Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([O:6][C@@H:7]1[C@@:37]2([CH3:38])[C:11](=[CH:12][CH2:13][C@@H:14]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:32])[CH2:20][CH2:21][CH2:22][C:23]([O:26]C(OCC)C)([CH3:25])[CH3:24])[CH2:10][C@@H:9]([O:40]C(OCC)C)[CH2:8]1)C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>CO>[OH:6][C@@H:7]1[C@@:37]2([CH3:38])[C:11](=[CH:12][CH2:13][C@@H:14]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:32])[CH2:20][CH2:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])[CH2:10][C@@H:9]([OH:40])[CH2:8]1
Reactant: CCOC(C)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)(C)OC(C)OCC)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)OCC)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 89.2 %

Procedure:
A solution of 36.2 g of 1α,3β,25-tris(1-ethoxyethoxy)-cholest-5-ene in 0.75 liters of methanol was treated with 5.6 g (29 mmol) of p-toluenesulphonic acid monohydrate, and the mixture was stirred at room temperature for 45 minutes. 1.8 liters of water was dropped into the solution. The suspension was suction filtered, and the residue was washed neutral with water and dried. There was obtained 21.3 g of 1α,3β,25-trihydroxycholest-5-ene which melted at 172°-175° C. after recrystallization from acetone.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[CH:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1I>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[F:20])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#Cc1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Reactant: Fc1ccccc1I
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2F)cc1[N+](=O)[O-]
Yield: 106.5 %

Procedure:
Prepared from (4-ethynyl-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example F2) (525 mg, 2.0 mmol) and 2-fluoro-1-iodobenzene (0.35 mL, 3 mmol) according to the general procedure F. Obtained as a yellow solid (759 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pt].[H][H]>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]([CH2:8][CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CC2CCCCCN2)cc1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Product: Nc1ccc(CC2CCCCCN2)cc1

Procedure:
Hydrogenate 12 g of the title compound of Example 16 in 300 ml of ethyl alcohol with platinum/hydrogen. After the absorption of hydrogen has ceased, filter off the catalyst and concentrate the filtrate to obtain 10.5 g (100% of theory) of the title compound as a dark brown viscous oil.
Reaction SMILES: [NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:27][C:28]([NH:30][CH2:31][C:32]#[CH:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[NH:1]([C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:33]#[C:32][CH2:31][NH:30][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])=[CH:18][CH:17]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: Brc1cnc(Nc2ccc(I)cc2)nc1Nc1ccccc1
Product: CC(C)(C)OC(=O)NCC#Cc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1

Procedure:
Using an analogous procedure to that described in Example 37, starting from 4-anilino-5-bromo-2-(4-iodoanilino)pyrimidine (Method 12) and 3-(t-butoxycarbonylamino) propyne, the product was obtained. NMR: 1.4 (s, 9H), 3.9 (d, 2H), 7.1–7.3 (m, 4H), 7.4 (m, 2H), 7.6 (m, 4H), 8.2 (s, 1H), 8.6 (s, 1H), 9.5 (s, 1H); MS (MH+): 494.3, 496.3.
Reaction SMILES: [NH2:1][C:2]1[C:14]2[C:15](=[O:21])[C:16]([C:18]([OH:20])=[O:19])=[CH:17][N:12]3[C:13]=2[C:5]([CH:6]2[CH:11]3[CH2:10][CH2:9][CH2:8][CH2:7]2)=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>[OH-].[K+]>[C:22]([NH:1][C:2]1[C:14]2[C:15](=[O:21])[C:16]([C:18]([OH:20])=[O:19])=[CH:17][N:12]3[C:13]=2[C:5]([CH:6]2[CH:11]3[CH2:10][CH2:9][CH2:8][CH2:7]2)=[CH:4][CH:3]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c3c1c(=O)c(C(=O)O)cn3C1CCCCC21
Agent: [K+]
Agent: [OH-]
Product: CC(=O)Nc1ccc2c3c1c(=O)c(C(=O)O)cn3C1CCCCC21

