Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[NH2:24])[C:17]([O:19][CH3:20])=[O:18].CO.O>CN1CCCC1=O>[OH:2][C:1]1[NH:24][C:23]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[N:13]=1
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc2[nH]c(O)nc2c1
Temperature: 100 °C

Procedure:
The solution of 5.9 g of carbonyldiimidazole in 10 ml of N-methylpyrrolidone is added dropwise to the solution of 5 g of methyl 3,4-diaminobenzoate in 10 ml of N-methylpyrrolidone, and the mixture is heated to 100° C. for 2 hours. After cooling to 60° C., 5 ml of methanol were added dropwise and then the mixture was stirred at room temperature with 150 ml of water, and the precipitate was filtered off with suction, washed with isopropanol and dried under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=2[O-])=[CH:4][CH:3]=1.COS(OC)(=O)=O.[C-:24]#[N:25].[Na+]>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[N:11]=[C:12]([C:24]#[N:25])[CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: [O-][n+]1ccccc1C=Cc1ccc(Cl)cc1
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)O
Product: N#Cc1cccc(C=Cc2ccc(Cl)cc2)n1

Procedure:
Following the general method described in example 2b, 2-[2-(4-chloro-phenyl)-vinyl]-pyridine 1-oxide was reacted first with dimethylsulfate and then with NaCN. After extraction and crystallization the title compound was obtained as a beige crystalline material. Mp. 113-115° C.(isopropanol), MS: m/e=240 (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[CH3:11][O:12][CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][NH:15]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[CH3:11][O:12][CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1
Reactant: O=[N+]([O-])c1cccc(Br)c1
Reactant: COCC1CCCN1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COCC1CCCN1c1cccc([N+](=O)[O-])c1
Yield: 71.5 %

Procedure:
To a mixture of 1-bromo-3-nitrobenzene (300 mg, 1.48 mmol), 2-(methoxymethyl)pyrrolidine (187 mg, 1.63 mmol), Cs2CO3 (800 mg, 2.45 mmol), X-Phos (50 mg, 0.1 mmol), Pd(dba)2 (50 mg, 0.087 mmol) in 50 mL of dioxane were stirred at reflux overnight under N2 atmosphere. The excess of dioxane was removed under reduced pressure and the residue was purified by silica gel chromatography, eluting with a mixture of petroleum ether and ethyl acetate (5:1) to give 2-(methoxymethyl)-1-(3-nitrophenyl)pyrrolidine (250 mg, 72%) as a yellow solid. LC-MS: 237 [M+H]+, tR=1.71 min.
Reaction SMILES: [Br-:1].[C:2]([C:4]1[CH:5]=[CH:6][C:7]([NH:30][C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])=[C:8]([CH2:10][P+:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=1)#[N:3].C>CN(C=O)C>[Br-:1].[Br:1][C:6]1[C:7]([NH:30][C:31](=[O:36])[C:32]([F:34])([F:33])[F:35])=[C:8]([CH2:10][P+:11]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:9]=[C:4]([C:2]#[N:3])[CH:5]=1
Reactant: N#Cc1ccc(NC(=O)C(F)(F)F)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Br-]
Solvent: CN(C)C=O
Product: N#Cc1cc(Br)c(NC(=O)C(F)(F)F)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
({5-Cyano-2-[(trifluoroacetyl)amino]phenyl}methyl)(triphenyl)phosphonium bromide (Intermediate 7, 32 g) was dissolved in DMF (150 mL) and decolorising charcoal (32 g) was added. The reaction mixture was stirred at room temperature for 2 hrs. The reaction mixture was then filtered washing with DMF (100 mL). N-Bromosuccinimide (34.9 g) was then added to the filtrate and the reaction mixture was then stirred at room temperature overnight. The reaction mixture was quenched with a saturated solution of sodium metabisulfite (500 mL) and stirred at room temperature for 30 min. The reaction mixture was then extracted with ethyl acetate (2×400 mL) and the organic extracts where combined, dried (MgSO4), filtered and the solvent was removed to give ({3-bromo-5-cyano-2-[(trifluoroacetyl)amino]phenyl}methyl)(triphenyl)phosphonium bromide as a crude product which was then used in the next reaction without further purification (37.2 g);
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[N:5]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]([CH:30]3[CH2:32][CH2:31]3)=[CH:22][CH:21]=2)[C:6]([S:9][CH2:10][C:11]([NH:13][CH2:14][C:15]([O:17]CC)=[O:16])=[O:12])=[N:7][N:8]=1>C1COCC1.O>[Br:3][C:4]1[N:5]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]([CH:30]3[CH2:32][CH2:31]3)=[CH:22][CH:21]=2)[C:6]([S:9][CH2:10][C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[N:7][N:8]=1
Reactant: CCOC(=O)CNC(=O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CNC(=O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Aqueous lithium hydroxide solution (1M, 0.8 mL, 0.8 mmol) is added to a solution of ethyl 2-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)acetate (0.4 mmol) in 3:1, THF/H2O (1.6 mL) and the mixture stirred for 18 h at room temperature. The crude reaction mixture is concentrated and acidified with aqueous HCl (1M, 1.2 mL) and then is extracted with ethyl acetate (3×3 mL). The combined organic extracts are dried (sodium sulfate), filtered and concentrated to provide 2-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)acetic acid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:10]=[C:9]([CH3:11])[C:6]([C:7]#[N:8])=[C:5]([O:12][CH3:13])[N:4]=1>CC(O)=O.C(O)C.[Ni]>[NH2:8][CH2:7][C:6]1[C:9]([CH3:11])=[CH:10][C:3]([CH2:2][OH:1])=[N:4][C:5]=1[O:12][CH3:13]
Reactant: COc1nc(CO)cc(C)c1C#N
Agent: [Ni]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1nc(CO)cc(C)c1CN
Yield: 58.6 %

