Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[CH:30]=[CH:29][C:12]2[CH2:13][C@@H:14]3[C@H:19]([CH3:20])[C@:18]([CH3:21])([C:11]=2[CH:10]=1)[CH2:17][CH2:16][N:15]3C(OC(C)(C)C)=O)=[O:8].[ClH:37].O1CCOCC1>>[ClH:37].[CH3:1][O:2][C:3]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[CH:30]=[CH:29][C:12]2[CH2:13][C@@H:14]3[C@H:19]([CH3:20])[C@:18]([CH3:21])([C:11]=2[CH:10]=1)[CH2:17][CH2:16][NH:15]3)=[O:8]
Reactant: COc1ccc(CNC(=O)c2ccc3c(c2)[C@]2(C)CCN(C(=O)OC(C)(C)C)[C@H](C3)[C@@H]2C)c(OC)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(CNC(=O)c2ccc3c(c2)[C@]2(C)CCN[C@H](C3)[C@@H]2C)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
A mixture of (2R,6R,11R)-tert-butyl 8-((2,4-dimethoxybenzyl)carbamoyl)-6,11-dimethyl-1,2,5,6-tetrahydro-2,6-methanobenzo[d]azocine-3(4H)-carboxylate (4.00 g, 8.09 mmol) in 4N HCl/dioxane was stirred at ambient temperature overnight. The majority of the solvent was decanted and the residue washed with diethyl ether (500 mL). The resulting solid was dried under reduced pressure giving (2R,6R,11R)-N-(2,4-dimethoxybenzyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxamide hydrochloride (3.35 g, 96% yield); LC/MS (M+H)+=395.5.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1.[Cl-].[Na+].O.CCOC(C)=O>[CH3:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:8][CH:9]=[CH:10][N:11]=1
Reactant: COC(=O)c1cccnc1C
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncccc1CO
Reaction time: 0.33 h
Yield: 72.7 %

Procedure:
To a stirring solution of 1.5 g of methyl 2-methylnicotinate in 20 mL of THF at 0° C. was added 844 mg of LiAlH4. After 20 min., 0.84 mL of H2O, 0.84 mL of 15% aqueous NaOH, and 2.5 mL of brine. EtOAc was added, the ice bath removed, and stirring was continued for 1 h. The mixture was filtered through Celite and concentrated to give 889 mg of crude (2-methylpyridin-3-yl)methanol which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].O=[C:16]([CH3:20])[CH:17]=[N:18][OH:19].S([O-])([O-])(=O)=O.[Mg+2].C>CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[C:16]([CH3:20])[CH:17]=[N:18][OH:19]
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CC(=O)C=NO
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CC(C=NO)=NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2,6-dichloro-4-trifluoromethylphenylhydrazine (10.2 g) in ether (15 ml) was added with cooling to a solution of `2-oxopropanal 1-oxime (3.62 g) in ether (15 ml) at 0°. The mixture was stirred at room temperature overnight and magnesium sulphate and charcoal added. The mixture was filtered and solvent evaporated under reduced pressure. The residue was purified by column chromatography to give 2-(2,6-dichloro-4-trifluoromethylphenylhydrazono)propanal 1-oxime, m.p, c.108°.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4](Cl)[N:3]=1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([NH:18][CH3:19])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:18]([C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH3:19])[N:3]=1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Reactant: CNc1ccc(OC)cc1
Product: COc1ccc(N(C)c2nc(Cl)nc3[nH]cnc23)cc1

Procedure:
The title compound was prepared from 2,6-dichloro-9H-purine (50 mg, 0.265) and 4-methoxy-N-methylaniline (40 mg, 0.291 mmol) by a procedure similar to example 1b and was isolated as off white powder (10 mg, 20%). 1H NMR (CDCl3): 7.81 (s, 1H), 7.37 (d, J=8.4 Hz, 2H), 7.04 (d, J=8.4 Hz, 2H), 3.93 (s, 3H), 3.77 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([SH:10])=[C:6]([CH:9]=1)[CH:7]=O.[F:11][C:12]([F:21])([F:20])/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])([O-])=O.[K+].[K+].Cl>C(OCC)(=O)C.CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH:13]([C:12]([F:11])([F:21])[F:20])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:9]=1
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: Cc1ccc(S)c(C=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(C)ccc2SC1C(F)(F)F
Yield: 69.4 %

