Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:48][CH2:49][C:50]1[C:59](=[O:60])[C:58]2[C:53](=[N:54][CH:55]=[CH:56][CH:57]=2)[N:52]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:51]=1[C:67]1[O:68][CH:69]=[CH:70][N:71]=1>C(Cl)Cl>[O:68]1[CH:69]=[CH:70][N:71]=[C:67]1[C:51]1[N:52]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:53]2[C:58]([C:59](=[O:60])[C:50]=1[CH2:49][NH:48][C:14]([C:11]1[CH:12]=[CH:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9](=[O:17])[CH:10]=1)=[O:16])=[CH:57][CH:56]=[CH:55][N:54]=2
Reactant: O=C(O)c1ccn(Cc2ccccc2)c(=O)c1
Reactant: NCc1c(-c2ncco2)n(-c2ccccc2)c2ncccc2c1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1c(-c2ncco2)n(-c2ccccc2)c2ncccc2c1=O)c1ccn(Cc2ccccc2)c(=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a 50 mL round-bottomed flask, 1-benzyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (21 mg, 0.93 mmol), 1-(3-dimethylaminopropyl-3-ethylcarbodiimide (23.0 mg, 0.148 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (20.0 mg, 0.148 mmol) and N,N-diisopropylethylamine were combined with methylene chloride (5 mL). The reaction mixture was stirred at room temperature for 10 min. After this time, 3-(aminomethyl)-2-(oxazol-2-yl)-1-phenyl-1,8-naphthyridin-4(1H)-one (intermediate B) was added. The reaction mixture was stirred at room temperature over the weekend. The reaction mixture was partitioned between methylene chloride and water. The organic phase was dried over sodium sulfate, then filtered and concentrated. The crude product was purified using flash chromatography (Isco, 0% ethyl acetate-hexanes ramped to 70% ethyl acetate-hexanes) to afford 1-Benzyl-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid (2-oxazol-2-yl-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridin-3-ylmethyl)-amide as a light brown powder (12 mg). MS calcd. for C31H24N5O4 [(M+H)+] 530.2, obsd. 530.3
Reaction SMILES: [F:1][CH:2]([F:41])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH:27]C(=O)OC(C)(C)C)[CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:35]=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:5]=2[N:4]=1.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>>[F:1][CH:2]([F:41])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH:27][S:43]([CH3:42])(=[O:45])=[O:44])[CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:35]=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)nc(N2CCOCC2)n1
Reactant: CS(=O)(=O)Cl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N[C@H]2CC[C@H](NS(C)(=O)=O)CC2)nc(N2CCOCC2)n1

Procedure:
Reaction of the above amine with methanesulfonyl chloride as in previous examples gave trans-N-(4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}cyclohexyl)methanesulfonamide in 90% yield: mp (CH2Cl2/MeOH) 269-272° C.; 1H NMR (DMSO-d6) δ 8.10 and 7.97 (d, J=8.3 Hz, 1H), 7.88 and 7.73 (2t, JHF=53.2, 53.9 Hz, 1H) 7.86 and 7.80 (d, J=7.6, 8.0 Hz, 1H), 7.38 (q, J=8.1 Hz, 1H), 7.02-6.92 (m, 2H), 3.98 and 3.97 (2s, 3H), 3.77-3.69 (m, 9H), 3.13 (br, 1H), 2.93 and 2.92 (2s, 3H), 1.98-1.96 (m, 4H), 1.42-1.32 (m, 4H); Anal. Calcd. for C23H30F2N8O4S: C, 50.0; H, 5.5; N, 20.3. Found: C, 50.0; H, 5.4; N, 20.5%.
