Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4].[C:44]([NH:54][CH2:55][C:56]([NH:58][CH2:59][C:60](O)=[O:61])=[O:57])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]>O1CCCC1>[C:44]([NH:54][CH2:55][C:56]([NH:58][CH2:59][C:60]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4])=[O:61])=[O:57])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]
Reactant: O=C(O)CNC(=O)CNC(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)CNC(=O)CNC(=O)OCc1ccccc1
Yield: 52 %

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-dodecanamide and N-carbobenzoxy-glycyl-glycine. Yield 52%. [α]D =+14.7° (c=1.01, tetrahydrofuran). m.p., 99-100°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.[Br-].[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24]([CH:45]=[CH:46][CH:47]=1)[CH2:25][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:21].CC(C)([O-])C.[K+].[PH4+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:25][C:24]2[CH:23]=[C:22]([CH:47]=[CH:46][CH:45]=2)[C:20]([O:19][CH3:18])=[O:21])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: O=C(Cc1ccc(F)cc1)Cn1ccnc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)c1cccc(C=C(CCn2ccnc2)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of product from step C (2.00 g, 9.17 mmol) in dichloromethane (25 ml) was added 3-methoxycarbonylbenzyltriphenylphosphonium bromide (4.50 g, 9.17 mmol) and potassium tert-butoxide (1.03 g, 9.17 mmol). The mixture was stirred at room temperature for 18 hrs. A further portion of the phosphonium salt (0.88 g, 1.83 mmol) and potassium tert-butoxide (0.21 g, 1.83 mmol) was added. After 16 hrs at room temperature the mixture was partitioned between brine (50 ml) and dichloromethane (50 ml). The organic phase was washed with brine (2×50 ml) and dried (MgSO4). Evaporation of the solvent left an orange gum which was purified by column chromatography on SiO2 (Merck 9385) eluting EtOAc/ammonia (1%) to give methyl 3-[2-(4-fluorophenyl)-4-(imidazol-1-yl)-but-1-enyl]-benzoate as Z isomer 0.57 g (18%), E isomer 0.38 g (12%) and a mixture of isomers 0.65 g (20%) as a yellow gum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][CH3:12])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.[C:13](O)(=[O:15])[CH3:14]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6]([OH:8])=[CH:14][C:13](=[O:15])[N:11]2[CH3:12])=[CH:9][CH:10]=1
Reactant: CNc1cc(Cl)ccc1C(=O)O
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cn1c(=O)cc(O)c2ccc(Cl)cc21

Procedure:
Refluxing a solution of 4-chloro-N-methyl anthranilic acid (13.6g; 0.073 mole) in acetic acid (37 ml) and acetic anhydride (37 ml) for 6 hours and work up as described in Example 35(a) gave the title compound; m.p. (AcOH, EtOH) 308°-9°. (Found; C, 56.97; H, 4.03; N, 6.89 Cl, 16.82; C10H8NClO 2 requires; C, 57.29; H, 3.85; N, 6.68; Cl, 16.91%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[Cl:14].[Cl:15][C:16]1[C:17]([N:22]2[C:26]([C:27](O)=O)=[CH:25][C:24]([O:30][CH3:31])=[N:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>O1CCCC1>[Cl:14][C:3]1[CH:4]=[C:5]2[CH:6]=[N:7][NH:8][C:9]2=[C:10]2[C:2]=1[N:1]=[C:27]([C:26]1[N:22]([C:17]3[C:16]([Cl:15])=[CH:21][CH:20]=[CH:19][N:18]=3)[N:23]=[C:24]([O:30][CH3:31])[CH:25]=1)[O:12][C:11]2=[O:13]
Reactant: Nc1c(Cl)cc2cn[nH]c2c1C(=O)O
Reactant: COc1cc(C(=O)O)n(-c2ncccc2Cl)n1
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1cc(-c2nc3c(Cl)cc4cn[nH]c4c3c(=O)o2)n(-c2ncccc2Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 400 mg (1.89 mmol) of 6-amino-5-chloro-1H-indazole-7-carboxylic acid in 16 mL of anhydrous tetrahydrofuran is added 479 mg (1.89 mmol) of 2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazole-3-carboxylic acid followed by 684 μL (8.50 mmol) of pyridine. The mixture is stirred at ambient temperature during 30 minutes. Then the suspension is cooled to 0° C. and 516 μL (6.66 mmol) of methanesulfonyl chloride are added dropwise. The mixture is stirred at ambient temperature for 5 hours. Then the solvent is evaporated and the residue is triturated with a minimum of cold water. The precipitate, which is formed is filtrated and washed with cold water. The pale yellowish product obtained (870 mg) is engaged in the next step; LC/MS:530/532 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:6]#[N:7].CC(C)=[O:17].OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[C:6]([C:5]1[CH:4]=[C:3]([CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=1)[C:2]([OH:17])=[O:1])#[N:7]
Reactant: N#Cc1cc(CO)cc(C(F)(F)F)c1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: N#Cc1cc(C(=O)O)cc(C(F)(F)F)c1
Reaction time: 12 h
Yield: 84.6 %

