Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([C:23]([NH:25][NH:26][C:27](=O)[C:28]([CH3:31])([CH3:30])[CH3:29])=O)[CH:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1COCC1>[C:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([C:23]2[S:42][C:27]([C:28]([CH3:31])([CH3:30])[CH3:29])=[N:26][N:25]=2)[CH:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(F)c(-c2ccc(OC(=O)C(C)(C)C)cc2C(=O)NNC(=O)C(C)(C)C)c1
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(OC(=O)C(C)(C)C)cc2-c2nnc(C(C)(C)C)s2)c1
Yield: 97 %

Procedure:
A solution of 2′-fluoro-5′-methoxy-2-(2-pivaloylhydrazinecarbonyl)-[1,1′-biphenyl]-4-yl pivalate (203 mg) and the Lawesson's reagent (194 mg) in THF (6.0 mL) was stirred at 80° C. for 50 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (196 mg) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:12])[CH2:6][CH2:5]2.[N+:18]([O-])([O:20]C(C)C)=[O:19].O>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:18]([O-:20])=[O:19])[CH:10]=1)[N:7]([C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:12])[CH2:6][CH2:5]2
Reactant: CC(C)O[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)N1CCc2cc(Br)ccc21
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)C(=O)N1CCc2cc(Br)cc([N+](=O)[O-])c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
To a solution of 5-bromo-N-ethoxalylindoline (5.23 g, 17.5 mmol) in concentrated sulfuric acid was added slowly isopropyl nitrate (1.87 mL, 18.5 mmol) at 0° C. The mixture was stirred for 1 h at 0° C. and poured into a mixture of water and crashed ice. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated. The crude residue was purified by silica gel column chromatography to give 5.02 g of 5-bromo-7-nitro-N-ethoxalylindoline (83%): 1H NMR (270 MHz, CDCl3) δ7.91 (d, 1H, J=1 Hz), 7.62 (d, 1H, J=1 Hz), 4.39 (t, 2H, J=8 Hz), 4.38 (q, 2H, J=7 Hz), 3.22 (t, 2H, J=8 Hz), 1.39 (t, 3H, J=7 Hz).
Reaction SMILES: [CH3:1][CH:2]([CH2:15][CH2:16][CH:17]([CH3:21])[CH:18]([CH3:20])[CH3:19])[CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1.[CH2:22](Br)[C:23]#[CH:24]>>[CH2:24]([O:11][C:10](=[O:12])[C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:15][CH2:16][CH:17]([CH3:21])[CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[C:23]#[CH:22]
Reactant: CC(CCOc1ccc(C(=O)O)cc1)CCC(C)C(C)C
Reactant: C#CCBr
Product: C#CCOC(=O)c1ccc(OCCC(C)CCC(C)C(C)C)cc1

Procedure:
By utilizing the procedure of Example 8, by reacting p-[(3,6,7-trimethyloctyl)oxy]benzoic acid with propargyl bromide, there is obtained p-[(3,6,7-trimethyloctyl)oxy]benzoic acid propargyl ester; B.P. 153°-154°C/0.05 mmHg.
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][NH2:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:14](OCC)(OCC)(OCC)[CH2:15][CH2:16][CH3:17]>>[Cl:1][C:2]1[C:11]2[N:10]([C:14]([CH2:15][CH2:16][CH3:17])=[N:13][N:12]=2)[C:9]2[C:4]([N:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: NNc1nc2ccccc2nc1Cl
Reactant: CCCC(OCC)(OCC)OCC
Product: CCCc1nnc2c(Cl)nc3ccccc3n12
Temperature: 25 °C
Yield: 53 %

Procedure:
2-Chloro-3-hydrazinoquinoxaline (3.0 g., 0.015 mole), the product of Example 1, was stirred with triethyl orthobutyrate (27 ml.) at 100° C. for 2 hours. The mixture was cooled to room temperature, and the precipitate was collected by filtration and washed with cyclohexane. The crude solid was taken up in chloroform and filtered to remove insoluble material. The chloroform solution was concentrated in vacuo to give a solid which was recrystallized from chloroform to give 1.96 g. (53% yield) of 4-chloro-1-n-propyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 173°-175° C. Mass spectrum: m/e, 246 (P).
Reaction SMILES: C([Li])CCC.CCCCCC.[CH2:12]([C@H:19]1[CH2:23][O:22][C:21](=[O:24])[NH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30].[Cl-].[NH4+]>O1CCCC1>[CH2:12]([C@H:19]1[CH2:23][O:22][C:21](=[O:24])[N:20]1[C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH3:25])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCCCC(=O)Cl
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 0.33 h
Yield: 101.2 %

