Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CN=CC=1C=O.[C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[C:30]1[C:35](/[CH:36]=[C:37](\[CH2:43][C:44]2[CH:49]=[C:48]3[O:50][CH2:51][O:52][C:47]3=[CH:46][C:45]=2[O:53][CH3:54])/[C:38]([O:40]CC)=[O:39])=[CH:34][CH:33]=[CH:32][N:31]=1)([O:12]C)=[O:11].CCCCCC.C(O)(C(F)(F)F)=O>C(O)C>[C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[C:30]1[C:35](/[CH:36]=[C:37](\[CH2:43][C:44]2[CH:49]=[C:48]3[O:50][CH2:51][O:52][C:47]3=[CH:46][C:45]=2[O:53][CH3:54])/[C:38]([OH:40])=[O:39])=[CH:34][CH:33]=[CH:32][N:31]=1)([OH:12])=[O:11]
Reactant: CCOC(=O)/C(=C/c1cccnc1-c1ccc(OC)cc1OCc1ccccc1C(=O)OC)Cc1cc2c(cc1OC)OCO2
Agent: O=Cc1cnccc1Cl
Solvent: CCO
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2ncccc2/C=C(\Cc2cc3c(cc2OC)OCO3)C(=O)O)c(OCc2ccccc2C(=O)O)c1

Procedure:
Following the procedures in Example 4(b)-(c) except substituting 2-chloro-3-formyl-pyridine for 4chloro-3-formyl-pyridine and for the preparation of E-Ethyl 3-[2-[(2-Carbomethoxyphenyl)methoxy-4-methoxyphenyl]-pyridin-3-yl]-2-[2-methoxy4,5-methylenedioxybenzyl]prop-2-enoate shown in Example 6 (b), the title compound was prepared as a tan solid. (58 mg, 10% ) (400 MHz, CDCl3) δ 8.67 (d, J=3.5 Hz, 1H), 8.14 (d, J=7.8 Hz, 1H) 7.72 (s, 1H), 7.49-7.37 (m, 4H), 7.14 (dd, J=8.4 Hz, 4.8 Hz 1H), 6.71 (d, J=7.8 Hz, 1H), 6.70 (s, 1H), 6.48 (s, 1H), 6.43 (s, 1H), 5.85 (s, 2H), 5.49 (s, 2H), 3.89 (s, 3H), 3.71 (s, 3H), 2.87 (s, 2H); MS(ESP) m/e 570 [M+H]+ ; MS(ESN) m/e 568 [M-H]- ; mp 135-140°; Anal. (C32H27NO9.0.5H2O) calcd. C, 66.43; H, 4.88; N, 2.42: found. C, 66.47; H, 4.89; N, 2.40; HPLC tR 11.8 min, (Bakerbond Chiracel OC®; 25 cm×4.6 mm; hexane:ethanol, 80% with0.1%TFA;
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[CH3:18])=[CH:4][N:3]=1.[H][H]>[Pd].CO>[CH3:18][C:10]1[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][CH:6]=1
Reactant: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2C)cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(Oc2ccc(N)cc2C)cn1
Reaction time: 2 h
Yield: 87.2 %