Procedure:
3-(Hydroxymethyl)-5-(trifluoromethyl)benzonitrile (2.70 g, 13.4 mmol) synthesized by the method described in Japanese Patent Unexamined Publication (Kokai) No. 2003-221376 was dissolved in acetone (30 mL), the solution was added with 2 M Jones reagent (26.8 mL, 53.6 mmol), and the mixture was stirred for 12 hours. The reaction mixture was added with water (15 mL) for dilution, and then extracted with ether. The organic layers were combined, and inversely extracted with 2 M aqueous sodium hydroxide, and then the aqueous layer was added with 1 M hydrochloric acid for neutralization, and extracted with chloroform. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3-cyano-5-(trifluoromethyl)benzoic acid (2.44 g, 85%) as colorless solid.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[C:18]([NH:20][CH3:21])[N:17]=[C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH:15]=2)[CH:11]=[N:12][CH:13]=1>COCCOC.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:21][NH:20][C:18]1[N:17]=[C:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH:15]=[C:14]([C:10]2[CH:11]=[N:12][CH:13]=[C:8]([C:8]3[CH:13]=[C:1]([OH:4])[CH:11]=[CH:10][CH:9]=3)[CH:9]=2)[CH:19]=1
Reactant: CNc1cc(-c2cncc(Br)c2)cc(-c2ccccn2)n1
Reactant: O=C([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CNc1cc(-c2cncc(-c3cccc(O)c3)c2)cc(-c2ccccn2)n1

