Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([CH2:14][N+:15]([O-])=O)[CH2:9][C:10](OC)=[O:11])=[CH:6][CH:5]=[CH:4][N:3]=1.[BH4-].[Na+]>CCO.[Ni](Cl)Cl>[F:1][C:2]1[C:7]([CH:8]2[CH2:14][NH:15][C:10](=[O:11])[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)CC(C[N+](=O)[O-])c1cccnc1F
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C1CC(c2cccnc2F)CN1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 3-(2-fluoropyridin-3-yl)-4-nitrobutanoate (0.991 g, 4.09 mmol) in EtOH (20 mL) at 0° C. was added nickel chloride (0.532 g, 4.10 mmol) and sodium borohydride (1.60 g, 42.3 mmol). The reaction mixture was stirred at 0° C. for 30 min, warmed to room temperature over 30 min, and stirred at room temperature for 30 min. The reaction mixture was quenched with saturated aqueous KH2PO4 and diluted with water and EtOAc. The mixture was filtered through a pad of Celite. The filtrate was extracted with EtOAc (6×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (5% to 10% MeOH in DCM) gave 4-(2-fluoropyridin-3-yl)pyrrolidin-2-one as a colorless oil. MS (ESI, pos. ion) m/z: 181.1 (M+1).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]/[C:8]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=1)=[O:9].[BH4-].[Na+]>CO>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][CH:8]([OH:9])[CH:7]=[CH:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])=[CH:13][C:14]=1[O:19][CH3:20]
Reactant: CCCCC/C=C/C(=O)CCc1ccc(O)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCC=CC(O)CCc1ccc(O)c(OC)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of [6]-shogaol (138 mg, 0.5 mmol) in methanol (10 mL) was cooled to −78° C., CeCl3.7H2O (745 mg, 2.0 mmol) was added and the mixture was stirred at −78° C. for 10 min. Then, NaBH4 (48 mg, 1.25 mmol) was added to the mixture and allowed to react at −78° C. for 30 min. The reaction was quenched by saturated aqueous NH4Cl solution (20 mL) and extracted with ethyl acetate (20 mL×3). The organic phases were separated, pooled, washed with water (10 mL×2) and brine (10 mL×1), dried over Na2SO4, and evaporated in vacuo. The residue was subjected to preparative TLC (hexane/EtOAc=3:1) to produce the title compound M6 as a colorless oil (139 mg, yield 100%); 1H NMR (600 MHz, CDCl3) δ 6.70 (1H, d, J=1.7 Hz, H-2′), 6.82 (1H, d, J=8.0 Hz, H-5′), 6.68 (1H, dd, J=8.0, 1.7 Hz, H-6′), 2.62 (2H, m, H-1), 1.85 (1H, m, H-2a), 1.78 (1H, m, H-2b), 4.07 (1H, m, H-3), 5.49 (1H, dd, J=15.3, 6.7 Hz, H-4), 5.65 (1H, dt, J=15.3, 6.7 Hz, H-5), 2.03 (2H, m, H-6), 1.38 (2H, m, H-7), 1.32-1.25 (4H, m, H-8 and H-9), 0.89 (3H, t, J=6.9 Hz, H-10), and 3.87 (3H, s, OMe-3′); positive APCIMS: m/z 279 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.[CH3:13][S:14]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)(=[O:16])=[O:15].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.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[Pd]Cl>[NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([C:20]2[CH:21]=[CH:22][C:17]([S:14]([CH3:13])(=[O:16])=[O:15])=[CH:18][CH:19]=2)=[CH:6][N:7]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1nc(Br)cnc1N
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1nc(-c2ccc(S(C)(=O)=O)cc2)cnc1N
Temperature: 110 °C
Yield: 30.2 %