Procedure:
A mixture of 2-methyl-5-(2-methyl-4-nitro-phenoxy)-pyridine (11.5 g, 47.1 mmol) and palladium on carbon (300 mg, 10 wt. %, wet) in MeOH (200 mL) was flashed with hydrogen. A hydrogen balloon was then applied to the reaction mixture. The reaction was stirred for 2 hours and the solution was filtered through a pad of celite, and the pad was washed with MeOH (300 mL). Concentration of the solution gave crude product (8.8 g, 87%) as light yellow solid.
Reaction SMILES: CO[C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[CH:5]=[N:6][CH:7]([CH3:9])[CH3:8].Br[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[CH3:22].[Mg].[NH4+].[Cl-]>C1COCC1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[CH:5]=[N:6][CH:7]([CH3:9])[CH3:8])=[C:16]([CH3:22])[CH:17]=1
Reactant: Cc1cc(F)ccc1Br
Reactant: COc1ccccc1C=NC(C)C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1ccccc1C=NC(C)C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
A solution of 14.57 g (81 mmol) N-(2-methoxybenzylidene)isopropylamin in 50 ml THF was added dropwise to a Grignard reagent prepared from 18.01 g (90 mmol) 2-bromo-5-fluorotoluene and 2.19 g (90 mmol) magnesium turnings in 50 ml THF. The mixture was heated at reflux for 12 hrs. The mixture was poured with vigorous stirring into an aqueous solution of NH4Cl (25 %) and stirred for 1 h. Extraction with CH2Cl2, drying (Na2SO4) and evaporation gave 20.83 g (98%) (4′-fluoro-2′-methyl-biphenyl-2-ylmethylene)-isopropyl-amine as a pale yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16]CC1C=CC=CC=1>C(O)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16]
Reactant: c1ccc(CNCCCCCCOCCc2ccccn2)cc1
Agent: [Pd]
Solvent: CCO
Product: NCCCCCCOCCc1ccccn1
Yield: 69.6 %

Procedure:
A solution of N-[6-[2-(2-pyridinyl)ethoxy]hexyl]benzenemethanamine (2.00 g) in ethanol (10 ml) was added to a pre-hydrogenated suspension of 10% palladium on carbon (50% paste, 800 mg) in ethanol (120 ml) and hydrogenated at room temperature and pressure. The catalyst was removed by filtration through hyflo and the solvent evaporated in vacuo. The residual oil was purified by FCC eluting with System A (39:10:1→32:17:1) to afford the title compound as a colourless liquid (0.99 g), t.l.c. (System A 39:10:1) Rf 0.16.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[O:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[C:8](F)[CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>C(O)C.[Pd]>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[O:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(C=Cc2ccc3c(c2)CCC(=O)O3)c(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCc1ccc(CCc2ccc3c(c2)CCC(=O)O3)cc1
Yield: 68.9 %

Procedure:
Palladium-on-carbon (5%, 0.3 g) was added to a solution of 6-(2-(4-pentyl-2-fluorophenyl)ethenyl)-3,4-dihydrocoumarin (3.2 g) in ethanol (30 ml), and the mixture was stirred in a hydrogen atmosphere for 24 hours. The catalyst was removed from the reaction mixture by filtration, and the resulting solution was concentrated in vacuo and subjected to isolation and purification by silica gel column chromatography, thereby obtaining a while crystal (2.1 g) of a titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[N:13]1[C:17]([CH2:18][N:19]([CH3:21])[CH3:20])=[N:16][C:15]([C:22]([NH2:24])=O)=[N:14]1)=[O:5].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.CCOCC>N1C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[N:13]1[C:17]([CH2:18][N:19]([CH3:21])[CH3:20])=[N:16][C:15]([C:22]#[N:24])=[N:14]1)=[O:5]
Reactant: CN(C)Cc1nc(C(N)=O)nn1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CN(C)Cc1nc(C#N)nn1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4.18 g (0.01 mole) of 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-[(dimethylamino)-methyl]-1H-1,2,4-triazole-3-carboxamide and 2.86 g (0.015 mole) of p-toluenesulphonic acid chloride in 2.42 ml of pyridine and 24 ml of N,N-dimethylformamide is stirred for 2 hours at room temperature. The initially yellow colour of the reaction mixture changes during this time to green and then to red-brown. The reaction solution is poured into ice water, and extraction is performed twice with ether. The organic phase is washed three times with water and once with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated in vacuo to dryness. The residue is crystallised from isopropanol. After filtration with suction followed by drying, there is obtained 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-[(dimethylamino)-methyl]-1H-1,2,4-triazole-3-carbonitrile, m.p. 117°-119°.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[N:6][CH:5]=1.[OH-].[Na+]>CO>[N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:22])=[O:2])=[CH:5][N:6]=1
Reactant: COC(=O)c1ccc(OCc2ccc3ccccc3n2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OCc2ccc3ccccc3n2)nc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 92.5 %