Reaction SMILES: C(N(CC)CC)C.[C:8](Br)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:28][C:29]([CH3:39])([CH2:37][CH3:38])[CH2:30][C:31]1[N:32]=[C:33]([CH3:36])[NH:34][CH:35]=1>C(Cl)Cl>[CH3:28][C:29]([CH3:39])([CH2:37][CH3:38])[CH2:30][C:31]1[N:32]=[C:33]([CH3:36])[N:34]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:35]=1
Reactant: CCC(C)(C)Cc1c[nH]c(C)n1
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (34 mL, 0.24 mol) followed by trityl bromide (62 g, 0.19 mol) (portionwise) were added to a 0° C. solution of 4-(2,2-dimethylbutyl)-2-methyl-1H-imidazole (26.4 g, 0.16 mol) in methylene chloride (300 mL). After stirring at ambient temperature overnight, the reaction mixture was filtered and washed with water and brine, dried (magnesium sulfate), filtered and concentrated in vacuo. Chromatography over silica eluting with 10-40% ethyl acetate/hexane afforded the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12]CC)=O.[OH-].[NH4+:16]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH2:16])=[O:12]
Reactant: [NH4+]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: [OH-]
Product: NC(=O)c1cc2ccccc2[nH]1
Temperature: 80 °C

Procedure:
A mixture of ethyl indole-2-carboxylate (5 g, 26.5 mmol) and ammonium hydroxide (30 mL) was heated at 80° C. in a sealed glass vessel overnight. The reaction was cooled and the title compound (3.06 g, 73%) was collected by filtration as a colorless solid: 1H NMR (400 MHz, DMSO-d6) δ 7.95 (br, 1H), 7.61 (d, 1H), 7.41 (d, 1H), 7.36 (br, 1H), 7.12, (t, 1H), 7.01 (t, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:3]=12.[NH2:16][CH:17]1[CH2:22][CH2:21][CH:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1>C(#N)C>[C:26]([O:25][C:23]([CH:20]1[CH2:19][CH2:18][CH:17]([NH:16][C:2]2[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]3[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:3]=23)[CH2:22][CH2:21]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCn1ncc2c(Cl)c(C(=O)O)cnc21
Reactant: CC(C)(C)OC(=O)C1CCC(N)CC1
Solvent: CC#N
Product: CCn1ncc2c(NC3CCC(C(=O)OC(C)(C)C)CC3)c(C(=O)O)cnc21

Procedure:
A solution of 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (0.0088 mol) (example 4a) in acetonitrile is treated with tert-butyl 4-aminocyclohexanecarboxylate (0.026 mol). The reaction mixture is refluxed for about 3-4 hrs. Solvent is evaporated off and water is added and extraction is done with ethyl acetate. The organic layer is washed with brine, dried and concentrated under reduced pressure to give crude compound, which is purified by column chromatography.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:42])[CH2:16][C:17]3[N:18]=[C:19]([NH:22][C:23]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[S:20][CH:21]=3)[C:12](=[O:43])[N:7]2[C:8]=1[C:9]([O-:11])=[O:10].[Na+].[CH3:45][N:46]=[C:47]=[O:48].C([O-])(O)=O.[Na+]>CN(C)C=O>[CH3:45][NH:46][C:47]([O:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:42])[CH2:16][C:17]3[N:18]=[C:19]([NH:22][C:23]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[S:20][CH:21]=3)[C:12](=[O:43])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10])=[O:48]
Reactant: O=C(Cc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CO)CS[C@H]12
Reactant: CN=C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1 g of the raw product of Step A of Example 1 was added under nitrogen to a mixture of 5 ml of dimethylformamide and 0.5 ml of methyl isocyanate at 5° C. and 0.5 ml of methyl isocyanate was added thereto. After 30 minutes at 5° C., another 0.5 ml of methyl isocyanate was added and after stirring 2 hours at room temperature, the mixture was poured into 75 ml of an aqueous 6% NaHCO3 solution. The mixture was extracted with ethyl acetate and the extracts were washed with sodium bicarbonate solution. The combined aqueous phases were added to ethyl acetate and the mixture was acidified with 6 N hydrochloric acid to a pH of 2. The mixture was decanted and the aqueous phase was extracted with ethyl acetate. The organic extracts were washed with water, dried and concentrated to dryness and the residue was empasted with isopropyl ether and was vacuum filtered. The product was taken up with methylene chloride and the solution was treated with activated carbon and was vacuum filtered. The filtrate was evaporated to dryness and the residue was crystallized from isopropyl ether to obtain 331 mg of 3-methylcarbamoyloxymethyl-7β-[2-(2-tritylamino-4-thiazolyl)-acetamido]-ceph-3-eme-4-carboxylic acid melting at about 210° C. Thin layer chromatography: Rf=0.42 (80-15-5-ethyl acetate-acetic acid-water).