Procedure:
90 ml of a solution of n-butyllithium in n-hexane (1.60 mol/l) (144 mmol) was added to a solution of 25.0 g of (S)-4-benzyl-2-oxazolidinone (141 mmol) in tetrahydrofuran (600 ml) under a nitrogen atmosphere and at −78° C. over 10 minutes, and the mixture was stirred at the same temperature for 20 minutes. Then, 19.0 ml of n-valeryl chloride (159 mmol) was added over 10 minutes. The mixture was stirred at the same temperature for 20 minutes and then further stirred at room temperature for three hours. 90 ml of a saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was further stirred at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure and diluted with 300 ml of water, followed by extraction with methylene chloride. Then, the organic layer was washed with a saturated sodium bicarbonate aqueous solution and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain 37.3 g of the crude title compound.
Reaction SMILES: [CH:1](=[CH:8][C:9](=[O:13])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(O[CH2:18][CH3:19])=O>>[CH:1](=[CH:8][C:9](=[O:13])[C:10]([O:12][CH2:18][CH3:19])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(=O)C=Cc1ccccc1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)C(=O)C=Cc1ccccc1

Procedure:
Furthermore, the pyruvic acid compound (I) can also be produced, for example, in accordance with: (1) the process in which benzaldehyde and sodium pyruvate are condensed together to give benzalpyruvic acid, and the benzalpyruvic acid is then reacted with ethyl chloroformate to give ethyl benzalpyruvate, and the ethyl benzalpyruvate is then reduced [EP387058]; or (2) the process in which phenetyl bromide is reacted with carbon monoxide in the presence of a cobalt carbonyl catalyst [J. Mol. Cat., 88, 295(1994)]. The process for producing the pyruvic acid compound (I) as the starting material is not limited to these processes, either of which can be used as the production process for the starting material in the present invention.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:17])[CH:4]=[C:5]([CH3:16])[C:6](=[O:15])[C:7]=1[C:8]([CH3:14])([CH3:13])[CH2:9][C:10]([OH:12])=[O:11].[Cl:18][CH2:19][CH2:20][N:21]([CH2:29][CH2:30][Cl:31])[C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1>>[CH3:1][C:2]1[C:3](=[O:17])[CH:4]=[C:5]([CH3:16])[C:6](=[O:15])[C:7]=1[C:8]([CH3:13])([CH3:14])[CH2:9][C:10]([O:12][C:25]1[CH:24]=[CH:23][C:22]([N:21]([CH2:20][CH2:19][Cl:18])[CH2:29][CH2:30][Cl:31])=[CH:27][CH:26]=1)=[O:11]
Reactant: CC1=CC(=O)C(C)=C(C(C)(C)CC(=O)O)C1=O
Reactant: Oc1ccc(N(CCCl)CCCl)cc1
Product: CC1=CC(=O)C(C)=C(C(C)(C)CC(=O)Oc2ccc(N(CCCl)CCCl)cc2)C1=O
Yield: 9 %

Procedure:
Using an analogous procedure to that described in Example 5, 3-(2,5-dimethyl-1,4-benzoquinonyl)-3-methylbutyric acid was reacted with 4-[bis(2-chloroethyl)amino]phenol to give 4-[bis(2-chloroethyl)amino]phenyl 3-(2,5-dimethyl-1,4-benzoquinonyl)-3-methylbutyrate as a solid in 9% yield; NMR Spectrun: (CDCl3) 1.52 (s, 6H), 1.98 (m, 3H), 2.16 (s, 3H), 3.2 (s, 2H), 3.55-3.73 (m, 8H), 6.42 (m, 1 H), 6.6-6.9 (m, 4H); Mass Spectrum: (M+H+) 452.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[O:10]=[C:11](Cl)OC(Cl)(Cl)Cl>O1CCCC1>[CH3:5][CH:4]([CH3:6])[CH2:3][C@H:2]1[C:7](=[O:9])[O:8][C:11](=[O:10])[NH:1]1
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)C[C@@H]1NC(=O)OC1=O

