Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[CH:9]1([CH2:12][NH2:13])[CH2:11][CH2:10]1.[Cl:14][C:15]1[C:16]([N:21]2[C:25]([C:26]3[O:31][C:30](=[O:32])[C:29]4[CH:33]=[CH:34][CH:35]=[C:36]([CH3:37])[C:28]=4[N:27]=3)=[CH:24][C:23]([C:38]([F:41])([F:40])[F:39])=[N:22]2)=[N:17][CH:18]=[CH:19][CH:20]=1>O1CCCC1>[CH:9]1([CH2:12][NH:13][C:30]([C:29]2[C:28]([NH:27][C:26]([C:25]3[N:21]([C:16]4[C:15]([Cl:14])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:22]=[C:23]([C:38]([F:40])([F:39])[F:41])[CH:24]=3)=[O:31])=[C:36]([CH3:37])[CH:35]=[CH:34][CH:33]=2)=[O:32])[CH2:11][CH2:10]1
Reactant: Cc1cccc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reactant: NCC1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)NCC2CC2)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
1.49 g of triethylamine was gradually dropwise added to a mixed solution comprising 0.8 g of cyclopropylmethylamine hydrochloride and 40 ml of tetrahydrofuran under cooling with ice, followed by stirring at room temperature for 30 minutes. Then, a mixed solution comprising 1 g of 2-[1-(3-chloro-2-pyridyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one and 10 ml of tetrahydrofuran was gradually dropwise added. After completion of the dropwise addition, the mixed solution was reacted for 4 hours under reflux. After completion of the reaction, the solvent was distilled off under reduced pressure, and to the residue, ethyl acetate and water were added for extraction. The organic layer was washed with water and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1) to obtain 0.54 g of the desired product having a melting point of 199.4° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:4][N:3]=1.[F:15][C:16]([F:24])([F:23])[C:17](=O)[CH2:18][C:19](=O)[CH3:20]>>[CH2:8]([S:7][C:5]1[N:6]=[C:2]2[N:1]=[C:19]([CH3:20])[CH:18]=[C:17]([C:16]([F:24])([F:23])[F:15])[N:3]2[N:4]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Product: Cc1cc(C(F)(F)F)n2nc(SCc3ccccc3)nc2n1
Yield: 84 %

Procedure:
This material was prepared in 84% yield from 3-amino-5-benzylthio-1,2,4-triazole and 1,1,1-trifluoro-2,4-pentanedione following the general procedure described in Example 34. The product was purified by recrystallization from benzene-hexane to yield a tan solid, m.p. 83.5°-84.5° C. IR, 1H NMR and 19F NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24](O)=[O:25])=[O:21])[CH3:19])([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:41]([O:43][C:44](=[O:55])[C@H:45]([CH2:47][C:48]1[CH:53]=[CH:52][C:51]([OH:54])=[CH:50][CH:49]=1)[NH2:46])[CH3:42].CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:41]([O:43][C:44](=[O:55])[C@H:45]([CH2:47][C:48]1[CH:49]=[CH:50][C:51]([OH:54])=[CH:52][CH:53]=1)[NH:46][C:24](=[O:25])[C@@H:23]1[CH2:27][CH2:28][CH2:29][N:22]1[C:20](=[O:21])[C@H:18]([CH3:19])[NH:17][P:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9])[CH3:42]
Reactant: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NP(=O)(Cc1ccccc1)Cc1ccccc1
Temperature: -15 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
Dibenzylphosphoryl-L-alanyl-L-proline (1.2 g, 2.5 m mole), HOBt (338 mg, 2.5 m mole) and L-tyrosine ethylester hydrochloride (737 mg, 3 m mole) was suspended in DMF (10 ml), and WSC (0.5 ml) was added gradually thereto while cooling to -15° C. and stirring. The reaction was carried out for 3 hours under cooling and then overnight at room temperature. To the reaction solution ethyl acetate (100 ml) was added, and the mixture was washed with 1N hydrochloric acid and water in order, and dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain an oily dibenzylphosphoryl-L-alanyl-L-prolyl-L-tyrosine ethylester (1.4 g). This oily material gave a single spot with Rf 0.50 by thin layer chromatography (developing solvent; chloroform:methanol:acetic acid=95:5:3, colour forming method: spraying of 25% hydrobromic acid and 0.1% ninhydrine, and heating).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][NH2:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:14](N1C=CN=C1)(N1C=CN=C1)=[S:15]>C(Cl)Cl.N#N>[N:13]([CH2:12][CH2:11][C:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2)=[C:14]=[S:15]
Reactant: NCCC12CC3CC(CC(C3)C1)C2
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: N#N
Solvent: ClCCl
Product: S=C=NCCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.9 %