Procedure:
To a solution 3-Hydroxphenolboronic acid, pinacol ester (2.0 eq, 1.172 mmol, 0.258 g) and 2M Na2CO3 (2.0 eq, 1.172 mmol, 0.586 ml) in DME (2.5 ml) is added (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-methyl-amine (Example 2.1; step1) (1 eq, 0.586 mmol, 0.200 g) followed by [1,1′-Bis(diphenylphosphino)-ferrocene]dichloropalladium (II), complex with DCM (0.1 eq, 0.059 mmol, 0.048 g). The reaction mixture is heated using microwave radiation at 90° C. for 90 mins. The reaction mixture is dissolved in DCM and washed with water. The organic layer is washed with brine, dried over drying agent MgSO4, filtered and the organic solvent is reduced in vacuo. The crude residue is purified by flash chromatography (0-100% EtOAc in iso-hexane and up to 10% MeOH in EtOAc), to yield intermediate to afford the title compound; [M+H]+ 355.
Reaction SMILES: CO.[O:3]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([NH:19][C:20](=[O:30])[CH2:21]/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[C].[Pd].C(OCC)(=O)C>[O:3]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([NH:19][C:20](=[O:30])[CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(C/C=C/c1ccccc1)Nc1cc(Oc2ccccc2)ccc1C(=O)O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(CCCc1ccccc1)Nc1cc(Oc2ccccc2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1.3 mg of 10% palladium-carbon was added to a mixed solution of 1.0 mL of methanol and 1.0 mL of ethyl acetate containing 10 mg of 4-phenoxy-2-((E)-4-phenyl-3-butenamido)benzoic acid and stirred under hydrogen atmosphere at room temperature for 6 hours. After insoluble were removed by filtration, the solvent was evaporated under reduced pressure. Hexane and diisopropyl ether were added to the obtained residue and a solid substance was separated by filtration to obtain 4.6 mg of 4-phenoxy-2-(4-phenylbutanamido)benzoic acid as white solid.
Reaction SMILES: [CH2:1]([CH:4]1[CH:7]([S:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[NH:6][C:5]1=[O:18])[CH2:2][CH3:3].C=O.C(=O)([O-])[O-].[Cs+].[Cs+].[C:27]([O:30][C:31](=O)C)(=[O:29])[CH3:28]>O1CCCC1.N1C=CC=CC=1>[C:27]([O:30][CH2:31][N:6]1[CH:7]([S:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH:4]([CH2:1][CH2:2][CH3:3])[C:5]1=[O:18])(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: CCCC1C(=O)NC1Sc1ccc([N+](=O)[O-])cc1
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCC1C(=O)N(COC(C)=O)C1Sc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 273 mg (0.94 mmole) azetidinone from Step A, 26.3 mg paraformaldehyde and 178 mg (0.56 mmole) cesium carbonate was stirred in 20 ml dry tetrahydrofuran at ambient temperature 16.5 hours under nitrogen. A mixture of 430 μl pyridine and 2.56 ml acetic anhydride was added to the reaction mixture and the stirring continued 5 more hours. The solvents were removed in vacuo to give 604 mg crude product which was chromatographed on a silica gel flash column in hexane-ethyl acetate 3/1. This gave 102 mg (30%) of 1-acetoxymethyl-4-p-nitrophenylthio-3-n-propylazetidin-2-one.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15](=[N:18][C:19]#[N:20])OC)[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH3:21][NH2:22]>O>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]([NH:22][CH3:21])=[N:18][C:19]#[N:20])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: COC(=NC#N)NCCSCc1csc(NC(=N)N)n1
Reactant: CN
Solvent: O
Product: CNC(=NC#N)NCCSCc1csc(NC(=N)N)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-guanidino-4-[2-(3-cyano-2-methylisoureido)ethylthiomethyl]thiazole (1.88 g.) and 30% w/v aqueous methylamine (6.0 ml.) was stirred together at room temperature. After 1 hour 40 minutes water (20 ml.) was added, and stirring was continued for 15 minutes. The white solid (1.265 g.) was collected, washed with water (3 ml.) and dried in vacuo overnight. Recrystallization from aqueous dimethylformamide gave 2-guanidino-4-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]thiazole, m.p. 160°-161.5° C.
Reaction SMILES: [N:1]1([C:7](=[O:22])[CH2:8][CH:9]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]([OH:12])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:23][CH:24]([CH2:38][CH3:39])[C@@H:25]([C:27]1[N:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][N:28]=1)[OH:26]>>[C:32]1([C:30]2[O:29][N:28]=[C:27]([C:25]([C@@H:24]([NH:23][C:10](=[O:12])[CH:9]([CH2:8][C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[O:22])[CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:38][CH3:39])=[O:26])[N:31]=2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCC(N)[C@H](O)c1noc(-c2ccccc2)n1
Reactant: O=C(O)C(CCCc1ccccc1)CC(=O)N1CCOCC1
Product: CC[C@H](NC(=O)C(CCCc1ccccc1)CC(=O)N1CCOCC1)C(=O)c1noc(-c2ccccc2)n1