Procedure:
The title compound is prepared by the procedure of Example 262 using 3.93 g of L-leucine, 2.7 ml of diphosgene, 0.075 g of activated carbon, and 40 ml of dry tetrahydrofuran to give 2.74 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([NH2:12])=[O:11])[CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[K].[C:14]1([SH:24])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>CN(C)C=O.O>[Cl:9][C:6]1[CH:5]=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=[C:2]([Cl:1])[C:7]=1[S:24][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Sc1cccc2ccccc12
Reactant: NC(=O)c1cc(Cl)c(Cl)c(Cl)c1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc(Cl)c(Sc2cccc3ccccc23)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3,4,5-trichlorobenzene carboxamide (25 g) in 220 ml of dry dimethylformamide (DMF), 26 g of 1-naphthalenethiol potassium salt is added and the reaction mixture stirred at room temperature for two days. The reaction mixture is then diluted with water and extracted with methylene chloride. The combined extracts are washed with water, dried with anhydrous magnesium sulfate and concentrated. The product can be purified by chromatography on silica gel.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][C:25]([C:28]2[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[O:30][N:29]=2)=[CH:24][C:20]=1[C:21](O)=[O:22]>>[F:18][C:19]1[CH:27]=[CH:26][C:25]([C:28]2[N:32]=[C:31]([C:33]([F:36])([F:34])[F:35])[O:30][N:29]=2)=[CH:24][C:20]=1[C:21]([NH:15][CH2:14][C:13]([C:11]1[N:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[O:9][CH:10]=1)([CH3:17])[CH3:16])=[O:22]
Reactant: O=C(O)c1cc(-c2noc(C(F)(F)F)n2)ccc1F
Reactant: CC(C)(CN)c1coc(-c2ccc(F)cc2)n1
Product: CC(C)(CNC(=O)c1cc(-c2noc(C(F)(F)F)n2)ccc1F)c1coc(-c2ccc(F)cc2)n1
Yield: 32 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and 2-fluoro-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (75 mg, yield 32%) as a yellow viscous liquid. 1H NMR (400 MHz, MeOD) δ 8.46-8.43 (dd, J=6.8 Hz, 2.3 Hz, 1H), 8.29-8.25 (ddd, J=8.7 Hz, 4.8 Hz, 2.4 Hz, 1H), 8.09-8.05 (dd, J=9.0 Hz, 5.3 Hz, 2H), 7.77 (s, 1H), 7.47-7.42 (dd, J=10.3 Hz, 8.8 Hz, 1H), 7.25-7.20 (t, J=8.9 Hz, 2H), 3.67 (s, 2H), 1.41 (s, 6H). MS (ESI) m/z: Calculated for C23H17F6N4O3: 492.12. found: 493.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2([CH3:13])[CH3:12].C(O)(=O)C.[Br:18]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[Br:18][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([F:1])[CH:3]=1)[NH:9][C:8](=[O:11])[C:7]2([CH3:13])[CH3:12]
Reactant: BrBr
Reactant: CC1(C)C(=O)Nc2c(F)cccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC1(C)C(=O)Nc2c(F)cc(Br)cc21
Reaction time: 24 h
Yield: 81.9 %

Procedure:
7-Fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (4.1 g, 22.9 mmol) was dissolved in dichloromethane (100 mL) and acetic acid (2 mL) at room temperature. Bromine (1.2 mL, 23 mmol) was added and the solution allowed to stir for 24 hours. The reaction mixture was poured into sodium thiosulfate solution, extracted with diethyl ether, dried (MgSO4), evaporated and the crude product triturated with hexane to give 5-bromo-7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (4.84 g, 82%): HRMS: calc'd for C10H9BrFNO, 256.9852; found (ESI, [M−H]−), 255.9781.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([CH2:21][O:18][C:15]2[CH:16]=[CH:17][N:12]([C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[C:10]([CH3:11])[N:2]([CH3:1])[N:3]=4)[CH:8]=3)[C:13](=[O:19])[CH:14]=2)=[CH:27][CH:26]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c2cc(-n3ccc(OCc4ccc(C(C)(C)C)cc4)cc3=O)ccc2nn1C
Reaction time: 18 h
Yield: 25.4 %