Procedure:
2.84 g of 3-amino-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid was dissolved in 50 ml of a 2% aqueous potassium hydroxide, and acetic anhydride was added dropwise thereto while ice cooling whereby orange-colored crystals were precipitated. The resulting crystals were separated by filtration, washed with water and recrystallized from dimethylformamide-water to obtain 3 g of 3-acetylamino-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid having a melting point of 187°-190° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]([O:22][CH3:23])=[O:21].N1C=CC=CC=1>ClCCl>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([O:22][CH3:23])=[O:21])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1sccc1N
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)C)cc1
Yield: 64.5 %

Procedure:
Synthesized as described for 52 using commercially available 4-iso-propylbenzenesulfonyl chloride (1.0 g; 4.57 mmol), methyl 3-aminothiophene-2-carboxylate (0.72 g; 4.57 mmol), pyridine (0.55 mL; 6.86 mmol), and anhydrous dichloromethane (3 mL). This afforded the title compound as a white solid (1.0 g).
Reaction SMILES: C[O:2][C:3]([CH:5]([O:8][C:9]1[CH:21]=[CH:20][C:12]([CH:13]=[CH:14][C:15]2[N:19]=[CH:18][NH:17][N:16]=2)=[CH:11][CH:10]=1)[CH2:6][CH3:7])=O.[NH3:22].C(O)C>CC(C)=O>[C:3]([CH:5]([O:8][C:9]1[CH:21]=[CH:20][C:12]([CH:13]=[CH:14][C:15]2[N:19]=[CH:18][NH:17][N:16]=2)=[CH:11][CH:10]=1)[CH2:6][CH3:7])(=[O:2])[NH2:22]
Reactant: CCC(Oc1ccc(C=Cc2nc[nH]n2)cc1)C(=O)OC
Reactant: N
Solvent: CCO
Solvent: CC(C)=O
Product: CCC(Oc1ccc(C=Cc2nc[nH]n2)cc1)C(N)=O

Procedure:
3-[4-(1-methoxycarbonylpropoxy)styryl]-1,2,4-triazole (0.5 g--prepared as the intermediate for Example 22 above), concentrated ammonia (5 ml) and ethanol (10 ml) were placed in a Carius tube, and further saturated with gaseous ammonia for 20 minutes. The tube was cooled in acetone/solid carbon dioxide and sealed, and then heated at 110° for 24 hours. The tube was cooled and opened, and the contents were evaporated to dryness to give the required 3-[4-(1-carbamoylpropoxy)styryl]-1,2,4-triazole, crystallised from methanol, softened at 50° and mp~150°.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH:8]1[CH2:12][CH2:11][O:10][C:9]1=[O:13])(C)(C)[CH3:2].C(O)(=[O:16])C>>[C:1]([O:5][CH2:6][CH2:7][CH:8]1[CH2:12][CH2:11][O:10][C:9]1=[O:13])(=[O:16])[CH3:2]
Reactant: CC(C)(C)OCCC1CCOC1=O
Reactant: CC(=O)O
Product: CC(=O)OCCC1CCOC1=O
Temperature: 120 °C
Reaction time: 19 h
Yield: 98 %

Procedure:
In a stirred vessel, a mixture of 10 g of 3-(2'-tert-butoxyethyl)-dihydro-2(3H)furanone, 50 g of glacial acetic acid, and 5 g of Nafion is heated to 120° C. Following a period of 19 h, the reaction is terminated (conversion: 100%) and the catalyst is separated by filtration. Following purification by distillation, there is obtained 98% of 3-(2'-acetoxyethyl)-dihydro-2(3H)furanone.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH3:10].[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1)([O-:13])=[O:12]>N1C=CC=CC=1>[N+:11]([C:14]1[CH:15]=[CH:16][C:17]([S:20]([O:1][C:2]2[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=2[CH3:10])(=[O:22])=[O:21])=[CH:18][CH:19]=1)([O-:13])=[O:12]
Reactant: Cc1c(O)c(=O)ccn1C
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1c(OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)c(=O)ccn1C
Yield: 50 %

