Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[C:15]([NH:17][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:14]=[CH:13][N:12]=1)([O-:3])=[O:2].[H-].[Na+].[Cl:27][C:28]1[C:33]([N:34]=[C:35]=[O:36])=[C:32]([Cl:37])[C:31]([O:38][CH3:39])=[CH:30][C:29]=1[O:40][CH3:41].O>C1COCC1>[Cl:27][C:28]1[C:29]([O:40][CH3:41])=[CH:30][C:31]([O:38][CH3:39])=[C:32]([Cl:37])[C:33]=1[NH:34][C:35](=[O:36])[N:17]([C:15]1[CH:16]=[C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[N:12]=[CH:13][N:14]=1)[CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=[N+]([O-])c1ccccc1Nc1cc(NCc2cccnc2)ncn1
Reactant: COc1cc(OC)c(Cl)c(N=C=O)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC)c(Cl)c(NC(=O)N(Cc2cccnc2)c2cc(Nc3ccccc3[N+](=O)[O-])ncn2)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
To a solution of N-(2-nitro-phenyl)-N′-pyridin-3-ylmethyl-pyrimidine-4,6-diamine (150 g, 0.467 mmol) in THF (15 mL) was added NaH (60%, 48 g, 1.2 mmol) at 0° C., and the mixture was stirred for 30 minutes at room temperature. A solution of 2,4-dichloro-3-isocyanato-1,5-dimethoxy-benzene (procedure 2A, steps a-d; 180 g, 0.73 mmol) was added dropwise at room temperature. The resulting mixture was stirred for 2 hours. Water (2 mL) was added to quench the reaction. The mixture was concentrated, and the residue was purified by flash chromatography on silica to obtain the title compound (85 mg, yield: 32%). MS (ESI): 570 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2([CH3:18])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10](=S)[NH:9]2)[CH:7]=1.[NH3:20].CO>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2([CH3:18])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10](=[NH:20])[NH:9]2)[CH:7]=1
Reactant: N
Reactant: CC1(c2cc(Br)ccc2F)NC(=S)COCC1(F)F
Solvent: CO
Product: CC1(c2cc(Br)ccc2F)NC(=N)COCC1(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5-methyl-1,4-oxazepane-3-thione (1.0 g, 2.83 mmol) and 10% NH3/MeOH (25 mL) was stirred in a sealed tube at rt for 24 h. Reaction mixture was concentrated and purified by column chromatography on silica gel with 5% MeOH, 2% NH3 in chloroform to furnish the title compound as a pale brown gum. Yield=1.1 g ( ) LCMS: RtH8=0.146 [M+H]+=337.0, 339.0,
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([N:5]([C@H:13]1[CH2:15][C@@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:4].[CH:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:23][C:2]([F:1])([F:22])[C:3]([N:5]([CH2:6][CH:7]1[CH2:8][CH2:9][N:10]([CH2:24][C:26]2[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=2)[CH2:11][CH2:12]1)[C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:4]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: O=C(N(CC1CCNCC1)[C@H]1C[C@@H]1c1ccccc1)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(O)c1ccc(CN2CCC(CN(C(=O)C(F)(F)F)[C@@H]3C[C@H]3c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.5 %

