15]2)[C:12](=[O:14])[N:13]=1
Reactant: C=C(C)CC1(CCO)SC(N[C@H]2C[C@@H]3CC[C@H]2C3)=NC1=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC1(C)CC2(CCO1)SC(N[C@H]1C[C@@H]3CC[C@H]1C3)=NC2=O
Reaction time: 16 h

Procedure:
To a solution of 2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-(2-hydroxyethyl)-5-(2-methylallyl)thiazol-4(5H)-one (120 mg) in CH2Cl2 (3 mL) was added concentrated H2SO4 (200 uL). The resulting mixture was stirred for 16 h, then concentrated in vacuo. The residue was treated with sat'd NaH2PO4 and extracted with CH2Cl2. The organic layer was washed with sat'd NH4Cl, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (4:1; Hexane:EtOAc) to give the title compound as solid. MS (ES+): 309 (M+H)+. The diastereomers were separated using standard HPLC methods described within this text.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:54]([O:56]CC)=[O:55])[CH2:11][CH:10]1/[CH:12]=[CH:13]/[C:14]1[C:15]([CH3:53])([CH3:52])[C@H:16]2[C@:29]([CH3:32])([CH2:30][CH:31]=1)[C@@H:28]1[C@:19]([CH3:51])([C@@:20]3([CH3:50])[C@H:25]([CH2:26][CH2:27]1)[C@H:24]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:23]1([NH:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][S:45](=[O:49])(=[O:48])[CH2:44][CH2:43]1)[CH2:22][CH2:21]3)[CH2:18][CH2:17]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1.CO>[C:1]([O:5][C:6]([NH:8][C:9]1([C:54]([OH:56])=[O:55])[CH2:11][CH:10]1/[CH:12]=[CH:13]/[C:14]1[C:15]([CH3:53])([CH3:52])[C@H:16]2[C@:29]([CH3:32])([CH2:30][CH:31]=1)[C@@H:28]1[C@:19]([CH3:51])([C@@:20]3([CH3:50])[C@H:25]([CH2:26][CH2:27]1)[C@H:24]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:23]1([NH:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][S:45](=[O:49])(=[O:48])[CH2:44][CH2:43]1)[CH2:22][CH2:21]3)[CH2:18][CH2:17]2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(/C=C/C6CC6(NC(=O)OC(C)(C)C)C(=O)OCC)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(/C=C/C6CC6(NC(=O)OC(C)(C)C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.4 %

Procedure:
To a solution of ethyl 1-((tert-butoxycarbonyl)amino)-2-((E)-2-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)vinyl)cyclopropanecarboxylate (12 mg, 0.015 mmol) in dioxane (2 mL) and MeOH (1 mL) was added 1N NaOH (1 mL, 1 mmol). The mixture was stirred at 25° C. for 2 h. The crude product was purified by prep HPLC (method 4) to give 1-((tert-butoxycarbonyl)amino)-2-((E)-2-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)vinyl)cyclopropanecarboxylic acid as a white solid (1 mg, 8.63%). MS: m/e 796.55 (M+H)+, 2.57 min (method 2). 1H NMR (400 MHz, METHANOL-d4) δ 7.37-5.41 (m, 2H), 5.36-5.10 (m, 1H), 4.73 (br. s., 1H), 4.57 (br. s., 1H), 3.19-2.97 (m, 8H), 2.80-2.62 (m, 4H), 2.58-2.41 (m, 1H), 2.36-1.78 (m, 7H), 1.72 (s, 3H), 1.69-1.21 (m, 25H), 1.16 (m, 6H), 1.09-1.00 (m, 6H), 0.98-0.82 (m, 6H).
Reaction SMILES: C(C1C=C(C=O)C(O)=C(C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)(C)C.Br[C:26]1[C:27]([OH:38])=[C:28]([CH:31]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:33]=1)[CH:29]=[O:30].[Cl:39][C:40]1[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[CH:42][C:41]=1B(O)O>>[C:34]([C:32]1[CH:31]=[C:28]([CH:29]=[O:30])[C:27]([OH:38])=[C:26]([C:41]2[CH:42]=[CH:43][C:44]([C:46]([F:49])([F:48])[F:47])=[CH:45][C:40]=2[Cl:39])[CH:33]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Agent: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(OC(F)(F)F)cc2)c1
Product: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(C(F)(F)F)cc2Cl)c1

Procedure:
5-(tert-Butyl)-2′-chloro-2-hydroxy-4′-(trifluoromethyl)-[1,1′-biphenyl]-3-carbaldehyde was prepared as a yellow oil using the procedure described in Intermediate 5 from 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde (Intermediate 4) and 2-chloro-4-(trifluoromethyl)phenylboronic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[N:13]1[C:17](=[O:18])[N:16]([CH2:19]O)[C:15](=[O:21])[O:14]1)([O-:3])=[O:2].S(Cl)([Cl:24])=O>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[N:13]1[C:17](=[O:18])[N:16]([CH2:19][Cl:24])[C:15](=[O:21])[O:14]1)([O-:3])=[O:2]
Reactant: O=c1on(-c2c([N+](=O)[O-])cccc2[N+](=O)[O-])c(=O)n1CO
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=c1on(-c2c([N+](=O)[O-])cccc2[N+](=O)[O-])c(=O)n1CCl

Procedure:
2-(2,6-Dinitrophenyl)-4-hydroxymethyl-1,2,4-oxadiazolidin-3,5-dione (0.03 mole) dissolved in chloroform (40 ml) and thionyl chloride (0.06 mole) dissolved in chloroform (10 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 2 hours. Aftr this time the reaction mixture is stripped of solvent under reduced pressure, leaving a residue. This residue is dissolved in toluene, and the toluene solution is stripped of solvent and unreacted starting materials to yield the desired product 2-(2,6-dinitrophenyl)-4-chloromethyl-1,2,4-oxadiazolidin-3,5-dione as the residue.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)=[N:6][NH:7][CH:8]=1)([O-])=O.[H][H]>CN(C=O)C.[Pd]>[NH:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[C:5]1[C:4]([NH2:1])=[CH:8][NH:7][N:6]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1c[nH]nc1-c1nc2ccccc2[nH]1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Yield: 27.5 %

Procedure:
A mixture of 2-(4-nitro-1H-pyrazol-3-yl)-1H-benzimidazole (1.34 g, 5.85 mmol) and 10% Pd/C (0.13 g) in DMF (200 ml) was subjected to an atmosphere of hydrogen at room temperature for 36 h. The reaction mixture was filtered through a plug of Celite and reduced in vacuo. The residue was partitioned between EtOAc and water and the organic portion dried (MgSO4), filtered and reduced in vacuo. The residue was azeotroped with toluene (3×150 ml) yielding 3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine as a purple solid (0.32 g, 26%). (LC/MS: Rt 0.97, [M+H]+ 199.62).
Reaction SMILES: [ClH:1].O[C:3]([CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25]([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[O:26])[CH2:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>C(O)(C)C>[ClH:1].[C:10]1([C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[C:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][C:25]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)=[O:26])[CH2:20][CH2:21]2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(CCCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1)c1ccc2ccccc2c1
Agent: Cl
Solvent: CC(C)O
Product: O=C(CCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1)c1ccc2ccccc2c1

Procedure:
A mixture of 17.6 g (0.038 mole) of 4-[4-(α-hydroxy-α-phenylbenzyl)piperidino]-1-(2-naphthyl)butan-1-one hydrochloride, 400 ml of concentrated HCl and 1500 ml of isopropyl alcohol is heated on a steam bath for 16 hours after which the solvent and excess acid are removed at reduced pressure. The remaining residue is recrystallized from isopropyl alcohol and ethyl acetate to give 4-[4-(diphenylmethylene)piperidino]-1-(2-naphthyl)butan-1-one hydrochloride.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH:4]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Br:16])[CH:10]=1)C(OC)=O.[OH-].[Na+]>CO>[Br:16][C:11]1[CH:10]=[C:9]([CH2:4][C:3]([OH:17])=[O:2])[CH:14]=[C:13]([Cl:15])[CH:12]=1
Reactant: COC(=O)C(C(=O)OC)c1cc(Cl)cc(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1cc(Cl)cc(Br)c1

Procedure:
2-(3-Bromo-5-chloro-phenyl)-malonic acid dimethyl ester (19 g, 59 mmol) in MeOH (500 mL) was treated with 1N aqueous NaOH (237 mL, 237 mmol) at 50° C. for 1.5 hours. The mixture was concentrated, and the residue was acidified and extracted twice with EtOAc. The combined organic layers were dried, filtered, and concentrated to give the title compound.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[O:4]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>ClCCl.N1C=CC=CC=1>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:9][CH2:8][CH:5]2[O:4][CH:3]([CH2:2][O:1][S:16]([C:13]3[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=3)(=[O:18])=[O:17])[CH2:7][CH2:6]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCC(CO)O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCC(COS(=O)(=O)c3ccc(C)cc3)O2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
34.0 g (261 mmol) of 2,5-bis(hydroxymethyl)tetrahydrofuran are dissolved in 260 ml of dichloromethane. A solution of 99.0 g (521 mmol) of p-toluenesulfonyl chloride in 52 ml of pyridine and 130 ml of dichloromethane is added dropwise thereto. After stirring at room temperature for 24 hours, the precipitate is filtered off with suction and washed with dichloromethane. The filtrate and the washing phases are combined, washed with dilute hydrochloric acid and then with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated to dryness. The crude product is recrystallized from ethanol.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1>CN(C=O)C>[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][N:2]([CH3:3])[CH3:1])=[CH:7][CH:6]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CNC
Solvent: CN(C)C=O
Product: CN(C)Cc1ccc(Cl)cc1

Procedure:
Referring to the problem (i), the present inventors have used safer and less expensive alkali metal hydroxide instead of sodium hydride; and they also found that dimethylamine resulting from the decomposition of DMF sometimes reacts with 4-chlorobenzyl bromide to give (4-chlorobenzyl)dimethylamine as a by-product and that a solvent containing dimethylsulfoxide can be used in place of DMF for avoiding the production of the (4-chlorobenzyl)dimethylamine to afford the vinyl imidazole derivatives (I) in high yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][CH:24]1[CH2:27][C:26](F)(F)[C:25]1([F:31])[F:30]>CN(C)C=O.O.C(OCC)C>[F:30][C:25]1([F:31])[C:26]([O:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6])=[CH:27][C:24]1=[CH2:23]
Reactant: FC1(F)CC(CCl)C1(F)F
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=C1C=C(Oc2cc(C(=O)OC)ccc2OC)C1(F)F
Temperature: 75 °C
Reaction time: 6 h

Procedure:
A stirred solution of methyl 3-hydroxy-4-methoxybenzoate (1.72 g), potassium iodide (0.1 g), and potassium carbonate (1.55 g) in dimethylformamide (50 mL) is treated with 1-chloromethyl-2,2,3,3-tetrafluorocyclobutane (2.0 g), and the solution is stirred at 70-80° C. for 6 hours. After cooling, the reaction mixture is diluted with water (100 mL) and extracted with ethyl acetate (2×50 mL). The organic extracts are combined, dried over magnesium sulfate and concentrated, to give a golden oil. The oil is subjected to flash chromatography, using diethyl ether as eluent, to give methyl 3-(4,4-difluoro-3-methylenecyclobut-1-enyloxy)-4-methoxybenzoate, m.p. 60-62° C. [Elemental analysis: C,59.5; H,4.3%; calculated: C,52.2; H,4.4%].
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:15]([NH:24][C:25](=[O:28])[CH2:26][OH:27])[C:14](Br)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:30]([C:32]1[O:33][CH:34]=[CH:35][C:36]=1B1OC(C)(C)C(C)(C)O1)=[O:31].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O.C(OCC)(=O)C>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:15]([NH:24][C:25](=[O:28])[CH2:26][OH:27])[C:14]([C:36]3[CH:35]=[CH:34][O:33][C:32]=3[CH:30]=[O:31])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1NC(=O)CO
Reactant: CC1(C)OB(c2ccoc2C=O)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2C=O)c1NC(=O)CO
Temperature: 140 °C
Yield: 99.9 %

Procedure:
A mixture of tert-butyl 6-(benzenesulfonylmethyl)-3-bromo-2-(2-hydroxyacetylamino)benzoate (Intermediate 36, 0.165 g), 2-formylfuran-3-boronic acid pinacol ester (0.091 g), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride DCM complex (0.028 g) and cesium carbonate (0.311 g) in THF (4.3 mL) and water (0.7 mL) were sealed, under nitrogen, in a microwave vial and heated in the microwave at 140° C. for 10 minutes. After cooling, the mixture was diluted with ethyl acetate and water and the organic layer was separated, washed with brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give tert-butyl 6-(benzenesulfonylmethyl)-3-(2-formylfuran-3-yl)-2-(2-hydroxyacetylamino)-benzoate (0.17 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.IC.[C:11](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH3:11])[CH:7]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(Br)ccc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.7 %

Procedure:
To a solution of 5-bromopyridin-2(1H)-one (0.18 g, 1.03 mmol) in DMF (5 mL) was added iodomethane (0.2 mL, 3.1 mmol) and potassium carbonate (0.8 g, 6.2 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated under reduced pressure, the residue dissolved in ethyl acetate (200 mL), washed with water (50 mL) and brine solution. The organic layers were combined and dried over sodium sulfate, filtered and concentrated under vacuum to afford 5-bromo-1-methylpyridin-2(1H)-one [Albrecht, US Patent Application Publication No. 2009/0318436] as yellow solid (40 mg, 21%). 1H NMR (DMSO-d6): δ 8.01 (d, 1H), 7.49 (dd, 1H), 6.34 (d, 1H), 3.38 (s, 3H); LC-MS m/z calculated for [M+H]+ 187.96. found 188.2.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:15][NH2:16]>>[CH3:15][NH:16][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: CN
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Product: CNc1ncc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
1.6 g (7.4 mmol) of methyl 6-chloro-5-nitronicotinate (see Bernie et al., J. Chem. Soc. 1951, 2590) were stirred in 20 mL of 40% aqueous methylamine solution at room temperature for 30 minutes. The reaction mixture was then diluted with ice water, the yellow precipitate formed was filtered off and dried. Yield: 1.2 g (80% of theory); Rf value: 0.66 (silica gel; ethyl acetate/ethanol/glacial acetic acid=90:5:5).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:35])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[CH:33]=[CH:32][CH:31]=[N:30]2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:35])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N:29]4[CH:33]=[CH:32][CH:31]=[N:30]4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cccn3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3cccn3)c1)=N2

Procedure:
The title compound was prepared from {5-methyl-2-[3-oxo-3-(3-pyrazol-1-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M54) (0.36 g, 0.72 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (182 mg, 66%).
Reaction SMILES: C(OC([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH3:28])=[CH:21][CH:20]=3)=[CH:18][C:13]=2[CH:12]=[C:11]([C:29]([O:31][CH3:32])=[O:30])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[OH-].[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH2:26]([O:25][C:22]1[CH:21]=[CH:20][C:19]([C:17]2[CH:16]=[CH:15][C:14]3[NH:8][CH2:9][CH2:10][C:11]([C:29]([O:31][CH3:32])=[O:30])=[CH:12][C:13]=3[CH:18]=2)=[CH:24][CH:23]=1)[CH2:27][CH3:28]
Reactant: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
In a mixture of water:ethanol toluene (1:1:10, v/v. 42.0 ml) were dissolved 4-propoxyphenyl borate (746 mg) and methyl 7-bromo-1-(t-butoxycarbonyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1320 mg). To the solution was added potassium carbonate (1145 mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (160 mg), and the mixture was heated to reflux under argon atmosphere for 14.5 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (75 g, hexane:ethyl acetate=3:1) to give methyl 1-(t-butoxycarbonyl)-7-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate as yellow amorphous. The obtained methyl 1-(t-butoxycarbonyl)-7-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate was dissolved in ethyl acetate (80 ml). To the solution was added 6N hydrochloric acid (20 ml) at room temperature, and the mixture was stirred at 100° C. for 30 minutes and neutralized with 1N sodium hydroxide and saturated sodium hydrogen carbonate solution. The separated organic layer was washed with saturated sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give methyl 7-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (947 mg) as yellow crystals. The mother liquor was concentrated, and the residue was purified with silica gel column chromatography (15 g, hexane:ethyl acetate=4:1) to give desired product (147 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:9]=2)[C:4]=1[C:21](O)=[O:22].[C:24]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CCOCC>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:9]=2)[C:4]=1[C:21]([N:34]1[CH2:33][CH2:32][N:31]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:36][CH2:35]1)=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cccc(-c2ccc3c(C(=O)O)c(OC)ccc3c2)c1
Solvent: CCOCC
Product: COc1cccc(-c2ccc3c(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)c(OC)ccc3c2)c1

Procedure:
The compound was prepared by reaction of 2-methoxy-6-(3-methoxyphenyl)-1-naphthoic acid (300 mg, 0.97 mmol, 1 eq) with Boc-piperazine (1 eq) according to method D. Characterization of the compound was not effected. The raw product was directly employed for ether cleavage.