Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH2:8].[CH2:9]([O:11][C:12]([C:14]1C(Cl)=NC(SC)=N[CH:19]=1)=[O:13])[CH3:10].C([O-])([O-])=O.[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:9]([O:11][C:12](=[O:13])[CH2:14][CH2:19][NH:8][CH:2]1[CH2:3][CH:4]2[CH2:7][CH:1]1[CH2:6][CH2:5]2)[CH3:10]
Reactant: NC1CC2CCC1C2
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Product: CCOC(=O)CCNC1CC2CCC1C2
Temperature: 80 °C
Yield: 39.4 %

Procedure:
Bicyclo[2.2.1]hept-2-ylamine (2.0 g, 18.0 mmol) and 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (2.45 g, 18.0 mmol) were combined neat and K2CO3 (3.72 g, 27.0 mmol) and a catalytic amount of tetrabutylammonium iodide (ca. 2 mg) was added. The mixture was heated at 80° C. overnight. The resulting mixture was then partitioned between water and DCM. The organic layer was dried (MgSO4) and concentrated to provide 1.5 g of 3-(bicyclo[2.2.1]hept-2-ylamino)-propionic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ (ppm): 5.29 (s, 1H), 4.13 (q, 2H, J=7.1 Hz), 2.77-2.92 (m, 2H), 2.57 (dd, 1H, J=3.1 Hz, J=7.3 Hz), 2.50 (t, 2H, J=6.6 Hz), 2.16-2.20 (m, 2H), 1.57 (ddd, 1H, J=2.2 Hz, J=7.5 Hz, J=12.3 Hz), 1.41-1.49 (m, 3H), 1.25 (t, 3H, J=7.2 Hz), 1.01-1.10 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1.[CH2:11]([N:13]([CH2:17][CH3:18])[C:14](Cl)=[O:15])[CH3:12]>>[CH2:11]([N:13]([CH2:17][CH3:18])[C:14]([NH:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1)=[O:15])[CH3:12]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: CCN(CC)C(=O)Cl
Product: CCN(CC)C(=O)Nc1cc(C(C)(C)C)on1
Yield: 98.2 %

Procedure:
Using 3-amino-5-t-butylisoxazole and N,N-diethylcarbamoyl chloride, the reaction is effected as in Example 1, whereby 1,1-diethyl-3-(5-t-butyl-3-isoxazolyl)urea is obtained. Yield is 98.2%. Melting point is 122.0° to 123.5° C.
Reaction SMILES: [Na].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5](Cl)[N:4]=1.[CH2:14]([OH:17])[CH:15]=[CH2:16]>>[CH2:14]([O:17][C:5]1[N:4]=[C:3]([NH2:2])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)[CH:15]=[CH2:16]
Reactant: C=CCO
Reactant: Nc1nc(Cl)nc2ccccc12
Agent: [Na]
Product: C=CCOc1nc(N)c2ccccc2n1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To the solution of sodium metal (0.7 g) in dried allylalcohol (90 ml) was added 4-amino-2-chloroquinazoline (3.5 g) and the mixture was stirred for 5 hours at 100° C. After the resultant mixture was concentrated under reduced pressure, to the residue was added a small volume of water. The aqueous mixture was extracted twice with ethyl acetate. The organic layer was washed with water and with aqueous solution saturated with sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crystalline residue, which was recrystallized from a mixture of ethyl acetate and hexane to give crystalline 2-allyloxy-4-aminoquinazoline (2.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[C:24]1([CH3:33])[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([CH3:33])[CH:25]=2)=[CH:17][CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Reactant: Cc1cccc(B(O)O)c1
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: [I-]
Solvent: COCCOC
Solvent: O
Product: Cc1cccc(Cc2ccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)cc2)c1
Yield: 47.5 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(3-methylbenzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.073 g; 0.209 mmol), m-tolylboronic acid (0.030 g; 0.220 mmol), tetrakis(triphenylphosphine)palladium(0) (0.012 g; 0.010 mmol), sodium carbonate (0.044 g; 0.419 mmol), sodium iodide (0.063 g; 0.419 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.040 g (46%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][N:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]([O:20]C)=[O:19])=[CH:17][C:12]=3[NH:11][C:10]2=[S:22])=[O:7])=[CH:4][C:3]=1[S:25](=[O:28])(=[O:27])[NH2:26].Cl>[OH-].[Na+]>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][N:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]([OH:20])=[O:19])=[CH:17][C:12]=3[NH:11][C:10]2=[S:22])=[O:7])=[CH:4][C:3]=1[S:25](=[O:27])(=[O:28])[NH2:26]
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=S)n2NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NS(=O)(=O)c1cc(C(=O)Nn2c(=S)[nH]c3cc(C(=O)O)ccc32)ccc1Cl