Procedure:
3-Hydroxy-1,2-dimethylpyridin-4(1H)-one (0.2 g, 1.5 mmol) was reacted with 4-nitrobenzenesulfonyl chloride (0.488 g, 2.2 mmol) in 10 mL of pyridine to afford PZBG-3c in 50% yield (0.23 g, 0.7 mmol). 1H NMR (400 MHz, CDCl3) δ=8.41-8.34 (m, 4H), 7.26 (d, J=7.6 Hz, 1H), 6.33 (d, J=7.6 Hz, 1H), 3.67 (s, 3H), 2.53 (s, 3H). 13C NMR (100 MHz, CDCl3) 6=170.9, 150.9, 144.9, 143.2, 140.9, 140.1, 130.4, 124.0, 118.4, 41.9, 14.6. ESI-MS(+): m/z 325.11 [M+H]+, 346.96 [M+Na]+.
Reaction SMILES: [C:1]([N:5]1[C:9]([Cl:10])=[C:8]([CH2:11]O)[C:7]([C:13]([F:16])([F:15])[F:14])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].P(Br)(Br)[Br:18]>C(OCC)C>[Br:18][CH2:11][C:8]1[C:7]([C:13]([F:16])([F:15])[F:14])=[N:6][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:9]=1[Cl:10]
Reactant: CC(C)(C)n1nc(C(F)(F)F)c(CO)c1Cl
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: CC(C)(C)n1nc(C(F)(F)F)c(CBr)c1Cl
Temperature: -10 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
A solution of 9.2 g (35.7 mmoles) of (1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol dissolved in 100 ml of diethyl ether was cooled to −10° C. Thereto was added 11.6 g (42.9 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature overnight to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into ice water and extraction with diethyl ether was conducted. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein, to obtain 10.0 g (yield: 87.3%) of 4-bromomethyl-1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyra-zole.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10]C)=O)#[N:2].[C-]#N.[Na+].CO.[CH:19]([NH2:22])([CH3:21])[CH3:20]>CS(C)=O>[CH:19]([NH:22][C:8](=[O:10])[C:7]1[CH:12]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=1[OH:13])([CH3:21])[CH3:20]
Reactant: CC(C)N
Reactant: COC(=O)c1cc(C#N)ccc1O
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: CC(C)NC(=O)c1cc(C#N)ccc1O
Temperature: 60 °C
Yield: 93 %

Procedure:
Methyl 5-cyano-2-hydroxybenzoate (8.85 g; 50 mmol; see Example 10(b) above) and NaCN (250 mg; 5 mmol) were dissolved in DMSO (10 mL) and MeOH (50 mL) and iso-propyl amine (25 mL) was added. The reaction mixture was heated (60° C. ) in a sealed steel vessel for 10 h, the MeOH was removed under reduced pressure and H2O (500 mL) was added. The solution was acidified with HCl (pH 1), filtered and the precipitate was washed with H2O giving the sub-title compound in a 93% yield.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br>CN(C=O)C.C(OCC)(=O)C>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[CH:17][C:5]=2[C:1]([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: Clc1ccccc1CBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2Cl)CCCC1=O
Reaction time: 0.08 h
Yield: 53.5 %

Procedure:
40% Methanolic Triton B (2.42 mL, 5.3 mM) was slowly added dropwise to a solution of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (873.7 mg, 3.59 mM) in 10 mL of DMF at 25° C. After 5 minutes, 2-chlorobenzyl bromide (1.11 g, 5.39 mM) was added and the resultant mixture stirred at room temperature for 72 hours. The mixture was diluted with ethyl acetate, washed five times with H2O, once with saturated brine, dried over anhydrousmagnesium sulfate, filtered, and concentrated. The residue was purified by crystallization from ethyl acetate to afford 706.3 mg (53%) of the 9-[(2-chlorophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a yellow solid. 1H NMR (DMSO-d6) δ7.6 (m, 2H), 7.4-7.1 (m, 4H), 6.5 (d, 1H, J=8 Hz), 5.6 (s, 2H), 3.8 (s, 3H), 2.9 (t, 2H, J=6 Hz), 2.4 (t, 2H, J=6 Hz), and 2.1 (m, 2H). IR (CDCl3, cm−1) 3050, 2950, 1725, 1655, 1462, 1446, 1435, 1288 and 1120. MS (ES) m/e 368, 370.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[C:6]([NH2:8])[CH:7]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].Cl>N1C=CC=CC=1>[CH3:12][S:13]([NH:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[C:6]([NH:8][S:13]([CH3:12])(=[O:15])=[O:14])[CH:7]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(N)cc([N+](=O)[O-])c1
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(NS(C)(=O)=O)cc([N+](=O)[O-])c1