Procedure:
Similarly prepared according to the procedure for Example 43 but using 2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid and (S)-2-amino-1-(5-phenyl-[1,2,4]oxadiazol-3-yl)-butan-1-ol; MS: 541 (M+Na), LCMS retention time 4.44 and 4.53 min; 1H NMR (CDCl3) 8.18 (d, J=7 Hz, 2H), 7.69–7.51 (m, 3H), 7.27–7.10 (m, 5H), 6.99–6.7 (d, J=7 Hz, 1H), 5.38 (m, 1H), 3.70–3.36 (m, 8H), 2.99–2.56 (m, 4H), 2.27 (m, 1H), 2.11 (m, 1H), 1.87–1.60 (m, 4H), 1.44 (m, 1H), 1.02–0.97 (dt, J=7 Hz, 3H).
Reaction SMILES: [N-]=C=O.NC(OCC)=O.[C:10]1([CH3:28])[C:11]([NH:22][C:23](OCC)=[O:24])=[CH:12][C:13]([NH:16][C:17](OCC)=[O:18])=[CH:14][CH:15]=1>>[CH3:28][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][C:11]=1[N:22]=[C:23]=[O:24]
Reactant: CCOC(=O)Nc1ccc(C)c(NC(=O)OCC)c1
Agent: CCOC(N)=O
Agent: [N-]=C=O
Product: Cc1ccc(N=C=O)cc1N=C=O

Procedure:
A more recent British Pat. No. 1,247,451 (1971) discloses that it was known that organic isocyanates can be produced by the non-catalytic pyrolysis of urethanes at temperatures above 250° C. but the yield is undesirably low, and if lower temperatures are employed the isocyanate and alcohol will react to reform the original urethane. This confirms the findings discussed hereinbefore wherein various expedients such as catalysts and low pressures were employed with specific carbamates. The aforementioned British patent proposes to pyrolyze diethyl toluene-2,4-dicarbamate in the presence of a Lewis acid such as ferric chloride catalyst to produce toluene-2,4-diisocyanate (TDI). A yield of approximately 59 mole percent is shown. In general, the reaction is carried out at from 400° C. to 600° C. in the presence of the catalyst at subatmospheric pressures to form vapors, and condensing the vapors to recover the organic isocyanate product.
Reaction SMILES: [O-]CC.[Na+].[F:5][C:6]1[C:7]([CH3:14])=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O.[N:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N+:16]=[N-:17].[Cl-].[NH4+]>C(O)C.O1CCCC1>[F:5][C:6]1[C:7]([CH3:14])=[C:8]([CH:9]=[C:18]([N:15]=[N+:16]=[N-:17])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: Cc1c(F)cccc1C=O
Agent: CC[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(=Cc1cccc(F)c1C)N=[N+]=[N-]
Yield: 61.5 %

Procedure:
A solution of sodium ethoxide (11.1 g, 163 mmol) in ethanol (100 ml) was cooled to -45° C. and then a solution of 3-fluoro-2-methylbenzaldehyde (9.00 g, 65.2 mmol) and ethyl azidoacetate (21.0 g, 163 mmol) in tetrahydrofuran (30 ml) were slowly added dropwise therein. The reaction temperature of the mixture was raised from -35° C. to -10° C. over 5 hours and the reaction solution was poured in a cooled aqueous ammonium chloride solution. The resulting mixture was extracted with ethyl acetate and the extract was washed with a saturated ammonium chloride solution and then 5% aqueous sodium chloride solution followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was treated with silica gel column chromatography (eluated with ethyl acetate/n-hexane=3/97) to give 10.0 g of ethyl 3-(3-fluoro-2-methylphenyl)-2-azidopropenoate.
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22]([OH:24])=O.[C:25]1([C@@H:31]([NH2:39])[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([C@@H:31]([NH:39][C:22]([C@H:10]2[CH2:9][CH2:8][C@H:7]3[C@H:6]4[C@H:15]([CH2:14][CH2:13][C@:11]23[CH3:12])[C@:16]2([CH3:21])[C:3]([N:2]([CH3:1])[C:19](=[O:20])[CH2:18][CH2:17]2)=[CH:4][CH2:5]4)=[O:24])[CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N[C@@H](Cc1ccccc1)c1ccccc1
Reactant: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC[C@@H]12
Product: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)N[C@@H](Cc4ccccc4)c4ccccc4)[C@@]3(C)CC[C@@H]12
Yield: 91 %

