Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:10][CH2:9][C:8]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][C:6]=2[CH:20]=1.B([O-])([O-])O[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:33]([O:32][CH2:31][CH2:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:10][CH2:9][C:8]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][C:6]=3[CH:20]=2)=[CH:28][CH:27]=1)[CH2:34][CH2:35][CH3:36]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(CC(C)C)CC1
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
Methyl 7-bromo-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylate (0.90 g) was dissolved in toluene/ethanol/water (=10/1/1, 41 ml). To the solution were added 4-(2-butoxyethoxy)phenyl borate (0.76 g) and potassium carbonate (0.18 g), and the mixture was stirred under argon atmosphere for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (123 mg), and the mixture was heated to reflux for 14 hours. After cooled to room temperature, the reaction solution was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=8/1) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylate (0.75 g).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]([CH3:15])[C:5]2[C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][O:8][C:4]=2[CH:3]=1>CO.[C].[Pd]>[OH:1][C:2]1[CH:14]=[C:13]([CH3:15])[C:5]2[CH:6]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1cc(O)cc2occ(CC(=O)O)c12
Agent: [Pd]
Solvent: CO
Product: Cc1cc(O)cc2c1C(CC(=O)O)CO2
Temperature: 25 °C
Reaction time: 24 h
Yield: 102.5 %

Procedure:
10% palladium carbon (40 mg) was added to a solution of 2-(6-hydroxy-4-methylbenzofuran-3-yl)acetic acid (200 mg) in methanol (3 mL), and the mixture was stirred at room temperature for 24 hours under a hydrogen atmosphere. The insoluble matter was filtered off, and then, the obtained filtrate was concentrated under reduced pressure to obtain the title compound (207 mg).
Reaction SMILES: FC1C=C(C[C@H](C2C([C:34]3[CH:35]=[CH:36][C:37]([F:43])=[C:38]([CH:42]=3)[C:39]([NH2:41])=[O:40])=CN=C(NCCOC)N=2)NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)C=C(F)C=1.Br[C:50]1[C:51]([C@@H:64]([NH:74][C:75](=[O:93])[CH2:76][N:77]2[C:85]3[C:84]([F:87])([F:86])[CH2:83][CH2:82][C:81]([F:89])([F:88])[C:80]=3[C:79]([CH:90]([F:92])[F:91])=[N:78]2)[CH2:65][C:66]2[CH:71]=[C:70]([F:72])[CH:69]=[C:68]([F:73])[CH:67]=2)=[N:52][C:53]([NH:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH3:63])=[N:54][CH:55]=1>>[F:91][CH:90]([F:92])[C:79]1[C:80]2[C:81]([F:89])([F:88])[CH2:82][CH2:83][C:84]([F:86])([F:87])[C:85]=2[N:77]([CH2:76][C:75]([NH:74][C@H:64]([C:51]2[C:50]([C:34]3[CH:35]=[CH:36][C:37]([F:43])=[C:38]([CH:42]=3)[C:39]([NH2:41])=[O:40])=[CH:55][N:54]=[C:53]([NH:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH3:63])[N:52]=2)[CH2:65][C:66]2[CH:71]=[C:70]([F:72])[CH:69]=[C:68]([F:73])[CH:67]=2)=[O:93])[N:78]=1
Reactant: COCCOCCNc1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Reactant: COCCNc1ncc(-c2ccc(F)c(C(N)=O)c2)c([C@@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1
Product: COCCOCCNc1ncc(-c2ccc(F)c(C(N)=O)c2)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1

Procedure:
The title compound (17B) was prepared according to the method presented for the synthesis of compound 11J of Example 11 utilizing 17A. 1H NMR (400 MHz, CD3OD) δ 8.82 (d, J=8.2 Hz, 1H), 8.06 (s, 1H), 7.52-7.31 (m, 2H), 7.21 (dd, J=10.7, 8.5 Hz, 1H), 7.01-6.56 (m, 2H), 6.44 (d, J=6.0 Hz, 2H), 5.23 (t, J=6.7 Hz, 1H), 5.05 (s, 2H), 3.84-3.63 (m, 6H), 3.57 (m, 2H), 3.37 (s, 3H), 3.17-2.90 (m, 2H), 2.65-2.39 (m, 4H). MS (m/z) 774.58 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[CH3:8])=[O:5].Cl[C:21](OC(Cl)(Cl)Cl)=[O:22].[OH-].[Na+]>C1COCC1>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:1][C:21]2=[O:22])[CH3:8])=[CH:10][CH:11]=1
Reactant: CC(NC(=O)c1ccccc1N)c1ccc(Cl)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(c1ccc(Cl)cc1)n1c(=O)[nH]c2ccccc2c1=O
Temperature: 90 °C
Reaction time: 4 h
Yield: 166.3 %