Procedure:
The 5-methyl-2-mercaptobenzaldehyde (Step 1) (3.25 g, 21.3 mmol) was added to DMF (5 mL) and ethyl 4,4,4-trifluorocrotonate (4.32 g, 25.7 mmol). With stirring, K2CO3 (3.78 g, 27.3 mmol) was added causing the reaction to become a deep red. The reaction was stirred at room temperature for 20 hours, acidified with 3N HCl, diluted with ethyl acetate and washed with water, saturated NaHCO3 solution, brine, dried over MgSO4, filtered and concentrated in vacuo yielding an oil. The oil was crystallized from diethyl ether-petroleum ether to give ethyl 6-methyl-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylate as a light yellow solid (4.47 g, 69%): mp 93.1-94.7° C. 1H NMR (acetone-d6/300 MHz) 7.94 (s, 1H), 7.41 (s, 1H), 7.31 (d, 1H, J=7.9 Hz), 7.25 (d, 1H, J=7.9 Hz), 4.96 (q, 1H, J=8.5 Hz), 4.33 (m, 2H), 2.34 (s, 3H), 1.35 (t, 3H, J=7.0 Hz). FABLRMS m/z 309 (M+Li).
Reaction SMILES: C(O)=O.[CH2:4]([N:11]1[CH2:25][CH2:24][N:14]2[C:15]3[N:23]=[CH:22][CH:21]=[CH:20][C:16]=3[NH:17][CH2:18][CH2:19][CH:13]2[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:26]=O>C(Cl)Cl>[CH2:4]([N:11]1[CH2:25][CH2:24][N:14]2[C:15]3[N:23]=[CH:22][CH:21]=[CH:20][C:16]=3[N:17]([CH3:26])[CH2:18][CH2:19][CH:13]2[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C=O
Reactant: c1ccc(CN2CCN3c4ncccc4NCCC3C2)cc1
Solvent: ClCCl
Solvent: O=CO
Product: CN1CCC2CN(Cc3ccccc3)CCN2c2ncccc21
Temperature: 110 °C