Procedure:
To a solution of 6-(quinol-2-ylmethoxy)nicotinic acid methyl ester (5.06 g, 17.2 mmol), prepared as in step 2, in methanol (100 ml) at room temperature with stirring was added. 1N NaOH (18.9 ml, 18.9 mmol). The resulting mixture was allowed to stir at room temperature for 14 hours. The mixture was then refluxed for 3 hours, cooled to room temperature and concentrated in vacuo. The residue was diluted with water and the aqueous layer was extracted with ethyl acetate. The aqueous layer was acidified to pH 3 with 10% citric acid to give a white precipitate. The precipitate was filtered and washed with water and diethyl ether. The solid was dried overnight at 80° C. under reuced pressure to give 4.46 g of 6-(2-quinolylmethoxy)nicotinic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[F:23].OS(O)(=O)=O.[N:30]([O-])=O.[Na+]>C1COCC1.O.CCOC(C)=O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]2[C:7](=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[F:23])[N:13]=[N:30][CH:11]=[C:10]2[OH:12])=[O:24]
Reactant: COC(=O)c1cc(C(C)=O)c(N)c(F)c1Nc1ccc(Br)cc1F
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc2c(O)cnnc2c(F)c1Nc1ccc(Br)cc1F
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 5-acetyl-4-amino-2-(4-bromo-2-fluorophenylamino)-3-fluorobenzoic acid methyl ester (1.00 equiv.) in THF and conc H2SO4 (4.00 equiv.) is added a solution of NaNO2 (1.50 equiv.) in water at 0° C. The reaction mixture is warmed to 60° C. and stirred for 3 hours. The reaction mixture is cooled to room temperature and diluted with EtOAc. The organic layer is washed with water, dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is purified by flash column chromatography to afford the desired product as necessary.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15](O)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.CN(C)C=O.C(Cl)(=O)C([Cl:28])=O>C(Cl)Cl>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([Cl:28])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1.67 h

Procedure:
To a mixture of 4′-trifluoromethylbiphenyl-2-carboxylic acid (5.06 g), dimethylformamide (catalytic amount) and methylene chloride (30 mL) was added dropwise oxalyl chloride (2.43 mL) under ice-cooling. The mixture was stirred at room temperature for 100 minutes and the solvent was removed by evaporation. After azeotropic distillation with toluene, the residue was dried in vacuo to give the title compound (5.40 g).
Reaction SMILES: [F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([N:29]3[CH:33]=[C:32]([C:34]([OH:36])=O)[CH:31]=[N:30]3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2.[NH3:37]>C1COCC1>[F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([N:29]3[CH:33]=[C:32]([C:34]([NH2:37])=[O:36])[CH:31]=[N:30]3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:9](=[O:16])[NH:10][C:11](=[O:15])[NH:12][C:13]1=[O:14])[CH2:7]2
Reactant: C[C@@H]1CN2c3c(cc4c(-n5cc(C(=O)O)cn5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Reactant: N
Solvent: C1CCOC1
Product: C[C@@H]1CN2c3c(cc4c(-n5cc(C(N)=O)cn5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1