Procedure:
To a solution of 2-amino-N-[1-(4-chloro-phenyl)-ethyl]-benzamide (115 mg, 0.42 mmol) in THF (30 mL) is added trichloromethyl chloroformate (50 mg, 0.25 mmol). The mixture is stirred at 90° C. for 4 hours. The reaction mixture is allowed to cool to room temperature, neutralizes with 1M NaOH aq. The reaction mixture is extracted with EtOAc (50 mL×3). The organic layer is dried over sodium sulfate and is concentrated to give the desired 3-[1-(4-chloro-phenyl)-ethyl]-1H-quinazoline-2,4-dione (125 mg, 99%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](=[C:17](\[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])/[CH2:18][CH3:19])/[C:12]([O:14]CC)=[O:13])=[CH:7][CH:6]=1.[OH-].[Na+].Cl>CO>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8](/[C:11](=[C:17](\[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])/[CH2:18][CH3:19])/[C:12]([OH:14])=[O:13])=[CH:9][CH:10]=1
Reactant: CCOC(=O)/C(=C(\CC)c1ccccc1C)c1ccc(OCOC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC/C(=C(\C(=O)O)c1ccc(OCOC)cc1)c1ccccc1C
Temperature: 80 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
To a solution of 2a (240 mg, 0.677 mmol) in MeOH (7 ml) was added 2N NaOH (3.4 ml) and the mixture was stirred at 80° C. for 18 h. After cooling, 2 N HCl (3.4 ml) was added drop wise under ice cooling, and the whole was extracted with AcOEt, the organic layer was washed with brine, dried over Na2SO4, then concentrated. The residual solid was triturated with hexanes to give 3a (79%). 3a: colorless powder; 1H-NMR (CDCl3) δ 1.05 (3H, t, J=7.5 Hz), 2.08 (3H, s), 2.68 (1H, m), 2.77 (1H, m), 3.41 (3H, s), 5.07 (2H, s), 6.75 (2H, d, J=8.7 Hz), 6.93 (2H, d, J=8.7 Hz), 7.01 (2H, m), 7.05-7.09 (3H, m).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[CH2:21][C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[Cl:29])[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[Cl:29][C:23]1[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:22]=1[CH2:21][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][N:15]1[CH:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCC(N2CCCCC2Cc2cc(Cl)ccc2Cl)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(Cl)c(CC2CCCCN2C2CCCNCC2)c1
Yield: 90.7 %

Procedure:
A solution of 1-(tert-butyloxycarbonyl)-4-{[(2,5-dichlorophenyl)methyl]piperid-1-yl}hexahydro4 H-azepine (700 mg, 1.58 mmol) in trifluoroacetic acid (2 ml) and methylene chloride (0.5 ml) was stirred at room temperature for 15 min. The solution was concentrated in vacuo and the residue was dissolved in chloroform and extracted with saturated aqueous sodium carbonate. The chloroform extract was dried over sodium sulfate and concentrated in vacuo to give 4-{[(2,5-dichlorophenyl)methyl]piperid-1-yl}hexahydro-4 H-azepine (489 mg, 90%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.[N:21]1([CH2:26][CH2:27][NH2:28])[CH2:25][CH2:24][CH2:23][CH2:22]1>CS(C)=O>[N:21]1([CH2:26][CH2:27][NH:28][C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:14][CH2:13][CH2:12][CH:11]3[CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:9])=[CH:4][CH:3]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(c1ccc(F)cc1)N1CCCC1CN1CCCC1
Reactant: NCCN1CCCC1
Solvent: CS(C)=O
Product: O=C(c1ccc(NCCN2CCCC2)cc1)N1CCCC1CN1CCCC1

Procedure:
For example, (4-fluoro-phenyl)-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone (where Y═F) is treated with a suitable nucleophile, in this case, 2-pyrrolidin-1-yl-ethylamine in a suitable solvent such as DMSO and 33% KF/Al2O3 and the reaction is heated for 1-3 days to yield [4-(2-pyrrolidin-1-yl-ethylamino)-phenyl]-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone.
Reaction SMILES: [CH:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=O)[CH:9]([NH:19][C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:39]2)=CC=1>C1(C)C=CC=CC=1>[CH:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[S:39])[CH:9]([NH:19][C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NC1N=C(C2CCCCC2)c2ccccc2NC1=O)OCc1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: O=C(NC1N=C(C2CCCCC2)c2ccccc2NC1=S)OCc1ccccc1

Procedure:
1,3-Dihydro-5-cyclohexyl-3(R,S)-[(benzyloxycarbonyl)-amino]-2H-1,4-benzodiazepin-2-one (M. Chambers, et. al. Biomed. Chem. Lett. 1993, in press) (1.09 g, 2.79 mmole) was mixed with 1.13 g (2.79 mmole) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide in 26 ml of toluene. The resulting suspension was heated to reflux for 1 hour. The reaction mixture was cooled, filtered, and concentrated in vacuo. The residue was flash chromatographed on silica gel (ethyl acetate-hexane, 1:3) and the product containing fractions were pooled and concentrated to give the title compound in approximately 85% purity. This material was recrystallized from hexane-ethyl acetate (1:1) to give 850 mg (75%) of the title compound in analytical form: m.p. 164°-165° C.
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([O:11][CH2:12][CH:13]([C:20]2[N:21]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[N:22]=[C:23]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:24]=23)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:6]([CH3:37])[CH:5]=1.[OH-].[Li+]>C1COCC1.CO>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([N:21]2[C:20]([CH:13]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:12][O:11][C:7]3[C:8]([CH3:10])=[CH:9][C:4]([C:3]([OH:38])=[O:2])=[CH:5][C:6]=3[CH3:37])=[C:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:23]3=[N:22]2)=[CH:31][CH:32]=1
Reactant: COC(=O)c1cc(C)c(OCC(c2c3c(nn2-c2ccc(Cl)cc2)CCCCC3)C2CCCCC2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)cc(C)c1OCC(c1c2c(nn1-c1ccc(Cl)cc1)CCCCC2)C1CCCCC1

Procedure:
In analogy to the procedure described in example 2, 4-{2-[2-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-cycloheptapyrazol-3-yl]-2-cyclohexyl-ethoxy}-3,5-dimethyl-benzoic acid methyl ester was hydrolysed using aqueous lithium hydroxide solution in THF and MeOH to give the title compound as off-white solid. MS: m/e=507.2 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[N:23]=[CH:22][C:21]([C:24]3[CH2:25][CH2:26][N:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:28][CH:29]=3)=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pt]=O>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[N:23]=[CH:22][C:21]([CH:24]3[CH2:29][CH2:28][N:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C3=CCN(C(C)(C)C)CC3)cn2)c2ccccc21
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C3CCN(C(C)(C)C)CC3)cn2)c2ccccc21
Reaction time: 4 h
Yield: 37.6 %

Procedure:
4-(1′-(tert-Butyl)-1′,2′,3′,6′-tetrahydro-3,4′-bipyridinyl-6-yl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester (0.44 g, 0.98 mmol) is placed in 60 ml of ethyl acetate in a Parr apparatus bottle. Platinum oxide (0.089 g, 0.39 mmol) is added. After stirring for 4 h under 32 psi H2, the catalyst is filtered off and rinsed with ethyl acetate. The filtrate is concentrated to dryness and then the residue is again stirred in 60 ml of ethyl acetate in the presence of 90 mg of platinum oxide under 35 psi for 18 h. The operation is repeated for 5 h and then 7 h. After filtering off the catalyst and rinsing with ethyl acetate, the filtrate is concentrated and then chromatographed on silica gel, elution being carried out with a methanol/aqueous ammonia gradient in dichloromethane varying from 100/0/0 to 9/1/0.1 (dichloromethane/methanol/aqueous ammonia). 0.166 g of 4-(1′-(tert-butyl)-1′,2′,3′,4′,5′,6′-hexahydro-3,4′-bipyridinyl-6-yl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester is obtained.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C@H:3]([CH3:18])[CH:4]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[CH2:17])=[CH:12][CH:11]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].COCCOC.[Cl:27][C:28]([Cl:33])(Cl)[C:29](Cl)=[O:30].ClCCl>C(OCC)C.[Cu].[Zn]>[Cl:27][C:28]1([Cl:33])[C:29](=[O:30])[CH2:17][CH:16]1[C:13]1[CH:12]=[CH:11][C:10]([CH:4]([C@@H:3]([CH3:18])[C:2]([F:1])([F:19])[F:20])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:15][CH:14]=1
Reactant: C=Cc1ccc(C(C(=O)OCC)[C@@H](C)C(F)(F)F)cc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Cu]
Agent: [Zn]
Solvent: COCCOC
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C(c1ccc(C2CC(=O)C2(Cl)Cl)cc1)[C@@H](C)C(F)(F)F
Reaction time: 8 h

Procedure:
3.83 g (13.38 mmol) of ethyl (3R)-4,4,4-trifluoro-3-methyl-2-(4-vinylphenyl)butanoate were dissolved in 50 ml of diethyl ether, and 2.67 g (20.74 mmol) of zinc-copper couple and 6.5 ml of 1,2-dimethoxyethane were added in succession. 4 ml (36.1 mmol) of trichloroacetyl chloride were then slowly added dropwise to the suspension obtained. The reaction solution was then heated under reflux and stirred overnight. After addition of dichloromethane, the reaction mixture was washed successively with water and saturated sodium chloride solution. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product obtained was purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1). This gave 4.57 g (86% of theory) of the title compound in the form of a yellowish oil which was used without further characterization in subsequent reactions.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=C=O.[C:12]([O-:15])(=[O:14])[CH3:13].[K+]>>[C:12]([OH:15])(=[O:14])[CH:13]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)[O-]
Reactant: O=Cc1ccccc1
Agent: C=C=O
Agent: [K+]
Product: O=C(O)C=Cc1ccccc1
Yield: 22 %

Procedure:
It is also known that benzaldehyde and ketene can be reacted in the presence of potassium acetate to give a primary product from which about 22% of cinnamic acid is obtained (J.Am.Chem.Soc. 55, 275 (1933)). Under similar conditions, 30% of cinnamic acid and 70% of styrene were also obtained (Organic Synthesis, Volume I, 215 and 216 C. D. Hurd. C. L. Thomas, (1942)).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH:17]([C:20]#[N:21])[CH2:16]1>CCO>[NH2:3][CH2:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH:17]([C:20]#[N:21])[CH2:16]1
Reactant: N#CC1CCN(CCCN2C(=O)c3ccccc3C2=O)C1
Solvent: CCO
Product: N#CC1CCN(CCCN)C1
Temperature: 5 °C

Procedure:
A solution of phthalimide 303 (5.96 g, 21.0 mmol) and N2H4.H2O (2.04 mL, 42.0 mmol in EtOH (60 mL) was stirred at reflux temperature for 2 h. The solution was cooled to 5° C. for 2 h, the precipitate filtered, washed with EtOH (5 mL) and the filtrate evaporated to half volume. The solution was cooled at 5° C. for a further 2 h, the precipitate filtered, washed with EtOH (5 mL) and the filtrate evaporated to give diamine 304 which was used without further purification: 1H NMR δ 2.94-3.02 (m, 1H, CHCN), 2.90 (dd, J=9.0, 7.9 Hz, 1H, CH2), 2.82 (t, J=6.8 Hz, 2H, CH2N), 2.61-2.68 (m, 2H, CH2N), 2.48-2.58 (m, 3H, CH2N), 2.05-2.15 (m, 1H, CH2), 2.03-2.11 (m, 1H, CH2), 1.68 (p, J=7.0 Hz, 2H, CH2), NH2 not observed.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].COC(C1C(N)=CC=CC=1)=O.NN.C1C2C(=CC=CC=2)C=CC=1O.C=O.C1N2CN3CN(C2)CN1C3.Cl.[OH:49][C:50]1[CH:59]=[CH:58][C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:51]=1[CH:60]=O>C(O)(=O)C>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][N:7]=[CH:60][C:51]1[C:52]2[C:57](=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:58]=[CH:59][C:50]=1[OH:49])=[O:5]
Reactant: O=Cc1c(O)ccc2ccccc12
Reactant: NNC(=O)c1ccccc1N
Agent: C1N2CN3CN1CN(C2)C3
Agent: C=O
Agent: COC(=O)c1ccccc1N
Solvent: CC(=O)O
Product: Nc1ccccc1C(=O)NN=Cc1c(O)ccc2ccccc12
Yield: 80 %

Procedure:
In reaction (1), o-aminobenzhydrazide in 70% yield is prepared by reacting the methyl ester of o-amino benzoic acid (methyl anthranilate) with 64% aqueous hydrazine. Equation (2) illustrates the preparation of 2-hydroxy-1-naphthaladehyde from beta-naphthol, paraformaldehyde, hexamethylene tetramine, acetic acid and hydrochloric acid. o-Aminobenzhydrazide and 2-hydroxy-1-naphthaldehyde are reacted, in Equation (3), to produce the preferred hydrazone, 2-hydroxy-1-naphthaldehyde-o-aminobenzoyl hydrazone in 80-90% yield.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[Br:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.[OH-].[K+]>>[CH2:2]([N:11]([CH2:2][CH2:3][CH2:4][CH3:5])[C:10]1[CH:12]=[CH:13][C:7]([Br:6])=[CH:8][CH:9]=1)[CH2:3][CH2:4][CH3:5]
Reactant: Nc1ccc(Br)cc1
Reactant: CCCCBr
Agent: [K+]
Agent: [OH-]
Product: CCCCN(CCCC)c1ccc(Br)cc1
Yield: 42.6 %

Procedure:
1-Bromobutane (41.1 g, 300 mmol), 4-bromoaniline (17.2 g, 100 mmol) and KOH (16.8 g, 300 mmol) were heated at reflux under nitrogen gas for about 18 hours. After cooling, the mixture was partitioned between water and hexane and the organic layer washed with water followed by brine. After drying over MgSO4 and filtering, the solvent was evaporated and the mixture distilled under reduced pressure. Distillate fractions collected between 25-100° C. and pressure of 360-210 mTorr contained a mixture of products and starting material. The fractions collected at 100-107° C. and 200 mTorr pressure afforded 12.1 g (43%) of pure product.
Reaction SMILES: C(Cl)(Cl)Cl.CO.O.C(O)(=O)/C=C/CCCCCCCCC(O)=O.C(Cl)(Cl)Cl.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O.C[C@@H](N)[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3OC[C@@](O)(C)[C@H](NC)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](N)CC1.[CH3:73][C@@H:74]([NH:104][CH3:105])[C@H:75]1[O:80][C@H:79]([O:81][C@H:82]2[C@H:87]([OH:88])[C@@H:86]([O:89][C@H:90]3[O:95][CH2:94][C@@:93]([OH:97])([CH3:96])[C@H:92]([NH:98][CH3:99])[C@H:91]3[OH:100])[C@H:85]([NH2:101])[CH2:84][C@@H:83]2[NH2:102])[C@H:78]([NH2:103])[CH2:77][CH2:76]1.C[C@@]1(O)[C@H](NC)[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H](CN)CC[C@H]3N)[C@@H](N)C[C@H]2N)OC1.OS(O)(=O)=O>CO>[CH3:73][CH:74]([NH:104][CH3:105])[CH:75]1[O:80][CH:79]([O:81][CH:82]2[CH:87]([OH:88])[CH:86]([O:89][CH:90]3[O:95][CH2:94][C:93]([OH:97])([CH3:96])[CH:92]([NH:98][CH3:99])[CH:91]3[OH:100])[CH:85]([NH2:101])[CH2:84][CH:83]2[NH2:102])[CH:78]([NH2:103])[CH2:77][CH2:76]1
Reactant: CN[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H]([C@@H](C)NC)CC[C@H]3N)[C@@H](N)C[C@H]2N)OC[C@]1(C)O
Agent: CN[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H](CN)CC[C@H]3N)[C@@H](N)C[C@H]2N)OC[C@]1(C)O
Agent: CN[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H]([C@@H](C)N)CC[C@H]3N)[C@@H](N)C[C@H]2N)OC[C@]1(C)O
Agent: O=C(O)/C=C/CCCCCCCCC(=O)O
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CNC(C)C1CCC(N)C(OC2C(N)CC(N)C(OC3OCC(C)(O)C(NC)C3O)C2O)O1

Procedure:
TLC: eluent chloroform/methanol/water/28% NH3 50:40:7:3; RF=0.67 (traumatic acid): eluent chloroform,/methanol/28% NH3 1:1:1 ninhydrin as indicator: three stains are observed like in gentamycin sulfate used as standard sample.
Reaction SMILES: [CH:1]1([NH:8][C:9]([NH2:11])=[O:10])[NH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[I:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br.[H-].[Na+]>CN(C=O)C>[I:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][N:4]1[C:2](=[O:3])[CH:1]([NH:8][C:9]([NH2:11])=[O:10])[NH:7][C:5]1=[O:6]
Reactant: NC(=O)NC1NC(=O)NC1=O
Reactant: BrCc1cccc(I)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)NC1NC(=O)N(Cc2cccc(I)c2)C1=O
Yield: 13.6 %

Procedure:
Allantoin (1.58 g) was stirred with meta-iodobenzyl bromide (2.97 g) in DMF (25 ml) at 21° under nitrogen and sodium hydride (60% oil dispersion; 0.40 g) was added over 5 min. After 2 h the solution was partitioned between EtOAc and water and hydrochloric acid was added to give pH 3. The separated aqueous layer was extracted with more EtOAc and the combined organic layers were washed with water and brine twice. After drying (MgSO4), the solution was concentrated to 20 ml. After 1 h the solid was collected by filtration and washed with EtOAc. The residue was boiled with EtOAc (50 ml) and the slurry was allowed to cool. The solid was collected by filtration, washed with ethyl acetate and dried to give the title compound (0.507 g). LCMS RT=2.44 min
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][Si:9](Cl)([CH3:11])[CH3:10]>>[CH3:8][Si:9]([CH3:11])([CH3:10])[O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCC1
Reactant: C[Si](C)(C)Cl
Product: C[Si](C)(C)OC1CCCCC1

Procedure:
Trimethyl-cyclohexyloxy-silane was prepared according to the same procedure of Example 2, except that the raw materials were changed as cyclohexanol and trimethylsilyl chloride.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[F:22][C:23]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:24]=1[NH2:25]>CN(C=O)C.CCOC(C)=O>[CH2:1]([NH:8][C:9](=[O:12])[CH2:10][NH:25][C:24]1[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:23]=1[F:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)NCc1ccccc1
Reactant: Nc1ccc(F)cc1F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNc1ccc(F)cc1F)NCc1ccccc1
Temperature: 100 °C
Reaction time: 40 h

Procedure:
A mixture of N-benzyl-2-chloroacetamide (700 mg—obtained as described for intermediate 1), DIPEA (0.76 mL) and 2,4-difluoro-aniline (0.4 mL) in anhydrous DMF (5 mL) was stirred at 100° C. for 40 hours under a Nitrogen atmosphere. Then, more DIPEA (0.2 mL) was added and the mixture was heated to 100° C. for further 4 hours. After cooling to room temperature, the solution was diluted with AcOEt and washed with water and ice. The separated aqueous phase was extracted with further AcOEt (3×20 mL). The combined organic extracts were dried and concentrated in vacuo. The residue was purified by flash chromatography (CH/AcOEt 7:3) to give the title compound (600 mg) as a beige solid.
Reaction SMILES: [Na].FC1C=C(C=CC=1F)C[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=1.CS([C:25]1[N:30]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[Cl:38])[C:28]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)=[C:27](S(C)(=O)=O)[N:26]=1)(=O)=O>>[F:16][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[F:15])[CH2:8][O:7][C:25]1[N:26]=[C:27]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=2)[C:28]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[Cl:38])[N:30]=1
Reactant: Fc1ccc(COCc2ccc(F)c(F)c2)cc1F
Reactant: CS(=O)(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c(S(C)(=O)=O)n1
Agent: [Na]
Product: Fc1ccc(COc2nc(OCc3ccc(F)c(F)c3)c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)n2)cc1F

Procedure:
In Examples 17-19, the procedure described in Example 16 was followed but with substitution of the appropriate sodium alkoxide (2 eq) for sodium-3,4-difluorobenzyloxide in the reaction with 2,4-bis(methylsulfonyl)-5-[4-chlorophenyl]-6-[2,4-dichlorophenyl]pyrimidine (Reference Example 5) to afford the following compounds: