Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[NH:6][C@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][CH2:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1C=CC=CC=1>[S:23]=[C:2]1[NH:6][C@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)[C@@H]1CCC(=S)N1
Yield: 191.1 %

Procedure:
To a solution of t-butyl pyroglutamate (1a) (10.12 g, 54.6 mmol) in benzene (250 mL), was added Lawesson's reagent (11.05 g, 27.3 mmol). The mixture was stirred at reflux for 15.5 h, then concentrated. The resultant residue was purified by flash chromatography (0 to 2 to 3 to 4% MeOH/CHCl3) to afford 10.50 g (95%) of the title compound, 1b. 1H NMR (300 MHz, CDCl3) δ 7.27 (br s, 1H), 4.46–4.39 (m, 1H), 3.03–2.84 (m, 2H), 2.58–2.46 (m, 1H), 2.37–2.23 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15]([C:17]1[NH:18][CH:19]=[CH:20][C:21]=1[CH3:22])=[O:16])[CH3:13].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.ClCCCl>[CH2:12]([O:14][C:15]([C:17]1[NH:18][CH:19]=[C:20]([C:9](=[O:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:21]=1[CH3:22])=[O:16])[CH3:13]
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CCOC(=O)c1[nH]ccc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)c1[nH]cc(C(=O)Cc2ccc(Cl)cc2)c1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of (4-chlorophenyl)-acetyl chloride (3 mmol) in dichloromethane or 1,2-dichloroethane (4 ml) was added to a solution cooled at −40° C. of 84 (0.229 g, 1.5 mmol) and AlCl3 was added (0.400 g, 3 mmol). The reaction mixture was stirred for 30 minutes at the same temperature. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with NaOH (2 M) and brine, dried over Na2SO4, and evaporated to dryness under vacuum to give crude product 85. Crude yield: 96%
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([O:12][C:13](=O)[O:14]C(C)(C)C)([CH3:11])([CH3:10])[CH3:9].C(OCC)(=O)C.CCCCCC>O1CCCC1>[C:8]([O:12][C:13]([N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: OC1CCNCC1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(O)CC1
Reaction time: 3 h

Procedure:
A solution of 4-hydroxypiperidine (5.05 g; 0.05 mole) in 100 ml of tetrahydrofuran was stirred and cooled in an ice-water bath. Di-tert.butylcarbonate (10.9 g; 0.05 mole) was added and stirring was continued at room temperature for 3 hrs. The solvent was removed under reduced pressure. An oily residue was triturated with petroleum ether. Recrystallization from petroleum ether yielded 9.21 g (92%). Rf (silica gel)=0.42 (ethyl acetate/n-hexane 1:
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH3:21][C:22]1[S:26][C:25]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)=[N:24][CH:23]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([C:25]3[S:26][C:22]([CH3:21])=[CH:23][N:24]=3)[CH:28]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: Cc1cnc(-c2cccc(C=O)c2)s1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-c2ncc(C)s2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 3-(5-methylthiazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.89 min.; [M+H]+: 423.09 g/mol.
Reaction SMILES: [Cl:1][C:2]1[C:15]([N:16]=[C:17]=S)=[C:14]([Cl:19])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:20][O:21][C:22](=[O:36])[C:23]1[CH:28]=[C:27]([NH2:29])[C:26]([NH2:30])=[N:25][C:24]=1[O:31][CH2:32][CH:33]([F:35])[F:34].C(Cl)CCl>CC#N.O>[Cl:1][C:2]1[C:15]([NH:16][C:17]2[NH:29][C:27]3[C:26]([N:30]=2)=[N:25][C:24]([O:31][CH2:32][CH:33]([F:35])[F:34])=[C:23]([C:22]([O:21][CH3:20])=[O:36])[CH:28]=3)=[C:14]([Cl: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: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Reactant: COC(=O)c1cc(N)c(N)nc1OCC(F)F
Solvent: CC#N
Solvent: ClCCCl
Solvent: O
Product: COC(=O)c1cc2[nH]c(Nc3c(Cl)ccc(CNC(=O)C(C)(C)C)c3Cl)nc2nc1OCC(F)F
Reaction time: 2.5 h

Procedure:
A mixture of N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (4.00 g, 12.6 mmol) and 5,6-diamino-2-(2,2-difluoro-ethoxy)-nicotinic acid methyl ester (3.10 g, 12.5 mmol, prepared according to WO2010/034799) in MeCN (30 ml) is stirred for 2.5 h, then EDC (2.75 g, 14.3 mmol) is added and it is stirred at reflux for 15 min. The mixture is diluted with water, concentrated and extracted with DCM. The organic phase is dried with MgSO4, filtered and concentrated.
Reaction SMILES: [N-:1]=[C:2]=[S:3].[N+:4]([C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1)([O-:6])=[O:5].N[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([N:11]([C:10]1[CH:12]=[CH:13][C:7]([N+:4]([O-:6])=[O:5])=[CH:8][CH:9]=1)[C:2]([NH2:1])=[S:3])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: [N-]=C=S
Reactant: NCc1ccccc1
Product: NC(=S)N(Cc1ccccc1)c1ccc([N+](=O)[O-])cc1
Reaction time: 16 h
Yield: 76 %

Procedure:
In Example 106, reaction of compound 340 with aminomethylbenzene 341 yielded the model compound 342 containing a thiourea linkage, as follows: To a solution of isothiocyanate 340 (1.80 g, 10 mol, prepared in Example 105 from the p-nitro aniline 339), benzylamine 341 (1.64 mL, 15 mmol) was added dropwise. The resulting mixture was stirred for 16 hours, then evaporated. The solid residue was washed on a filter sequentially with 2N HCl (5×10 mL), and H2O (5×5 mL), then dried in vacuo to produce a crude product that was crystallized from EtOAc to yield 2.190 g (76% yield) of benzyl-(4-nitrophenyl) thiourea 342 as an orange powder. Relevant data: mp 151°-152° C. (from EtOAc); 1H NMR (DMSO-d6): δ4.74 (s, 2H), 7.34 (m, 5H), 7.84 (d, 2H, J=9 Hz), 8.15 (d, 2H, J=9 Hz), 8.65 (s, 1H, NH), 10.21 (s, 1H, NH); 13C NMR (DMSO-d6): δ48.17, 121.62, 125.34, 128.04, 128.55, 129.30, 139.11, 142.92, 147.28, 181.36; MS m/e (1%): 287 (M+, 22), 180 (100), 150 (51), 138 (21), 122 (43), 106 (81), 107 (56), 91 (95).
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[OH:18])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:32].CC(=O)CC>C(O)(C)C>[OH2:18].[ClH:32].[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH:16]=[CH:17][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH2:12][CH2:13]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C:1]1([CH:7]([CH:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH:16]=[CH:17][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH2:12][CH2:13]2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[ClH:32]
Reactant: OC(CCCN1CCC(C(c2ccccc2)c2ccccc2)CC1)c1ccc(F)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCC(C)=O
Product: Fc1ccc(C=CCCN2CCC(C(c3ccccc3)c3ccccc3)CC2)cc1
Product: O

Procedure:
A mixture of 24 g (0.057 mole) of 4-(diphenylmethyl)-α-(p-fluorophenyl)-1-piperidinebutanol, 500 ml of 37% HCl, 100 ml of butanone and 200 ml of isopropyl alcohol was heated to reflux under an atmosphere of nitrogen for 18 hours. The solvent and excess acid were removed under vacuum and the residue was dissolved in toluene. Ether was added to the toluene solution, and an oily precipitate formed. The toluene and ether were decanted, and the precipitate was recrystallized from ethyl acetate to give the desired product, M.P. 143°-148° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH2:15])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[F:16][CH:17]([F:29])[O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[C:21]([CH3:28])[CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([O:18][CH:17]([F:16])[F:29])=[CH:20][C:21]=2[CH3:28])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: Cc1cc(OC(F)F)ccc1C(=O)O
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2ccc(OC(F)F)cc2C)Cc2ccccc2C1
Yield: 88.8 %

Procedure:
2-Amino-indane-2-carboxylic acid ethyl ester (2) (250 mg, 1.2 mmol), 4-difluoromethoxy-2-methyl-benzoic acid (242) (246 mg, 1.2 mmol) and HATU (555 mg, 1.46 mmol) are taken in a vial, evacuated and refilled with nitrogen Anhydrous DMF (2 mL) is added and stirring is initiated. After few min, DIPEA (0.302 mL, 1.82 mmol) is added and stirred at RT overnight. Analysis by tlc of the reaction mixture (silica, 50% EtOAc/heptanes) indicates complete consumption of the starting amine. Water (10 mL) is added, extracted with EtOAc (3×5 mL), dried over Na2SO4, concentrated and the crude product is chromatographed on a 25 g silica gel column using 20-50% EtOAc in heptane as a gradient to afford 2-(4-difluoromethoxy-2-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (415 mg, 89%).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Cs+].[Cs+].O[C:8]1[C:9]([CH3:28])=[C:10]([NH:14][C:15](=[O:27])[CH2:16][C:17]23[CH2:26][CH:21]4[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]4)[CH2:18]2)[CH2:24]3)[CH:11]=[CH:12][CH:13]=1.[CH3:29][N:30]([CH2:32][CH2:33]C[Cl:35])[CH3:31].Cl>C(#N)C.CO.CCOCC>[ClH:35].[CH3:29][N:30]([CH2:32][CH2:33][CH2:1][O:4][C:12]1[CH:13]=[CH:8][C:9]([CH3:28])=[C:10]([NH:14][C:15](=[O:27])[CH2:16][C:17]23[CH2:18][CH:19]4[CH2:20][CH:21]([CH2:22][CH:23]([CH2:25]4)[CH2:24]2)[CH2:26]3)[CH:11]=1)[CH3:31]
Reactant: CN(C)CCCCl
Reactant: O=C([O-])[O-]
Reactant: Cc1c(O)cccc1NC(=O)CC12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: [Cs+]
Solvent: CO
Solvent: CCOCC
Solvent: CC#N
Product: Cc1ccc(OCCCN(C)C)cc1NC(=O)CC12CC3CC(CC(C3)C1)C2
Temperature: 80 °C

Procedure:
Caesium carbonate (1.31 g) was added to a suspension of N-(3-hydroxy-2-methylphenyl)-tricyclo[3.3.1.13,7]decane-1-acetamide (0.473 g, Example 26) in acetonitrile (35 ml) and the mixture heated at 80° C. for 5 minutes. After cooling to room temperature solid N,N-dimethyl-3-chloropropylamine (0.274 g) was added and the reaction heated at reflux overnight. The reaction was concentrated under reduced pressure and the residue partitioned between dichloromethane (100 ml) and water (100 ml). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with dichloromethane:ethanol:triethylamine (95:4:1) to give a yellow gumn. This was dissolved in methanol (10 ml) and treated with an excess of ethereal hydrogen chloride is (1M, 5 equivalents). The solution was concentrated under reduced pressure to give a gum that was stirred for 2 days in ether (20 ml) to give a solid which was isolated by filtration (0.588 g).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]3[CH2:28][CH2:29][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][N:36]4C(OC(C)(C)C)=O)=[O:34])[CH2:31][CH:32]=3)[CH:25]=2)[CH:20]=[N:19]1)[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]3[CH2:28][CH2:29][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][NH:36]4)=[O:34])[CH2:31][CH:32]=3)[CH:25]=2)[CH:20]=[N:19]1)[CH3:17]
Reactant: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(C3=CCN(C(=O)[C@H]4CCCN4C(=O)OC(C)(C)C)CC3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(C3=CCN(C(=O)[C@H]4CCCN4)CC3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.5 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of (R)-t-butyl 2-(4-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-indazol-6-yl)-1,2,3,6-tetrahydropyridine-1-carbonyl)pyrrolidine-1-carboxylate (0.037 g, 0.065 mmol) in dichloromethane (1 mL) and the resulting solution was stirred at room temperature for 30 min. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane (10 mL). The organic layer was neutralized with saturated aqueous sodium bicarbonate, and the aqueous layer was further extracted with dichloromethane (2×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 15% methanol in dichloromethane) to give the title compound as a white solid (0.012 g, 0.025 mmol, 38%). 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1 H), 7.66 (d, J=8.0 Hz, 1 H), 7.39 (s, 1 H), 7.19-7.12 (m, 4 H), 6.20 (d, J=6.8 Hz, 1 H), 6.11-6.08 (m, 1 H), 4.82-4.74 (m, 1 H), 4.29-4.09 (m, 2 H), 3.98-3.70 (m, 2 H), 3.46-3.34 (m, 3 H), 2.70-2.48 (m, 3 H), 2.16-1.98 (m, 3 H), 2.00 (d, J=7.2 Hz, 3H); MS: (ES) m/z calculated for C25H27Cl2N4O [M+H]+ 469.2, found 469.4.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[C:15]([O:21][CH2:22][CH2:23][CH3:24])(=[O:20])[CH2:16][C:17]([CH3:19])=[O:18].C(O)(=O)C.N1CCCCC1>ClCCl>[CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:16]([C:17](=[O:18])[CH3:19])[C:15]([O:21][CH2:22][CH2:23][CH3:24])=[O:20]
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: CCCOC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CCCOC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O

Procedure:
2-Methyl-4-oxo-4H-chromene-8-carbaldehyde (2 g, 10.62 mmol) and propyl acetoacetate (1.53 g, 10.62 mmol) are dissolved in 500 ml of dichloromethane and, after addition of glacial acetic acid (0.76 ml, 13.28 mmol) and piperidine (0.1 ml, 1.06 mmol), heated under reflux with a water trap for 18 h. After cooling, the reaction mixture is diluted with 50 ml of dichloromethane and washed with 20 ml of sodium chloride solution, the organic phase is dried over sodium sulfate, and the solvent is removed in vacuo. 3.3 g (99% of theory) of the title compound are obtained as an E/Z isomer mixture.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7](=O)[NH:6][C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1.Cl>C1COCC1.CO>[CH3:1][C:2]1([CH3:16])[CH2:7][NH:6][C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2NC1=O
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)CNc2cc([N+](=O)[O-])ccc2O1

Procedure:
2,2-Dimethyl-6-nitro-4H-benzo[1,4]oxazin-3-one was added to BH3-THF complex (Aldrich) in THF with ice cooling. The mixture was heated to reflux for 2 h then carefully diluted with 12 mL of MeOH and heated to reflux for an additional 1 h. Concentrated HCl (12 mL) was added and heated to reflux for 1 h. The mixture was concentrated and the resulting solid was suspended in a dilute aqueous solution of NaOH (1 M) and extracted with EtOAc (100 mL×4). The organic layers were washed with H2O and dried over MgSO4. Evaporation of solvent gave a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:29])[CH3:28])[C:22]=1[N:30]=[C:31]=[O:32])([CH3:20])[CH3:19]>>[CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:28])[CH3:29])[C:22]=1[NH:30][C:31](=[O:32])[N:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([N:2]([CH3:17])[CH3:1])=[CH:8][CH:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:19])[CH3:20]
Reactant: CN(C)c1ccc(CNc2ccccc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)N(Cc1ccc(N(C)C)cc1)c1ccccc1

Procedure:
By the reaction and treatment in the same manner as in Example 2 using [(4-dimethylaminophenyl)methyl]phenylamine (0.70 g) and 2,6-diisopropylphenyl isocyanate (0.74 mL) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(4-dimethylaminophenyl)methyl]-N-phenylurea (0.46 g) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]1)[CH2:5]2.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]1)[CH2:5]2
Reactant: CN(C)CCO
Reactant: O=C1Nc2ccc(O)cc2CN1C1CCN(Cc2ccccc2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc2c(c1)CN(C1CCN(Cc3ccccc3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 1.1 g (3.26 mmol) of 3,4-dihydro-6-hydroxy-3-(1-phenylmethyl-4-piperidinyl)-2(1H)-quinazolinone, 50 mL of tetrahydrofuran, 0.30 g (3.366 mmol) of 2-dimethylaminoethanol, 0.94 g (3.584 mmol) of triphenylphosphine, and 0.56 g (3.216 mmol) of azodicarboxylic acid ester was stirred for one hour at ambient temperature, 6 hours at reflux temperature and another 13 hours at ambient temperature. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (30-60 μm) using dichloromethane/EE/cyclohexane/methanol/concentrated ammonia 60/16/5/5/0.6 v/v/v/v/v as eluant. Working up the corresponding fractions yielded 0.9 g (69% of theoretical) of a colorless crystalline substance, Rf=0.47 (dichloromethane/EE/cyclohexane/methanol/concentrated ammonia 60/16/5/5/0.6 v/v/v/v/v).
Reaction SMILES: [Na].[C:2]([NH:5][NH2:6])([NH2:4])=[NH:3].Cl.[C:8]1([N:14]=[C:15]=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:17][C:18]([CH3:20])=O>>[NH:14]([C:15]([NH:3][C:2]([NH:5][N:6]=[C:18]([CH3:20])[CH3:17])=[NH:4])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N=C(N)NN
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)=O
Agent: Cl
Agent: [Na]
Product: CC(C)=NNC(=N)NC(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a suspension of sodium (19 g, 0.82 mol) in acetone (1000 mL) and was added aminoguanidine hydrochloride (100 g, 0.91 mol) in portions. The mixture was refluxed for 60 minutes. The heating bath was removed, and phenyl isocyanate (78.4 g, 0.65 mol) was added dropwise during 30 minutes. The mixture was refluxed for another 30 minutes. The mixture was poured into ice water (2.5 L). The oil solidified at room temperature during an overnight stirring. The solid was filtered and washed with petroleum ether to afford the product as a yellow solid (150 g, 70
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].IN1[C:18](=O)[CH2:17][CH2:16]C1=O.[CH3:21][C:22]([CH3:24])=O>>[CH3:21][C:22]1([CH3:24])[O:6][C@H:5]2[C@@H:7]3[O:8][C:17]([CH3:18])([CH3:16])[O:10][C@:9]3([CH2:11][OH:12])[O:4][C@H:3]2[CH2:2][O:1]1
Reactant: CC(C)=O
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Reactant: O=C1CCC(=O)N1I
Product: CC1(C)OC[C@@H]2O[C@@]3(CO)OC(C)(C)O[C@H]3[C@@H]2O1
Temperature: 60 °C
Reaction time: 6 h
Yield: 58.4 %

Procedure:
To 200 ml of acetone were added 10.0 g of L-sorbose and 225 mg of N-iodosuccinimide and the mixture was refluxed with stirring in a water bath at 60° C. for 6 hours. During this reaction, the refluxing solvent was dried with 20 g of Molecular Sieves 3A interposed between the reaction vessel and the cooling jacket. The reaction mixture was then subjected to an after-treatment similar to that described in Example 11 to give 8.43 g (58.4%) of 2,3:4,6-di-O-isopropylidene-L-sorbofuranose (purity ≥97%).
Reaction SMILES: FC1C=C([C:12]2[S:16][C:15]([NH2:17])=[N:14][C:13]=2[CH3:18])C=CC=1S(C)(=O)=O.[F:19][C:20]1[CH:21]=[C:22](CC(=O)C)[CH:23]=[CH:24][C:25]=1[S:26]([CH3:29])(=[O:28])=[O:27].FC1C=CC(CC(=O)C)=CC=1S(C)(=O)=O>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:12]2[S:16][C:15]([NH2:17])=[N:14][C:13]=2[CH3:18])=[CH:24][C:25]=1[S:26]([CH3:29])(=[O:27])=[O:28]
Reactant: CC(=O)Cc1ccc(S(C)(=O)=O)c(F)c1
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Agent: CC(=O)Cc1ccc(F)c(S(C)(=O)=O)c1
Product: Cc1nc(N)sc1-c1ccc(F)c(S(C)(=O)=O)c1

Procedure:
The titled compound is prepared via an analogous method to 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Intermediate AA) by replacing 1-(3-fluoro-4-methanesulfonyl-phenyl)-propan-2-one (AA3) in step AA4 with 1-(4-fluoro-3-methanesulfonyl-phenyl)-propan-2-one (AG3).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:16][NH:17][NH2:18]>CO>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:17]([CH3:16])[NH2:18])[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CNN
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(N)c1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 112.7 %

Procedure:
2 g of 4,6-dichloropyrimidine were dissolved in 30 ml of methanol, mixed with 1.37 g of triethylamine and 0.63 g of methyl hydrazine and stirred for 2 days at room temperature. 0.1 ml of methyl hydrazine and 0.2 ml of triethylamine were then added and stirred for 4 days at room temperature. After rotating out the solvent, a residue of 2.4 g of crude 6-chloro-4-(1-methyl-hydrazino)-pyrimidine were obtained, which was immediately processed further.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].O1CCCC1>C(O)C.[C].[Pd]>[NH2:18][C:14]1[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]2[CH:21]=[CH:22][CH:23]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc([N+](=O)[O-])c2)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(N)c2)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)-N-(3-nitrophenyl)benzamide (495 mg, 1.60 mmol) in ethanol (12 mL)/tetrahydrofuran (4 mL) was added 10% palladium-carbon (85 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) for 14 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give N-(3-aminophenyl)-3-(1-cyano-1-methylethyl)benzamide as a pale-brown oil. The obtained compound was used for the next reaction without further purification.