Procedure:
To a solution of 2,2,2-trifluoro-N-((1S,2R)-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (243 mg, 0.745 mmol) in 1,2-dichloroethane (DCE) (4 mL) were added 4-formylbenzoic acid (134 mg, 0.894 mmol) and sodium triacetoxyborohydride (252 mg, 1.191 mmol), and the mixture was stirred at room temperature for 18 h. The reaction was quenched with water (4 mL) and extracted with CH2Cl2 (3×). The extract was dried (Na2SO4) and concentrated. The residue was purified using column chromatography (silica gel, 0 to 5% MeOH/EtOAc) to give 180 mg of product as pale yellow solid. MS: (M+H)+=461.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.32 (m, 2H), 1.35-1.47 (m, 1H),1.53-1.82 (m, 3H), 1.88-2.05 (m, 2H), 2.81 (br. s., 2H), 3.09-3.22 (m, 2H), 3.26-3.41 (m, 2H), 3.27-3.43 (m, 2H), 7.09-7.35 (m, 5H), 7.39-7.50 (m, 2H), 7.86-7.94 (m, 2H).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=O)[C:5]1=[O:29])[CH:2]=[CH2:3].[C@@H:31]12[CH2:37][C@@H:34]([NH:35][CH2:36]1)[CH2:33][O:32]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[C@@H:31]12[CH2:37][C@@H:34]([N:35]([CH2:25][C@@H:24]([N:6]3[C@H:7]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[C@@H:8]([C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=4)[CH2:9][C@@:4]([CH2:1][CH:2]=[CH2:3])([CH3:30])[C:5]3=[O:29])[CH2:27][CH3:28])[CH2:36]1)[CH2:33][O:32]2
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Reactant: C1O[C@H]2CN[C@@H]1C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN2C[C@H]3C[C@@H]2CO3)C1=O
Reaction time: 8 h

Procedure:
To a solution of (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal (100 mg, 0.224 mmol; Example 91, Step C) in DCE (2 mL) was added (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane (Butora, G.; Goble, S.; Pastemak, A.; Yang, L.; Zhou, C.; Moyes, C. U.S. Patent Publication No. 2008/0081803 (50 mg, 0.504 mmol) followed by sodium triacetoxyborohydride (95 mg, 0.448 mmol) and acetic acid (1.2 μL, 0.022 mmol). After stirring overnight, the mixture was quenched with sat. aq. NaHCO3 solution. The mixture was extracted with ethyl acetate (2×). The combined organic layers were washed with sat. aq. NaCl solution, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel (eluent: 1 to 5% methanol/dichloromethane) to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=2)=[CH:4][C:3]=1[C@:17]1([CH3:29])[C:23]([F:25])([F:24])[C:22]([CH3:27])([CH3:26])[O:21][CH2:20][C:19](=O)[NH:18]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=2)=[CH:4][C:3]=1[C@:17]1([CH3:29])[C:23]([F:25])([F:24])[C:22]([CH3:27])([CH3:26])[O:21][CH2:20][C:19](=[S:39])[NH:18]1
Reactant: COc1ncc(-c2cc([C@@]3(C)NC(=O)COC(C)(C)C3(F)F)c(F)cc2F)cn1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: COc1ncc(-c2cc([C@@]3(C)NC(=S)COC(C)(C)C3(F)F)c(F)cc2F)cn1
Yield: 62.3 %

Procedure:
The reaction of (R)-5-[2,4-difluoro-5-(2-methoxy-pyrimidin-5-yl)-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one (82 mg, 198 μmol) with Lawesson's reagent (80.2 mg, 198 μmol) in 1,4-dioxane (3 ml) yielded the (R)-5-[2,4-difluoro-5-(2-methoxy-pyrimidin-5-yl)-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-thione (53 mg, 62% yield) as a white solid. MS (ISP): m/z=430.3 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[N:5]([CH2:20][O:21][CH3:22])[N:4]=1.[NH:23]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:22][O:21][CH2:20][N:5]1[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)=[CH:7][C:3]([CH2:2][N:23]2[CH2:29][CH2:28][CH2:27][N:26]([CH2:2][C:3]3[CH:7]=[C:6]([C:8]4[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=4)[N:5]([CH2:20][O:21][CH3:22])[N:4]=3)[CH2:25][CH2:24]2)=[N:4]1
Reactant: C1CNCCNC1
Reactant: COCn1nc(CCl)cc1-c1cc(OC)c(OC)c(OC)c1
Product: COCn1nc(CN2CCCN(Cc3cc(-c4cc(OC)c(OC)c(OC)c4)n(COC)n3)CC2)cc1-c1cc(OC)c(OC)c(OC)c1