Procedure:
To a solution of 1.5 g. (0.01 mol) of 3,5-diaminonitrobenzene in 3 ml. of pyridine cooled to 5° C. was added 1.6 ml. (0.02 mol) of methanesulfonyl chloride, dropwise, and the mixture was stirred for 90 minutes at room temperature. The reaction mixture was decomposed by adding dilute hydrochloric acid and ice. The solid was filtered, washed with water and dried to give 3,5-bis-methylsulfonamidonitrobenzene, m.p. 223°-224° C.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10]1(C(O)=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>O>[C:10]1([C:1]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[O:9])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=C(O)C1CCCCC1
Solvent: O
Product: O=C(c1ccccc1)C1CCCCC1

Procedure:
A mixture of 11.5 g/h of benzoic acid, 36 g/h of cyclohexanecarboxylic acid and 13 g/h of water was evaporated in an evaporator and passed, together with 10 l/h of nitrogen, at 450° C., over 100 ml of a catalyst which contained 2% by weight of potassium oxide, the remainder being anatase. The reaction gases were then cooled and were collected in a receiver. From the discharged two-phase mixture, the organic phase was analyzed by gas chromatography. The conversion of benzoic acid was 98%. The selectivity with respect to cyclohexyl phenyl ketone was 60%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[C:16]([NH:33][C:30]3[CH:29]=[CH:28][C:27]([CH2:26][N:23]4[CH2:22][CH2:21][N:20]([CH3:19])[CH2:25][CH2:24]4)=[CH:32][CH:31]=3)=[O:18])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Product: CN1CCN(Cc2ccc(NC(=O)/C=C/c3ccc(-c4ccc(Cl)cc4)cc3)cc2)CC1

Procedure:
Prepared analogously to Example 172 starting from (E)-3-(4′-chloro-biphenyl-4-yl)-acrylic acid and 4-(4-methyl-piperazin-1-ylmethyl)-phenylamine. The crude product was purified by column chromatography (silica gel, dichloromethane/MeOH/conc. aqueous ammonia 90:10:0.1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6](O)=O)=[CH:2]1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[NH2:31][C:32]1[CH:50]=[CH:49][C:35]2[N:36]=[C:37]([NH:40][C:41]3[C:46]([Cl:47])=[CH:45][CH:44]=[CH:43][C:42]=3[Cl:48])[N:38]([CH3:39])[C:34]=2[C:33]=1[C:51]([NH2:53])=[O:52]>CN(C=O)C.CCOC(C)=O>[Cl:48][C:42]1[CH:43]=[CH:44][CH:45]=[C:46]([Cl:47])[C:41]=1[NH:40][C:37]1[N:38]([CH3:39])[C:34]2=[C:33]3[C:32](=[CH:50][CH:49]=[C:35]2[N:36]=1)[N:31]=[C:6]([C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)[NH:53][C:51]3=[O:52]
Reactant: Cn1c(Nc2c(Cl)cccc2Cl)nc2ccc(N)c(C(N)=O)c21
Reactant: O=C(O)c1ccoc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(Nc2c(Cl)cccc2Cl)nc2ccc3nc(-c4ccoc4)[nH]c(=O)c3c21
Reaction time: 24 h

