Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6](=[O:7])[O:5][C:4]2[CH:8]=[CH:9][C:10]3[C:15]([C:3]1=2)=[CH:14][C:13]([CH3:16])=[C:12]([C:17]#[N:18])[CH:11]=3.[Br:20]Br.C(=O)([O-])O.[Na+]>ClCCl.FC(F)(F)S([O-])(=O)=O.[Ag+]>[Br:20][C:14]1[C:13]([CH3:16])=[C:12]([C:17]#[N:18])[CH:11]=[C:10]2[C:15]=1[C:3]1[C:2]([CH3:19])([CH3:1])[C:6](=[O:7])[O:5][C:4]=1[CH:8]=[CH:9]2
Reactant: Cc1cc2c3c(ccc2cc1C#N)OC(=O)C3(C)C
Reactant: BrBr
Agent: [Ag+]
Agent: O=C([O-])O
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C#N)cc2ccc3c(c2c1Br)C(C)(C)C(=O)O3
Reaction time: 0.5 h

Procedure:
A mixture of 1,2-dihydro-1,1,8-trimethyl-2-oxonaphtho[2,1-b]furan-7-carbonitrile (0.25 g), silver trifluoromethanesulphonate (0.34 g) and dichloromethane (10 ml) was stirred in the dark, while a solution of bromine (0.19 g) in dichloromethane (2 ml) was added over 10 minutes. The mixture was stirred a further 0.5 h, then treated with aqueous sodium hydrogen carbonate solution, and the resulting mixture was filtered through a pad of diatomaceous earth ("Celite" -trade mark). The organic phase was separated, dried and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography, using chloroform:pentane, 1:1 v/v, as eluant, to give 9-bromo-1,2-dihydro-1,1,8-trimethyl-2-oxonaphtho[2,1-b]furan-7-carbonitrile, m.p. 235°-237° after recrystallisation from a mixture of ethyl acetate and petroleum ether (b.p. 60°-80°), which was brominated by the process described in the last part of Example 4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[C:10]([CH2:39][CH:40]=O)([CH2:26][CH2:27][O:28][Si:29]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[NH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([CH2:21][CH:22]3[CH2:23][CH2:24]3)[C:11](=[O:25])[C:10]([CH2:39][CH2:40][N:42]3[CH2:46][CH2:45][CH2:44][CH2:43]3)([CH2:26][CH2:27][O:28][Si:29]([CH:33]([CH3:34])[CH3:35])([CH:36]([CH3:37])[CH3:38])[CH:30]([CH3:32])[CH3:31])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[Si](OCCC1(CC=O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O)(C(C)C)C(C)C
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)[Si](OCCC1(CCN2CCCC2)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 1.02 g (1.66 mmol) of crude 2-((5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxo-3-(2-(triisopropylsilyloxy)ethyl)piperidin-3-yl)acetaldehyde (Example 69, Step B, mixture of diastereomers), 0.55 mL (6.6 mmol) of pyrrolidine, 880 mg (4.15 mmol) of sodium triacetoxyborohydride and 285 μL (4.98 mmol) of acetic acid was suspended in a mixture of 1,2-dichloroethane (36 mL) and DMF (12 mL). After being stirred at room temperature for 20 h, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with DCM (3×). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The crude title compound (mixture of C-3 epimers) was used directly in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:18][CH2:17][C:16]([CH2:20][CH2:21][CH2:22][CH3:23])(Br)[C:15](=[O:24])[C:8]=2[S:9][C:10]=1[NH:11][C:12](=[O:14])[CH3:13])=[O:5])[CH3:2].[Li+].[Br-]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:18]=[CH:17][C:16]([CH2:20][CH2:21][CH2:22][CH3:23])=[C:15]([OH:24])[C:8]=2[S:9][C:10]=1[NH:11][C:12](=[O:14])[CH3:13])=[O:5])[CH3:2]
Reactant: CCCCC1(Br)CCc2c(sc(NC(C)=O)c2C(=O)OCC)C1=O
Agent: [Br-]
Agent: [Li+]
Product: CCCCc1ccc2c(C(=O)OCC)c(NC(C)=O)sc2c1O
Yield: 52.3 %