Procedure:
To a solution of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (100 mg) in N,N-dimethylformamide (2 ml) were added 1-(bromomethyl)-4-(tert-butyl)benzene (98 mg) and potassium carbonate (108 mg) at room temperature, and the mixture was stirred at the same temperature for 18 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/methanol) and recrystallized from ethyl acetate to give the title compound (40 mg).
Reaction SMILES: [Cl-].[CH2:2]([NH2+:9][CH2:10][CH2:11]Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:13][C:14]1[C:15]([CH3:23])=[C:16]([N:20]=[C:21]=[S:22])[CH:17]=[CH:18][CH:19]=1>>[Cl:13][C:14]1[C:15]([CH3:23])=[C:16]([N:20]=[C:21]2[N:9]([CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:10][CH2:11][S:22]2)[CH:17]=[CH:18][CH:19]=1
Reactant: Cc1c(Cl)cccc1N=C=S
Reactant: ClCC[NH2+]Cc1ccccc1
Agent: [Cl-]
Product: Cc1c(Cl)cccc1N=C1SCCN1Cc1ccccc1

Procedure:
2-Hydroxyethylamine was reacted with benzyl bromide according to Method B2a to give N-benzyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-benzyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 3-chloro-2-methylphenyl isothiocyanate to give 2-(3-chloro-2-methylphenylimino)-3-benzyl-1,3-thiazolidine.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].[Cl:18][C:19]1[S:23][C:22]([C:24]2[S:25][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:27][CH:28]=2)=[CH:21][CH:20]=1>>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:29]([C:26]2[S:25][C:24]([C:22]3[S:23][C:19]([Cl:18])=[CH:20][CH:21]=3)=[CH:28][CH:27]=2)(=[O:30])=[O:31])[C:4]1=[O:17])#[N:13]
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(Cl)s2)s1
Agent: Cl
Product: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3ccc(-c4ccc(Cl)s4)s3)C2=O)c1

Procedure:
The title compound is prepared from 3-(3-(S)-amino-2-oxo-pyrrolidin-1-ylmethyl)-benzonitrile hydrochloride as described in EXAMPLE 1, Part E using 5'-chloro-[2,2']bithiophenyl-5-sulfonyl chloride in place of benzo[b]thiophene-2-sulfonyl chloride. The crude product is triturated with EtOAc/CH2Cl2 to yield a beige solid.
Reaction SMILES: [CH2:1]([N:5]([CH3:11])[C:6](=O)[N:7]([CH3:9])[CH3:8])[CH2:2][CH2:3][CH3:4].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH2:1]([N:5]([CH3:11])[C:6]([N:7]([CH3:9])[CH3:8])=[N:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C)C(=O)N(C)C
Reactant: Nc1ccccc1N1CCOCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCCCN(C)C(=Nc1ccccc1N1CCOCC1)N(C)C

Procedure:
Reaction of 3-n-butyl-1,1,3-trimethylurea (7 g) in benzene (60 ml) with 4-(2-aminophenyl)morpholine (7.2 g) in benzene (30 ml) in the presence of phosphorus oxychloride (4 ml) for 18 hours at 80°-85° C. gave 1-n-butyl-2-(2-morpholinophenyl)-1,3,3-trimethyl guanidine (bp. 162°-163° C. at 0.7 mm Hg).
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)(=O)[CH3:12].C(O)C>O1CCOCC1>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11](=[N:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:12]
Reactant: NNC(=O)c1ccccc1
Reactant: CC(=O)c1ccccn1
Solvent: CCO
Solvent: C1COCCO1
Product: CC(=NNC(=O)c1ccccc1)c1ccccn1
Temperature: 25 °C
Yield: 63.6 %

Procedure:
A mixture of 6.81 gm (0.05 mole) of benzhydrazide, 6.06 gm (0.05 mole) of 2-acetylpyridine and 100 ml of ethanol is stirred at reflux 2 hr. Then sufficient dioxane is added to the boiling mixture to furnish a solution. The hot solution is filtered. The filtrate is diluted to the cloud point with water, cooled to room temperature, and then chilled in the refrigerator. The product is collected and dried to yield 7.61 gm (64%) of the title compound having a melting point of 151.6° C.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([NH:15][C@@H:16]([CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([O:28][CH3:29])[CH:23]=1)[C:17]([O:19][CH3:20])=[O:18])=O)(C)(C)C>C(Cl)Cl>[NH2:15][C@@H:16]([CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([O:28][CH3:29])[CH:23]=1)[C:17]([O:19][CH3:20])=[O:18].[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2]
Reactant: COC(=O)[C@H](Cc1ccnc(OC)c1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](N)Cc1ccnc(OC)c1

Procedure:
TFA (5 mL) was added to a solution of (S)-methyl 2-(tert-butoxycarbonylamino)-3-(2-methoxypyridin-4-yl)propanoate (2.4 g, 7.7 mmol) in CH2Cl2 (10 mL) at 0° C. with stirring. The mixture was stirred for 1 h and then concentrated to dryness. The residue was azeotroped three times with EtOAc (10 mL for each portion) to remove residual TFA to afford crude (S)-methyl 2-amino-3-(2-methoxypyridin-4-yl)propanoate as its TFA salt.
Reaction SMILES: [NH2:1][C:2]1[S:21][C:5]2[CH2:6][N:7]([C:10]([C:12]3[CH:20]=[CH:19][C:15]4[NH:16][N:17]=[N:18][C:14]=4[CH:13]=3)=[O:11])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:22]([N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1>N1C=CC=CC=1.CS(C)=O>[NH:16]1[C:15]2[CH:19]=[CH:20][C:12]([C:10]([N:7]3[CH2:8][CH2:9][C:4]4[C:3]([C:22]([N:24]5[CH2:28][CH2:27][CH2:26][CH2:25]5)=[O:23])=[C:2]([NH:1][C:37]([NH:36][C:33]5[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][CH:32]=5)=[O:38])[S:21][C:5]=4[CH2:6]3)=[O:11])=[CH:13][C:14]=2[N:18]=[N:17]1
Reactant: Nc1sc2c(c1C(=O)N1CCCC1)CCN(C(=O)c1ccc3[nH]nnc3c1)C2
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: O=C(Nc1ccc(Cl)cc1)Nc1sc2c(c1C(=O)N1CCCC1)CCN(C(=O)c1ccc3[nH]nnc3c1)C2
Temperature: 25 °C
Yield: 4 %

Procedure:
Starting material 13 (1.2 g, 20% content, 0.6 mmol) was dissolved in 5 ml pyridine and one half of 112 mg (0.7 mmol) p-chlorphenyl isocyanate was added. The reaction mixture was stirred over night at ambient temperature. Then the other half of the p-chlorphenyl isocyanate was added and the reaction was again stirred over night at ambient temperature. The reaction was now concentrated in vacuo and the thereby isolated crude product was dissolved in 7 ml DMSO and purified by prep. HPLC (Method 3). The pure fractions were combined, the solvent reduced and the product finally lyophilized. The desired product 14 could thereby be isolated as yellow solid (16.2 mg, 4%; and additional 17 mg, 84% content 14, 4% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:28][CH3:29].O>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:28][CH3:29])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.5 %

Procedure:
To a stirred solution of 1.0 g (0.0033 mole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-20) in 10 mL of dimethylformamide was added 3.23 g (0.0099 mole) of cesium carbonate followed by 0.8 mL (0.0099 mole) of iodoethane. The mixture was stirred at room temperature for 18 hours, then water was added. After 15 minutes, the mixture was extracted with ethyl acetate. The organic layer was washed with water, 5% aqueous sodium metabisulfite solution and then brine. The aqueous layers were reextracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexanes-dichloromethane to give 0.90 g of 2-chloro-9-cyclopentyl-5-ethyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-138) as white crystals.
Reaction SMILES: [F:1][C:2]1[C:15]([N:16]=[C:17]=S)=[C:14]([F:19])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8].[NH2:20][C:21]1[C:22]([NH:45][CH3:46])=[N:23][C:24]([O:40][CH2:41][CH:42]([F:44])[F:43])=[C:25]([CH:39]=1)[C:26]([NH:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([C:35]([F:38])([F:37])[F:36])[CH2:31][CH2:30]1)=[O:27].CC(C)N=C=NC(C)C>>[F:1][C:2]1[C:15]([NH:16][C:17]2[N:45]([CH3:46])[C:22]3=[N:23][C:24]([O:40][CH2:41][CH:42]([F:44])[F:43])=[C:25]([C:26](=[O:27])[NH:28][C@H:29]4[CH2:30][CH2:31][C@H:32]([C:35]([F:37])([F:36])[F:38])[CH2:33][CH2:34]4)[CH:39]=[C:21]3[N:20]=2)=[C:14]([F:19])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CNc1nc(OCC(F)F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Reactant: CC(C)(C)C(=O)NCc1ccc(F)c(N=C=S)c1F
Agent: CC(C)N=C=NC(C)C
Product: Cn1c(Nc2c(F)ccc(CNC(=O)C(C)(C)C)c2F)nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(OCC(F)F)nc21

Procedure:
The title compound is prepared from N-(2,4-difluoro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (150 mg, 0.38 mmol) and 5-amino-2-(2,2-difluoro-ethoxy)-N-(trans-4-trifluoromethyl-cyclohexyl)-6-methylamino-nicotinamide (150 mg, 0.38 mmol) with DIC in analogy to examples 8a/8b.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:11][CH:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][C:8]2[CH:19]=[CH:20][C:21]([I:23])=[CH:22][C:7]=2[C:6]1=[O:24].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:26].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CN(C)C=O.O>[C:2]([CH2:3][CH2:4][N:5]1[CH2:11][CH:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][C:8]2[CH:19]=[CH:20][C:21]([I:23])=[CH:22][C:7]=2[C:6]1=[O:24])([OH:26])=[O:1]
Reactant: O=C1c2cc(I)ccc2OC(Cc2ccccc2)CN1CCCO
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CCN1CC(Cc2ccccc2)Oc2ccc(I)cc2C1=O
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a magnetically stirred solution of 2-(3-hydroxypropyl)-4-benzyl-8-iodo2,3,4,5-tetrahydro-1H-5-oxa-2-benzazepin-1-one (0.75 grams, 1.7mmol) in 5 mL dimethylformamide at room temperature was added a solution of pyridinium dichromate (2.58 grams, 6.86mmol) in 5 mL dimethylformamde. The reaction mixture was stirred overnight, diluted with 75 mL water, washed 3×75 mL diethyl ether, made acidic to a pH of 2 with conc. HCl and extracted 3×75 mL diethyl ether. The combined organics were extracted 3×40 mL 1N sodium hydroxide. The combined aqueous layers were acidified to a pH of 2 with canc HCl and extracted 3×50 mL diethyl ether. These ether layers were combined and dried over magnesium sulfate, filtered, and concentrated in vacuo to yield 0.557 grams (73%) of 2-(2-carboxyethyl)-4-benzyl-8-iodo-2,3,4,5-tetrahydro-1H-5-oxa-2-benzazepin-1-one. 1H NMR (CDCl3, dTMS) 8.07 (1H, d, 4JHH =2 Hz, C9-H), 7.69 (1H, dd, 4JHH =2 Hz, 3JHH =8 Hz, C7-H), 7.4-7.2 (5H, m, C6H5), 6.75 (1H, d, 3JHH =8 Hz, C6-H), 4.75 (1H, m, ArOCH), 3.89 (1H, dt, 2JHH =14 Hz, 3JHH =6 Hz, NCHHCH2CO2), 3.69 (1H, dt, 2JHH =14 Hz, 3JHH =6 Hz, NCHHCH2CO2), 3.44 (2H, d, 3JHH =3 Hz, CH2Ph), 3.07 (1H, dd, 2JHH =14 Hz, 3JHH =7 Hz, C3-H), 2.8-2.7 (3H, m, C3-H, CH2CO2), 13C NMR (CDCl3) 176.1 167.6, 164.4, 152.8, 141.7, 139.5, 136.4, 129.4, 129.1, 128.9, 128.8, 127.0, 124.7, 86.7, 84.7, 51.4, 45.0, 38.8, 33.0.