Procedure:
2-adamantan-1-yl-ethylamine (380 mg, 2.12 mmol) was dissolved in CH2Cl2 (10 ml) under a dry atmosphere of N2. To this solution was added 1,1'-thiocarbonyl-diimidazole (420 mg, 2.12 mmol). After stirring at ambient temperature for 12 hours, the solution was partitioned between 0.1 N HCl and CH2Cl2. The CH2Cl2 layer was washed with water, then saturated NaHCO3 solution and finally brine. The CH2Cl2 layer was dried over MgSO4, filtered and concentrated under vacuum to give 417 mg of a yellow solid. The product was chromatographed on silica gel using hexanes to give 125 mg of the titled compound as a white solid: 1H NMR (CDCl3)δ 3.52 (m, 2H), 1.98 (br s, 3H), 1.49-1.76 (m, 17H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[Br:19]N1C(=O)CCC1=O>>[Br:19][C:7]1[CH:6]=[C:5]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCS(=O)(=O)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Product: CCCS(=O)(=O)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A suspension of 1-fluoro-4-(propylsulfonyl)benzene (Intermediate 105; 1.00 g; 4.94 mmol) in conc. sulfuric acid (3.97 ml; 74.2 mmol) was treated with N-bromosuccinimide (968 mg; 5.44 mmol) and stirred at RT for 6 hours. The reaction mixture was carefully poured on crushed ice, extracted with AcOEt and the organic phase was washed with a 0.1 N solution of NaOH in water twice, then with brine twice. The organic phase was dried on MgSO4, filtered and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[CH:19]=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[CH2:19][OH:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc2ccccc2c1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc2ccccc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.9 %

Procedure:
To a solution of 1-(benzyloxy)-2-naphthaldehyde (7.00 g, 26.7 mmol) in methanol (250 mL) at 0° C. is added sodium borohydride (1.51 g, 40.0 mmol) and the reaction mixture is allowed to stir at room temperature for 24 h. The solvent is removed in vacuo to give a crude solid which is partitioned between ethyl acetate (300 mL) and water (300 mL). The organic layer is separated and washed with water (300 mL), aqueous sodium chloride (300 mL), dried (magnesium sulfate) and filtered through a plug of silica (10 cm×5 cm). The solvent is removed in vacuo to give 6.98 g (99%) of [1-(benzyloxy)-2-naphthyl]methanol as white crystalline solid. Rf=0.36 (silica, dichloromethane:hexanes 3:2); mp 85-87° C. Anal. Calcd. for C18H16O2: C, 81.24; H, 6.14. Found: C, 81.03; H, 5.98.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([C:12]1[S:13][CH:14]=[CH:15][N:16]=1)([OH:11])[C:7]([F:10])([F:9])[F:8].[H-].[Na+].[CH3:19]I>C(COC)OC>[CH3:19][O:11][C:6]([C:12]1[S:13][CH:14]=[CH:15][N:16]=1)([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[C:7]([F:9])([F:10])[F:8]
Reactant: OC(c1nccs1)(c1nccs1)C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(c1nccs1)(c1nccs1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.2 %

Procedure:
1,1-Di(2-thiazolyl)-2,2,2-trifluoroethanol (1 g) was added to a stirred suspension of sodium hydride (80%, 225 mg) in dry dimethoxyethane (50 ml) at 0° C. After 15 minutes, methyl iodide (2.1 g) was added dropwise. The mixture was allowed to warm to room temperature and was then left stirring overnight. The mixture was concentrated by evaporation, then poured into saturated aqueous sodium chloride solution and extracted with dichloromethane. The material thus obtained was purified by flash chromatography to give the title compound as a white solid (950 mg).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:6]2[S:13][C:12]([S:14][CH3:15])=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1.C1C=C(Cl)C=C(C(OO)=[O:31])C=1>C(Cl)Cl>[F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:6]2[S:13][C:12]([S:14]([CH3:15])=[O:31])=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cc2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Solvent: ClCCl
Product: CS(=O)c1cc2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Reaction time: 2 h
Yield: 101.7 %