Procedure:
The title compound was prepared in a yield of 91% in a similar manner to that described in Example 1 by reacting 4-methyl-3-oxo-4-azaandrost-5-ene-17β-carboxylic acid (prepared as described in Preparation 5) and (S)-1,2-diphenylethylamine.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[C:7]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:5][C:4]=1[Cl:13].C(N(CC)CC)C.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.CCOC(C)=O>C1COCC1>[Cl:9][C:8]1[C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=[C:4]([Cl:13])[C:3]=1[CH2:2][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)c(CBr)c1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Cl)c(CN2CCCCC2)c1Cl
Temperature: 25 °C

Procedure:
To a solution of 2-bromomethyl-1,3-dichloro-4-nitro-benzene (20) (8.79 g, 30.8 mmol) and triethylamine (6.06 g, 60 mmol) in anhydrous THF (50 mL), piperidine (2.72 g, 32 mmol) was added at 0° C. under stirring. The reaction mixture was allowed to warm to room temperature gradually, and the reaction was monitored by TLC (SiO2, Hexanes:EtOAc, 1:1). After stirring for about 14 hours, the reaction mixture was evaporated to dryness, and the product was extracted in EtOAc (250 mL) and washed with water (2×100 mL) and dried (MgSO4). The product was purified by column chromatography (SiO2, hexanes:EtOAc 95:5 to 8:2) and was obtained as a yellow solid, yield: 7.38 g, 83%, mp 67-68° C. 1H-NMR (CDCl3) δ 1.37 (m, 2H), 1.46-1.49 (m, 4H), 2.45 (m, 4H), 3.7 (s, 2H); MS (CI) m/z 290 (M+H), 291 (M+2H). Anal Calc for C12H14Cl2N2O2 : C, 49.85; H, 4.88; N, 9.69. Found: C, 49.86; H, 4.88; N, 9.73.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[C:12]([O:16][C:17]([N:19]1[CH2:27][CH2:26][CH2:25][C:21]2([NH:24][CH2:23][CH2:22]2)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>C(Cl)Cl>[N:24]1([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[C:21]2([CH2:25][CH2:26][CH2:27][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:20]2)[CH2:22][CH2:23]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC2(CCN2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC2(CCN2C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of benzyl chloroformate (0.148 mL, 1.039 mmol) in DCM (1 mL) was added to a mixture of tert-butyl-1,6-diazaspiro[3.5]nonane-6-carboxylate (200 mg, 0.866 mmol) and DIPEA (0.378 mL, 2.165 mmol) in DCM (3 mL) and the mixture was stirred at RT for 16 h. The solvent was evaporated off under reduced pressure and the crude product was purified by flash chromatography (Silica gel column, 4 g, n-hexane/DCM from 20% to 100% DCM) to give the title product as a yellow resin. UPLC-MS (Condition 3) tR=1.21 min, m/z=361.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:18][C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:10]2[CH2:15][CH2:14][N:13]([C:16]#[N:17])[CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:26][OH:27].Cl.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:18][C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:10]2[CH2:15][CH2:14][N:13]([C:16]([NH:26][OH:27])=[NH:17])[CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C#N)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=N)NO)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 24.9 %