Procedure:
48.4 g of the ester obtained as described above were stirred with 330 ml of 2N sodium hydroxide solution at 50° C. for 4 hours. The clear yellow solution was cooled down and acidified to pH 3 to 4 by adding 2N hydrochloric acid. The precipitate was filtered by suction, washed with water and dried at 80° C. The crude product obtained was recrystallized from a mixture of dimethylformamide and water (1:1) under clarifying by activated carbon. Thus, 1-(4'-chloro-3'-sulfamoylbenzoyl)amino-5-carboxybenzimidazole-2-thione containing 1 molecule of dimethylformamide was obtained in the form of snow-white tiny crystalls.
Reaction SMILES: Br[C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:18])[N:15]=1.[CH:27]([O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)([CH3:29])[CH3:28]>>[C:7]([N:6]1[C:2]([C:34]2[CH:35]=[CH:36][C:31]([O:30][CH:27]([CH3:29])[CH3:28])=[CH:32][CH:33]=2)=[C:3]([C:11]2[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:19][CH2:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:18])[N:15]=2)[CH:4]=[N:5]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)NCC3CCOCC3)cs2)c1Br
Product: CC(C)Oc1ccc(-c2c(-c3nc(CC(=O)NCC4CCOCC4)cs3)cnn2C(C)(C)C)cc1

Procedure:
Using 2-(2-(5-bromo-1-tert-butyl-1H-pyrazol-4-yl)thiazol-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide and (4-isopropoxyphenyl)boronic acid and by reaction and purification in the same manner as in the method described in Example 43, the title compound was obtained.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:22]([CH2:23][CH2:24][C@:4]12[CH2:5][C:6]([OH:8])=[O:7])[C@:20]1([CH3:21])[C:15](=[CH:16][C@@H:17]([OH:25])[CH2:18][CH2:19]1)[N:14]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:13]3.O=[Cr](=O)=O.C1C=CC=CN=1.C1C=CC=CN=1>C(Cl)Cl>[CH:2]([C@H:3]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:22]([CH2:23][CH2:24][C@:4]12[CH2:5][C:6]([OH:8])=[O:7])[C@:20]1([CH3:21])[C:15](=[CH:16][C:17](=[O:25])[CH2:18][CH2:19]1)[N:14]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:13]3)=[O:1]
Reactant: CC(C)(C)N1C[C@H]2[C@@H]3CC[C@H](CO)[C@@]3(CC(=O)O)CC[C@@H]2[C@@]2(C)CC[C@H](O)C=C12
Agent: O=[Cr](=O)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)N1C[C@H]2[C@@H]3CC[C@H](C=O)[C@@]3(CC(=O)O)CC[C@@H]2[C@@]2(C)CCC(=O)C=C12

Procedure:
A solution of 17β-hydroxymethyl-3β-hydroxy-6-t-butylcarboxy-6-azaandrost-4-ene (182 mg, 0.448 mmol), prepared in part A above, in methylene chloride (7 mL) is added to freshly prepared Collins' reagent. (CrO3 ·2 pyridine) in methylene chloride (12 mL) at 0° C. After 15 minutes the solvent is decanted from the tar, the tar is triturated with methylene chloride (2×30 mL), the combined methylene chloride washed with 2N NaOH, saturated aqueous NaHSO4, saturated aqueous NaCl, dried over MgSO4, concentrated and chromatographed on silica gel (50% ehtyl acetate/hexanes) to give crude 17β-formyl-6-t-butylcarboxy-6-azaandrost-4-en-3-one of sufficient purity to carry on to the following steps; yield: 125 mg (69%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:20][C:19]3=[CH:21][N:22]=[C:23]([CH3:24])[N:18]3[C:17]2=[O:25])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl>[C].[Pd].CO>[CH3:24][C:23]1[N:18]2[C:17](=[O:25])[N:16]([CH2:15][CH2:14][N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH2:20][C:19]2=[CH:21][N:22]=1
Reactant: Cc1ncc2n1C(=O)N(CCN1CCN(Cc3ccccc3)CC1)C2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1ncc2n1C(=O)N(CCN1CCNCC1)C2
Yield: 61.9 %

Procedure:
2-(2-(1-Benzyl-4-piperazinyl)ethyl)-5-methyl-1,2-dihydroimidazo[1,5-c]imidazol-3-one (0.22 g) obtained in Example 97b), 1 N hydrochloric acid (1 ml) and 10% palladium carbon (74 mg) were added to methanol (10 ml), and mixed under hydrogen atmosphere at room temperature for 3 days. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in a small amount of water, and the reaction mixture was basified with potassium carbonate and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (0.10 g, 63%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.C(OC([N:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH:38]=[C:37]([CH:39]=O)[CH:36]=[N:35]2)[CH2:30][CH2:29]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:39]([C:37]3[CH:36]=[N:35][N:34]([CH:31]4[CH2:32][CH2:33][NH:28][CH2:29][CH2:30]4)[CH:38]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(C=O)cn2)CC1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4cnn(C5CCNCC5)c4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 64 %

Procedure:
(1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 4-(4-formyl-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester were reacted in a similar fashion as for the synthesis of III. The resulting product was treated with 20 equivalents of trifluoroacetic acid in dichloromethane at 40° C. overnight. The solution was concentrated and neutralized to afford the title compound as a tan solid (64%). Mp. 203-5° C. 1H NMR (d-4 methanol): 8.27 (s, 1H), 8.07 (s, 1H), 7.89 (s, 1H), 6.42 (m, 1H), 6.37 (m, 1H), 5.32 (m, 1H), 4.87 (m, 3H), 4.44 (m, 1H), 3.33 (m, 2H), 3.25 (m, 2H), 2.98 (s, 1H), 2.90-2.72 (m, 4H), 2.36 (d, J=8 Hz, 1H), 2.20 (m, 2H), 2.04 (m, 2H), 1.57 (d, J=8 Hz, 1H). MS: 452.9 (M+H). HPLC retention time: 1.60 minutes (G Method).
Reaction SMILES: [F:1][CH2:2][C:3]1[C:8]2[CH:9]=[CH:10][C:11]([O:13][C:14](=[O:18])[N:15]([CH3:17])[CH3:16])=[CH:12][C:7]=2[O:6][C:5](=[O:19])[C:4]=1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[C:22]=1[F:30].O.O.[Sn](Cl)Cl.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[NH2:27][C:23]1[C:22]([F:30])=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][C:4]1[C:5](=[O:19])[O:6][C:7]2[CH:12]=[C:11]([O:13][C:14](=[O:18])[N:15]([CH3:17])[CH3:16])[CH:10]=[CH:9][C:8]=2[C:3]=1[CH2:2][F:1]
Reactant: CN(C)C(=O)Oc1ccc2c(CF)c(Cc3cccc([N+](=O)[O-])c3F)c(=O)oc2c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)C(=O)Oc1ccc2c(CF)c(Cc3cccc(N)c3F)c(=O)oc2c1
Temperature: 25 °C
Yield: 102.5 %

Procedure:
Ethyl acetate (2.0 mL) was added to dimethylcarbamic acid 4-fluoromethyl-3-(2-fluoro-3-nitrobenzyl)-2-oxo-2H-1-benzopyran-7-yl ester (20.5 mg) (6c-1-4), and tin(II) chloride dihydrate (60 mg) was added to the resultant suspension while stirring at room temperature. The suspension was heated under reflux for 1.5 hours, and after cooling to room temperature, saturated sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The resultant organic layer extraction liquid was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was then distilled away under reduced pressure to yield the title compound (19.5 mg).
Reaction SMILES: Cl.[CH2:2]([S:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[N:21]=[CH:20]3)[C@@H:13]([NH2:15])[CH3:14])=[CH:8][CH:7]=1)[CH3:3].CN(C)C(N(C)C)=N.[F:41][C:42]([F:49])([F:48])[C:43](OCC)=[O:44]>CO>[CH2:2]([S:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C@@H:12]([O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[N:21]=[CH:20]3)[C@@H:13]([NH:15][C:43](=[O:44])[C:42]([F:49])([F:48])[F:41])[CH3:14])=[CH:10][CH:11]=1)[CH3:3]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CCSCc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)cc1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CO
Product: CCSCc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C(F)(F)F)cc1

Procedure:
(1R,2S)-1-(4-(ethylthiomethyl)phenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-amine hydrochloride (50 mg, 0.11 mmol), 1,1,3,3-tetramethylguanidine (100 μl, 0.79 mmol) and ethyl trifluoroacetate (200 μl, 1.68 mmol) in MeOH (2.5 mL) was stirred at r.t. for 1 h. The reaction mixture was concentrated by evaporation and the residual material was purified by HPLC. Yield 35 mg (62%).
Reaction SMILES: [Br-:1].C(=[N:9][N+:10]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[O:17])[C:11]=1[CH2:25][CH3:26])C1C=CC=CC=1.Br.C(=O)C1C=CC=CC=1>O>[Br-:1].[NH2:9][N+:10]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[O:17])[C:11]=1[CH2:25][CH3:26]
Reactant: CCc1n(CC(=O)c2ccc(Cl)cc2)cc[n+]1N=Cc1ccccc1
Agent: Br
Agent: [Br-]
Solvent: O
Solvent: O=Cc1ccccc1
Product: CCc1n(CC(=O)c2ccc(Cl)cc2)cc[n+]1N

Procedure:
864 mg (2 mmol) of 1-(benzylideneamino)-3-(p-chlorophenacyl)-2-ethylimidazolium bromide are subjected to a steam distillation in 5 ml of water and 2 ml of 48 percent hydrobromic acid until benzaldehyde no longer evolves. The solution is concentrated and te precipitated product is filtered off. There is obtained 1-amino-3-(p-chlorophenacyl)-2-ethylimidazolium bromide of melting point 209°-210°.
Reaction SMILES: [F:1][C:2]([F:24])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C:3]([NH:5][C:6]1[CH:14]=[C:13](OC)[CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=[O:9])=[O:4].NC1C=C(OC)C=CC=1C(N)=O.NC1C([F:47])=CC=CC=1C(N)=O>>[F:1][C:2]([F:24])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C:3]([NH:5][C:6]1[C:14]([F:47])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=[O:9])=[O:4]
Reactant: NC(=O)c1cccc(F)c1N
Reactant: COc1ccc(C(N)=O)c(NC(=O)C(F)(F)c2ccc(F)cc2)c1
Agent: COc1ccc(C(N)=O)c(N)c1
Product: NC(=O)c1cccc(F)c1NC(=O)C(F)(F)c1ccc(F)cc1

Procedure:
2-(2,2-Difluoro-2-(4-fluorophenyl)acetamido)-3-fluorobenzamide was prepared according to the procedure described in Example 32 for preparation of 2-(2,2-difluoro-2-(4-fluorophenyl)acetamido)-4-methoxybenzamide, substituting 2-amino-4-methoxybenzamide in Example 32 with 2-amino-3-fluorobenzamide. The product was purified on silica gel column using DCM/MeOH as eluent (20%); LC-MS (ESI) m/z 327 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH2:16])=O.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:16]
Reactant: COCCCCCCCCCCCC(N)=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COCCCCCCCCCCCC#N
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.1 %

Procedure:
To the title compound of Example 12 (5.0 g, 22 mmol) in 30 mL pyridine at 0° C. was added in portions p-toluenesulfonyl chloride (5.1 g, 27 mmol). After stirring at room temperature for 3 days, the reaction mixturewas filtered, the cake washed with methylene chloride and the filtrate concentrated. The resulting residue was dissolved in methylene chloride, washed successively with 1N HCl, water, saturated NaHCO3, water and brine, dried with magnesium sulfate, filtered and concentrated. Chromatography of the crude product on silica gel using 20-80 diethyl ether-hexane as eluant gave the title compound (3.4 g) as a pale yellow liquid. The structure was supported by NMR, infrared spectroscopy, elemental analysis and mass spectroscopy.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.S(OC)(O[CH3:14])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].O>C1C=CC=CC=1>[CH3:14][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc(C=O)cc1
Yield: 99.7 %

Procedure:
20 g of p-hydroxybenzaldehyde (0.164 mol) was reacted with 29.0 g of dimethyl sulfate (0.230 mol) and 22.0 g of sodium carbonate (0.20 mol) for 2 hr. at 75°-80° C. A total of 12 ml of water was added in small portions over the last hour. Work-up by addition of water, acidification and benzene extraction yielded 22.27 g of p-methoxybenzaldehyde (99.9%) containing not more than 0.1% p-hydroxybenzaldehyde.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:31]([O:33]C(C)(C)C)=[O:32])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][F:30])=[CH:22][CH:21]=1)[C:12]([O:14]C(C)(C)C)=[O:13])=O)(C)(C)C.COC1C=CC=CC=1>FC(F)(F)C(O)=O>[F:30][CH2:29][CH2:28][CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][C@H:11]([C:12]([OH:14])=[O:13])[CH2:10][C@@H:9]([C:31]([OH:33])=[O:32])[NH2:8])=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(OCCCF)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: N[C@@H](C[C@H](Cc1ccc(OCCCF)cc1)C(=O)O)C(=O)O