Procedure:
A mixture of 281 (1.1 g, 3.2 mmol) and m-CPBA (77%, 890 mg, 12.8 mmol) in DCM at 0° C. was stirred for 2 hours, diluted with DCM, washed with ice water, NaHCO3 solution and water again; dried and concentrated to give the title compound 284 (1.15 g, quantitative) as a yellowish solid. MS (m/z): 354.0 (M+H) (found).
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.[F:25][C:26]([F:30])([F:29])[CH2:27][NH2:28]>>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:28][CH2:27][C:26]([F:30])([F:29])[F:25])=[O:24])=[CH:5][N:6]=3)=[CH:16][O:15][N:14]=2)=[CH:22][CH:21]=1
Reactant: NCC(F)(F)F
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Product: O=C(NCC(F)(F)F)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Yield: 41 %

Procedure:
As described for example 324, 6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.61 mmol) was converted, using 2,2,2-trifluoroethylamine instead of 4-aminotetrahydropyran, to the title compound (100 mg, 41%) which was obtained as a light brown solid. MS: m/e=396.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:19]([O:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:15]([F:16])([F:17])[F:18])[CH:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(O)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])c(OCc2ccccc2)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 6 h
Yield: 52.2 %

Procedure:
Methyl 4-hydroxy-5-nitro-2-(trifluoromethyl)benzoate (3.0 g) was dissolved in N,N-dimethyl-formamide (50 ml), and thereto were added benzyl bromide (2.3 g) and potassium carbonate (2.3 g), and the mixture was stirred at 80° C. for 6 hours. The reaction mixture was cooled, and water was added thereto. The mixture was extracted with ethyl acetate, and the organic layer was washed twice with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (the developing solvent: hexane/ethyl acetate=8:1→5:1→3:1) to give methyl 4-(benzyloxy)-5-nitro-2-(trifluoromethyl)benzoate (2.1 g), which was treated in a similar manner to Reference Example 5 to give the title compound (1.9 g).
Reaction SMILES: [I:1][C:2]1[C:3]([CH:11](C(OCC)=O)C(OCC)=O)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.C([O-])([O-])=O.[Na+].[Na+]>S(=O)(=O)(O)O>[I:1][C:2]1[C:3]([CH3:11])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ncc([N+](=O)[O-])cc1I
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1ncc([N+](=O)[O-])cc1I

Procedure:
Diethyl (3-iodo-5-nitropyridin-2-yl)malonate (0.250 g, 0.000612 mol) was heated in 6 M sulfuric acid (3 mL) at 100° C. for 16 hours. The reaction was neutralized with solid Na2CO3, extracted with EtOAc and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and stripped in vacuo. NMR analysis indicated that it was clean enough for the next reaction. 1H NMR (400 MHZ, CDCl3): δ 9.27 (d, 1H), 8.82 (d, 1H), 2.87 (s, 3H); MS (ES) (M+H)=265.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].ClCCl>CN(C)C=O>[CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccccc2[nH]1
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Yield: 45.4 %

Procedure:
A mixture of 2-butylbenzimidazole (2.6 g), the bromomethyl compound (C) (5.0 g) and potassium carbonate (1.55 g) in N,N-dimethylformamide (DMF) (40 ml) was heated at 100° C. for 3 hours. Dichloromethane (200 ml) was added and insoluble material was removed by filtration. The filtrate was concentrated and the residue purified by flash chromatography, eluting with triethylamine/ethyl acetate/hexane (1:40:60 v/v), to give methyl 4'-[2-butyl-1H-benzimidazol-1-yl)methyl]biphenyl-2-carboxylate (A) as a clear oil (2.7 g); NMR (CDCl3): 0.95(t,3H), 1.45(m,2H), 2.9(t,2H), 3.6(s,3H), 5.4(s,2H), 7.2(d,2H), 7.2-7.6 (complex m,3H), 7.8(m,2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[CH:27]=[C:26]([C:28]([C:30]2[CH:40]=[C:39]([CH3:41])[C:33]3[N:34]([CH3:38])[C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)=[O:29])[CH:25]=[CH:24][N:23]=1>CN1C(=O)CCC1.CO>[CH3:38][N:34]1[C:33]2[C:39]([CH3:41])=[CH:40][C:30]([C:28]([C:26]3[CH:25]=[CH:24][N:23]=[C:22]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[CH:27]=3)=[O:29])=[CH:31][C:32]=2[O:36][C:35]1=[O:37]
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(C(=O)c2ccnc(Cl)c2)cc2oc(=O)n(C)c12
Solvent: CN1CCCC1=O
Solvent: CO
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)ccn3)CC1)C(=O)N2

Procedure:
350 mg (1.27 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 180 mg (0.600 mmol) 6-(2-chloro-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one were stirred overnight in 3 mL NMP at 120° C. The reaction mixture was diluted with MeOH and purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:16][C:15]3([CH3:18])[CH2:17][CH:11]2[CH2:12][C:13]([CH3:20])([CH3:19])[CH2:14]3)=[O:9])=[CH:4][CH:3]=1.[C:21](Cl)(=[O:24])[CH:22]=[CH2:23]>C1COCC1>[CH3:18][C:15]12[CH2:17][CH:11]([N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:21](=[O:24])[CH:22]=[CH2:23])=[CH:7][CH:6]=3)=[O:9])[CH2:16]1)[CH2:12][C:13]([CH3:20])([CH3:19])[CH2:14]2
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(N)cc2)C1
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc(C(=O)N2CC3(C)CC2CC(C)(C)C3)cc1
Reaction time: 0.75 h
Yield: 47.3 %

Procedure:
To a solution of (4-amino-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone (3.0 g, 11.01 mmol) and TEA (3.1 ml, 22.03 mmol) in dry THF (40 ml) was added dropwise acryloyl chloride (1.07 ml, 13.22 mmol). The mixture was stirred for 45 min., the volatiles evaporated and to the residue added water 25 (ml). The aqueous phase was extracted with EtOAc (2×25 ml) and the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified on column chromatography (silicagel) using EtOAc-Heptane 1:1 as eluent. Pure fractions were collected, the solvent evaporated in vacuo affording 1.7 g (47%) of N-[4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-acrylamide as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([O:19]C)=[O:18])=[CH:14][CH:15]=3)[N:10]([CH3:21])[CH:9]=2)=[CH:4][CH:3]=1.O[Li].O>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=3)[N:10]([CH3:21])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(-c3ccc(F)cc3)cn(C)c2c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc(F)cc2)c2ccc(C(=O)O)cc21
Yield: 100.6 %

Procedure:
To a solution compound 53f (264 mg, 0.93 mmol), and LiOH.H2O (156.4 mg, 3.73 mmol) in THF/H2O (10 mL/10 mL) was stirred at 45° C. for 5 h. The resulting mixture was concentrated and diluted with water. The water layer was acidified with 1N aqueous HCl to pH˜4 and extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated to give compound 53g (252 mg), which was used in the next reaction without further purification. MS m/z (M+H+) 270.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH2:25]Br)[CH:7]=1)[CH3:2].Cl[C:29]1[CH:34]=[CH:33][C:32]([C@@H:35]2[O:39][C:38](=[O:40])[NH:37][C@@H:36]2[CH3:41])=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH2:25][N:37]2[C@H:36]([CH3:41])[C@H:35]([C:32]3[CH:33]=[CH:34][CH:29]=[CH:30][CH:31]=3)[O:39][C:38]2=[O:40])[CH:7]=1)[CH3:2]
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2CBr)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 10, Step 7, using the following starting materials: [3-(2-Bromomethyl-4-trifluoromethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and (4R,5S)-5-(4-chloro-phenyl)-4-methyl-oxazolidin-2-one.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:8][CH2:9][CH2:10][CH2:11][NH2:12].[O-]CC.[Na+]>C(O)C>[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:2]1[N:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCN
Reactant: Clc1cccnn1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: NCCCNc1cccnn1

Procedure:
Reacting 3-chloropyridazine with 1,3-diaminopropane in ethanol containing sodium ethoxide according to the procedure of Example 89 gives 3-(3-aminopropylamino)-pyridazine. Using this intermediate as the starting material in the procedure of Example 18 gives N-cyano-N'-[3-(3-pyridazinylamino)propyl]guanidine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:17]3[NH:21][CH:20]=[C:19]([C:22]([O:24][CH3:25])=[O:23])[CH:18]=3)[CH:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>CCOC(C)=O.CCO>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:17]3[NH:21][CH:20]=[C:19]([C:22]([O:24][CH3:25])=[O:23])[CH:18]=3)[CH:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1c[nH]c(-c2cc(Nc3cccc([N+](=O)[O-])c3)ccn2)c1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1c[nH]c(-c2cc(Nc3cccc(N)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.6 %

Procedure:
Methyl 5-(4-((3-nitrophenyl)amino)pyridin-2-yl)-1H-pyrrole-3-carboxylate (1.32 g, 3.9 mmol) was taken up in EtOAc/EtOH (1:1; 90 mL) and purged with N2. Pd/C (10%, 0.145 g) was added and the mixture was stirred under an atmosphere of H2 at rt for 18 h. The mixture was filtered over celite, washing with EtOAc/EtOH. The filtrate was concentrated, taken back up in EtOAc and filtered over celite again to remove any residual catalyst. The filtrate was concentrated again and taken back up in EtOAc. The solution was filtered and the filtrate was concentrated to afford a tan solid. The solid was washed with CH2Cl2/hexanes (1:2) and dried under high vacuum to afford methyl 5-(4-((3-aminophenyl)amino)pyridin-2-yl)-1H-pyrrole-3-carboxylate (1.15 g, 96% yield) as a tan solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[CH:10]=1.[Br:11]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[CH:10]=1
Reactant: Cc1ccc2ocnc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClC(Cl)Cl
Product: BrCc1ccc2ocnc2c1
Temperature: 25 °C

Procedure:
A solution of 5-methylbenzoxazole (0.5 g) in chloroform (20 ml) containing N-bromosuccinimide (0.18 g) and azoisobutyronitrile (0.05 g) was refluxed for 2 hours. After allowing to cool to room temperature the reaction mixture was treated with water (30 ml). The organic phase was separated and the aqueous phase extracted with dichloromethane (30 ml). The combined organic phases were washed with brine (30 ml), dried over magnesium sulphate and evaporated. The residue was triturated with pentane giving the title compound (0.36 g) as an off-white solid, m.p. 90-93° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]#[N:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl:20][C:21]([CH2:23]Cl)=[CH2:22].[NH4+]=[S:26]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:23][C:21]([Cl:20])=[CH2:22])[C:10]([NH2:11])=[S:26])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C=C(Cl)CCl
Reactant: N#CNc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(Cl)CN(C(N)=S)c1cc(Cl)cc(Cl)c1
Temperature: 50 °C
Yield: 90 %

Procedure:
N-(3,5-dichlorophenyl)cyanamide (2.81 g) was dissolved in DMF (14.03 g), to which powdered potassium carbonate (3.11 g) and potassium iodide (0.26 g) were added at room temperature with stirring. Further, 2,3-dichloro-1-propene (2.00 g) was added dropwise at room temperature with stirring. The mixture was heated to 50° C. and stirred at the same temperature for 2.5 hours. After cooling to room temperature, DMF (9.00 g) and ammonium sulfide solution, yellow (8.00 g) having an S content of 6% were added dropwise to the reaction mixture at room temperature with stirring. The mixture was heated to 50° C. and stirred at the same temperature for 4 hours. After cooling to room temperature, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water. The solvent was removed by distillation under reduced pressure, which afforded 4.00 g of N-(3,5-dichlorophenyl)-N-(2-chloro-2-propenyl)thiourea as a dark red solid (90% yield in appearance). The percentage area of liquid chromatography was 94%.