Procedure:
Starting materials: 1-[(2R,4S,4aS)-rel-11-fluoro-2,4-dimethyl-2′,4′,6′-trioxo-1,1′,2,3′,4,4′,4a,6′-octahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidin]-8-yl]-1H-pyrazole-4-carboxylic acid (Example 186) and saturated NH3 in THF (2 mL). Purification by reverse phase HPLC.
Reaction SMILES: B(F)(F)F.CSC.C[O:9][C:10]1[CH:11]=[C:12]([C:17]2[N:21]([CH2:22][C:23]#[N:24])[N:20]=[CH:19][C:18]=2[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][C:34]([N:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=3)[CH:26]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1>ClCCl>[OH:9][C:10]1[CH:11]=[C:12]([C:17]2[N:21]([CH2:22][C:23]#[N:24])[N:20]=[CH:19][C:18]=2[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:32]=[CH:33][C:34]([N:37]([CH3:38])[CH3:39])=[CH:35][CH:36]=3)[CH:26]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: COc1cc(C)cc(-c2c(-c3ccnc(-c4ccc(N(C)C)cc4)c3)cnn2CC#N)c1
Agent: FB(F)F
Solvent: CSC
Solvent: ClCCl
Product: Cc1cc(O)cc(-c2c(-c3ccnc(-c4ccc(N(C)C)cc4)c3)cnn2CC#N)c1
Reaction time: 24 h

Procedure:
Borontrifluoride-dimethylsulfide (0.13 mL, 1.2 mmol) was dropwise added to a solution of the methoxy compound (50.1 mg, 0.12 mmol) prepared in Example 41 in dichloromethane (4 mL) at room temperature under nitrogen atmosphere, and stirred for 24 hours. The reaction mixture was concentrated by vacuum distillation. The residue was treated in ethyl acetate (100 mL) and brine (50 mL) and the organic layer was dried over anhydrous magnesium sulfate and distilled under vacuum. Purification through column chromatography (silica gel, ethyl acetate) afforded pure hydroxy products (19 mg, 39%).
Reaction SMILES: [CH2:1]([C:3]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:6][O:5][CH2:4]1)[CH3:2].C1COCC1.CCO.[Cl-].[NH4+]>[Fe].O>[CH2:1]([C:3]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)[CH2:4][O:5][CH2:6]1)[CH3:2]
Reactant: CCC1(COc2ccc([N+](=O)[O-])cc2)COC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCC1(COc2ccc(N)cc2)COC1
Temperature: 90 °C
Yield: 98.4 %

Procedure:
To a solution of 3-ethyl-3-((4-nitrophenoxy)methyl)oxetane (8.28 g, 34.9 mmol) in a 3:3:1 mixture of THF:EtOH:water (140 mL) at room temperature was added ammonium chloride (2.80 g, 52.3 mmol) followed by iron powder (9.74 g, 174 mmol). The mixture was heated to 90° C. for 1 hour, then it was filtered hot through diatomaceous earth with a THF wash to complete the transfer. The filtrate was concentrated under reduced pressure, and the residue was taken up in ethyl acetate then washed with brine, dried (Na2SO4), and concentrated to provide the title compound (7.12 g, 98% yield) without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:12])[CH3:11].[CH2:14]([S:19][C:20]([CH3:24])([CH3:23])[CH:21]=O)[CH2:15][CH2:16][CH:17]=[CH2:18].C(O)(=O)C.C([BH3-])#N.[Na+].Cl>CO>[SH:13][C:10]([CH3:11])([CH3:12])[CH2:9][NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:21][C:20]([S:19][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])([CH3:24])[CH3:23]
Reactant: C=CCCCSC(C)(C)C=O
Reactant: CC(C)(S)CNc1ccccc1N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C=CCCCSC(C)(C)CNc1ccccc1NCC(C)(C)S
Temperature: 25 °C
Reaction time: 17 h
Yield: 96.8 %