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH:4]=[CH:3][C:2]1=O.P(Cl)(Cl)([Cl:15])=O.[OH-].[Na+]>C(#N)C>[Cl:15][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:11])[CH2:7][CH2:8][CH2:9][C:10]=2[N:1]=1
Reactant: O=C1CCCc2[nH]c(=O)ccc21
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: O=C1CCCc2nc(Cl)ccc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To a suspension of 7,8-dihydroquinoline-2,5(1H,6H)-dione (1.5 g, 9.19 mmol) in acetonitrile (22 mL) was added dropwise phosphorous oxychloride (1.714 mL, 18.39 mmol). The resulting solution was heated to 100° C. and stirred for 2 h. The reaction was cooled to RT and poured into ice-cold water. After basifying the mixture with 2 M sodium hydroxide solution it was extracted with ethyl acetate (3×). After each extraction the pH of the aqueous phase was checked and if necessary adjusted by adding 1 M sodium hydroxide solution. The combined organic layers were dried over sodium sulfate, filtered, and evaporated to dryness. The crude was purified by flash chromatography (silica gel, cyclohexane/ethyl acetate) yielding a colourless solid. Amount 1.23 g. Yield 74%.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[S:24]1[C:28]([C:29](O)=[O:30])=[CH:27][C:26]2[CH:32]=[CH:33][CH:34]=[CH:35][C:25]1=2>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:29]([C:28]3[S:24][C:25]4[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=4[CH:27]=3)=[O:30])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Product: C[C@@]1(c2cc(NC(=O)c3cc4ccccc4s3)ccc2F)CCOC(N)=N1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F1 (R3=Me) and benzo[b]thiophene-2-carboxylic acid followed by deprotection using procedure H yielded the title compound.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[CH:15]1[CH:20]=[CH:19][C:18]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH2:31])=[CH:25][C:24]=2[O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:17][CH:16]=1.Cl.C(N(CC)CC)C>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:31][CH2:30][CH2:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][C:18]2[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=2)=[C:24]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:25]=1)#[N:2]
Reactant: NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: CC(C)OC(=NC#N)c1cccnc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: N#CNC(=NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 23.1 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.25 g, 1.3 mmol) was dissolved in methanol (10 ml), and 3,4-(dibenzyloxy)phenethylamine hydrochloride (0.54 g, 1.5 mmol) and triethylamine (0.15 g, 1.5 mmol) were added. The mixture was stirred at room temperature for 45 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate thus obtained was extracted with ethyl acetate (100 ml×3). The ethyl acetate layer was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual concentrate was subjected to chromatography on a silica gel column (WAKO GEL C-200, 50 g) eluting with chloroform-methanol (100:1). The eluted fractions were concentrated under reduced pressure to give N-cyano-N'-[2-(3,4-dibenzyloxyphenyl)ethyl]-3-pyridinecarboximidamide (0.13 g, 0.3 mmol, yield: 21%) as colorless syrup. Next, to this syrup was added a 5% hydrogen chloride in methanol (2 ml). The solution was crystallized from methanol-diethyl ether to give N-cyano-N'-[ 2-(3,4-dibenzyloxyphenyl)ethyl]-3-pyridinecarboximidamide hydrochloride as colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21](I)[S:22][C:13]=12.[CH3:24][N:25]1[C:29]([Sn](CCCC)(CCCC)CCCC)=[CH:28][N:27]=[C:26]1[CH:43]=[O:44].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:29]3[N:25]([CH3:24])[C:26]([CH:43]=[O:44])=[N:27][CH:28]=3)[S:22][C:13]=12
Reactant: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)c(Cl)cc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(C=O)n1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4cnc(C=O)n4C)sc23)c(Cl)cc1Cl
Temperature: 110 °C
Yield: 52.2 %

Procedure:
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile (443.2 mg, 0.93 mmol), 1-methyl-5-(tributylstannyl)-1H-imidazole-2-carbaldehyde (743.1 mg, 1.86 mmol), dichlorobis(triphenylphosphine)palladium(II) (33.0 mg, 0.047 mmol) and triethylamine (103.2 mg, 1.02 mmol) in 8.0 mL of 1,4-dioxane is heated at 110° C. for 3 hours. After cooling, the mixture is treated with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phases are washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of 5% ethyl acetate in dichloromethane to 50% ethyl acetate in dichloromethane to provide 222.7 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(2-formyl-1-methyl-1H-imidazol-5-yl)thieno[3,2-b]pyridine-6-carbonitrile as a yellow solid, mp 225–227° C.; 1H NMR (DMSO-d6) δ 3.86 (s, 3H), 4.08 (d, 3H), 7.41 (s, 1H), 7.63 (s, 1H), 7.77 (s, 1H), 7.90 (s, 1H), 8.67 (s, 1H), 9.77 (s, 1H), 9.87 (s, 1H); MS 458.1, 460.1 (M+H)+.