Procedure:
Furan-3-carboxylic acid (20 mg, 0.18 mmol), hydroxybenzotriazole (24 mg, 0.18 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (35 mg, 0.18 mmol) were stirred together in DMF (1 mL) for 15 min. 5-Amino-2-(2,6-dichlorophenylamino)-3-methyl-3H-benzoimidazole-4-carboxylic acid amide (Example 7)(50 mg, 0.15 mmol) was added, and stirring continued for 24 h. The solution was diluted with EtOAc and washed in turn with aqueous Na2CO3, water and brine. The organic layer was evaporated and the residue dissolved in MeOH (2 mL). Sodium methoxide in MeOH (25%, 0.1 mL) was added and the solution heated to reflux for 45 min. The cooled solution was partitioned between water and CH2Cl2. The organic layer was evaporated and the crude product stirred with MeOH (1 mL) for 1 h. The solid was filtered, washed with a few drops of MeOH and dried to yield the title compound, 8 (14 mg, 22%). mp>300° C. MS (ES) 428, 426 (MH+).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[NH2:8][C@@H:9]([CH3:29])[CH2:10][NH:11][C:12]1[CH:13]=[C:14]([NH:20][C:21]2[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[N:22]=2)[C:15]([C:18]#[N:19])=[N:16][CH:17]=1.OO.[OH-:32].[Na+]>CS(C)=O>[OH:3][C:2]([C:4]([F:7])([F:6])[F:5])=[O:1].[NH2:8][C@@H:9]([CH3:29])[CH2:10][NH:11][C:12]1[CH:13]=[C:14]([NH:20][C:21]2[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[N:22]=2)[C:15]([C:18]([NH2:19])=[O:32])=[N:16][CH:17]=1
Reactant: Cc1cc(C)nc(Nc2cc(NC[C@H](C)N)cnc2C#N)c1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)nc(Nc2cc(NC[C@H](C)N)cnc2C(N)=O)c1
Reaction time: 16 h

Procedure:
To a solution of 5-{[(2S)-2-aminopropyl]amino}-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carbonitrile TFA salt (166 mg, 0.404 mmol) in DMSO (3 ml) were added hydrogen peroxide (35% aqueous solution, 0.053 ml, 0.61 mmol) and sodium hydroxide (4.0 M aqueous solution, 0.32 mL, 1.3 mmol) at 20° C. After 16 hour, the reaction mixture was purified directly by reverse phase HPLC (acetonitrile/water with 0.1% TFA) to give 5-{[(2S)-2-aminopropyl]amino}-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide TFA salt. MS ESI calc'd. for C16H23N6O [M+H]+ 315. found 315. 1H NMR (500 MHz, CD3OD) δ 7.81 (s, 1H), 7.59 (s, 1H), 7.10 (s, 1H), 6.90 (s, 1H), 3.72-3.49 (m, 1H), 3.52-3.33 (m, 2H), 2.53 (s, 3H), 2.40 (s, 3H), 1.39 (d, J=6.6 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH3:12][C@@H:13]([CH2:16][CH3:17])[CH2:14]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([O:7][CH2:12][C@@H:13]([CH3:14])[CH2:16][CH3:17])=[O:6]
Reactant: O=C(O)c1ccc(O)c(F)c1
Reactant: CC[C@H](C)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC[C@H](C)COC(=O)c1ccc(O)c(F)c1
Reaction time: 8 h
Yield: 66 %

Procedure:
In a 250-ml, round-bottomed flask equipped with a heating mantle, magnetic stirrer, condenser and Dean Stark trap, were placed 2.5 g (16.0 mmol) of 3-fluoro-4-hydroxybenzoic acid, ten g (113.4 mmol) of (S)-2-methyl-1-butanol, 0.347 g of p-toluenesulfonic acid monohydrate and 100 ml of benzene. The reaction mixture was stirred overnight under reflux. The reaction mixture was extracted using saturated aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate, filtered through cotton and evaporated to an oil. The product was purified by flash chromatography on silica gel with 3% diethyl ether in dichloromethane. Fractions containing the desired product were combined and evaporated to a pale-yellow oil. Analysis by NMR showed that considerable starting alcohol remained. The oil was placed under vacuum (at 70° C.) for two days. No alcohol was shown by gas chromatography to be present. The desired product was obtained in the amount of 2.39 g (66% yield) and had the following structure. ##STR30##
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH2:6]([NH:9][CH2:10][CH2:11][CH3:12])[CH2:7][CH3:8]>>[CH2:6]([N:9]([CH2:10][CH2:11][CH3:12])[CH2:1][CH:3]1[O:5][CH2:4]1)[CH2:7][CH3:8]
Reactant: CCCNCCC
Reactant: ClCC1CO1
Product: CCCN(CCC)CC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.9 %

Procedure:
A stirred solution of epichlorohydrin (20.0 g, 0.22 mole) is treated dropwise with dipropylamine (23.14 g, 0.23 mole) over a 1 hour period followed by continuous stirring at room temperature overnight. The reaction mixture is washed with 20% K2CO3 (50 ml). The organic layer is then stirred with 40% NaOH for 1 hour. The organic layer is separated and the aqueous layer is extracted with 3×100 ml portions of ether. The etheral extracts are pooled with the organic layer and washed with H2O (100 ml). The organic layer is dried over anhydrous Na2SO4 and filtered. The filtrate is concentrated under reduced pressure to yield the crude product (I) weighing 35.3 g. The crude product is distilled at 34°/0.1 mmHg to yield 7.23 g (21.0%) pure product to be used as an intermediate in Part B.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].Cl[C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)=[CH:8][C:9]=1[NH:10][C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[O:4]
Reactant: C=CCOC(=O)Cl
Reactant: COC(=O)c1sc(-c2cccc(Cl)c2)cc1N
Solvent: Cc1ccccc1
Product: C=CCOC(=O)Nc1cc(-c2cccc(Cl)c2)sc1C(=O)OC

Procedure:
To a solution of 3-Amino-5-(3-chloro-phenyl)-thiophene-2-carboxylic acid methyl ester (15 g, 56.0 mmol) in toluene (200 mL) was added a solution of allyl chloroformate (8.10 g, 67.2 mmol) in toluene (5.0 mL) and the resulting reaction solution was heated under reflux for 3 h. Toluene was stripped down and the crystals were collected and washed with ether/hexane to afford a yellow crystalline compound, mp 101-103° C. 1H NMR (DMSO-d6) δ3.85 (s, 3H), 4.68-4.71 (d, 2H, J=5.46 Hz), 5.26-5.30 (dd, 1H, J=1.35, 9.84 Hz), 5.36-5.42 (dd, 1H, J=1.57, 15.68 Hz), 5.96(m, 2H), 7.50-7.52 (m, 2H), 7.67-7.71 (m, 1H), 7.79 (s, 1H), 8.10 (s, 1H); MS(+APCI) m/z 352(M+H); Anal. Calc. For C16H14CINO4S: C, 54.63; H, 4.01; N, 3.97. Found: C, 54.05; H, 4.17; N, 3.84.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[C:2]1=[N:11][OH:12].C(=O)([O-])[O-].[Na+].[Na+].[C:19]([O:22][CH2:23][CH2:24]Br)(=[O:21])[CH3:20].O>CN1CCCC1=O>[C:19]([O:22][CH2:23][CH2:24][O:12][N:11]=[C:2]1[C:3](=[O:10])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1]1)(=[O:21])[CH3:20]
Reactant: CC(=O)OCCBr
Reactant: O=C1C(=NO)Oc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(=O)OCCON=C1Oc2ccccc2C1=O
Reaction time: 2 h
Yield: 63 %

Procedure:
1.63 g (0.01 mol) of benzofuran-2,3-dione2-oxime (XI-1) in 5 ml of N-methyl-2-pyrrolidinone are stirred with 1.14 g (0.0108 mol) of sodium carbonate at 20° C. for 30 minutes. After the addition of 1.7 g (0.0102 mol) of 2-bromoethyl acetate, stirring is continued at 70° C. for 2 hours. The mixture is poured into 30 ml of water and the product is filtered off. The product is dried to afford 1.57 g (63% of theory) of crystalline 2-(3-oxo-3H-benzofuran-2-ylideneaminooxy)-ethyl acetate (XIV-1).
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@@H:14]([F:16])[CH2:13][C@H:9]1[C:10](O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[F:16][C@@H:14]1[CH2:15][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[C@H:9]([CH2:10][OH:11])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1CO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-Boc-cis-4-fluoro-L-proline (2 g, 8.575 mmol) was dissolved in tetrahydrofuran (20 ml), the solution was cooled and boron hydride-tetrahydrofuran complex (1 mol/l, 12.86 ml) was added slowly at 0° C. The reaction mixture warmed slowly to room temperature, after stirring for 3 h it was cooled again to 0° C., water (5 ml) was slowly added dropwise, potassium carbonate (2 g, 14.477 mmol) was added and the mixture was stirred for 30 min. After separation of the phases, the aqueous phase was extracted with diethyl ether (3×20 ml) and the combined organic phases were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with diethyl ether/hexane (4:1). Yield: 1.73 g, 92%