Procedure:
2-Amino-1-(2-mercapto-2-methylpropylamino)benzene (0.155 g, 7.91×10-4 mol) and 0.30 g (1.74×10-3 mol, 220 M %) of 2-(4-pentenylthio)-2-methylpropanal were dissolved in 40 ml methanol. Acetic acid (0.09 ml, 1.59×10-3 mol, 200M %) was added followed by 0.155 g (2.37×10-3 mol, 300 M %) sodium cyanoborohydride. The reaction was stirred at room temperature under nitrogen for 17 hr, then 20 ml 0.5 M HCl was added and the mixture was extracted with 2×40 ml diethyl ether. The ether layer was washed with 30 ml saturated NaCl solution and dried (Na2SO4), and the solvent was removed on the rotary evaporator. The product was purified by radial chromatography on a 2 mm silica plate eluting with 50 ml 100% hexane and 100 ml 90% hexane/ether to give 0.27 g (97% yield) of 2-(2-mercapto-2-methylpropylamino)-1-[2-(4-pentenylthio)-2-methylpropylamino]-benzene as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:14])[CH:11]([CH3:13])[CH3:12].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(#N)C>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][O:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:14])[CH:11]([CH3:12])[CH3:13])[CH3:27]
Reactant: COc1ccc(C(=O)C(C)C)c(O)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)COc1cc(OC)ccc1C(=O)C(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of the above prepared 1-(2-hydroxy-4-methoxy-phenyl)-2-methyl-propan-1-one (5.43 g, 28 mmol) in 56 mL acetonitrile were successively added Cs2CO3 (10.9 g, 1.2 eq.) and ethyl bromoacetate (3.25 mL, 1.05 eq.) and the mixture vigorously stirred at ambient temperature for 2.5 h. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents left 8.01 g of the title product as light yellow oil, sufficiently pure to be used for the next step.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[CH3:26][C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=1[NH:34]N>>[CH3:26][C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=1[N:34]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: Cc1cccc(NN)c1C
Product: Cc1cccc(-n2nccc2-c2nn(-c3cccc(OC(F)(F)F)c3)ccc2=O)c1C

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and (2,3-dimethyl-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=425.8 (M)+
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:20]([NH:22][C:23]2[CH:24]=[C:25]([CH:56]=[CH:57][CH:58]=2)[C:26]([NH:28][C@H:29]([C:38]([NH:40][C@H:41]([C:53]([OH:55])=[O:54])[CH2:42][C:43]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[CH:46]=[CH:45][CH:44]=2)=[O:39])[CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])=[O:27])=[O:21])[NH:12]C(OC(C)(C)C)=O)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[F:59][C:60]([F:65])([F:64])[C:61]([OH:63])=[O:62]>C(Cl)Cl>[F:59][C:60]([F:65])([F:64])[C:61]([OH:63])=[O:62].[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:20]([NH:22][C:23]2[CH:24]=[C:25]([CH:56]=[CH:57][CH:58]=2)[C:26]([NH:28][C@H:29]([C:38]([NH:40][C@H:41]([C:53]([OH:55])=[O:54])[CH2:42][C:43]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[CH:46]=[CH:45][CH:44]=2)=[O:39])[CH2:30][C:31](=[O:32])[OH:33])=[O:27])=[O:21])[NH2:12])=[CH:6][CH:5]=1)(=[NH:2])[NH2:3]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)c1cccc(NC(=O)C(Cc2ccc(C(=N)N)cc2)NC(=O)OC(C)(C)C)c1)C(=O)N[C@@H](Cc1cccc2ccccc12)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)c1ccc(CC(N)C(=O)Nc2cccc(C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc3cccc4ccccc34)C(=O)O)c2)cc1
Reaction time: 2 h
Yield: 84 %