Procedure:
Compound 04-5 (4.74 g, 10.9 mmol) was converted with LiBr (1.1 g, 12.5 mmol, 1.1 equiv.), Li2CO3 (0.9 g, 12.5 mmol, 1.1 equiv.) to 04-6 using the procedure for 02-6. The crude product was filtered off after aqueous workup, washed with H2O and Et2O (25 mL) to give 04-6 (1.9 g, 5.7 mmol, 50%) as a grey solid. The mother liquor was evaporated and treated with Et2O to give a second crop of 04-6 (0.6 g, 1.9 mmol, 17%) as a brownish solid (total yield of 04-6: 2.6 g, 7.6 mmol, 67%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9](O)[C:8]1=[O:18])[CH3:2].C1(C)C=CC=CC=1.S(Cl)([Cl:28])=O>CN(C)C=O>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([Cl:28])[C:8]1=[O:18])[CH3:2]
Reactant: CCOCCCn1c(=O)c(O)nc2ccccc21
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOCCCn1c(=O)c(Cl)nc2ccccc21

Procedure:
To 22.5 g of (1), 330 ml of toluene, 10 ml of dimethylformamide and 10 ml of thionyl chloride are added and the resulting mixture is heated to reflux for 2 hours. The mixture is then subjected to filtration during hot and the filtrate is concentrated. The resultant is purified by silica gel column chromatography (ethyl acetate:hexane=1:3-1:2) to obtain 23.5 g of (2) in the form of yellow oil.
Reaction SMILES: [Br:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([OH:10])=O)[CH:4]=1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:26][C@@H:27]([CH3:44])[CH2:28][N:29]1[CH:33]=[CH:32][C:31]([C:34]2[CH:41]=[C:40]([F:42])[C:37]([C:38]#[N:39])=[C:36]([Cl:43])[CH:35]=2)=[N:30]1.C(N(CC)CC)C>C(Cl)Cl.C1COCC1>[Br:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([NH:26][C@@H:27]([CH3:44])[CH2:28][N:29]2[CH:33]=[CH:32][C:31]([C:34]3[CH:41]=[C:40]([F:42])[C:37]([C:38]#[N:39])=[C:36]([Cl:43])[CH:35]=3)=[N:30]2)=[O:10])[CH:4]=1
Reactant: O=C(O)c1cc(CBr)on1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cc(CBr)on1
Temperature: 25 °C
Yield: 38.2 %

Procedure:
5-(Bromomethyl)isoxazole-3-carboxylic acid (0.718 mmol, 0.148 g) was dissolved in DCM (5 ml) and THF (1 ml). 1,3-Dicyclohexylcarbodiimide (0.718 mmol, 0.148 g) was added and the resulting mixture was stirred at RT. The precipitate formed was filtered and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.359 mmol, 0.1 g), triethylamine (0.359 mmol, 0.036 g) and dry DCM (5 ml) was added to the filtrate. The filtrate was stirred at RT under nitrogen atmosphere for two days during which more 1,3-dicyclohexylcarbodiimide (0.148 g), triethylamine (0.050 ml) and 5-(bromomethyl)isoxazole-3-carboxylic acid (0.1 g) were added. The reaction mixture was diluted with DCM and washed with NaHCO3. The organic phase was dried, filtered and evaporated. The crude product was purified with flash chromatography. 0.064 g of the title compound was obtained. 1H-NMR (400 MHz, CDCl3): δ 1.25 (d, 3H), 4.00-4.09 (m, 2H), 4.23-4.31 (m, 1H), 4.41-4.48 (m, 1H), 4.53-4.63 (m, 1H), 6.60-6.66 (m, 1H), 6.74-6.78 (m, 1H), 7.48-7.53 (m, 1H), 7.64 (d, 1H), 7.79-7.88 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)=[O:3].CC(C)([O-])C.[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Cl-].[Ru+2].[Fe]>[C:4]1([CH:2]([OH:3])[CH3:1])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1cccc2ccccc12
Agent: [Fe]
Agent: [Ru+2]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: CC(O)c1cccc2ccccc12
Temperature: 105 °C
Reaction time: 2 h

