Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]=[CH:9][C:8]=1[Cl:19].CN(C)[CH:22]=[O:23].C(OCC)(=O)C>O1CCCC1>[Cl:19][C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:7]=1[CH:22]=[O:23])=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2
Reactant: CN(C)C=O
Reactant: COc1ccc2ncc(Cl)c(Br)c2c1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2ncc(Cl)c(C=O)c2c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
A solution of n-butyllithium (1.6 M in tetrahydrofuran, 0.46 mL, 0.73 mmol, 1.0 eq) is added at −78° C. to a stirred solution of 4-bromo-3-chloro-6-methoxy-quinoline (200 mg, 0.73 mmol, 1.0 eq) in tetrahydrofuran (10 mL). After 2 hours stirring at −78° C., N,N-dimethylformamide (0.3 mL) is added and the reaction mixture is stirred at 60° C. for two hours. Then solvent is evaporated and the residue is extracted with ethyl acetate (3×10 mL) and water (10 mL). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 5:1, v/v) to afford 3-chloro-6-methoxy-quinoline-4-carbaldehyde as a light yellow solid (78 mg, 48% yield).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:32](=[O:33])[N:31]([CH3:34])[C:23]4[N:24]=[C:25](S(C)=O)[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:35])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][C@@H:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:32](=[O:33])[N:31]([CH3:34])[C:23]4[N:24]=[C:25]([NH:44][C@@H:37]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH3:36])[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:35])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(=O)c(-c2ccc(F)c(NC(=O)Nc3cc(C(C)(C)C)no3)c2)cc2cnc(S(C)=O)nc21
Reactant: C[C@@H](N)c1ccccc1
Product: C[C@@H](Nc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cc(C(C)(C)C)no4)c3)c(=O)n(C)c2n1)c1ccccc1
Yield: 29.5 %

Procedure:
Using a procedure analogous to Example 57, 1-(3-t-butylisoxazol-5-yl)-3-(2-fluoro-5-(8-methyl-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea from Example 43 (0.150 g, 0.311 mmol, 1.00 eq) and (R)-(+)-alpha-methylbenzylamine (0.0846 ml, 0.656 mmol, 3.00 eq) were combined to afford (R)-1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(8-methyl-7-oxo-2-(1-phenylethylamino)-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (51 mg, 42% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.34 (s, 1H), 8.73 (brs, 1H), 8.65 (brs, 1H), 8.51 (d, J=7.6 Hz, 1H), 8.37 (d, J=7.6 Hz, 1H), 7.85 (s, 1H), 7.447.38 (m, 2H), 7.31-7.25 (m, 4H), 7.20-7.16 (m, 1H), 6.06 (s, 1H), 5.16-5.09 (m, 1H), 3.48 (s, 3H), 1.48 (d, J=7.2 Hz, 3H), 1.23 (s, 9H); MS (ESI) m/z: 556.3(M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.O>[F:17][C:16]([F:19])([F:18])[C:13]1[CH:14]=[CH:15][C:10]([O:8][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[NH2:1])=[CH:11][CH:12]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1cccc(Oc2ccc(C(F)(F)F)cc2)c1
Temperature: 85 °C
Reaction time: 16 h
Yield: 58.6 %

Procedure:
EX-656A) 3-Aminophenol (5.0 g, 45.8 mmol) and 4-bromo-α,α,α-trifluorotoluene (14.0 g, 62.2 mmol) were dissolved in anhydrous dimethylacetamide (20 mL), then anhydrous cesium carbonate (30 g, 92.3 mmol) and copper triflate benzene complex (200 mg) were added. The mixture was stirred and heated to 85° C. using a reflux condenser under an argon atmosphere. After 16 h, the mixture was diluted with water (120 mL), and the aqueous layer was extracted with diethyl ether (4×60 mL). The combined ether layers were washed with 3% HCl, 5% NaOH and water, then dried over anhydrous MgSO4. The ether was removed in vacuo, and the recovered oil purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:8) to give 6.8 g (59%) of the desired 3-(4-trifluoromethylphenoxy)aniline product as a yellow oil, which solidified to a yellow powder, 98% pure by HPLC analysis. HRMS calcd. for C13H10F3NO: 254.0792 [M+H]+, found: 254.0798.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26]([OH:28])=O)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.[NH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1>>[N:4]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:20]=[CH:21][C:22]([CH2:25][C:26]([NH:29][C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)=[O:28])=[CH:23][CH:24]=3)[N:8]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: O=C(O)Cc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: Nc1cccnc1
Product: O=C(Cc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1)Nc1cccnc1
Yield: 44 %