Procedure:
60 mg (0.11 mmol) of di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-[4-(3-fluoropropoxy)-benzyl]-L-glutamate were taken up in 2 mL of trifluoro acetic acid and 1 mL of methoxybenzene and stirred overnight at room temperature. The excess of trifluoro acetic acid was evaporated and the residue was taken up three times in tetrahydrofuran and then evaporated. The resulting oil was chromatographed on C-18 reversed phase silica gel using a water/acetonitrile gradient, the appropriate fractions were combined and concentrated.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7])=[CH:4][CH:3]=1.Cl[C:20](Cl)(Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[CH2:9]([NH:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:20](=[N:1][C:2]2[CH:3]=[CH:4][C:5]([C:6](=[O:7])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:17][CH:18]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=1)=[O:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCNC(=O)c1ccc(N)cc1
Reactant: ClC(Cl)(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCNC(=O)c1ccc(N=C(Nc2ccc(C(=O)NCCCCCCCC)cc2)c2ccccc2)cc1

Procedure:
N,N'-Bis(4-n-octylcarbamylphenyl)benzamidine (4) was prepared from 4-amino-N-n-octylbenzamide and α,α,α-trichlorotoluene; pale-yellow oil: 1H-NMR (CDCl3) 7.7-6.9 (m, 14H), 6.2 (br t, 2H, J=6 Hz), 3.3 (br q, 4H, J=6 Hz), 1.7-0.7 (m, 30H); IR (CHCl3) 3430, 1640, 1590; MS (m/e) 582 (M+), 335 (base).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[I:7]I.C(OC(=O)C)(=O)C.S(=O)(=O)(O)O.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][CH:23]=1.S([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+].[Cl-].[Na+]>O.C(OCC)(=O)C.C(O)(=O)C>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[C:24]([I:7])[CH:23]=1
Reactant: CCc1ccc(Cl)cc1
Reactant: II
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCc1ccc(Cl)cc1I
Temperature: 0 °C
Reaction time: 18 h
Yield: 76.1 %

Procedure:
A mixture of sodium periodate (12 g, 56 mmol), iodine (9.5 g, 37 mmol), acetic acid (80 ml) and acetic anhydride (40 ml) was cooled to 0° C. Sulfuric acid (18 ml) was added dropwise followed by 1-chloro-4-ethyl benzene (15 ml, 110 mmol) dropwise. After stirring for 18 hours, a solution of sodium sulfite (20 g) in water (300 ml) was added. The mixture was adjusted to about pH 7 by addition of 50% aqueous sodium hydroxide solution and treated with ethyl acetate (200 ml) and saturated aqueous sodium chloride solution (200 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residual oil was purified by vacuum distillation (95-100° C., 5-10 mm) followed by flash chromatography on silica gel eluting with hexane to afford 4-chloro-1-ethyl-2-iodo-benzene (7.5 g, 25% yield) as a colorless oil.
Reaction SMILES: [CH:1]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1I)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:30]([N:34]1[C:42](=[O:43])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]1=[O:44])[CH2:31][C:32]#[CH:33].O>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH:1]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[C:33]#[C:32][CH2:31][CH2:30][N:34]1[C:42](=[O:43])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]1=[O:44])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(NC(c2ccccc2)c2ccccc2)c(I)c1
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCC#Cc1cc(Cl)ccc1NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
5 g(11.93 mmol, 1 eq) benzhydryl-(4-chloro-2-iodo-phenyl)-amine made in Example 1 was combined with 5 mL DMF. 0.42 g(0.598 mmol, 0.05 eq) dichlorobis-(triphenylphosphine)-palladium, 0.24 g(1.26 mmol, 0.11 eq) copper iodide and 1.8 g (17.58 mmol, 1.5 eq) triethylamine were added. The mixture was stirred at 25 C and 2.72 g (13.65 mmol, 1.14 eq) 2-but-3-ynyl-isoindole-1,3-dione was added in one portion. The mixture warmed to 40 C and was cooled back to room temperature. It became semi-solid after 2 h; an LC showed that at this time the reaction was complete. The mixture was diluted with 10 mL DMF and then 5 mL water was added slowly. Stirring was continued until solids precipitated. The vessel was cooled to 0-5 C and stirred at this temperature for 30 min. The resulting solid was collected by filtration and washed with 10 mL DMF/water 2:1 and 2×10 mL MeOH. The 8.78 g wet solid was dried at 40 C in vacuo for 14 h to obtain 5.55 g product (95%) with 95% purity.