Procedure:
A mixture of methyl 3-amino-6-bromo-pyrazine-2-carboxylate (1.5 g, 6.465 mmol), (4-methylsulfonylphenyl)boronic acid (1.552 g, 7.758 mmol), bis(triphenylphosphine) palladium(II)dichloride (226.9 mg, 0.3233 mmol), and Na2CO3 (9.700 mL of 2 M, 19.40 mmol) in DME (18.75 mL) were heated in the microwave at 110° C. for 1 hour. The resultant mixture was diluted with EtOAc and washed with water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography (50% EtOAc/hexanes) to afford the title compound (600 mg, 53% Yield).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6](=[O:13])[N:5]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1.C(N(CC)CC)C.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:7](=[O:12])[C:6](=[O:13])[N:5]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)CCn1c(=O)c(=O)[nH]c2cnc(Cl)nc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CCn1c(=O)c(=O)n(-c2ccccc2)c2cnc(Cl)nc21
Temperature: 25 °C
Reaction time: 60 h
Yield: 17.2 %

Procedure:
To a stirred solution of 2-chloro-8-(3-methylbutyl)-5,8-dihydropteridine-6,7-dione (500 mg, 1.86 mmol), triethylamine (1.88 g, 18.61 mmol) in dichloromethane (20 mL) was added copper acetate (678 mg, 3.73 mmol), phenyl boronic acid (455 mg, 3.73 mmol) and molecular sieves (4 Å, 2 g). The resulting mixture was and stirred at rt for 60 h with an air balloon. The reaction mixture was then diluted with dichloromethane (20 mL) and filtered through celite to remove insoluble material. The bulk of solvent from filtration was then removed under reduced pressure to give a crude residue, which was purified by a silica gel column chromatography (eluent: 40% ethyl acetate in hexanes) to provided the desired compound (110 mg). 1H NMR (CDCl3, 300 MHz) δ 1.05 (d, J=6.8 Hz, 6H), 1.60-1.79 (m, 3H), 4.38-4.42 (m, 2H), 7.21-7.38 (m, 3H), 7.48-7.65 (m, 2H), 7.79 (s, 1H).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=[O:4].[CH3:13][C:14]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:15]=1[O:16][CH2:17][CH:18]([OH:21])[CH2:19]O.CC1C=CC(S(O)(=O)=O)=CC=1.C(O)CCC>O.C1C=CC=CC=1>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=2[Cl:12])[O:21][CH:18]([CH2:17][O:16][C:15]2[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:14]=2[CH3:13])[CH2:19][O:4]1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Reactant: Cc1ccc(C)c(OCC(O)CO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: CCCCO
Product: Cc1ccc(C)c(OCC2COC(CBr)(c3ccc(Cl)cc3Cl)O2)c1

Procedure:
A mixture of 13.6 parts of 2-bromo-1-(2,4-dichlorophenyl)-1-ethanone, 12 parts of 3-(2,5-dimethylphenoxy)-1,2-propanediol, 3 parts of 4-methylbenzenesulfonic acid, 80 parts of butanol and 180 parts of benzene is stirred and refluxed for 24 hours with water-separator. The reaction mixture is evaporated and the residue is dissolved in trichloromethane. The solution is stirred with silicagel for 30 minutes. The latter is filtered off and the filtrate is evaporated, yielding A + B 2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-(2,5-dimethylphenoxymethyl)-1,3-dioxolane as a residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C:10](=O)[CH2:9][CH2:8]2.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[N:14]1([C:10]2[CH2:9][CH2:8][C:7]3[C:12]([CH:11]=2)=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=3)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNC1
Reactant: COc1cccc2c1CC(=O)CC2
Solvent: Cc1ccccc1
Product: COc1cccc2c1C=C(N1CCCC1)CC2

Procedure:
To 75 ml of toluene were added 3.52 g (20 mmol) of 8-methoxy-2-tetralone followed by 2.5 g of pyrrolidine. The mixture was heated to reflux for three hours after which the solvent was evaporated in vacuo to give 3-pyrrolidino-5-methoxy-1,2-dihydronaphthalene as a dark oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:53](=[NH:66])([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.Br[C:68]1[CH:102]=[CH:101][C:71]([CH2:72][O:73][CH2:74][CH2:75][O:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][N:83]2[CH2:87][C@@H:86]([C:88]3[CH:99]=[CH:98][C:91]4[O:92][C:93]([CH3:97])([CH3:96])[O:94][CH2:95][C:90]=4[CH:89]=3)[O:85][C:84]2=[O:100])=[CH:70][CH:69]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClCCl>[CH3:96][C:93]1([CH3:97])[O:92][C:91]2[CH:98]=[CH:99][C:88]([C@H:86]3[O:85][C:84](=[O:100])[N:83]([CH2:82][CH2:81][CH2:80][CH2:79][CH2:78][CH2:77][O:76][CH2:75][CH2:74][O:73][CH2:72][C:71]4[CH:70]=[CH:69][C:68]([N:66]=[C:53]([C:60]5[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=5)[C:54]5[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=5)=[CH:102][CH:101]=4)[CH2:87]3)=[CH:89][C:90]=2[CH2:95][O:94]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4ccc(Br)cc4)C(=O)O3)ccc2O1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4ccc(N=C(c5ccccc5)c5ccccc5)cc4)C(=O)O3)ccc2O1

Procedure:
A mixture of palladium (II) acetate (40 mg), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (166 mg) and cesium carbonate (811 mg) under nitrogen was treated with toluene (15 ml) and benzophenone imine (0.36 ml) followed by a solution of (5R)-3-(6-{2-[(4-bromobenzyl)oxy]ethoxy}hexyl)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (1.00 g) in toluene (10 ml). The stirred mixture was heated to 100° for 18 h. The mixture was cooled to 20°, dichloromethane (25 ml) was added and the mixture was filtered. The filtrate was evaporated in vacuo and the residue purified by chromatography on flash silica gel (30 mm diameter column). Elution with EtOAc-PE (3:2) gave the title compound (890 mg). LCMS RT=4.07 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:12]([NH:27][C:28]([NH2:30])=[S:29])([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Br[CH:32]([CH3:36])[C:33](=O)[CH3:34]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C@@:12]([NH:27][C:28]2[S:29][C:32]([CH3:36])=[C:33]([CH3:34])[N:30]=2)([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CC(=O)C(C)Br
Reactant: NC(=S)N[C@@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(C(F)(F)F)c1
Solvent: CCO
Product: Cc1nc(N[C@@](Cc2ccccc2)(c2ccc(F)cc2)c2cc(F)cc(C(F)(F)F)c2)sc1C
Temperature: 90 °C
Yield: 99.2 %

Procedure:
The thiourea (28 mg, 0.064 mmol) in ethanol (0.3 mL) in a two drum vial was added 3-bromobutan-2-one (28 mg, 0.18 mmol). The vial was heated in a shaker at 90° C. for 1 hour. The reaction was concentrated and crude mixture was purified by prep HPLC to give the (S)-N-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)4,5-dimethylthiazol-2-amine as a white solid (31 mg, 99% yield). LCMS: 3.63 min [M+1] 498.34 (4 min gradient, MeOH/H2O 0.1% TFA); 1H NMR (400 MHz, CDCl3) δ ppm 2.06 (s, 3H), 2.22 (s, 3H), 3.62-3.73 (m, 1H), 3.74-3.85 (m, 1H), 6.57 (d, J=7.58 Hz, 2H), 7.06-7.16 (m, 4H), 7.17-7.23 (m, 2H), 7.24-7.31 (m, 1H), 7.39 (dd, J=8.59, 5.05 Hz, 2H) 11.25(s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[C:29]([F:31])[CH:30]=1)[CH2:5][C@H:6]([NH:20]C(=O)OC(C)(C)C)[C@H:7]([OH:19])[CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>C(Cl)Cl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[NH2:20][C@@H:6]([CH2:5][C:4]1[CH:28]=[C:29]([F:31])[CH:30]=[C:2]([F:1])[CH:3]=1)[C@H:7]([OH:19])[CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1
Reactant: COc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reaction time: 1 h

Procedure:
tert-Butyl (1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propylcarbamate (VII, EXAMPLE 4, 258 mg, 0.59 mmol) is dissolved in methylene chloride (1 mL) at 20–25 degrees C., and trifluoroacetic acid (1 mL) is added with stirring under nitrogen. The reaction mixture is stirred at 20–25 degrees C. for 1 hour, whereupon the reaction mixture is concentrated under reduced pressure to give the title compound. The title compound is used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].O[CH:14]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[O:12][CH:14]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3cc(C(F)(F)F)ccc3F)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 2-fluoro-5-(trifluoromethyl)phenol and N-{3-[1-(6-hydroxy-6-phenylhexyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 585.3 (M+H)+.
Reaction SMILES: CS[C:3](=[NH:8])[NH:4][N+:5]([O-:7])=[O:6].[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>C(#N)C>[N+:5]([NH:4][C:3]([N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)=[NH:8])([O-:7])=[O:6]
Reactant: C1CCNC1
Reactant: CSC(=N)N[N+](=O)[O-]
Solvent: CC#N
Product: N=C(N[N+](=O)[O-])N1CCCC1
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
To a mixture of 1.0 g of S-methyl-N-nitroisothiourea and 15 ml of acetonitrile was dropwise added 0.61 g of pyrrolidine within 2 minutes, followed by stirring for 30 minutes. The reaction mixture was concentrated. The resulting precipitate was washed with ethyl ether to afford 1.09 g of 1-(N-nitroamidino)pyrrolidine as white crystals.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][OH:5].[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:7]([NH:14][C:3](=[O:2])[CH2:4][OH:5])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)CO
Reactant: NCc1ccccc1
Product: O=C(CO)NCc1ccccc1
Reaction time: 8 h

Procedure:
The procedure of 84A was followed with methyl2-hydroxyethanoate (8 g) and benzylamine (10 ml in 30 ml H2O). After one hour material precipitated out of solution. The mixture was stirred overnight, and the solid recovered by filtration to provide 4.12 g of white solid. The solvent was removed from the filtrate by vacuum to provide 4.71 g of material The solid and filtrate were combined and passed over a silica column eluting with a gradient of ethyl acetate to ethyl acetate/methanol (v:v, 1:1). Removal of solvent provided 8 g of white crystal product.
Reaction SMILES: C(O)(=O)C.O.[CH2:6]([NH:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][C:12]([C:18]([F:21])([F:20])[F:19])=[CH:11][N:10]=1)[CH3:7]>[Fe].C(O)C>[CH2:6]([NH:8][C:9]1[C:14]([NH2:15])=[CH:13][C:12]([C:18]([F:21])([F:19])[F:20])=[CH:11][N:10]=1)[CH3:7]
Reactant: CCNc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CCNc1ncc(C(F)(F)F)cc1N
Temperature: 70 °C
Yield: 67.8 %

Procedure:
A mixture of iron powder (700 mg), acetic acid (60 μl), ethanol (5 ml), and water (3 ml) was stirred with heating at 70° C., and then a mixture of N-ethyl-(3-nitro-5-trifluoromethylpyridin-2-yl)-amine (490 mg) and ethanol (10 ml) was added dropwise. The mixture was stirred with heating at 70° C. for 3 hours. The reaction mixture cooled to room temperature was filtered through Celite®, and the resulting filtrate was concentrated under reduced pressure. The resulting residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.29 g of N2-ethyl-5-trifluoromethylpyridin-2,3-diamine (Compound (1F)-8).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].[N-:25]=[N+:26]=[N-].[Na+].C(OCC)(=O)C>C(O)(=O)C>[N:1]([C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1)=[N+:25]=[N-:26]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)cc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N=[N+]=[N-])cc2)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 49 %

Procedure:
(S)-tert-Butyl 2-(4-aminophenyl)morpholine-4-carboxylate (150 mg, 0.54 mol) was dissolved in 3 M acetic acid, then cooled to 0° C. Sodium nitrite (93 mg, 1.35 mmol) was added and the yellow solution was stirred at 0° C. for 5 min. Then sodium azide (70 mg, 1.08 mmol) was added to the mixture and stirring was continued for 15 min. Ethyl acetate was added to dissolve the precipitate and stirring was continued for 15 min. The organic layer was separated and the aqueous layer was re-extracted with ethyl acetate. The combined organic layers were extracted with 0.1M citric acid solution and with 1M sodium bicarbonate solution subsequently. After drying with MgSO4 the organic layer was evaporated to yield crude (S)-tert-butyl 2-(4-azidophenyl)morpholine-4-carboxylate as an yellow oil (161 mg) which was used for the following cycloaddition reaction.
Reaction SMILES: C(OC([N:8]1[CH2:34][CH2:33][C:11]2([CH2:14][N:13]([C@H:15]3[C:23]4[C:18](=[CH:19][C:20]([C:24]5[CH:29]=[N:28][C:27]([C:30](=[O:32])[NH2:31])=[CH:26][N:25]=5)=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:35]>O1CCOCC1>[ClH:35].[ClH:35].[CH2:12]1[C:11]2([CH2:33][CH2:34][NH:8][CH2:9][CH2:10]2)[CH2:14][N:13]1[C@H:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]3[N:25]=[CH:26][C:27]([C:30]([NH2:31])=[O:32])=[N:28][CH:29]=3)=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN([C@@H]1CCc3cc(-c4cnc(C(N)=O)cn4)ccc31)C2
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)c1cnc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCNCC3)C2)cn1
Reaction time: 3 h
Yield: 45 %

Procedure:
To 2-[(R)-5-(5-carbamoyl-pyrazin-2-yl)-indan-1-yl]-2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester (10-1b, 150 mg, 0.32 mmol) was added 5 mL of 4N HCl in dioxane. The mixture was stirred for 3 hours. The volatiles were removed under reduced pressure to give the title compound as a brown solid (65 mg, 45%). MS (APCI) 364.2 (M+H)+. 1H NMR (CD3OD) δ 2.20-2.24 (m, 4H), 2.63 (s, 1H), 3.15 (d, 4H), 3.29-3.38 (m, 3H), 4.25 (s, 3H), 4.48 (s, 1H), 5.10 (br s, 1H), 7.79 (d, 1H), 8.18 (d, 1H), 8.24 (s, 1H), 9.22 (s, 1H), 9.30 (s, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:14]([CH3:16])[CH3:15])[C:6]([O:8][CH3:9])=[O:7])=[O:2].[Li+].[BH4-]>O1CCCC1>[OH:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:14]([CH3:16])[CH3:15])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(OC(C)C)c(C=O)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(C)C)c(CO)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Methyl 3-formyl-4-isopropoxy-benzoate (180 mg, 0.81 mmol) was dissolved in tetrahydrofuran (4.8 mL) and LiBH4 (35 mg, 1.6 mmol) was added. The reaction was stirred at room temperature for 30 minutes before it was quenched with methanol (3 mL). The reaction was neutralized by the addition of a saturated aqueous solution of sodium bicarbonate (3 mL) and was then extracted with ethyl acetate (3×10 mL). The combined organics were washed with a saturated aqueous solution of sodium chloride (1×10 mL), dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield methyl 3-(hydroxymethyl)-4-isopropoxy-benzoate (99%) as a viscous liquid. ESI-MS m/z calc. 224.3, found 225.3 (M+1)+; Retention time: 1.26 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 8.09 (s, 1H), 7.89 (d, J=8.6 Hz, 1H), 7.13 (d, J=8.6 Hz, 1H), 5.25 (t, J=5.6 Hz, 1H), 4.86-4.68 (m, 1H), 4.54 (d, J=5.6 Hz, 2H), 3.87 (s, 3H), 1.35 (d, J=6.0 Hz, 6H).
Reaction SMILES: [O:1]([CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][N:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12][CH:11]1O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[OH-]>S(=O)(=O)(O)O>[CH2:17]([N:13]1[CH2:14][C:15](=[O:16])[N:10]2[CH2:9][CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[CH:11]2[CH2:12]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CN(Cc2ccccc2)CC(O)N1CCOc1ccccc1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: O=C1CN(Cc2ccccc2)CC2c3ccccc3OCCN12
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
1-(2-Phenoxyethyl)-4-benzyl-2-hydroxy-6-oxopiperazine (4 g) was added to concentrated sulphuric acid (50 ml) at 0°-10° and the mixture stirred for 30 min. The resulting solution was poured onto ice, basified with NH4OH and extracted with chloroform to give the title compound as a pale oil (2 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][N:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12])[CH:5]=[CH:6][CH:7]=1.BrC1C=C(C=CC=1)N.C(#N)CC#N.O.[NH2:29][NH2:30]>>[NH2:14][C:13]1[C:10](=[N:9][NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[C:11]([NH2:12])=[N:30][N:29]=1
Reactant: N#CC(C#N)=NNc1cccc(Br)c1
Reactant: NN
Solvent: Nc1cccc(Br)c1
Solvent: O
Solvent: N#CCC#N
Product: NC1=NN=C(N)C1=NNc1cccc(Br)c1
Yield: 66 %

Procedure:
This compound was prepared using 125 mg (0.5 mmol) of 2-[(3-bromophenyl)-hydrazono]malononitrile, which was derived from 3-bromoaniline (172 mg, 1.0 mmol) and malononitrile (1.5 mmol) as. described in Example 8, and hydrazine hydrate. The hydrazine hydrate was added to the solution at a temperature of 75° C. despite the fact that the starting material had not fully dissolved. The solution cleared briefly and then a precipitate formed. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 93 mg (66%) of the title compound as an orange solid. 1H NMR (ppm, DMSO-d6): 6.2 (br s, 4H), 7.21-7.32 (m, 2H), 7.50-7.62 (m, 1H), 7.90 (s, 1H), 10.71 (s, 1H).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7]Cl.[CH3:9][C:10]1([CH3:30])[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:13]2[C:22]([CH3:29])=[C:23]([NH2:28])[C:24]([CH3:27])=[C:25]([CH3:26])[C:12]=2[O:11]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[ClH:2].[CH3:9][C:10]1([CH3:30])[CH:14]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:13]2[C:22]([CH3:29])=[C:23]([N:28]3[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]3)[C:24]([CH3:27])=[C:25]([CH3:26])[C:12]=2[O:11]1
Reactant: Cc1ccc(C2c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: Cc1ccc(C2c3c(C)c(N4CCNCC4)c(C)c(C)c3OC2(C)C)cc1
Temperature: 25 °C

Procedure:
Bis(2-chloroethyl)amine hydrochloride (18.7 g, 105 mmol) was added to a suspension of 2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine (29.5 g, 100 mmol) in 1-butanol (300 mL) and the mixture was refluxed for 24 hours under argon atmosphere. The reaction mixture was cooled to room temperature and then sodium carbonate (12.7 g, 120 mmol) was added. The resulting mixture was refluxed for 24 hours and concentrated under reduced pressure. The residue was diluted with water (500 ml) and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified on basic silica gel column chromatography (hexane/ethyl acetate=10/1) to obtain a free base of the title compound as an oil residue.