Procedure:
Tris(triphenylphosphine)ruthenium(II) chloride (3.8 mg, 4 μmol, 1 mol %) and a chiral ligand (M=Fe, R=Me, Ar=C6H5—, 2.6 μmol, 0.65 mol %) were dissolved in 1,4-dioxane (3 mL) under nitrogen atmosphere, and then heated and stirred for 2 h at 105° C. After the mixture was cooled to room temperature, 1-acetonaphthone (0.4 mmol), 1,4-dioxane (2 mL) and a solution of potassium t-butoxide in 1,4-dioxane (0.4 mL, 0.4 M) were added thereto. Thereafter, the reaction system was placed in an autoclave, and stirred for 24 h under H2 (40 atm) at 0° C. The solvent was removed under reduced pressure, and the resultants were separated by column chromatography (silica gel column; eluent: ethyl acetate/petroleum ether=1/5). Accordingly, pure 1-(1-naphthyl)ethanol was obtained and the ee value (ee=98%) was measured by GC analysis.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([O:9][CH3:10])[C:5]([O:11][CH:12]([F:14])[F:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH:22]([CH3:24])[CH3:23]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH:12]([F:13])[F:14])=[C:6]([O:9][CH3:10])[C:7]=1[O:8][CH2:21][CH:22]([CH3:24])[CH3:23]
Reactant: COc1c(OC(F)F)ccc(Br)c1O
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1c(OC(F)F)ccc(Br)c1OCC(C)C
Temperature: 80 °C
Yield: 248.7 %

Procedure:
To a stirring solution of 6-bromo-3-(difluoromethoxy)-2-methoxyphenol (100 mg, 0.371 mmol) in acetonitrile (10 mL), was added potassium carbonate (153.8 mg, 1.114 mmol) and isobutyl bromide (152.6 mg, 1.114 mmol) and the resultant reaction mixture was heated to 80° C. for 3 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure to afford 300 mg of 1-Bromo-4-(difluoromethoxy)-2-isobutoxy-3-methoxybenzene as a solid. To a stirring solution of 1-bromo-4-(difluoromethoxy)-2-isobutoxy-3-methoxybenzene (200 mg, 0.615 mmol) in dimethylformamide (5 mL) was purged with argon for 1 h. To this cesium carbonate (599 mg, 1.84 mmol), tetrakis(triphenylphosphine) palladium(0) (35 mg, 0.030 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (191 mg, 0.738 mmol) were added and the resultant reaction mixture was heated to 80-90° C. for 3 h. The reaction mixture was cooled to RT, filtered and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded the title compound as a (30 mg, 13%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:16].[Na+]>CC(C)=O.CCCCCC>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][I:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1cccc(Oc2ccccc2)c1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: ICc1cccc(Oc2ccccc2)c1
Reaction time: 8 h

Procedure:
To a solution of 3-phenoxybenzyl chloride (10.0 g, 45.7 mmol) in 200 ml acetone was added sodium iodide (7.6 g, 507 mmol). The mixture was stirred at temperature overnight. The mixture was diluted with 300 ml hexane and the organic layer was washed twice with 5% sodium bicarbonate, once with brine and then dried over MgSO4. Evaporation of the filtrate gave a light yellow oil. The product was used in next step without purification. 1H NMR (CDCl3) 4.4 (s, 2H), 6.8-7.4 (m, 9H).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Cl[C:37]1[N:42]=[N:41][C:40]([C:43]([OH:46])([CH3:45])[CH3:44])=[CH:39][CH:38]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:37]3[N:42]=[N:41][C:40]([C:43]([OH:46])([CH3:45])[CH3:44])=[CH:39][CH:38]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CC(C)(O)c1ccc(Cl)nn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccc(C(C)(C)O)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
A solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (50 mg, 0.104 mmol), 2-(6-chloropyridazin-3-yl)-propan-2-ol (20 mg, 0.151 mmol), Pd(PPh3)2Cl2 (30 mg, 0.046 mmol), 2 M aq Cs2CO3 (0.4 mL) in dioxane (5 mL) was heated at reflux for 2 h. The reaction mixture was concentrated, and the residue was treated with water (20 mL) and extracted with EtOAc (3×10 mL). The combined organic layer was washed with satd aq NaCl solution, dried with anhydrous Na2SO4, and concentrated to give an oil, which was purified by preparative TLC and HPLC to give the product. LC-MS Method 2 tR=1.031 min, m/z=490.3; 1H NMR (CD3OD): δ0.89 (s, 1H), 0.96 (s, 3H), 1.28 (m, 6H), 1.57 (d, 3H), 1.66 (m, 6H), 2.15 (s, 2H), 2.28 (m, 1H), 2.56 (m, 2H), 3.08 (m, 1H), 5.62 (m, 1H), 7.13 (d, 2H), 7.38 (m, 5H), 7.82 (m, 2H), 8.05 (m, 2H).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=O)=[CH:11][CH:10]=1)([CH3:8])[CH3:7])(=[O:4])=[O:3].[CH3:19][C:20]1[C:21]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1>>[CH3:19][C:20]1[C:21]([N:27]2[CH2:28][CH2:29][N:30]([C:13]([C:12]3[CH:11]=[CH:10][C:9]([C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])([CH3:7])[CH3:8])=[CH:18][CH:17]=3)=[O:15])[CH2:31][CH2:32]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: COC(=O)c1ccc(C(C)(C)NS(C)(=O)=O)cc1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(C(C)(C)NS(C)(=O)=O)cc3)CC2)c(C)c1
Yield: 78.5 %

Procedure:
Using methyl 4-(1-methanesulfonylamino-1-methylethyl)benzoate (126 mg) described in Preparation Example 71 and 1-(3,5-dimethylpyridin-2-yl)piperazine (89 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 109, the title compound (157 mg) was obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])=[O:11])=[C:8]([OH:23])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:24]I.Cl>[OH-].[Na+].C(O)C.O>[CH2:1]([O:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])=[O:11])=[C:8]([O:23][CH3:24])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C(=O)c2cccc(C(=O)O)c2)c(O)c1
Reactant: CI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCOc1ccc(C(=O)c2cccc(C(=O)O)c2)c(OC)c1
Temperature: 60 °C

Procedure:
A solution of 3-(4-butoxy-2-hydroxybenzoyl)benzoic acid (0.85 g), prepared as described in Example 26, is heated under reflux in a mixture of 2N sodium hydroxide (2.8 ml) and ethanol (10 ml) for 30 minutes. The reaction mixture is then cooled to 60° C. and methyl iodide (10 ml) is added. The resulting mixture was heated at 60° for 72 hours, cooled, acidified with concentrated hydrochloric acid and diluted with water (100 ml). The product is extracted with ether (3×25 ml). The extracts are dried over magnesium sulfate, filtered and evaporated to dryness. 2N Sodium hydroxide (2 ml) is added to the residue and the mixture heated under reflux for 6 hours. The reaction mixture is acidified with concentrated hydrochloric acid, diluted with water (100 ml), and extracted with ether (3×25 ml). The residue is chromatographed on silica (hexane:ether:acetic acid at 90:10:1) to yield 3-(4-butoxy-2-methoxybenzoyl)benzoic acid (0.46 g), m.p. 144°-145° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([N:15]([CH3:22])[C:16](=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])[C:12]([C:23]#[N:24])=[CH:11][C:10]=1[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1.[H-].[Na+]>>[NH2:24][C:23]1[C:12]2[C:13](=[N:14][C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[C:10]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)[CH:11]=2)[N:15]([CH3:22])[C:16](=[O:21])[C:17]=1[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)CC(=O)N(C)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Agent: [H-]
Agent: [Na+]
Product: CC(C)c1c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O

Procedure:
Using the procedure described in EXAMPLE 40, the product of Step A was reacted with NaH to afford the title compound. HPLC/MS: 472.2 (M+1), 474.2 (M+3); Rt=4.45 min.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:8][CH:7](S(C2C=CC=CC=2)(=O)=O)[C:6]2[CH:18]=[C:19]([C:22]([O:24][CH3:25])=[O:23])[CH:20]=[CH:21][C:5]=2[O:4][CH2:3]1.P([O-])([O-])(O)=O.[Na+].[Na+].CO.O1CCCC1.O>[Na].[Hg].ClCCl>[CH2:1]=[C:2]1[CH2:8][CH2:7][C:6]2[CH:18]=[C:19]([C:22]([O:24][CH3:25])=[O:23])[CH:20]=[CH:21][C:5]=2[O:4][CH2:3]1
Reactant: C=C1COc2ccc(C(=O)OC)cc2C(S(=O)(=O)c2ccccc2)C1
Agent: O=P([O-])([O-])O
Agent: [Hg]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: C=C1CCc2cc(C(=O)OC)ccc2OC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
728 mg (0.95 mmol) of 3% sodium amalgam are added portionwise at 0° C. to a suspension of 85 mg (0.23 mmol) of methyl 3-methylene-5-(phenylsulfonyl)-2,3,4,5-tetrahydro-1-benzoxepin-7-carboxylate, prepared according to example 1, and of 116 mg (0.95 mmol) of sodium hydrogenphosphate in 10 ml of a 1/1 methanol/tetrahydrofuran binary mixture. The reaction medium is subsequently stirred at ambient temperature for 4 hours. After addition of water and dichloromethane and filtering off the mercury, the phases are separated and the aqueous phase is extracted 3 times with dichloromethane. The combined organic phases are washed with a slightly acidic aqueous solution and then with brine. After drying and then concentrating under vacuum, 49 mg (98%) of methyl 3-methylene-2,3,4,5-tetrahydro-1-benzoxepin-7-carboxylate are obtained without additional purification in the form of an oil; 1H NMR (300 MHz, CDCl3): 2.53. (m, 2H), 2.93 (m, 2H), 3.89 (s, 3H), 4.49 (s, 2H), 5.0 (d, J=4.1 Hz, 2H), 7.0 (d, J=8.1 Hz, 1H), 7.86 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](O)=[O:25])=[CH:15][C:13]=2[N:14]=1.F[B-](F)(F)F.[N:32]1(OC(N(C)C)=[N+](C)C)[C:36]2C=[CH:38][CH:39]=[CH:40][C:35]=2N=N1.CN1CCOCC1.C(N)CCCC>C1COCC1.CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:32][CH2:36][CH2:35][CH2:40][CH2:39][CH3:38])=[O:25])=[CH:15][C:13]=2[N:14]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(Cl)cccc4Cl)[nH]c23)O1
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CCCCCN
Product: CCCCCNC(=O)c1cc2nc(Nc3c(Cl)cccc3Cl)[nH]c2c2c1OC(C)(C)C2
Yield: 30.4 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(2,6-dichlorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-6, 0.070 g, 0.178 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.114 g, 0.306 mmol), N-methyl morpholine (1.0 mL), DMF (1.0 mL), THF (5.0 mL) and pentan-1-amine (0.031 g, 0.356 mmol) to afford 0.025 g of the desired product. 1HNMR (DMSO-d6): δ 0.880 (m, 3H), 1.23-1.33 (m, 8H), 1.49 (s, 6H), 3.03 (s, 2H), 7.19 (m, 1H), 7.32 (s, 1H), 7.50 (d, J=7.8 Hz, 2H), 7.71 (s, 1H), 10.50-11 (s, 2H); MS [M+H]+: 461.55.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[F:23][C:24]([F:36])([F:35])[C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(Cl)Cl>[F:36][C:24]([F:23])([F:35])[C:25]1[CH:26]=[CH:27][C:28]([S:31]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)(=[O:33])=[O:32])=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1,1-dimethylethyl 1-piperazinecarboxylate (5.00 g, 26.8 mmol) in DCM (200 ml) was added DIPEA (9.85 ml, 56.4 mmol) and then 4-(trifluoromethyl)benzenesulfonyl chloride (7.22 g, 29.5 mmol). The reaction mixture was stirred for 1.5 hours at room temperature. The reaction mixture was then reduced to dryness in vacuo, to yield 1,1-dimethylethyl 4-{[4-(trifluoromethyl)phenyl]sulfonyl}-1-piperazinecarboxylate, (crude yield 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:19])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][CH2:21][C@@H:22]1[O:26][C:25](=[O:27])[N:24]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][C:35]3=[O:40])=[CH:30][CH:29]=2)[CH2:23]1>>[CH3:19][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:18])[NH:20][CH2:21][C@@H:22]1[O:26][C:25](=[O:27])[N:24]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][C:35]3=[O:40])=[CH:30][CH:29]=2)[CH2:23]1)[C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Reactant: CN(CCCCC(=O)O)C(=O)OCc1ccccc1
Product: CN(CCCCC(=O)NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)C(=O)OCc1ccccc1

Procedure:
32 mg (0.119 mmol) of 5-[[(benzyloxy)carbonyl](methyl)amino]valeric acid are reacted as carboxyl component by General Procedure 1 with compound (B).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Br)ccc1CO
Yield: 98.1 %

Procedure:
Borane tetrahydrofuran complex solution (1 M in tetrahydrofuran, 13 mL, 13 mmol) was added over 5 min to a solution of 4-bromo-2-nitrobenzoic acid (2.00 g, 8.13 mmol) at room temperature, then after 72 h the reaction mixture was carefully poured upon sat. aq. sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was dried (MgSO4) and evaporated to produce (4-bromo-2-nitro-phenyl)-methanol (1.85 g, 96%). White solid, 1H-NMR (300 MHz, CDCl3): 8.25 (d, J=1.8, 1 H), 7.80 (dd, J=8.1, 1.8, 1 H), 7.67 (d, J=8.1, 1 H), 4.96 (d, J=6.3, 2 H), 2.37 (t, J=6.3, 1 H).
Reaction SMILES: C(OC[N:10]1[C:18]2[C:17]([O:19]C)=[N:16][CH:15]=[N:14][C:13]=2[C:12]([CH2:21][N:22]([CH2:26][C@@H:27]2[CH2:31][O:30]C(C)(C)[O:28]2)[CH2:23][CH2:24][OH:25])=[CH:11]1)C1C=CC=CC=1>Cl>[OH:28][C@@H:27]([CH2:31][OH:30])[CH2:26][N:22]([CH2:21][C:12]1[C:13]2[N:14]=[CH:15][NH:16][C:17](=[O:19])[C:18]=2[NH:10][CH:11]=1)[CH2:23][CH2:24][OH:25]
Reactant: COc1ncnc2c(CN(CCO)C[C@@H]3COC(C)(C)O3)cn(COCc3ccccc3)c12
Agent: Cl
Product: O=c1[nH]cnc2c(CN(CCO)C[C@@H](O)CO)c[nH]c12
Temperature: 100 °C
Yield: 72.6 %

Procedure:
The product from Example 13.2 (0.165 g, 0.361 mmol) was dissolved in 37% HCl (4 ml) and heated to 100° C. for 1.5 h. The solvent was evaporated and the residue dissolved in MeOH and a little water and neutralized with Amberlyst A21 resin. The mixture was filtered and the solvent was evaporated. The residue was chromatographed on silica gel (iPrOH—H2O-28% NH4OH 9:0.5:0.5 then 8:1.5:0.5) to give (R)-7-(((2,3-dihydroxypropyl)(2-hydroxyethyl)amino)methyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one (0.074 g, 72.5%) as a colourless solid. [α]D20 +18.4 (c, 0.56, H2O). 1H NMR (D2O+NaOD, referenced to internal acetonitrile at 2.06 ppm) δ 8.07 (s, 1H), 7.35 (s, 1H), 3.94-3.65 (m, 3H), 3.68 (t, J=6.2 Hz, 2H), 3.50 (dd, J=11.7, 4.2 Hz, 1H), 3.40 (dd, J=11.6, 6.2 Hz, 1H), 2.75-2.48 (m, 4H). 13C NMR (D2O, 75.5 MHz, referenced to internal acetone at 31.5 ppm) δ 156.3, 145.4, 143.7, 132.0, 118.6, 109.2, 68.9, 65.1, 58.5, 56.7, 56.3, 48.8. +ESMS Found 283.1398 C12H19N4O4 (M+H)+ requires 283.1406.