Procedure:
Formic acid (88%, 3 mL) was added to a solution of the product of Example 52 (97 mg, 0.231 mmol) in CH2Cl2 (2 mL). Aqueous formalin (0.5 mL, 6.5 mmol) was added, and the mixture was heated at 110° C. for 45 minutes, then cooled to room temperature and concentrated under vacuum. The residue was purified by HPLC (30×100 mm XBridge™ column eluting with aqueous 0.1 M(NH4)2CO3-methanol, 80:20-0:100 over 15 minutes) to provide the title compound: 1H NMR (300 MHz, CD3OD) δ ppm 1.62-1.74 (m, 1H), 1.77-1.91 (m, 1H), 2.23 (t, J=10.5 Hz, 1H), 2.39 (td, J=11.0, 3.1 Hz, 1H), 2.70 (ddd, J=10.8, 2.4, 1.9 Hz, 1H), 2.79 (s, 3H), 2.80-2.88 (m, 1H), 2.96 (ddd, J=11.1, 6.5, 4.4 Hz, 1H), 3.23-3.29 (m, 1H), 3.32-3.40 (m, 2H), 3.50 (dt, J=12.9, 3.1 Hz, 1H), 3.59 (s, 2H), 6.87 (dd, J=7.8, 4.7 Hz, 1H), 7.08 (dd, J=7.8, 1.4 Hz, 1H), 7.22-7.39 (m, 5H), 7.71 (dd, J=4.9, 1.5 Hz, 1H); MS (ESI) m/z 309 (M+H)+.
Reaction SMILES: [Br:1]C(Br)(Br)C1C=C(C)C(O)=C(C)C=1.[Br:14][C:15]1[C:20]([CH3:21])=[C:19]([OH:22])[C:18]([CH3:23])=[C:17]([Br:24])[C:16]=1[CH3:25]>>[Br:1][CH2:25][C:16]1[C:15]([Br:14])=[C:20]([CH3:21])[C:19]([OH:22])=[C:18]([CH3:23])[C:17]=1[Br:24]
Reactant: Cc1cc(C(Br)(Br)Br)cc(C)c1O
Reactant: Cc1c(O)c(C)c(Br)c(C)c1Br
Product: Cc1c(O)c(C)c(Br)c(CBr)c1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The temperature is increased to 70° C.-75° C., and a solution is obtained. The solution is held at 70° C.-75° C. for 3 hours. The unreacted bromine is removed by distillation with the aid of 1 liter of carbon tetrachloride. When 1 liter of solvent remains with the product, the solution is cooled to 25° C. The light brown solid which is obtained is filtered and is dried under vacuum for 5 hours. A yield of 250 g (67 percent) is obtained, which analysis by gas chromatography shows to be 97 percent tribromomesitol and 3 percent dibromomesitol. The product has a melting point of 144° C.-146° C. and has the following proton nuclear magnetic resonance spectrum (CDCl3), δ: 2.30 (s, 6H), 4.90 (s, 2H), which is consistent with the structure of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][CH:29]([N:32]5[CH2:33][CH2:34][O:35][CH2:36][CH2:37]5)[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:16])[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1cccc(Cl)c1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(C#N)c2)cnn1-c1cccc(Cl)c1
Yield: 23.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(3-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (2.0 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (2.4 g), the title compound (1.0 g) was obtained, melting point: 210° C.
Reaction SMILES: [ClH:1].Cl.[Br:3][C:4]1[CH:5]=[C:6]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[C:7]([N:9]([CH2:11][C@H:12]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[CH2:13][CH2:14][N:15]1[CH2:18][CH:17]([N:19]2[CH2:24][CH2:23][N:22]3[C:25](=[O:29])[CH2:26][CH2:27][CH2:28][CH:21]3[CH2:20]2)[CH2:16]1)[CH3:10])=[O:8].N1CC(N2CCN(C(C3CC3)=O)CC2)C1.C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[ClH:1].[ClH:1].[Br:3][C:4]1[CH:5]=[C:6]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[C:7]([N:9]([CH2:11][C@H:12]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[CH2:13][CH2:14][N:15]1[CH2:16][CH:17]([N:19]2[CH2:20][CH2:21][N:22]([C:25]([CH:26]3[CH2:27][CH2:28]3)=[O:29])[CH2:23][CH2:24]2)[CH2:18]1)[CH3:10])=[O:8]
Reactant: CN(C[C@@H](CCN1CC(N2CCN3C(=O)CCCC3C2)C1)c1ccc(F)cc1)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C(C1CC1)N1CCN(C2CNC2)CC1
Agent: [BH3-]C#N
Solvent: CO
Product: CN(C[C@@H](CCN1CC(N2CCN(C(=O)C3CC3)CC2)C1)c1ccc(F)cc1)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.8 %

Procedure:
To a solution of 3-bromo-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-5-(trifluoromethyl)benzamide (see Method 3; 450 mg, 1.0 mmol) and 1-azetidin-3-yl-4-(cyclopropylcarbonyl)piperazine (see Method 14; ˜0.9 mmol) in methanol (50 mL) was added a solution of sodium cyano borohydride (250 mg, 4.0 mmol) and zinc chloride (270 mg, 2.0 mmol) in methanol (30 mL). The reaction mixture was stirred at RT for 15 min and then the solvent was removed by evaporation. The residue was partitioned between ethyl acetate (50 mL) and water (20 mL). The organic solution was washed with brine and then dried over Na2SO4. The solvent was removed by evaporation and the residue was dissolved in ethyl acetate. The product was purified by means of silica gel chromatography first eluting with ethyl acetate and then with a mixture of ethyl acetate, methanol and triethylamine (9:1:1). The proper fractions were combined and concentrated on a rotavapor and then the residue was co-evaporated twice using methylene chloride. The residue was dissolved in methylene chloride and to the solution was added HCl-saturated diethyl ether (1 mL). The solvent was removed by evaporation and then the residue was co-evaporated twice with methylene chloride. There was obtained 220 mg (30%) of the title compound. 1H NMR (400 MHz, CDCl3): 0.8-1.0 (cm, 4H), 1.2-4.7 (cm, 24H), 6.9-8.0 (cm, 7H): m/z 640 (M+1)+.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]2[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].CI.[C:17](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:4]1[CH:14]=[CH:13][C:7]2[O:8][CH2:9][C:10](=[O:12])[N:11]([CH3:17])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc2c(c1)NC(=O)CO2
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)N(C)C(=O)CO2
Yield: 83.9 %

Procedure:
6-Acetyl-2H-benzo[b][1,4]oxazin-3(4H)-one (1 g, 5.23 mmol), methyl iodide (1.13 g, 7.84 mmol) and cesium carbonate (2.55 g, 7.84 mmol) were dissolved in DMF (2 mL). The reaction mixture was irradiated by microwave for 30 minutes at 100° C. The solvent was removed and extracted with dichloromethane. Purification by silica chromatography (ISCO) produced 6-acetyl-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (0.9 g, 84%). 1H NMR (400 MHz, CDCl3): δ 7.63 (s, 1H), 7.60 (d, 1H), 7.01 (d, 1H), 4.70 (s, 2H), 3.42 (s, 3H), 2.60 (s, 3H); MS (ESI) m/z: Calculated for C11H11NO3: 205.1. found: 206.1 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](O)=[O:24])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[N:27]=[C:28]([NH2:34])[CH2:29][S:30]([CH3:33])(=[O:32])=[O:31]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:24][N:34]=[C:28]([CH2:29][S:30]([CH3:33])(=[O:32])=[O:31])[N:27]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: CS(=O)(=O)CC(N)=NO
Product: CCc1ccc(C2CC(c3nc(CS(C)(=O)=O)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
60 mg (0.17 mmol) of the compound from Example 38A and 40 mg (0.26 mmol) of N′-hydroxy-2-(methylsulphonyl)ethanimidamide were reacted according to the General Method 2. Yield: 15 mg (18% of theory)
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[CH2:11]1[C:15]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][N:12]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(#N)C.[CH3:31][S:32](Cl)(=O)=O>>[CH3:31][S:32][N:18]1[CH2:17][CH2:16][C:15]2([CH2:11][N:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][CH2:14]2)[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CSN1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Reaction time: 1 h

Procedure:
N,N-Diisopropylethylamine (30.0 μL, 0.000172 mol) was added to tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate hydrochloride (18.5 mg, 0.0000668 mol) in acetonitrile (1.0 mL, 0.019 mol), followed by methanesulfonyl chloride (10.0 μL, 0.000129 mol). After stirring for 1 h the solvent was evaporated, and the residue was dried under high vacuum and was used in the next step without further purification.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[F:20][CH:21]([F:35])[O:22][C:23]1[CH:24]=[C:25]([CH:32]=[CH:33][CH:34]=1)[CH2:26][NH:27][C:28](=[O:31])[CH2:29][NH2:30]>CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:30][CH2:29][C:28]([NH:27][CH2:26][C:25]2[CH:32]=[CH:33][CH:34]=[C:23]([O:22][CH:21]([F:20])[F:35])[CH:24]=2)=[O:31])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NCC(=O)NCc1cccc(OC(F)F)c1
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C(NCC(=O)NCc2cccc(OC(F)F)c2)=C(c2ccccc2)S1(=O)=O
Temperature: 130 °C
Yield: 41.2 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.175 g, 0.58 mmol), N-[3-(difluoromethoxy)benzyl]glycinamide (0.159 g, 0.69 mmol) and TEA (0.23 g, 2.31 mmol) was dissolved in dry DMF (3 ml) and heated in a microwave reactor at 130° C. for 30 mins. The reaction mixture was purified by preparative HPLC to yield the title compound (0.118 g, 41%). 1H NMR (500 MHz, CDCl3): δ 7.46-7.35 (m, 5H), 7.35-7.28 (m, 1H), 7.09-7.01 (m, 2H), 6.99-6.94 (m, 1H), 6.50 (t, 1H), 6.02-5.94 (m, 1H), 5.91-5.82 (m, 1H), 4.37-4.31 (m, 2H), 3.53-3.48 (m, 2H), 1.71 (s, 9H); 13C NMR (125 MHz, CDCl3): δ 167.3, 159.3, 139.9, 134.9, 131.5, 130.5, 130.2, 129.0, 125.1, 124.5, 119.4, 119.0, 116.0, 113.9, 109.9, 62.0, 46.8, 43.4, 27.8; Mass Spectrum: M−H+ 494.
Reaction SMILES: N1([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]3([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:14])=[CH:8][CH:7]=2)C=NC=N1.[O:21]1[C:25](C2C=CC(N)=CC=2)=[CH:24][N:23]=[CH:22]1>>[NH2:20][C:15]1([C:13]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([C:25]3[O:21][CH:22]=[N:23][CH:24]=3)=[CH:11][CH:10]=2)=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: NC1(C(=O)Nc2ccc(-n3cncn3)cc2)CCCC1
Reactant: Nc1ccc(-c2cnco2)cc1
Product: NC1(C(=O)Nc2ccc(-c3cnco3)cc2)CCCC1