Procedure:
3-Chloromethyl-1-methoxymethyl-5-(3,4,5-trimethoxyphenyl)pyrazole (95 mg) and homopiperazine (14 mg) were reacted in the same manner in Example 1 to obtain the title compound.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][C:8]=1[CH2:16][N:17]1[CH2:22][CH2:21][N:20]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:19][CH2:18]1)C.[OH-].[Na+:34]>C1COCC1.CO>[CH3:15][CH:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([O-:32])=[O:3])=[C:8]([CH2:16][N:17]2[CH2:18][CH2:19][N:20]([S:23]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)(=[O:25])=[O:24])[CH2:21][CH2:22]2)[CH:9]=1)[CH3:14].[Na+:34]
Reactant: CCOC(=O)COc1ccc(C(C)C)cc1CN1CCN(S(=O)(=O)c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1ccc(OCC(=O)[O-])c(CN2CCN(S(=O)(=O)c3ccccc3)CC2)c1

Procedure:
A solution of the product from step (e) (113 mg) in NaOH (0.25 ml, 1M), THF (1.5 ml) and MeOH (1 ml) was stirred for 4 h. The solvent was removed in vacuo and the residue triturated with ether to give the title compound (97 mg)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:19]O)[CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=2)[CH:7]=1.S(Cl)([Cl:23])=O.O>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH2:19][Cl:23])[CH:3]=1)[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(Br)cc(Oc2ccc(C(F)(F)F)cn2)c1
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)c1ccc(Oc2cc(Br)cc(CCl)c2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
To a solution of (3-bromo-5-(5-(trifluoromethyl)pyridin-2-yloxy)phenyl)methanol (5.5 g, 15.8 mmol) in dry THF (30 mL) cooled to 0° C. was added thionyl chloride (3.22 mL, 44.3 mmol) dropwise. The reaction was warmed to RT and stirred for 2 h. The reaction mixture was then cooled and water was added. The mixture was extracted with ethyl acetate three times. The organic layer was washed with saturated NaHCO3 solution and brine, dried over Na2SO4, and evaporated to dryness to give the title compound (4.7 g). 1H NMR (500 MHz, CDCl3): δ 8.44 (s, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.43 (s, 1H), 7.29 (s, 1H), 7.15 (s, 1H), 7.05 (d, J=8.5 Hz, 1H), 4.54 (s, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:33])([CH3:32])[C@@H:11]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])(=[O:7])=[O:6].[N-:34]=[N+:35]=[N-:36].[Na+]>CS(C)=O>[N:34]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:33])([CH3:32])[C@@H:11]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])(=[O:7])=[O:6])=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(CO[C@@H](C(=O)OCc2ccccc2)C(C)(C)COS(=O)(=O)CCCCl)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CO[C@@H](C(=O)OCc2ccccc2)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-])cc1

Procedure:
Following the general procedure for the preparation of azides of Description 16, phenylmethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-2-[(4-methoxyphenyl)methoxy]-3,3-dimethylbutanoate (31a) (0.44 g, 0.9 mmol) dissolved in 5 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 81 mg (1.1 mmol) of sodium azide (NaN3). After work-up, the crude title compound (31b) was purified by silica gel column chromatography and used in the next step. Rf=0.59 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3): δ=1.02 (s, 6H), 1.98-2.10 (m, 2H), 3.07-3.13 (m, 2H), 3.63-3.65 (m, 2H), 3.81 (s, 3H), 3.85 (s, 1H), 3.94 (d, J=9.2 Hz, 1H), 4.18 (d, J=9.2 Hz, 1H), 4.27 (d, J=11.2 Hz, 1H), 4.53 (d, J=10.8 Hz, 1H), 5.20 (s, 2H), 6.85 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.8 Hz, 2H), 7.37-7.39 (m, 5H) ppm. MS (ESI) m/z 528.15 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [S:1]([NH:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[CH2:17]2)[C:7]=1[C:8]#[N:9])(=[O:4])(=[O:3])[NH2:2].[OH-].[Na+].Cl>CCO>[NH2:9][C:8]1[C:7]2[C:10]([O:14][CH2:15][C@H:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[CH2:17]3)=[CH:11][CH:12]=[CH:13][C:6]=2[NH:5][S:1](=[O:3])(=[O:4])[N:2]=1
Reactant: CCCC(=O)N1CCC[C@H](COc2cccc(NS(N)(=O)=O)c2C#N)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCC(=O)N1CCC[C@H](COc2cccc3c2C(N)=NS(=O)(=O)N3)C1
Yield: 63.2 %

Procedure:
To a stirred solution of (S)-2-sulfamoylamino-6-((1-butyrylpiperidin-3-yl)methoxy)benzonitrile (Example 1a, 9.5 g, 24.97 mmol) in EtOH (65 mL) was added at room temperature aq.NaOH (2.0 N, 37 mL, 74.91 mmol). The reaction mixture was refluxed for 4 hrs then cooled to 0° C. and neutralized carefully with 2N HCl. The precipitate was collected by filtration, re-crystallized from EtOH/H2O, and dried under vacuum to give the title compound as a white solid (6 g) in 63% yield. 1H NMR (400 MHz, DMSO-d6) δ 0.82-0.86 (m, 3H), 1.30-1.51 (m, 4H), 1.65 (m, 1H), 1.82 (m, 1H), 2.01-2.21 (m, 2H), 2.22-2.27 (m, 2H), 2.71-3.12 (m, 2H), 3.63-3.86 (m, 1H), 4.03 (m, 2H), 4.12 (m, 1H), 6.60 (m, 1H), 6.75 (t, J=8.0 Hz, 1H), 7.43-7.45 (m, 1H), 7.77 (d, J=20 Hz, 1H), 8.36 (m, 1H), 10.91 (s, 1H). MS 381 (MH+). Elem. Anal. Calcd.: C, 53.67%; H, 6.36%; N, 14.73%. Found: C, 53.64%; H, 6.63%; N, 14.73%
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:4][C:3]1=2.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=1.N1CCCCC1>C(O)(=O)C>[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=[C:11]2[CH2:10][CH2:9][C:8]3[CH:7]=[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:4][C:3]=3[C:2]2=[O:1])[CH:18]=1
Reactant: CCOC(=O)c1ccc2c(c1)CCCC2=O
Reactant: O=Cc1cccnc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCOC(=O)c1ccc2c(c1)CCC(=Cc1cccnc1)C2=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 79.5 %

Procedure:
5.0 g of ethyl 5-oxo-5,6,7,8-tetrahydro-2-naphthalenecarboxylate was mixed with 2.5 g of 3-pyridinealdehyde, 10 ml of acetic acid and 10 ml of piperidine and then the mixture was stirred at 100° C. for 4 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate. 10% Hydrochloric acid was added to the solution. The aqueous layer was separated and neutralized by addition of sodium bicarbonate. The mixture was extracted with chloroform. The extract was washed with water, dried and then concentrated in vacuo. The residue was purified by silica gel column chromatography to give 5.6 g of ethyl 6-(3-pyridylmethylidene)-5-oxo-5,6,7,8-tetrahydro-2-naphthalenecarboxylate as pale yellow crystals with m.p. 112°-114° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.[F:29][C:30]([F:41])([F:40])[O:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=O.C(OC)(OC)OC.[BH4-].[Na+]>CO>[CH:37]1[CH:36]=[C:33]([CH2:34][NH:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:21][C:19]([C:18]2[CH:27]=[CH:28][C:15]([CH2:14][N:7]([CH2:8][C:9]3[NH:13][CH:12]=[CH:11][N:10]=3)[CH2:6][C:2]3[NH:3][CH:4]=[CH:5][N:1]=3)=[CH:16][CH:17]=2)=[O:20])[C:32]([O:31][C:30]([F:29])([F:40])[F:41])=[CH:39][CH:38]=1
Reactant: O=Cc1ccccc1OC(F)(F)F
Reactant: NCCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: O=C(NCCCCNCc1ccccc1OC(F)(F)F)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (50.6 mg) obtained in Example 3-2 was dissolved in anhydrous methanol (2.0 ml) and added with 2-trifluoromethoxybenzaldehyde (manufactured by Avocado Co., Ltd.) (0.0290 ml) and trimethyl orthoformate (0.0430 ml), followed by stirring at room temperature for 30 minutes. Then, the solution was added with sodium borohydride (14.8 mg), followed by stirring at room temperature for 15 minutes. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution, followed by drying with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then treated with hydrochloric acid. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (39.7 mg) of the subject compound as a white solid.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=2)[CH:9]=[C:8]([CH3:19])[N:7]=1)=[O:5])C.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=1>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=3)[CH:9]=[C:8]([CH3:19])[N:7]=2)=[O:5])=[N:22][CH:23]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: CCOC(=O)c1cc(-c2cncc(F)c2)cc(C)n1
Product: Cc1cc(-c2cncc(F)c2)cc(C(=O)Nc2ccc(Cl)cn2)n1

Procedure:
The title compound, was prepared from 5-Fluoro-6′-methyl-[3,4′]bipyridinyl-2′-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 2-Amino-5-chloropyridine instead of 3-chloroaniline to yield the final compound as a white solid, MS (ISP): m/e=343.1, 345.0 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:20][C:6]2[C:7]3[NH:8][C:9](=[O:19])[C:10](=[O:18])[NH:11][C:12]=3[CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:5]=2[CH2:4]1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C>O>[CH3:1][N:2]([CH:3]1[CH2:20][C:6]2[C:7]3[NH:8][C:9](=[O:19])[C:10](=[O:18])[NH:11][C:12]=3[CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:5]=2[CH2:4]1)[C:21](=[O:23])[CH3:22]
Reactant: CNC1Cc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N(C)C1Cc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 8-methylamino-6-nitro-4,7,8,9-tetrahydro-1H-cyclopenta[f]quinoxaline-2,3-dione (0.5 g. 1.6 mmol), acetic anhydride (0.5 g, 5 mmol), triethylamine (0.5 g, 5 mmol) in water (5 mL) was stirred for 15 min at room temperature. The solid was collected by filtration, washed with 2N HCl, then washed with diethyl ether and dried (0.5 g). Calc'd for C14 H14N4O5 : C, 52.83; H, 4.43; N, 17.60; found: C, 48.62; H, 4.26; N, 15.50.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[C:7](/[CH:10]=[C:11]2\[NH:12][C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].[ClH:39].[NH2:40][C:41]1[S:42][CH:43]=[C:44]([CH2:46][Cl:47])[N:45]=1.Cl>CN(C=O)C.CCOCC>[ClH:47].[ClH:39].[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[C:7](/[CH:10]=[C:11]2\[N:12]([CH2:46][C:44]3[N:45]=[C:41]([NH2:40])[S:42][CH:43]=3)[C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C2\NC(=O)N(CCCC)C2=O)n1Cc1ccc(C(=O)OC)cc1
Reactant: Nc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCc1ncc(/C=C2/C(=O)N(CCCC)C(=O)N2Cc2csc(N)n2)n1Cc1ccc(C(=O)OC)cc1
Reaction time: 48 h

Procedure:
To a solution of methyl Z-4-[[2-butyl-5-[(1-butyl-2,5-dioxo-4-imidazolidinylidene) methyl]-1H-imidazol-1-yl]methyl]benzoate (0.569 g, 1.2 mmol) in DMF (5 mL) is added K2CO3 (2.0 g, 15 mmol). After stirring for 5 minutes 2-amino-4-chloromethylthiazole hydrochloride (0.222 g, 1.2 mmol) is added. The mixture is stirred for 48 hours and the filtered. The filtrate is concentrated in vacuo and dissolved in methylene chloride (30 mL). This solution is washed with water and drived over K2CO3 and charcoal. A viscous oil is obtained by evaporation of the solvents in vacuo. This oil is dissolved in ether and treated with ethereal HCl to precipitate a gum which is collected by decantation. This gum is recrystallized from 2-propanol/ether.
Reaction SMILES: [CH2:1]([C:3]([C:21]1[O:22][C:23]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][C:24]=2[CH:25]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].Cl.C([O:36][C:37](=[O:41])[CH2:38][NH:39][CH3:40])C.[OH-].[Na+]>>[CH2:4]([C:3]([C:21]1[O:22][C:23]2[CH:29]=[CH:28][C:27]([C:30]([N:39]([CH2:38][C:37]([OH:41])=[O:36])[CH3:40])=[O:31])=[CH:26][C:24]=2[CH:25]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:18])([CH3:16])[CH3:17])=[C:8]([CH3:20])[CH:7]=1)[CH2:1][CH3:2])[CH3:5]
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc2cc(C(=O)O)ccc2o1
Reactant: CCOC(=O)CNC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc2cc(C(=O)N(C)CC(=O)O)ccc2o1