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.Cl[Si:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][Cl:17].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)C.O>[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Si:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][Cl:17])=[CH:5][CH:4]=1
Reactant: C[Si](C)(Cl)CCCCCl
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: C[Si](C)(CCCCCl)Cc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
In a 500 ml glass reactor fitted with a mechanically driven stirrer, thermometer, nitrogen inlet, dropping funnel and water-cooled reflux condenser was charged 7.9 g magnesium chip. Via the dropping funnel was added a solution of 47.5 g 4-chlorobenzyl chloride in 200 ml diethyl ether with stirring over a period of 1/2 an hour. After the addition was complete, the reaction was refluxed for 1/2 hour, then cooled to room temperature. To the Grignard reagent was added a solution of 31.0 g chlorodimethyl-4-chloro-n-butylsilane (Petrarch Systems Inc., Bristol, PA) in 50 ml ether. The reaction mixture was refluxed for 1 hour after the addition was complete, then cooled to room temperature. A solution of 10 g citric acid in 200 ml water was added to hydrolyze the reaction. The organic layer was separated, dried over magnesium sulfate and the solvent removed at room temperature under vacuum. Low boiling impurities were removed by distillation at 150° C. under 15 mm vacuum. The residue was a yellow oil. Vapor phase chromatography showed the compound to be about 95 percent pure. Its NMR spectrum was consistent with the expected compound.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[NH:11][C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:25][C:26]#[CH:27].C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:27][C:26]#[CH:25])[C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc2N1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CCN1C(=O)CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
50 mg (0.17 mmol) of 4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 4 ml of DMF. 7 mg (0.18 mmol) of sodium hydride was added, to the obtained solution, and they were stirred at room temperature for 30 minutes. 30 mg (0.25 mmol) of 3-bromopropyne was added to the obtained solution, and they were stirred at room temperature overnight. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the obtained crude product was purified by the silica gel column chromatography.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[C:12]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C1CCCNC1
Solvent: ClCCl
Product: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a solution of ethyl piperidine-3-carboxylate (67.74 g, 266 mmol) in dry CH2Cl2 (300 mL) was added TEA (40.34 g, 399 mmol) at 0° C. Benzoyl chloride (41.13 g, 293 mmol) was added slowly to control any rise in reaction temperature. After addition was complete, the mixture was stirred at rt overnight. The mixture was washed with 1N aq HCl and brine. The organic layer was dried with anhydrous Na2SO4 and concentrated to leave a residue, which was purified by silica gel column chromatography (petroleum/ethyl acetate 5:1 to 3:1) to afford ethyl 1-benzoylpiperidine-3-carboxylate (62.63 g, 90%). 1H NMR (CD3OD, 400 MHz): δ=1.41 (t, 3H), 1.52 (m, 2H), 1.85 (m, 2H), 2.36 (s, 1H), 3.29 (m, 2H), 3.81 (m, 4H), 7.22 (m, 3H), 7.42 (m, 2H).
Reaction SMILES: [ClH:1].[F:2][C:3]([F:13])([F:12])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[CH3:14]/[C:15](/[C:18]([CH3:20])=O)=[N:16]\[OH:17]>CCOC(C)=O>[ClH:1].[CH3:14][C:15]1[N+:16]([O-:17])=[C:8]([C:7]2[CH:10]=[CH:11][C:4]([C:3]([F:12])([F:13])[F:2])=[CH:5][CH:6]=2)[O:9][C:18]=1[CH3:20]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)/C(C)=N/O
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)[n+]([O-])c1C
Temperature: 5 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
HCl gas (21.2 g, 58.1 mmol) was bubbled via syringe into 0° C. solution of 4-trifluoromethylbenzaldehyde (50 g, 28.7 mmol), 2,3-butanedione monoxime (26.40 g, 26.1 mmol), and EtOAc (105 ml). The reaction was stirred at 5° C. for 3 h. Ice cold ether (575 ml) was then added, and the resultant precipitate was filtered, washed with ether, and dried at 25° C. for 16 h to give the product as a white solid (54.79 g 71% yield, mp 149°-159° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1([C:17](O)=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH3:20][NH2:21]>>[CH3:20][NH:21][CH2:17][C:11]1([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(O)C1(c2ccc3ccccc3c2)CCCCC1
Reactant: CN
Product: CNCC1(c2ccc3ccccc3c2)CCCCC1
Yield: 74 %

Procedure:
The title compound was synthesized from 1-(naphthalen-2-yl)cyclohexane-carboxylic acid and methyl amine using General Procedure G, followed by General Procedure E in 74% yield as a clear oil. LCMS Rt=7.66 min, m/z=254 (M+1). 1H NMR (CDCl3, δ): 7.82 (m, 4H), 7.54 (dd, J=1.8, 8.7 Hz, 1H), 7.45 (m, 2H), 2.69 (s, 2H), 2.3 (m, 2H), 2.25 (m, 3H), 1.8-1.3 (m, 8H). 13C NMR (CDCl3, δ, mult): 142.7(0), 133.4(0), 131.7(0), 128.0(1), 127.9(1), 127.2(1), 126.1(1), 125.7(1), 125.4(1), 125.0(1), 64.4(2), 42.4(0), 37.3(3), 34.7(2), 26.7(2), 22.3(2).