Procedure:
A clear solution of 6-(hydroxymethyl)-2-methoxy-4-methylnicotinonitrile (0.50 g, 2.81 mmol) in HOAc (5 mL) and Ethanol (20 mL) was treated on an H-Cube apparatus (50 psi, 40° C., 1 mL/min, Raney Nickel cartridge) for 18 hr overnight. LCMS showed that the reaction was complete (crude contained 57% product and 43% dimeric side product). The reaction was evaporated to dryness under vacuum. Purified by silica gel chromatography (Analogix, SF25-40 g, 0 to 12% (5% NH4OH in MeOH) in CH2Cl2) (step gradient to 8% to elute off the dimeric side product then to 12% to elute off the product). The pure fractions were combined and evaporated to dryness under vacuum to give the product (5-(aminomethyl)-6-methoxy-4-methylpyridin-2-yl)methanol (0.30 g, 1.646 mmol, 58.7% yield) as a white solid. MS(ES)+m/e 183.1
Reaction SMILES: [CH2:1]([C@:4]12[CH2:12][CH2:11][C:10]3[C:13]4[CH:14]=[CH:15][C:16]([O:21][CH3:22])=[CH:17][C:18]=4[CH2:19][CH2:20][C:9]=3[C@@H:8]1[CH2:7][CH2:6][C:5]2=[O:23])[CH2:2][CH3:3].[BH4-].[Na+]>CO>[CH2:1]([C@:4]12[CH2:12][CH2:11][C:10]3[C:13]4[CH:14]=[CH:15][C:16]([O:21][CH3:22])=[CH:17][C:18]=4[CH2:19][CH2:20][C:9]=3[C@@H:8]1[CH2:7][CH2:6][C@@H:5]2[OH:23])[CH2:2][CH3:3]
Reactant: CCC[C@]12CCC3=C(CCc4cc(OC)ccc43)[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC[C@]12CCC3=C(CCc4cc(OC)ccc43)[C@@H]1CC[C@@H]2O
Reaction time: 0.5 h