Procedure:
A solution of 55 mg of N-[N-[m-[[3-(p-amidinophenyl)-N-(t-butoxycarbonyl)-DL-alanyl]amino]benzoyl]-3-(t-butoxycarbonyl)-L-alanyl]-3-(1-naphthyl)-L-alanine (1:1 epimer) in a mixture of 10 ml of methylene chloride and 5 ml of trifluoroacetic acid is held at room temperature for 2 hours while gassing with argon. After evaporation of the solvent there is obtained N-[N-[m-[[3-(p-amidinophenyl)-DL-alanyl]amino]benzoyl]-L-α-aspartyl]-3-(1-naphthyl)-L-alanine trifluoroacetate (1:2), m.p. 165° C. (dec.) (ethanol/ethyl acetate), yield: 84% of theory, MS: 639 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10][O:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][C@@H:48]([N:53]([CH3:70])[C:54](=[O:69])[C@H:55]([NH:67][CH3:68])[CH2:56][C:57]2[CH:66]=[CH:65][C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[CH:58]=2)[C:49](=[O:52])[NH:50][CH3:51])=[CH:43][CH:42]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10][O:11][CH2:12][C:13](=[O:15])[N:67]([C@@H:55]([C:54](=[O:69])[N:53]([C@@H:48]([C:49](=[O:52])[NH:50][CH3:51])[CH2:47][C:44]1[CH:43]=[CH:42][C:41]([F:40])=[CH:46][CH:45]=1)[CH3:70])[CH2:56][C:57]1[CH:66]=[CH:65][C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:58]=1)[CH3:68])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(COCC(=O)O)NC(=O)OC(C)(C)C
Reactant: CNC(=O)[C@@H](Cc1ccc(F)cc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)NC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@@H](Cc1ccc(F)cc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)COCC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.5 %

Procedure:
(2-tert-Butoxycarbonylamino-2-methylpropoxy)acetic acid (0.22 g; 0.89 mmol) was dissolved in methylene chloride (10 mL). 1-Hydroxy-7-azabenzotriazole (0.13 g; 0.98 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.20 g; 1.02 mmol) were added and the reaction mixture was stirred for 15 min at room temperature. (2R)-N-((1R)-2-(4-Fluorophenyl)-1-(methylcarbamoyl)ethyl)-N-methyl-2-methylamino-3-(2-naphthyl)propionamide (0.38 g; 0.89 mmol) and diisopropylethylamine (0.17 mL; 0.98 mmol) were added and the reaction mixture was stirred for 12 hours at room temperature. Methylene chloride (50 mL) was added and the reaction mixture was washed with water (50 mL), an aqueous solution of sodium hydrogen carbonate/sodium carbonate (pH 9; 50 mL), an aqueous solution of sodium hydrogen sulfate (10%; 50 mL) and water (50 mL) and dried (magnesium sulfate). The solvent was removed in vacuo to afford 0.53 g of (2-((((1R)-1-(((1R)-2-(4-fluorophenyl)-1-methylcarbamoylethyl)-methylcarbamoyl)-2-(2-naphthyl)ethyl)methylcarbamoyl)-methoxy)-1,1-dimethylethyl)carbamic acid tert-butylester.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[O:21][CH3:22])[CH2:3]1.[C:23](Cl)(=[O:27])[CH:24]([CH3:26])[CH3:25]>N1C=CC=CC=1.C(Cl)Cl>[C:23]([O:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[O:21][CH3:22])[CH2:3]1)(=[O:27])[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)C(=O)Cl
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CO[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(=O)C(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
A solution of 3α-hydroxy-17β-methoxy-5β-androstane (250 mg, 0.82 mmol) in dry pyridine (2 mL) was treated with isobutyryl chloride (0.12 mL, 1.15 mmol), and N,N-dimethylaminopyridine (5 mg) at 5° C. After stirring the mixture at 5-10° C. for 1 hr the mixture was quenched with HCl solution (0.5N, 25 mL). The mixture was extracted with EtOAc. The organic layer was washed with dil. HCl, water, and brine. After drying over anhyd. MgSO4 the solution was filtered and evaporated to yield the crude product. This crude product was then dissolved in a small amount of CH2Cl2 and poured on a column of silica gel. Elution with hexane:acetone mixture (9:1) gave 3α-isobutyryloxy-17β-methoxy-5β-androstane (266 mg); mp 82-87° C.; TLC Rf (hexane:acetone 9:1)=0.6.