Procedure:
The title compound was prepared as described above for N-(4-(1H-1,2,4-triazol-1-yl)phenyl)-1-aminocyclopentanecarboxamide using 4-(oxazol-5-yl)benzenamine as the amine counterpart. LCMS: m/e 272 (M+H)+, ret time 1.03 min, column 3, 2 minute gradient.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][C:15]([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)[CH2:14]1)C1C=CC=CC=1>CO.[Pd]>[C:18]1([C:15]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:16][CH2:17][N:13]([CH2:12][CH2:11][NH2:10])[CH2:14]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(NCCN1CCC(c2ccccc2)(c2ccccc2)C1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NCCN1CCC(c2ccccc2)(c2ccccc2)C1
Reaction time: 15 h

Procedure:
[2-(3,3-Diphenyl-pyrrolidin-1-yl)-ethyl]-carbamic acid benzyl ester (1.44 g, 3.6 mmol) is dissolved in MeOH (50 mL) and Pd—C (10%, 150 mg) is added. The mixture is stirred under hydrogen atmosphere for 15 h. The mixture is filtered and the filtrate evaporated to provide the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([N+:14]([O-])=O)=[CH:9][CH:10]=2)[CH:5]=1)([O-:3])=[O:2]>C(OC(=O)C)C.CN(C=O)C>[NH2:14][C:8]1[CH:7]=[C:6]2[C:11]([CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5]2)=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1ccc2ccc([N+](=O)[O-])cc2c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc2ccc([N+](=O)[O-])cc2c1
Reaction time: 2 h
Yield: 24 %

Procedure:
A suspension of 2,7-dinitro-naphthalene in ethylacetate (400 ml) and DMF (4 ml) was hydrogenated over P/C at 50° C. for 2 hours. After work-up and purification by chromatography 2.1 g (11.2 mmol, 24%) of the title compound, MS: m/e=251(M+) was obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[Cl:17][C:18]1[CH:19]=[C:20]([Mg]Br)[CH:21]=[CH:22][C:23]=1[Cl:24]>C1COCC1>[Cl:17][C:18]1[CH:19]=[C:20]([CH:1]([OH:2])[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:8]=2[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: Clc1ccc([Mg]Br)cc1Cl
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2ccncc2C(O)c2ccc(Cl)c(Cl)c2)c1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (30 mg, 0.15 mmol) in THF (1.5 mL) at −78° C. was added 0.5 M 3,4-dichlorophenylmagnesium bromide in THF (0.6 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichlordmethane to yield 3-{3-[(3,4-dichloro-phenyl)-hydroxy-methyl]-pyridin-4-yl}-benzonitrile as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][C:14](OC(C)(C)C)=O)=[CH:8][CH:7]=2.[C:21]1([C:27]2[N:32]=[N:31][C:30]([NH:33][NH2:34])=[CH:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>Cl>[CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][C:14]1[N:31]3[N:32]=[C:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:28]=[CH:29][C:30]3=[N:33][N:34]=1)=[CH:8][CH:7]=2
Reactant: COc1cnc2ccc(CC(=O)OC(C)(C)C)cc2c1
Reactant: NNc1ccc(-c2ccccc2)nn1
Agent: Cl
Product: COc1cnc2ccc(Cc3nnc4ccc(-c5ccccc5)nn34)cc2c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 2-(3-methoxyquinolin-6-yl)acetate (148 mg) and 1-(6-phenylpyridazin-3-yl)hydrazine (126 mg) in HCl (conc., 0.3 mL) was heated at 100° C. for 5 min and was subject to microwave heating (180° C., 15 min). The yellow sludge was quenched with NaOH(SN, 1 mL). The pink mixture was filtered and washed with NaOH (1 N, 1 mL), H2O (2 mL). The solid was suspended in DMF (2 mL)-DCM (2 mL). MeI (0.2 mL) was added followed by the addition of NaOH (2N, 1 mL). After 2 h, the mixture was partitioned between DCM (10 mL) and aqueous Na2SO3 (5 mL). The organic was dried over MgSO4, concentrated, and purified in silica (1-15% MeOH in DCM) to give the product as a yellow powder.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:10][C@@H:9]1[C@@H:22]([OH:37])[C@@H:23]([NH:33][C:34](=[O:36])[CH3:35])[CH2:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=1)=O)(C)(C)C.[ClH:38]>O1CCOCC1>[ClH:38].[F:31][C:29]1[CH:30]=[C:25]([CH:26]=[C:27]([F:32])[CH:28]=1)[CH2:24][C@H:23]([NH:33][C:34](=[O:36])[CH3:35])[C@H:22]([OH:37])[C@H:9]1[CH2:10][C@@H:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:12][NH:8]1
Reactant: COc1cccc(O[C@@H]2C[C@H]([C@@H](O)[C@H](Cc3cc(F)cc(F)c3)NC(C)=O)N(C(=O)OC(C)(C)C)C2)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cccc(O[C@H]2CN[C@@H]([C@@H](O)[C@H](Cc3cc(F)cc(F)c3)NC(C)=O)C2)c1