Procedure:
Add 13β-propyl-3-methoxygona-1,3,5(10),8-tetraen-17-one (3.5 g.) to a solution of sodium borohydride (1.16 g.) in methanol (120 cc.). Heat the reaction mixture to reflux with stirring for 30 minutes. Concentrate the resulting solution, adjust its pH to 6 with aqueous acetic acid and filter off the resulting white precipitate which is the title product, (3.1 g.), m.p. 134°-8°; ultra-violet absorption peak at 278 mμ (ε15,350); infrared showed a band due to hydroxyl but no ketone present.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[CH2:5]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1COCC1.CCN(CC)CC>[CH2:5]([N:12]1[CH2:17][CH2:16][N:15]([CH2:2][C:3]#[N:4])[CH2:14][CH2:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: N#CCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#CCN1CCN(Cc2ccccc2)CC1
Reaction time: 10 h

Procedure:
An excess of chloroacetonitrile (7 ml) was added in to a solution of benzylpiperazine (2 g, 10.5 mmol) in THF (100 ml) and Et3N (10 ml). The reaction was stirred for 10 hours before quenched with saturated aqueous NaHCO3 (100 ml). The aqueous phase was extracted with EtOAc (3×100 ml). The combined organic layer was dried over MgSO4 and concentrated to a residue, which was used in the further reactions without any purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][N:6]2[C:11]=1[CH:10]=[C:9]([C:12](O)=[O:13])[CH:8]=[CH:7]2)#[N:2].CC(C)CC(Cl)=O.CN1CCOCC1>O1CCCC1>[OH:13][CH2:12][C:9]1[CH:8]=[CH:7][N:6]2[C:11]([CH:10]=1)=[C:3]([C:1]#[N:2])[CH:4]=[CH:5]2
Reactant: N#Cc1ccn2ccc(C(=O)O)cc12
Agent: CC(C)CC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: N#Cc1ccn2ccc(CO)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
To a solution of 1-cyanoindolizine-7-carboxylic acid (0.20 g) in tetrahydrofuran (4.0 mL) were added 3-methylbutyrylchloride (0.16 g) and 4-methylmorpholine (0.13 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The insoluble material was removed from the reaction mixture by filtration. To the filtrate was added ethanol (4.0 mL) and sodium borohydride (0.20 g) was added under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 2 mol/L hydrochloric acid (5.0 mL), and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=30/70-100/0) to give the title compound (0.050 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1.[N+:11]([CH:14]=[C:15](SC)[S:16][CH3:17])([O-:13])=[O:12]>C(#N)C>[N+:11]([CH:14]=[C:15]([S:16][CH3:17])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)([O-:13])=[O:12]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCCCc1c[nH]cn1
Solvent: CC#N
Product: CSC(=C[N+](=O)[O-])NCCCCc1c[nH]cn1

Procedure:
A solution of 4-(4-aminobutyl)imidazole (from the dihydrobromine 3.6 g) and 1-nitro-2,2-bis-methylthioethylene (2.0 g) in acetonitrile (50 ml) is set aside at room temperature for 3 days. The product is chromatographed on a column of silica gel with elution by ethyl acetate to give 1-nitro-2-methylthio-2-[4-(4-imidazolyl)butylamino]ethylene. Reaction of this methylthio compound with hydrazine hydrate in the procedure of Example 3 results in the production of 1-nitro-2-[4-(4-imidazolyl)butylamino]-2-hydrazinoethylene.
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][NH:4][CH:3]([C:7]([O:9][CH3:10])=[O:8])[CH2:2]1.C(N(CC)C(C)C)(C)C.F[C:28]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:29]=1[C:30]#[N:31]>O1CCCC1>[C:30]([C:29]1[CH:32]=[C:33]([N+:36]([O-:38])=[O:37])[CH:34]=[CH:35][C:28]=1[N:4]1[CH2:5][CH2:6][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:2][CH:3]1[C:7]([O:9][CH3:10])=[O:8])#[N:31]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1c1ccc([N+](=O)[O-])cc1C#N

Procedure:
To a solution of 1-tert-butyl 3-methyl piperazine-1,3-dicarboxylate (80 g, 328 mmol) and N,N-diisopropylethylamine (192 mL, 741 mmol) in 300 mL of dry tetrahydrofuran was added 2-fluoro-5-nitrobenzonitrile (36 g, 219 mmol) at room temperature. The reaction mixture was heated to reflux for 36 hours. The reaction was concentrated and the resulting residue was purified by silica gel chromatography (30% ethyl acetate in hexane) to give the title compound: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.41 (s, 9H), 3.01-3.15 (m, 1H), 3.29-3.36 (m, 1H), 3.34-3.36 (m, 1H), 3.48-3.55 (m, 1H), 3.66 (s, 3H), 3.72-3.76 (m, 1H), 4.43-7.48 (m, 1H), 4.96-4.98 (m, 1H), 7.30 (d, J=9.1 Hz, 1H), 8.32 (dd, J=9.5, 2.8 Hz, 1H), 8.55 (d, J=2.8 Hz, 1H); MS (DCI/NH3) m/z 391 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:17]=[C:16](I)[C:10]3[N:11]([CH3:15])[C:12](=[O:14])[NH:13][C:9]=3[CH:8]=2)=[C:5]([CH3:19])[O:4][N:3]=1.[CH3:20][N:21]1[C:25](B(O)O)=[C:24]([CH3:29])[CH:23]=[N:22]1.C([O-])([O-])=O.[Cs+].[Cs+]>ICCC.COCCOC.O>[CH3:20][N:21]1[C:25]([C:16]2[C:10]3[N:11]([CH3:15])[C:12](=[O:14])[NH:13][C:9]=3[CH:8]=[C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:19])[CH:17]=2)=[C:24]([CH3:29])[CH:23]=[N:22]1
Reactant: Cc1cnn(C)c1B(O)O
Reactant: Cc1noc(C)c1-c1cc(I)c2c(c1)[nH]c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCI
Solvent: COCCOC
Solvent: O
Product: Cc1cnn(C)c1-c1cc(-c2c(C)noc2C)cc2[nH]c(=O)n(C)c12
Temperature: 140 °C
Reaction time: 1 h

Procedure:
To a microwave vial containing 5-(3,5-dimethylisoxazol-4-yl)-7-iodo-1-methyl-1H-benzo[d]imidazol-2(3H)-one (40 mg, 0.11 mmol, 1 equiv.) was added 1,4-dimethyl-1H-pyrazol-5-ylboronic acid (72 mg, 0.32 mmol, 3 equiv.), Cs2CO3 (141 mg, 0.43 mmol, 4 equiv.) and PEPPSI™-IPr catalyst (8 mg, 0.02 mmol, 0.1 equiv.) and dissolved in DME-H2O (20 mL, 0.2 M, 2/1, v/v). The mixture was heated to 140° C. After 1 hr, the reaction was complete. After cooling, the reaction was extracted with EtOAc and washed with water and saturated NH4C1. After drying with MgSO4, it was filtered and concentrated to dryness. Purification was carried out by reverse phase HPLC to furnish 7-(1,4-dimethyl-1H-pyrazol-5-yl)-5-(3,5-dimethylisoxazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)=[CH:10][C:9]([Cl:26])=[CH:8][CH:7]=2.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][S:48](Cl)(=[O:50])=[O:49])=[C:43]([N+:52]([O-:54])=[O:53])[CH:42]=1>>[CH:27]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([Cl:26])=[CH:8][CH:7]=2)[C:12]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[C:4]1[CH2:3][CH2:2][NH:1][S:48]([CH2:47][C:44]1[CH:45]=[CH:46][C:41]([Cl:40])=[CH:42][C:43]=1[N+:52]([O-:54])=[O:53])(=[O:50])=[O:49])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: COC(=O)c1ccc(OCCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CS(=O)(=O)Cl
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccc(Cl)cc3[N+](=O)[O-])n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 74 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step 6, Example 1)was added (4-chloro-2-nitro-phenyl)-methanesulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 74% yield.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:45]=[CH:44][C:36]([CH2:37][P:38](=[O:43])([O-:42])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4OC)[N:23]=3)=[C:14]3[C:18]=2[CH2:17][N:16]([CH3:19])[C:15]3=[O:20])[CH:7]=[N:6]1.[Na+:48].OCCCN1C=C(C2C=CC(NC3C(C(F)(F)F)=CN=C(NC4C=CC(CP(=O)(OCC)OCC)=CC=4)N=3)=C3C=2CN(C)C3=O)C=N1>>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:30])([F:31])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:34]=[CH:35][C:36]([CH2:37][P:38](=[O:42])([O-:43])[O:39][CH2:40][CH3:41])=[CH:44][CH:45]=4)[N:23]=3)=[C:14]3[C:18]=2[CH2:17][N:16]([CH3:19])[C:15]3=[O:20])[CH:7]=[N:6]1.[Na+:48]
Reactant: CCOP(=O)([O-])Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1
Agent: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)cc1)OCC
Agent: [Na+]
Product: CCOP(=O)([O-])Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)cc1