Procedure:
To a solution of 4-[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carbonitrile (0.2413 g, 0.72 mmol) in DMF (7 mL) was added NH2OH.HCl (0.1127 g, 1.44 mmol) and DIPEA (0.25 mL, 1.44 mmol), and stirred at 60° C. for 16 hours. Saturated NaHCO3 (15 mL) was added and extracted with CH2Cl2 (3×50 mL). The combined organic extracts were washed with brine (2×50 mL), dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) provided 66.1 mg (58%) of COMPOUND 286 as a yellow solid. 1H NMR (CD3OD) 1.70-1.87 (m, 4H), 2.15 (s, 6H), 2.36-2.58 (m, 3H), 3.71 (d, 2H), 3.82 (s, 4H), 7.19-7.24 (m, 2H), 7.53 (d, 2H, J=7.5 Hz), 8.25 (d, 2H, J=4.8 Hz). 13C NMR (CD3OD) δ 18.70, 28.15, 48.19, 55.78, 59.90, 124.62, 136.04, 140.60, 146.72, 158.48, 160.89. ES-MS m/z 369.3 (M+H). Anal. Calcd. for C20H28N6O.0.9H2O: C, 62.44; H, 7.81; N, 21.85. Found: C, 62.60; H, 7.82; N, 21.74.
Reaction SMILES: C(OC(OCC)[CH2:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][NH:20][C:21](OC(C)(C)C)=O)=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[OH-].[Na+]>C(O)CC.Cl.O>[CH:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[C:18]1[N:19]3[NH:20][CH:21]=[CH:5][C:6]3=[N:8][C:9]=1[CH:10]=[N:11]2
Reactant: CCOC(CC(=O)Nc1cnc2ccccc2c1NNC(=O)OC(C)(C)C)OCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCCO
Product: c1ccc2c(c1)ncc1nc3cc[nH]n3c12
Temperature: 125 °C
Reaction time: 4 h
Yield: 33.7 %

Procedure:
A solution of tert-butyl N′-[3-(3,3-diethoxypropionylamino)quinolin-4-yl]-hydrazinecarboxylate (13.75 g, 32.9 mmol) and pyridinium p-toluenesulfonate (0.206 g, 0.082 mmol) in 1-propanol (250 mL) was placed under a nitrogen atmosphere and heated to 125° C. After 4 h, the reaction was cooled to ambient temperature and concentrated under reduced pressure to yield a dark red oily solid. This material was suspended in HCl (55 mL, 3 M in ethanol) and heated to 100° C. After 1.5 h, the reaction mix was cooled to ambient temperature and concentrated under reduced pressure to give a brown solid. The solid was suspended in water (50 mL), stirred vigorously, and neutralized with drop-wise addition of 10% NaOH aqueous solution until the pH of the liquid was 8. The aqueous mixture was transferred to a separatory funnel and extracted with chloroform (4×25 mL). The combined organic extracts were concentrated under reduced pressure to give a dark red solid. This solid was purified by prep. HPLC (350 g silica gel eluted with 1-20% CMA in chloroform) to give a dark red solid. This material was triturated with ether (75 mL) and filtered to yield 2.31 g of 10H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]quinoline as a red solid.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[CH2:14][CH2:15][C@@:9]1([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@H:10]([OH:16])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:25][C:26]([F:40])([F:39])[C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:30]Br.O>C1COCC1>[CH2:1]([N:8]1[C@@H:13]2[CH2:14][CH2:15][C@@:9]1([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@H:10]([O:16][CH2:30][C:29]1[CH:32]=[C:33]([C:35]([F:37])([F:38])[F:36])[CH:34]=[C:27]([C:26]([F:25])([F:39])[F:40])[CH:28]=1)[CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: O[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3CC[C@]2(c2ccccc2)N3Cc2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 61 %

Procedure:
(1R*,2R*,5R*)-8-Benzyl-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 9; 1.69 g, 3.90 mmol) in THF (25 ml) at 0° C. was treated with sodium hydride (217 mg, 9.02 mmol) and allowed to warm to room temperature. The mixture was recooled to 0° C. then 3,5-bis(trifluoromethyl)benzyl bromide added and the mixture heated to 50° C. overnight. The mixture was poured into water then extracted with ethyl acetate (×2), dried (MgSO4) and concentrated in vacuo to give a yellow oil. This was purified by flash column chromatography [5% ethyl acetate in iso-hexane] to give the title compound as a yellow oil (1.43 g, 61%).