Procedure:
The title compound was prepared by following the procedure of example 473 step 3 using 2-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)acetic acid and 3-aminopyridine. Yield 21 mg, 44% yield; HPLC: Rt=1.91 min; MS 462 [M+H].
Reaction SMILES: ClS(O)(=O)=O.CO[CH:8](OC)[CH2:9][NH:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH3:12][C:11]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:9][N:10]=1
Reactant: COC(CNC(C)c1ccccc1)OC
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)Cl
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1nccc2ccccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 30.3 %

Procedure:
To cooled chlorosulfonic acid (−10° C.) (16 ml) was cautiously added N-(2,2-dimethoxyethyl)-(1-phenyl)ethylamine (D90) (5 g, 0.024 mol) over a period of 2 h. The reaction was allowed to warm to ambient temperature and stirring continued for 3 d. The reaction was then poured into ice-water slurry (500 ml), basified using solid potassium carbonate followed by extraction with DCM. The organic phase was separated, dried over MgSO4, filtered and concentrated in vacuo to give the crude product as an oil. Chromatography on silica gel eluting with ethyl acetate afforded the title compound as a yellow oil (1.04 g). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.40 (d, 1H), 8.13 (d, 1H), 7.81 (d, 1H), 7.68 (t, 1H), 7.60 (t, 1H), 7.51 (d, 1H), 2.97 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[N:18][O:19][CH2:20][C:21]([O:23]CC)=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[OH-].[K+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[N:18][O:19][CH2:20][C:21]([OH:23])=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CON=C(c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=NOCC(=O)O)c2ccc(OC)cc2)cc1
Reaction time: 16 h
Yield: 55 %

Procedure:
A solution of ethyl di-(4-methoxyphenyl)methyleneamino-oxyacetate (1.0 g.) in ethanol (20 ml.) and water (5 ml.) containing potassium hydroxide (1.0 g.) was left at ambient temperature for 16 hours. The solution was evaporated and the residue partitioned between ether and water. The aqueous layer was separated and acidified with concentrated hydrochloric acid. The mixture was extracted with ether, the extract dried (MgSO4) and evaporated to give di-(4-methoxyphenyl)methyleneamino-oxyacetic acid as a solid (0.5 g.), m.p. 105°-107° C. (55% yield).
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6]2[CH2:18][CH2:19][C:20](=[O:21])[C:5]=2[CH:4]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=2[S:30]([CH3:33])(=[O:32])=[O:31])[NH:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43].O>CN(C)C=O>[C:26]([C:25]1[CH:28]=[CH:29][C:22]([CH:4]2[N:3]([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[C:2](=[O:1])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=3)[C:6]3[CH2:18][CH2:19][C:20](=[O:21])[C:5]2=3)=[C:23]([S:30]([CH3:33])(=[O:31])=[O:32])[CH:24]=1)#[N:27]
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1S(C)(=O)=O
Temperature: 25 °C

Procedure:
A mixture of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)-3-(methylsulfonyl)benzonitrile (example 10, 1.78 g, 3.74 mmol) and cesium carbonate (1.83 g, 5.62 mmol) in N,N-dimethylformamide (25.0 mL) is treated with ethyl bromoacetate (0.50 mL, 4.50 mml), and the mixture is stirred at room temperature over night. Water (30 ml) is added, and the precipitate is filtered and dried. Yield: 1.80 g; ESI mass spectrum: [M+H]+=562; Retention time HPLC: 1.05 min (Z018_S04).
Reaction SMILES: [Cl:1][C:2]1[C:7](/[C:8](/O)=[CH:9]\[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:16])[N:11]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:18][S:19]([C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[F:29])(=[O:21])=[O:20].C1C(=O)N(Br)C(=O)C1.[CH3:38][C:39]([CH3:44])([CH3:43])[C:40](=[S:42])[NH2:41]>CC(N(C)C)=O.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[N:41]=[C:40]([C:39]([CH3:44])([CH3:43])[CH3:38])[S:42][C:9]=2[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:16])[N:11]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:18][S:19]([C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[F:29])(=[O:21])=[O:20]
Reactant: O=S(=O)(Nc1cccc(/C(O)=C\c2ccnc(Cl)n2)c1Cl)c1cc(F)ccc1F
Reactant: CC(C)(C)C(N)=S
Agent: O=C1CCC(=O)N1Br
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2Cl)c(-c2ccnc(Cl)n2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To a solution of N-{2-chloro-3-[(E)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,5-difluorobenzenesulfonamide (3.0 g, 6.55 mmol) in DMA (25 mL) was added NBS (1.165 g, 6.55 mmol). After stirring for 1 h at rt, 2,2-dimethylpropanethioamide (0.767 g, 6.55 mmol) was added and the reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was diluted with EtOAc (100 mL) and extracted five times with water. The organic layer was dried over anhydrous NaSO4, adsorbed onto silica gel, and purified via column chromatography, eluting with 0-50% EtOAc/DCM. The desired fractions were combined and concentrated to generate 1.31 g (2.36 mmol, 36.0% yield) of the title compound as a yellow powder. 1H NMR (400 MHz, DMSO-d6): δ 10.74 (s, 1H), 8.56 (d, J=5.4 Hz, 1H), 7.41-7.58 (m, 6H), 6.57 (d, J=5.4 Hz, 1H), 1.42 (s, 9H). MS (ESI): 555.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1Br)=[CH:12][C:11]([C:16](=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:10][CH:9]=2)=[O:5])[CH3:2].C([O-])=O.[NH4+].CN(C=O)C>[Pd].O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:16](=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccc(C(=O)CC(C)C)cc2c1Br
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2cc(C(=O)CC(C)C)ccc2[nH]1
Reaction time: 1.17 h

Procedure:
To the mixture of 3-Bromo-5-(3-methyl-butyryl)-1H-indole-2-carboxylic acid ethyl ester (408 mg, 1.1 mmol), ammonium formate (10 mg, 1.7 mmol), and 10% Pd/C (200 mg) was added DMF (5 mL) and water (0.625 mL). The mixture was slightly shaked at room temperature for 70 minutes and then filtered through celite. The solvent was evaporated under vacuum to give 5-(3-Methyl-butyryl)-1H-indole-2-carboxylic acid ethyl ester as light yellow liquid as crude product with the purity of 90%; E1-MS m/z 274.1 (M++H). The crude ethyl ester was dissolved in dioxane (10 mL), Then a solution of LiOH.H2O (195 mg, 4.6 mmol) in water (5 mL) was added to the flask. The mixture was stirred at room temperature for 2 days. Dioxane was stripped under vacuum. 10 mL water was added and extracted with CH2Cl2. Then the aqueous phase was acidified with 6N HCl and extracted with CH2Cl2. The CH2Cl2 phase was then washed with saturated brine and dried over anhydrous Na2SO4. Solvent was removed under vacuum to give 5-(3-Methyl-butyryl)-1H-indole-2-carboxylic acid (250 mg, 88% for two steps) as white solid. EIMS m/z 246.1 (M++H) (lab-ref: YS-053-141).
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[CH2:3][C:4]1[C:5]([O:14][CH3:15])=[CH:6][CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[CH2:10]2.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(O)(C)C>C1(C)C(C)=CC=CC=1>[CH3:15][O:14][C:5]1[CH:6]=[CH:7][C:8]([O:12][CH3:13])=[C:9]2[C:4]=1[CH2:3][C@@H:2]([N:27]1[CH2:26][CH2:25][N:24]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][CH3:16])[CH2:29][CH2:28]1)[C@H:11]([OH:1])[CH2:10]2
Reactant: COc1ccc(OC)c2c1CC1OC1C2
Reactant: COc1ccccc1N1CCNCC1
Solvent: Cc1ccccc1C
Solvent: CC(C)O
Product: COc1ccccc1N1CCN([C@@H]2Cc3c(OC)ccc(OC)c3C[C@H]2O)CC1
Yield: 50.4 %

Procedure:
A solution of 4.12 g of 6,7-epoxy-5,6,7,8-tetrahydro1,4-dimethoxynaphthalene, 4.81 g of 1-(o-methoxyphenyl)piperazine, and 1.53 ml of isopropyl alcohol in 20 ml of xylene is refluxed under nitrogen for 19 hours. The xylene is removed in vacuo and the residue triturated with ether to give 4.01 g of crude material. Two recrystallizations of this material from ethyl acetate yield 2.5 g of the title compound, melting point 182°-183° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]([C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[OH:26])=[O:18]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:26][C:20]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=1[C:17](=[O:18])[CH3:16]
Reactant: CC(=O)c1cc(F)ccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(F)cc3C(C)=O)c2cc1OC
Temperature: 160 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (58.2 mg), 5-fluoro-2-hydroxyacetophenone (409 mg), and 4-dimethylaminopyridine (317 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for 8 hr. The reaction solution was cooled to room temperature, and the solvent was then removed therefrom by distillation under the reduced pressure. Chloroform was added to the residue, and the organic layer was washed with a 1 N aqueous potassium hydroxide solution and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform and by thin layer chromatography using acetone-hexane to give the title compound (63.5 mg, yield 72%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][C@@H:13]3[CH2:15][C@H:10]2[CH2:11][O:12]3)=[CH:5][C:4]=1[NH2:16].[C:17]([N:25]=[C:26]=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[C:17]([NH:25][C:26]([NH:16][C:4]1[CH:5]=[C:6]([N:9]2[CH2:14][C@@H:13]3[CH2:15][C@H:10]2[CH2:11][O:12]3)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccc(N2C[C@@H]3C[C@H]2CO3)cc1N
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: COc1ccc(N2C[C@@H]3C[C@H]2CO3)cc1NC(=S)NC(=O)c1ccccc1
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a stirred solution of 4.20 g (19.1 mmol) 2-methoxy-5-{(1S,4S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)}-phenylamine in 200 ml acetone was added dropwise 2.88 ml (21.0 mmol) benzoyl isothiocyanate and stirring continued for 1 h at room temperature. The mixture was then concentrated in vacuo to afford 7.30 g (100%) 1-benzoyl-3-[2-methoxy-5-{(1S,4S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)}-phenyl]-thiourea as a yellow solid. ES-MS m/e (%): 406 (M+Na+, 13), 384 (M+H+, 100).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[C:21]1([CH2:20][CH2:19][CH2:18][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCCCc1ccccc1
Reactant: CCOC(=O)CCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(OCCCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
To a solution of ice-cooled ethyl 4-hydroxybenzenepropanoate (0.40 g, 2.1 mmol) in N,N-dimethylformamide (15 mL) was added 60% sodium hydride (0.11 g, 2.7 mmol), and the mixture was stirred for 30 minutes. Then, 1-bromo-3-phenylpropane (0.53 g, 2.7 mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added water, and the reaction mixture was extracted with ethyl acetate. The extract was washed with water, dried, and then concentrated. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=18:1) to give the title compound (0.29 g, yield 46%).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[C:13]([O:17][C:18](=[O:26])[NH:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][OH:23])([CH3:16])([CH3:15])[CH3:14].O[N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.ClCCl>[C:13]([O:17][C:18](=[O:26])[NH:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][O:23][N:28]1[C:32](=[O:33])[C:31]2[C:30](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:29]1=[O:38])([CH3:16])([CH3:14])[CH3:15]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(CO)CNC(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(CNC(=O)OC(C)(C)C)CON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.4 %

Procedure:
Diethylazodicarboxylate (8.26 mL, 52.4 mmol) was added to a solution of (3-hydroxy-2,2-dimethyl-propyl)-carbamic acid tert-butyl ester (10.2 g, 49.9 mmol), N-hydroxyphthalimide (8.15 g, 49.9 mmol) and triphenylphosphine (13.1 g, 49.9 mmol) in THF (200 mL). The solution was stirred at room temperature for 16 hours after which time it was diluted with dichloromethane and passed through a plug of silica gel, eluting with dichloromethane. The product containing fractions were concentrated to a yellow liquid, which was further purified by flash column chromatography (dichloromethane to 4:1 dichloromethane/ethyl acetate) to provide pure desired product (1.98 g, 11%) as a waxy white solid.
Reaction SMILES: CC1(C)[O:9][C:7](=[O:8])[CH2:6][C:4](=O)O1.[N+:11]([C:14]1[CH:21]=[CH:20][C:17](C=O)=[CH:16][CH:15]=1)([O-:13])=[O:12].C(O)=O>C(N(CC)CC)C>[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH2:4][CH2:6][C:7]([OH:9])=[O:8])=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: CCN(CC)CC
Solvent: O=CO
Product: O=C(O)CCc1ccc([N+](=O)[O-])cc1
Temperature: 105 °C

Procedure:
3.60 g (0.025 mol) of Meldrum's acid and 3.8 g (0.025 mol) of p-nitrobenzaldehyde were weighed in to 25 ml of the mixture of formic acid and triethylamine prepared as described in Example l. The reaction mixture was heated to 105° C. during 1 hour and reacted at the same temperature for 1 hour. The product was isolated according to Example 1.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OO.C(=[O:18])C1C=CC=CC=1>[Pt]>[C:1]([OH:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: OCc1ccccc1
Agent: [Pt]
Agent: OO
Product: O=C(O)c1ccccc1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 0.7 %

Procedure:
Platinum black (19.5 mg, 0.100 mmol) and benzyl alcohol (1.0 ml, 10 mmol) were mixed and stirred at 90° C. for 10 minutes. A 30% aqueous hydrogen peroxide solution (1.3 ml, 12 mmol) was gradually added dropwise to the mixed solution, followed by stirring at 90° C. for 15 hours, and then the reaction solution was cooled to room temperature. As a result of measurement by GLC, it was found that benzaldehyde was obtained in yield of 85%. Benzoic acid was obtained in yield of 0.7%.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.Cl[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[O:20][N:19]=1>>[Br:1][C:2]1[C:3]([C:12]([F:13])([F:15])[F:14])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:17][C:18]1[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=3)[O:20][N:19]=1)[C:6]([CH3:11])=[CH:5]2
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Reactant: Cc1cc2c(C(F)(F)F)c(Br)ccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)c(Br)ccc2n1Cc1noc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 4 using 5-bromo-2-methyl-4-(trifluoromethyl)-1H-indole and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole: 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.23 (d, J=7.8 Hz, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.65 (t, J=7.8 Hz, 1H), 7.44 (s, 2H), 6.58 (s, 1H), 5.41 (s, 2H), 2.63 (s, 3H).
Reaction SMILES: [Na].[N+]([O-])(O)=O.[NH2:6][C:7]([NH2:9])=[NH:8].N[C:11]1[N:16]([CH2:17][CH3:18])[C:15](=[O:19])[N:14]([CH2:20][CH3:21])[C:13](=[O:22])[C:12]=1[CH:23]=O>C(O)C>[NH2:8][C:7]1[N:9]=[C:11]2[N:16]([CH2:17][CH3:18])[C:15](=[O:19])[N:14]([CH2:20][CH3:21])[C:13](=[O:22])[C:12]2=[CH:23][N:6]=1
Reactant: N=C(N)N
Reactant: CCn1c(N)c(C=O)c(=O)n(CC)c1=O
Agent: [Na]
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: CCn1c(=O)c2cnc(N)nc2n(CC)c1=O
Reaction time: 0.17 h
Yield: 86.9 %

Procedure:
0.92 g of sodium was dissolved in 50 ml of absolute ethanol, and 6.40 g (53 mmol) of guanidine nitrate was added thereto. The solution was stirred for 10 minutes and filtered with Celite filter aid. 0.98 g (4.6 mmol) of 6-amino-1,3-diethyl-5-formyluracil was added to the filtrate and the reaction mixture was refluxed for 24 hours. After removal of the solvent under reduced pressure, 30 ml of water was added thereto. The crystalline precipitate was filtered off and recrystallized from ethanol to give 0.94 g of 7-amino-1,3-diethyl-pyrimido[4,5-d]pyrimidine-2,4-dione (compound 17) in a 87% yield.
Reaction SMILES: C(N)CCCCCCCCCCC.[CH2:14]([CH2:16][NH2:17])[OH:15].C=O.[CH2:20]([N:32]1[CH2:37]N(CCCCCCCCCCCC)[CH2:35][N:34]([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:33]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(O)C.CCOCC>[CH2:50]([N:34]1[CH2:35][N:17]([CH2:16][CH2:14][OH:15])[CH2:37][N:32]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:33]1)[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61]
Reactant: NCCO
Reactant: CCCCCCCCCCCCN1CN(CCCCCCCCCCCC)CN(CCCCCCCCCCCC)C1
Agent: C=O
Agent: CCCCCCCCCCCCN
Solvent: CCOCC
Solvent: CCO
Product: CCCCCCCCCCCCN1CN(CCO)CN(CCCCCCCCCCCC)C1
Reaction time: 24 h

Procedure:
48 g of dodecylamine (259 mmol) and 1.7 ml of ethanolamine (29 mmol) were dissolved in 100 ml of ethanol, after which 8.6 g of paraformaldehyde (287 mmol) were added and the mixture was stirred. The turbidity caused by 1,3,5-tridodecyl-1,3,5-triazacyclohexane was redissolved every now and again by addition of ether. After about 1 day, all the paraformaldehyde had dissolved. The solvent was then removed on a rotary evaporator, the residue was dissolved in a little toluene and the product was then again freed of solvent under reduced pressure. This left 55 g of a viscous colorless product which, according to NMR spectroscopy, consisted of about 75 mol % of 1,3,5-tridodecyl-1,3,5-triazacyclohexane and 25 mol % of 1,3-didodecyl-5-(2-hydroxyethyl)-1,3,5-triazacyclohexane and a little toluene.