Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)=O.[OH-].[K+].[C:20]([O:24][C:25](=[O:34])[CH2:26][C:27](OC(C)(C)C)=[O:28])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([C:26]1[C:27]([OH:28])=[N:1][C:2]2[C:3]([C:9]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)=[CH:4][C:5]([Cl:8])=[CH:6][CH:7]=2)=[O:34])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Reactant: Nc1ccc(Cl)cc1C(=O)c1cccc(Cl)c1
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)c1c(O)nc2ccc(Cl)cc2c1-c1cccc(Cl)c1
Temperature: 110 °C
Reaction time: 16 h
Yield: 50.8 %

Procedure:
A mixture of (2-amino-5-chloro-phenyl)-(3-chloro-phenyl)-methanone (550 mg, 2.07 mmol), KOH (58 mg, 1.03 mmol) and malonic acid di-tert-butyl ester (0.7 ml, 3.1 mmol) was placed in a sealed tube, and the resulting reaction mixture was stirred at 110° C. for 16 h. After cooling, the reaction mixture was purified by flash column chromatography (20-30% ethyl acetate in hexane) to give 6-chloro-4-(3-chloro-phenyl)-2-hydroxy-quinoline-3-carboxylic acid tert-butyl ester (410 mg, 51%) as an off white solid. LC-MS (ESI): 390 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19](Cl)[N:18]=1.C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:19]2[CH:20]=[N:21][CH:22]=[C:17]([Cl:16])[N:18]=2)[CH:10]([CH2:14][CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC1CN(Cc2ccccc2)CCN1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCC1CN(Cc2ccccc2)CCN1c1cncc(Cl)n1

Procedure:
The title compound was prepared according to the procedure of example 39, step 2, starting from the product obtained in step 1 above (4.60 g, 22.5 mmol), 2,6-dichloropyrazine (3.90 g, 26.2 mmol) and K2CO3 (6.22 g, 45.0 mmol). Yield: 6.15 g (86%). MS m/z 316/318 (M)+ (35Cl/37Cl-isotope pattern). HRMS m/z calcd for C17H21ClN4 (M)+ 316.1455, found 316.1455.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][C:4](=[CH:7][N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]1=[O:16].[C:17]([C:21]1[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([C:2]2([CH3:1])[CH2:6][CH2:5][C:4](=[CH:7][N:8]([CH3:15])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:3]2=[O:16])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: CC1CCC(=CN(C)c2ccccc2)C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CN(C=C1CCC(C)(c2ccc(C(C)(C)C)cc2)C1=O)c1ccccc1
Temperature: 40 °C
Reaction time: 0.02 h
Yield: 66.8 %

Procedure:
An oven dried Schlenk tube equipped with a rubber septum was cooled under an argon urge. The septum was removed and the tube was charged with palladium acetate (5.6 mg, 0.025 mmol, 5 mol % Pd), (±)-BINAP (23.3 mg, 0.0375 mmol, 7.5 mol %) and 2-methyl-5-(N-methyl-anilinomethylene)-cyclopentanone (108 mg, 0.5 mmol). Toluene (2 mL) was added and the mixture was stirred for 1 min at 40° C. 4-t-Butylbromobenzene (0.17 mL, 1.0 mmol) and sodium t-butoxide (96 mg, 1.0 mmol) were added to the tube, the tube was capped with the septum, purged with argon, and additional toluene (4 mL) was added through the septum. The mixture was heated to 100° C. with stirring until the starting ketone had been completely consumed as judged by GC analysis. The mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride (10 mL) and diluted with ether (20 mL). The mixture was poured into a separatory funnel and the layers were separated. The aqueous layer was extracted with ether (20 mL), and the combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 116 mg (67%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH2:7])[CH3:2].[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH:7][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][Cl:11])[CH3:2]
Reactant: CCOC(CCN)OCC
Reactant: O=C(Cl)CCCCCCl
Product: CCOC(CCNC(=O)CCCCCCl)OCC

Procedure:
This compound was prepared from [3,3-bis(ethyloxy)propyl]amine and 6-chlorohexanoyl chloride using methods similar to Example 669: step 1 to provide a yellow viscous oil: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.09 Hz, 6 H), 1.28-1.40 (m, 2 H), 1.44-1.56 (m, 2 H), 1.59-1.75 (m, 4 H), 2.04 (t, J=7.23 Hz, 2 H), 3.01-3.09 (m, 2 H), 3.41 (dq, J=9.55, 7.07 Hz, 2 H), 3.50-3.64 (m, 4 H), 4.48 (t, J=5.69 Hz, 1 H), 7.74 (t, J=5.33 Hz, 1 H); ES+ MS: 302 (M+Na+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:17]=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:20]([F:27])([F:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].ClCCl.S([O-])(O)(=O)=O.[K+]>C1COCC1.[Zn]>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:18])[C:20]([F:27])([F:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccccc1
Reactant: CCOC(=O)C(F)(F)Br
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Zn]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 27.1 %

Procedure:
To a solution of the target compound in step (2) (7.16 g, 28.5 mmol) in dichloromethane (85 mL) were added successively triethylamine (15.8 mL, 113.9 mmol) and a solution of sulfur trioxidepyridine complex (18.1 g, 113.9 mmol) in dimethylsulfoxide (85 mL). The resulting mixture was stirred at room temperature for 15 min, poured into a mixture of ice and saturated brine (300 mL), and then extracted with cold ether. The organic layer was washed successively with cold 10% aqueous citric acid solution and cold saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated and hexane was added to the obtained residue to suspend same. Insolubles were collected by filtration to give 6.41 g (90%) of N-tert-butoxycarbonylphenylalaninal. To a suspension of zinc powder (5.59 g, 85.5 mmol) in THF (1 mL) was added dropwise a solution of the above-mentioned N-tert-butoxycarbonylphenylalaninal (6.41 g, 25.7 mmol) and ethyl bromodifluoroacetate (11.1 mL, 85.5 mmol) in THF (16 mL) with ultrasonication. After 3 hr of ultrasonication, dichloromethane (200 mL) and 1N aqueous potassium hydrogensulfate solution (100 mL) were added. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was separated and purified by silica gel column chromatography (hexane-ethyl acetate, 75:25) to give 2.60 g (27%) of ethyl 4(S)-[(tert-butoxycarbonyl)amino]-2,2-difluoro-3(R)-hydroxy-5-phenylpentanoate as colorless crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]#[N:5].[NH:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[H-].[Na+]>>[C:4]([CH2:3][CH2:2][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)#[N:5]
Reactant: N#CCCCl
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Product: N#CCCn1ccnc1

Procedure:
Using 2.35 ml of 3-chloropropionitrile, 2.0 g of imidazole and 1.3 g of sodium hydride (60%), 3.2 g of 1-(2-cyanoethyl)imidazole was obtained by the same manner as the procedure of Reference Example 2.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Br.[C:6]([O:10][C:11]([NH:13][C:14]([CH3:27])([CH3:26])[CH2:15][C:16]1[NH:20][N:19]=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:17]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7].O.NN.C(O)(=O)C(O)=O.C(NN)CC.CC(C)([O-])C.[Na+]>C(O)C>[C:6]([O:10][C:11]([NH:13][C:14]([CH3:26])([CH3:27])[CH2:15][C:16]1[N:20]([CH2:4][CH2:3][O:2][CH3:1])[N:19]=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:17]=1)=[O:12])([CH3:8])([CH3:9])[CH3:7]
Reactant: CCOC(=O)c1cc(CC(C)(C)NC(=O)OC(C)(C)C)[nH]n1
Reactant: COCCBr
Agent: CC(C)(C)[O-]
Agent: CCCNN
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(CC(C)(C)NC(=O)OC(C)(C)C)n(CCOC)n1

Procedure:
Under a nitrogen atmosphere, 2-bromoethyl methyl ether (19.7 g, 142 mmol) was added to a mixture of ethyl 5-{2-[(tert-butoxycarbonyl)amino]-2-methylpropyl}-1H-pyrazole-3-carboxylate (40 g, 129 mmol, prepared according to the method of Example 64 Part A using hydrazine hydrate in lieu of propylhydrazine oxalate) and sodium tert-butoxide (12.4 g, 129 mmol) in ethanol (128 mL). The reaction mixture was heated at reflux for 5 hours; an additional 0.2 equivalents of both sodium tert-butoxide and 2-bromoethyl methyl ether were added, and the reaction mixture was heated at reflux for an additional 21 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water and tert-butyl methyl ether. The aqueous layer was extracted with tert-butyl methyl ether (×3). The combined organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 46.0 g of IFC (65 cartridge eluting with 1:1 tert-butyl methyl ether:hexanes) to provide a pale yellow oil. This material was triturated with 40 mL of 1:1 tert-butyl methyl ether:hexanes, seeded with product from an earlier run, stirred until a white solid formed, and then concentrated under reduced pressure to provide 24.83 g of ethyl 5-{2-[(tert-butoxycarbonyl)amino]-2-methylpropyl}-1-(2-methoxyethyl)-1H-pyrazole-3-carboxylate as a white solid, mp 92-93° C. MS (APCI) m/z 370 (M+H)+; Anal. Cacld for C18H31 N3O5: C, 58.52; H, 8.46; N, 11.37. Found: C, 58.65; H. 8.69; N, 11.47.
Reaction SMILES: [CH2:1]1[O:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2]1.[C:10]([OH:14])(=[O:13])[CH:11]=[O:12]>>[CH2:1]1[O:9][C:4]2[CH:5]=[CH:6][C:7]([CH:11]([OH:12])[C:10]([OH:14])=[O:13])=[CH:8][C:3]=2[O:2]1
Reactant: c1ccc2c(c1)OCO2
Reactant: O=CC(=O)O
Product: O=C(O)C(O)c1ccc2c(c1)OCO2

Procedure:
Addition reaction step in which 1,2-methylenedioxy-benzene and glyoxylic acid are reacted in the presence of a strong acid to form 3,4-methylenedioxymandelic acid.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[S:7][C:8]([C:14]([OH:16])=O)=[CH:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:19][O:20][C:21](=[O:30])[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([NH2:29])[CH:23]=1.N1C=CC=CC=1>O=S(Cl)Cl.C1COCC1>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[S:7][C:8]([C:14]([NH:29][C:24]4[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=4[Cl:28])[C:21]([O:20][CH3:19])=[O:30])=[O:16])=[CH:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc(Cl)c(N)c1
Reactant: O=C(O)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Cl)c(NC(=O)c2cc3c(s2)-c2ccc(Br)cc2OCC3)c1
Reaction time: 8 h
Yield: 86.7 %

Procedure:
A solution of 8-bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-2-carboxylic acid (25 g, 0.077 mol) in 200 mL of SOCl2 was heated at 80° C. for 3 h. Concentration gave the crude acid chloride. A suspension of the crude acid chloride (ca. 0.077 mol) from above in 1000 mL of THF at 0° C. was treated with a solution of 3-amino-4-chloro-benzoic acid methyl ester (15.7 g, 1.1 eq)/pyridine (30 mL) in 100 mL of THF. The mixture was allowed to reach room temperature overnight. The reaction solution was concentrated to ½ volume, diluted with water. The resulting precipitate was filtered, washed with water and Et2O. The filter cake was dried to a constant weight under vacuum to give methyl 3-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoate (32.9 g, yield 87%). LC-MS: (ESI, m/z)=494 [M+1]+
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C(COC)OC.[Zn].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:18]1([C:17]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[O:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Reactant: O=C(Cl)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Zn]
Solvent: O
Solvent: COCCOC
Product: COC=C(C(=O)OC)c1ccccc1CC(=O)c1ccccc1
Temperature: 50 °C
Yield: 29 %

Procedure:
A solution of 5 g (17.5 mmol) of methyl α-(2-bromomethylphenyl)-β-methoxyacrylate and 2.5 g (17.8 mmol) of benzoyl chloride in 50 ml of dimethoxyethane is added dropwise to 2.3 g (0.035 mol) of zinc powder and 600 mg (0.9 mmol) of Pd(Ph3P)2Cl2 under nitrogen and the mixture is then heated at 50° C. for 30 minutes. Water is added, the mixture is extracted with ethyl acetate and the organic phase is dried and evaporated down. The residue is chromatographed over silica gel using hexane/ethyl acetate. 1.6 g of compound No. 1 (Table 1) are obtained as a pale yellow solid of melting point 97°-99° C. Yield: 29%.
Reaction SMILES: CC(C)([O-])C.[K+].C[C:8]1(O)C=C[CH:11]=[N:10][CH2:9]1.CI.O.[CH2:18]1[CH2:22][O:21][CH2:20][CH2:19]1>>[CH3:20][O:21][C:22]1[CH:18]=[CH:19][C:9]([CH3:8])=[N:10][CH:11]=1
Reactant: C1CCOC1
Reactant: CC1(O)C=CC=NC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
Potassium tert-butoxide (5.4 g, 48 mmol) was added to 3-methyl-pyridin-3-ol (5 g, 45.87 mmol) in THF (200 mL) at 0° C. The mixture was stirred at room temperature for 30 min. MeI (3.2 mL, 48 mmol) was added dropwise at 0° C. and stirring was continued at room temperature for 8 h. Water was added and the mixture was evaporated to half its volume and extracted with EtOAc. The organic layer was washed with brine and water, dried over anhydrous MgSO4, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography to give 5-methoxy-2-methyl-pyridine (4.8 g, 85%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH2:21][C:22]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][N:26]2[C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([O:37][CH3:38])=[O:36].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.C(OCC)(=O)C>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][NH:21][C:22]2[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]3[C:23]=2[CH:24]=[N:25][N:26]3[C:32]2[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=2)[C:35]([O:37][CH3:38])=[O:36])[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Reactant: COC(=O)c1cccc(-n2ncc3c(N)cc(C)cc32)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-n2ncc3c(NCC(O)(CC(C)(C)c4cc(F)ccc4OC)C(F)(F)F)cc(C)cc32)c1
Temperature: 80 °C
Yield: 43.6 %

Procedure:
2-{2-[5-Fluoro-2-(methyloxy)phenyl]-2-methylpropyl}-2-(trifluoromethyl)oxirane (which may be prepared according to WO 04/063163, 96 mg, 0.33 mmol), methyl 3-(4-amino-6-methyl-1H-indazol-1-yl)benzoate (85 mg, 0.3 mmol) and ytterbium trifluoromethanesulfonate (28 mg, 0.045 mmol) were stirred in acetonitrile (0.4 mL) with some molecular sieves. The resulting mixture was then heated to reflux (80° C.) overnight and then allowed to cool to room temperature. The mixture was poured into ethyl acetate (5 mL) and washed successively with saturated aqueous sodium bicarbonate and aqueous brine. The organic phase was separated, dried over anhydrous sodium sulphate and then concentrated and the residue purified by silica gel column chromatography (10% ethyl acetate in cyclohexane) to give the title compound as a white solid (75 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[C:17]([OH:19])[C:16]([O:20][CH3:21])=[CH:15][C:14]=2[CH:22]([CH2:26][CH3:27])[C:23](=O)[CH3:24])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:28][NH2:29]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:13]3[CH:18]=[C:17]([OH:19])[C:16]([O:20][CH3:21])=[CH:15][C:14]=3[CH:22]([CH2:26][CH3:27])[C:23]([CH3:24])=[N:29][N:28]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCC(C(C)=O)c1cc(OC)c(O)cc1C(=O)c1ccc(OC)c(OC)c1
Reactant: NN
Product: CCC1C(C)=NN=C(c2ccc(OC)c(OC)c2)c2cc(O)c(OC)cc21

Procedure:
Annulation of 3-{2-[(3,4-dimethoxy-phenyl)carbonyl]-4-hydroxy-5-methoxyphenyl}pentan-2-one by reaction with hydrazine to yield 1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7-methoxy-8-hydroxy-5H-2,3-benzodiazepine.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][C:17](N(OC)C)=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1.I[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][C:17]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Ic1ccncc1
Reactant: CON(C)C(=O)CC1c2ccccc2CCc2ccccc21
Product: O=C(CC1c2ccccc2CCc2ccccc21)c1ccncc1

Procedure:
In analogy to example 55, step 2, from 2-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-N-methoxy-N-methyl-acetamide and 4-iodopyridine was prepared the title compound as a white solid, MS (ESI+): m/z=314.1 ([M+H]+).
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:17]CC3C=CC(OC)=CC=3)=[CH:16][C:11]=2[O:10][CH:9]=1)[C:4]([O:6][CH3:7])=[O:5]>[Pd].CO>[OH:1][CH2:2][CH:3]([CH:8]1[C:12]2[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:11]=2[O:10][CH2:9]1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(CO)c1coc2cc(OCc3ccc(OC)cc3)ccc12
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(CO)C1COc2cc(O)ccc21
Reaction time: 21 h
Yield: 96.4 %

Procedure:
To a mixture of methyl 3-hydroxy-2-(6-((4-methoxybenzyl)oxy)-1-benzofuran-3-yl)propanoate (86.9 mg) and MeOH (2.4 mL) was added 10% palladium on carbon (15 mg). The mixture was hydrogenated under balloon pressure for 21 h. The catalyst was removed by filtration and concentrated to give the title compound (56.0 mg).
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[CH:11]([OH:21])[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)([CH3:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[C:11](=[O:21])[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)([CH3:2])[CH3:3]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1C(O)CCCc1ccccn1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1C(=O)CCCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
To a solution of 1-((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)-4-(pyridin-2-yl)butan-1-ol (177 mg, 0.61 mmol) in methylene chloride (2.0 mL) were added activated 3 Å molecular sieves (0.75 g) and pyridinium dichromate (0.27 g, 3.5 mmol). The reaction was stirred overnight at room temperature then filtered through a pad of silica, which was washed with MTBE. After the organic solution was concentrated, the residue was purified by silica chromatography to give the title ketone (80 mg).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][N:20]([C:24](=[N:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]3)=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)C.[BH4-].[Li+].O>O1CCCC1.CO>[C:37]([O:36][C:34]([NH:33][C:24]([N:20]1[CH2:19][CH2:18][C:17]2[C:22](=[CH:23][C:14]([O:13][CH2:12][CH:9]3[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][OH:3])[CH2:11][CH2:10]3)=[CH:15][CH:16]=2)[CH2:21]1)=[N:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:35])([CH3:38])([CH3:39])[CH3:40]
Reactant: CCOC(=O)CN1CCC(COc2ccc3c(c2)CN(C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)CC3)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCN(CCO)CC3)cc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.2 %

Procedure:
To a solution of 4-[2-(N,N′-di-tert-butoxycarbonylamidino)-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl]piperidine-1-acetic acid ethyl ester (155 mg) in a mixture of tetrahydrofuran (2 ml) and methanol (0.008 ml) was added lithium borohydride (11 mg), and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:acetone=3:1) and dried under reduced pressure to give the title compound (65 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]([NH2:20])=[O:19])[CH:5]=[CH:6][C:7]=1B1OC(C)(C)C(C)(C)O1.[CH2:21]([O:28][C:29]1[CH:34]=[C:33]([O:35][CH2:36][CH3:37])[C:32](I)=[CH:31][N:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:21]([O:28][C:29]1[N:30]=[CH:31][C:32]([C:7]2[CH:6]=[CH:5][C:4]([CH2:17][C:18]([NH2:20])=[O:19])=[CH:3][C:2]=2[F:1])=[C:33]([O:35][CH2:36][CH3:37])[CH:34]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOc1cc(OCc2ccccc2)ncc1I
Reactant: CC1(C)OB(c2ccc(CC(N)=O)cc2F)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOc1cc(OCc2ccccc2)ncc1-c1ccc(CC(N)=O)cc1F
Yield: 100 %

Procedure:
A solution of 2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (100 mg, 0.358 mmol), 2-(benzyloxy)-4-ethoxy-5-iodopyridine (127 mg, 0.358 mmol), PdCl2(dppf) (26.2 mg, 0.036 mmol) and Cs2CO3 (233 mg, 0.717 mmol) in 1,4-dioxane (6 mL) and H2O (2 mL) was stirred at 110° C. for 15 min. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo. The residue was dissolved in EA (40 mL) and washed with H2O (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative TLC (PE/EA=1/1) to yield 2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-3-fluorophenyl)acetamide (20 mg, 0.358 mmol, 14.8% yield): 1H NMR (400 MHz, CD3OD) δ 7.87 (s, 1H), 7.56-7.43 (m, 2H), 7.43-7.22 (m, 4H), 7.21-7.11 (m, 2H), 6.50 (s, 1H), 5.38 (s, 2H), 4.13 (m, 2H), 3.58 (s, 2H), 1.32 (t, J=6.8 Hz, 3H); ES-LCMS m/z 381.1 (M+H).