Reaction SMILES: O=O.C(OCC)(=O)C.[CH:9]1([CH2:14][C:15]2[C:19](=[O:20])[O:18][CH2:17][C:16]=2[CH2:21][N:22]2[C:26](=[O:27])[C:25]([CH3:29])([CH3:28])[N:24]([CH3:30])[C:23]2=[O:31])[CH2:13][CH2:12][CH2:11][CH2:10]1>C1COCC1>[CH:9]1([CH2:14][C@H:15]2[C:19](=[O:20])[O:18][CH2:17][C@H:16]2[CH2:21][N:22]2[C:26](=[O:27])[C:25]([CH3:29])([CH3:28])[N:24]([CH3:30])[C:23]2=[O:31])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CN1C(=O)N(CC2=C(CC3CCCC3)C(=O)OC2)C(=O)C1(C)C
Agent: O=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1C(=O)N(C[C@@H]2COC(=O)[C@@H]2CC2CCCC2)C(=O)C1(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 104.2 %

Procedure:
In the glove box (O2 content<=2 ppm) a 10 ml measuring flask was charged with 68.3 mg [Rh((R)-3,5-iPr-MeOBIPHEP)(COD)]SbF6 (0.050 mmol) and filled to the graduation mark with 10 ml ethyl acetate. The suspension was stirred with a magnetic stirring bar for 15 min at r.t. A clear orange solution formed. The Rh-catalyst was prepared through reaction of (R)-3,5-iPr-MeOBIPHEP and [Rh(COD)2]SbF6 in THF at room temperature for 2 h in a known manner (J. Am. Chem. Soc., 93, 3089-91 (1971), J. Chem. Soc. Chem. Comm., 1990, 869-71). In the glove box a 185 ml stirred stainless steel autoclave was charged with 16.02 g 3-(4-cyclopentylmethyl-5-oxo-2,5-dihydro-furan-3ylmethyl)-1,5,5-trimethyl-imidazolidine 2,4-dione, 20 ml ethyl acetate and the above catalyst solution. The measuring flask was rinsed with a total of 11.5 ml ethyl acetate. The autoclave was then sealed and connected to a hydrogenation line. The hydrogenation was carried out while stirring at 80° C. at a total pressure of 100 bar. After 71 h the brown hydrogenation mixture was rotary evaporated and dried at 50° C./10 mbar for 2 h, affording 16.80 g of crude (3R,4R)-3-(4-cyclopentylmethyl-5-oxo-tetrahydrofuran-3ylmethyl)-1,5,5-trimethyl-imidazolidine-2,4-dione as a brown oil which solidified slowly on standing at r.t. ee: 98.2% (3R,4R). GC:98.4 area %. This crude material was employed directly in the next step.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:28]=[CH:27][C:16]2[NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[NH:20][C:21](=[O:22])[C:15]=2[CH:14]=1)=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>O1CCCC1.O>[O:22]=[C:21]1[NH:20][C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[NH:17][C:16]2[CH:27]=[CH:28][C:13]([NH:12][C:10]([NH2:9])=[S:11])=[CH:14][C:15]1=2
Reactant: O=C(NC(=S)Nc1ccc2c(c1)C(=O)Nc1ccccc1N2)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=S)Nc1ccc2c(c1)C(=O)Nc1ccccc1N2
Yield: 90.7 %

Procedure:
To a stirred solution of 1-benzoyl-3-(11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-2-yl)-thiourea (Example 8, 0.6 g, 1.54 mmol) in 10 mL of tetrahydrofuran was added 1.8 mL of 2.0 N aqueous sodium hydroxide. The mixture was heated to reflux for 3 hrs, diluted with water (10 mL) and extracted with ethyl acetate (3×100 mL). The combined organic fractions were dried with magnesium sulfate and concentrated under reduced pressure. The solid was washed with 1:1 ethyl acetate/hexanes (50 mL) to give a solid (yield 397 mg, 90.3%). H1 NMR (methanol d4) δ: 9.83 (s, 1H), 9.50 (s, 1H), 7.81 (s, 1H), 7.55-7.54 (d, 1H, J=1.9), 7.32-7.30 (m, 2H), 6.96-6.86 (m, 5H), 5.72 (s, 1H), MS (ES): MH+ 285.1.