Procedure:
2-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-benzofuran-5-carboxylic acid (152 mg, 346 mmol) HATU (145 mg, 380 mmol) DIEA (0.35 ml, 2.07 mmol) and sarcosine ethyl ester hydrochloride (63 mg, 0.415 mmol) are reacted followed by base hydrolysis with 2N NaOH in an analogous manner to example E from to yield (78 mg, 56%). MS (ES) m/e: 508.3 (M−1)
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH3:5][N:6]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[C:9]([C:15]([NH:17][NH2:18])=[O:16])[CH:8]=[N:7]1>O.Cl>[CH3:5][N:6]1[C:10]([S:11]([NH2:12])(=[O:13])=[O:14])=[C:9]([C:15]([N:17]=[N+:18]=[N-:1])=[O:16])[CH:8]=[N:7]1
Reactant: Cn1ncc(C(=O)NN)c1S(N)(=O)=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cn1ncc(C(=O)N=[N+]=[N-])c1S(N)(=O)=O
Reaction time: 0.25 h
Yield: 50.2 %

Procedure:
A solution of sodium nitrite (0.19 g) in 5 ml of water was added dropwise to a stirred solution of 1-methyl-5-sulfamoylpyrazole-4-carbohydrazide (0.55 g) in 8 ml of 1M hydrochloric acid at 0° C. The resulting mixture was stirred for 15 min and then filtered. The filter cake was washed with water and dried in vacuum to give 0.29 g (47%) of the title compound as a crystalline solid. The product was pure according to TLC (ethyl acetate) and was used immediately for the next step.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH:7]1[CH2:11][CH:10]=[C:9]([CH3:12])[C:8]1([CH3:14])[CH3:13])[CH:3]=[O:4].[CH3:15][Li].S([O-])([O-])(=O)=O.[Na+].[Na+].O>C(OCC)C>[CH3:1][CH:2]([CH2:5][CH2:6][CH:7]1[CH2:11][CH:10]=[C:9]([CH3:12])[C:8]1([CH3:13])[CH3:14])[CH:3]([OH:4])[CH3:15]
Reactant: CC1=CCC(CCC(C)C=O)C1(C)C
Reactant: [Li]C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC1=CCC(CCC(C)C(C)O)C1(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
A solution of 20.8 g (0.12 mole) of 2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)butanal dissolved in ethyl ether-anhydrous (50 ml) was added to a stirred solution of methyllithium (1.7 M) in ethyl ether (250 ml; 0.14 mole) which was previously cooled to 0° C. The mixture was stirred at 0°-5° C for 1.0 hour and then heated at reflux (36° C) for 3.0 hours. The mixture was cooled to 0° C and excess methyllithium was decomposed by slow dropwise addition of saturated sodium sulfate solution (50 ml). The mixture was poured into 150 ml of water, the lower aqueous layer was drawn off and extracted twice with 100 ml of ether. The ether extracts were combined, washed with 150 ml of brine, dried over sodium sulfate, filtered and the solvent removed by distillation. The residual oil was fractionally distilled to yield 3-methyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pentan-2-ol: 20.4 g (81% yield); bp 96°-98° (0.9 mm); mol wt. 210 (ms).