Procedure:
Prepared analogously to Compound 1A using diethyl (4-{[4-({7-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Compound 2B). 1H NMR (400 MHz, DMSO-d6) δ 10.66 (br s, 1H), 9.74 (s, 1H), 8.46-9.05 (m, 2H), 8.41 (s, 1H), 8.00 (br s, 1H), 7.82 (s, 1H), 7.10-7.53 (m, 4H), 4.62 (s, 2H), 4.20 (t, J=6.4 Hz, 2H), 3.70 (quin, J=7 Hz, 2H), 3.45 (t, J=6.1 Hz, 2H), 3.11 (s, 3H), 2.84 (d, J=20.2 Hz, 2H), 1.96 (quin, J=6.3 Hz, 2H), 1.01 (t, J=6.7 Hz, 3H) [OH proton obscured]. HRMS (ESI): m/z 646.14 [M+H]+. UPLC: tR=1.16 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:12][C:13]([CH3:15])=[CH2:14])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](OC)=[O:6].[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1.C(OCC)(=O)C>[OH:6][CH2:5][C:4]1[C:3]([CH2:12][C:13]([CH3:15])=[CH2:14])=[C:2]([OH:1])[CH:11]=[CH:10][CH:9]=1
Reactant: C=C(C)Cc1c(O)cccc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C(C)Cc1c(O)cccc1CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 101.5 %

Procedure:
Methyl 3-hydroxy-2-(2-methylallyl)benzoate (Intermediate 168, 410 mg, 1.99 mmol) was dissolved in tetrahydrofuran (5 ml) to give a colourless solution. The reaction mixture was cooled at 0° C. A solution of LiAlH4 2M in THF (1.09 ml, 2.19 mmol) was added dropwise and the reaction mixture was stirred at 0° C. for 30 min. After this time the reaction mixture was poured into ice and diluted with 60 ml of ethyl acetate. Phases were separated, the organic phase was dried over Na2SO4 and evaporated under vacuum to afford the title compound (360 mg) as a colorless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:28])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)=O)C.[BH4-].[Na+]>O1CCCC1>[CH:15]1([CH2:14][CH:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:12]([NH:11][C:8]2[S:9][CH:10]=[C:6]([CH2:4][OH:3])[N:7]=2)=[O:28])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CCOC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(Cl)c(Cl)c2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1nc(CO)cs1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 25 %

Procedure:
A solution of 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-4-carboxylic acid ethyl ester (prepared as in Example 1(B)(f), 200 mg, 0.45 mmol) in tetrahydrofuran (3 mL) at 25° C. was slowly treated with sodium borohydride (26.0 mg, 0.68 mmol). The reaction mixture was heated under reflux for 48 h. The reaction mixture was allowed to cool to 25° C. and then slowly quenched by the dropwise addition of water. The resulting reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(4-hydroxymethyl-thiazol-2-yl)-propionamide (44.9 mg, 25%) as a white solid: mp 88–90° C.; EI-HRMS m/e calcd for C18H20Cl2N2O2S (M+) 398.0623, found 398.0631.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[Cl:15][C:16]1[S:20][C:19]([C:21](O)=[O:22])=[CH:18][CH:17]=1>>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][CH:3]1[CH2:2][NH:1][C:21]([C:19]1[S:20][C:16]([Cl:15])=[CH:17][CH:18]=1)=[O:22])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)N1CCCC1CN
Product: CC(C)(C)OC(=O)N1CCCC1CNC(=O)c1ccc(Cl)s1

Procedure:
75.1 Using general procedure E, rac-2-aminomethyl-1-N-tert-butoxycarbonyl-pyrrolidine was coupled with 5-chlorothiophene-2-carboxylic acid to give rac-2-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester. Brown oil. MS 345.0 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][NH:22][CH:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][C:27]3[O:35][CH2:34][O:33][C:28]=3[CH:29]=2)[CH2:24]1>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:22]([CH3:21])[CH:23]3[CH2:32][CH2:31][C:30]4[C:25](=[CH:26][C:27]5[O:35][CH2:34][O:33][C:28]=5[CH:29]=4)[CH2:24]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: CNC1CCc2cc3c(cc2C1)OCO3
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C1CCc3cc4c(cc3C1)OCO4)CC2

Procedure:
The title compound is prepared from 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-chloropropane and 2-methylamino-6,7-methylenedioxy-1,2,3,4-tetra-hydronaphthalene analogously to Example 1. Mp: >148° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[CH2:4][N:5]1[C:9]([C:10](OCC)=[O:11])=[CH:8][N:7]=[CH:6]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1.C(OCC)(=O)C>[Cl:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:2]([Cl:1])[C:3]=1[CH2:4][N:5]1[C:9]([CH2:10][OH:11])=[CH:8][N:7]=[CH:6]1
Reactant: CCOC(=O)c1cncn1Cc1c(Cl)cccc1Cl
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1cncn1Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
220 mg (0.74 mmol) of the compound from Example 32A were dissolved in 3 ml of THF, and 0.74 ml (0.74 mmol) of a 1 M solution of lithium aluminum hydride in THF was added dropwise at 0° C. The mixture was stirred at RT for 1 h. For work-up, 5 ml of a saturated potassium sodium tartrate solution were added with ice cooling, the mixture was diluted with 10 ml of ethyl acetate and the precipitated solid was filtered off. The crude product was purified chromatographically [Method 19]. This gave 188 mg (99% of theory) of the target compound.
Reaction SMILES: C([Li])CCC.C[Si](C)(C)N[Si](C)(C)C.[CH2:15]([O:22][C:23]([CH2:25][N:26]1[C@H:29]([CH2:30]OS(C2C=CC=CC=2)(=O)=O)[CH2:28][C:27]1=[O:41])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH2:15]([O:22][C:23]([CH2:25][N:26]1[C:27](=[O:41])[C@@H:28]2[C@H:29]1[CH2:30]2)=[O:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(CN1C(=O)C[C@H]1COS(=O)(=O)c1ccccc1)OCc1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(CN1C(=O)[C@H]2C[C@H]21)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 40.9 %

Procedure:
n-Butyllithium (248)11 of 2.3M, 0.57 mmol) was added via syringe to a solution of hexamethyldisilazane (92 mg. 0.57 mmol) in freshly distilled tetrahydrofuran (3 ml) at -78° C. The resulting solution was stirred at -78° C. for 15 min prior to the addition of a solution of (S)-1-benzyloxycarbonylmethyl-4-benzene-sulfonyloxymethylazetidin-2-one (100 mg, 0.26 mmol) in tetrahydrofuran (1 ml). The reaction mixture was stirred at -78° C. for 1 hr., then was allowed to warm to 0° C. over about 30 min. After stirring an additional 15 min at 0° C. the reaction was quenched by addition of saturated aqueous ammonium chloride (5 ml), diluted with ether (50 ml) and washed with water (20 ml) and brine (10 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo to yield a yellow oil which was chromatographed on a 1000μ silica gel plate (ether) to yield 24.6 mg (41%) of (1R, 4S)-2-benzyloxycarbonylmethyl-2-azabicyclo[2.1,0]pentan-3-one. NMR (CHDl3) 7.33 (5H,S, aromatic), 5.15 (2H,S,CH2 --O), 3.8 (2H, ABq, CH2CO2 --), 3.9 (1H, ddd, J=1,3,4H1), 2.5 (1H, ddd, J=2,4,6.3, H4), 2.2 (1H, ddd, J=1,2,5,H5) 1.8 (1H, ddd, J=3,5,6,3,H5).