Procedure:
React (2R,4R)-2-[(1S,2S)-2-Acetylamino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-4-(3-methoxy-phenoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester With 4M HCl in dioxane essentially as described in EXAMPLE 1 to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:14][C:15]1([F:21])[CH2:17][CH:16]1[C:18](O)=[O:19].CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C>CN(C=O)C.C(O)C.CCCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:18]([CH:16]3[CH2:17][C:15]3([F:21])[F:14])=[O:19])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(N2CCNCC2)cc1
Reactant: O=C(O)C1CC1(F)F
Agent: CCN=C=NCCCN(C)C
Solvent: CCCCCCC
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C(C1CC1(F)F)N1CCN(c2ccc(Br)cc2)CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(4-bromophenyl)piperazine (2.53 g, 10.5 mmol) in DMF (10 mL) was added 2,2-difluorocyclopropanecarboxylic acid (1.92 g, 15.7 mmol) 1H-benzotriazol-1-ol (2.84 g, 21.0 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide (3.26 g, 21.0 mmol) and DIEA (7.31 mL, 42.0 mmol). The resulting mixture was stirred at 50° C. for 1 h. The reaction mixture was then quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and concentrated in vacuo. Purification by chromatography on silica gel (0 to 75% EtOAc in hexanes, then 75 to 100% EtOAc in hexanes) provided the racemic compound. The racemate was then dissolved in 10% ethanol in heptane and the enantiomers were separated on an OD chiral column by eluting column with 30% ethanol in heptane. The first eluting peak was defined as enantiomer A and the second eluting peak was defined as enantiomer B. LCMS m/z 346.8 [M+H]+; 1H NMR (500 MHz, CD2Cl2) δ 7.37 (d, J=9.0 Hz, 2 H),6.80 (d, J=9.0 Hz, 2 H), 4.00-3.93 (m, 1 H),3.84-3.61 (m, 3 H),3.31-3.02 (m, 4 H),2.60-2.50 (m, 1 H),2.23-2.11 (m, 1 H),1.75-1.64 (m, 1 H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[F:12][C:13]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:14]=1[C:15]([N:17]=[C:18]=[O:19])=[O:16]>C(#N)C>[F:12][C:13]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:14]=1[C:15]([NH:17][C:18]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:8][N:7]=1)=[O:19])=[O:16]
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: CC#N
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc(C(F)(F)F)cn1
Reaction time: 3 h

Procedure:
An 0.7 g. portion of 5-trifluoromethyl-2-aminopyridine was dissolved in 20 ml. of acetonitrile, and to the solution was added 0.85 g. of 2,6-difluorobenzoyl isocyanate under a nitrogen blanket at ambient temperature. A precipitate formed immediately. The mixture was stirred for 3 hours, and was then filtered and the solids were washed with acetonitrile. The solids were dried under vacuum to obtain 1.0 g. of the product named above, m.p. 215°-220° C. Elemental analysis gave the following results: