Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: IC.[Cl:3][C:4]1[CH:25]=[CH:24][C:7]([CH2:8][NH:9][C:10]([C:12]2[N:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([I:23])=[CH:17][CH:16]=3)=[O:11])=[CH:6][CH:5]=1.[C:26]([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([I:23])[CH:19]=3)[N:14]([CH3:26])[N:13]=2)=[O:11])=[CH:24][CH:25]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1nnc2ccc(I)cc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)ccc21
Temperature: 90 °C
Yield: 39 %

Procedure:
Iodomethane (0.028 mL) is added to a suspension of N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-cinnolinecarboxamide; (Prep. 4, 0.16 g) and K2CO3 (0.20 g,) in 6 mL anhydrous DMF. The reaction is heated at 90° C. for 1 h. The reaction is cooled to room temperature and poured into 75 mL H2O. The resulting yellow solid is filtered and dried. The solid is dissolved in CH2Cl2 and adsorbed onto silica. Purification by chromatography (CH2Cl2 (2L), 0.5% MeOH/CH2Cl2 (2L), 0.75% MeOH/CH2Cl2 (1L), 1% MeOH/CH2Cl2 (1L), 1.5% MeOH/CH2Cl2 (1L), 3.5% MeOH/CH2Cl2 (1L), 10% MeOH/CH2Cl2 (1L)) affords the product as an off-white solid (0.062 g, 39%). Physical characteristics are as follows: m.p. 194-195° C.; 1H NMR (300 MHz, DMSO-d6) δ9.86, 8.52, 8.24, 7.76, 7.40, 7.38, 4.55, 4.22; IR (drift) 1671, 1601, 1589, 1549, 1544, 1490, 1463, 1412, 1320, 1278, 1180, 819, 808, 723, 666 cm−1; MS (ESI) m/z 453.7 (M+H)+, 452.8 (M−H)−; Anal. Calcd for C17H13ClIN3O2: C, 45.01; H, 2.89; N, 9.26; Found: C, 44.63; H, 2.98; N, 8.91.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[N:13]=[CH:12][N:11]=2.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][CH:18]1[CH2:23][CH2:22][N:21]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:20][CH2:19]1)[N:13]=[CH:12][N:11]=2
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(NC4CCNCC4)ncnc32)cc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(Nc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Reaction time: 16 h
Yield: 92 %

Procedure:
To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-(piperidin-4-yl)-9H-purin-6-amine (18.4 mg, 0.042 mmol, 1 eq.) in 2 mL of THF was added methanesulfonyl chloride (0.005 mL, 0.063 mmol, 1.5 eq.) and triethylamine (0.02 mL, 0.126 mmol, 3 eq.). The mixture was stirred for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 20 mg (91%) of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-(1-methanesulfonylpiperidin-4-yl)-9H-purin-6-amine. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.58-1.76 (m, 2 H) 2.21 (d, J=10.64 Hz, 2 H) 2.76 (s, 3 H) 2.90 (t, J=10.93 Hz, 2 H) 3.77 (d, J=12.15 Hz, 2 H) 4.33 (br. s., 1 H) 5.84 (br. s., 1 H) 7.04-7.51 (m, 8 H) 8.36 (s, 1 H), [M−H]− 515.7.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=1>C(#N)C.C(Cl)Cl>[N+:21]([C:20]1[C:15]([N:1]2[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=[CH:2]2)=[N:16][CH:17]=[CH:18][CH:19]=1)([O-:23])=[O:22]
Reactant: C1CNCCNC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: O=[N+]([O-])c1cccnc1N1C=CC=NC=C1
Reaction time: 4 h

Procedure:
Homopiperazine (15.58 g) is dissolved in 100 ml of acetonitrile. Potassium carbonate (8.7 g) is added and then the 2-chloro-3-nitropyridine (5.0 g) dissolved in 25 ml of acetonitrile is added dropwise. The reaction is stirred at 20°-25° 4 hr, then diluted with methylene chloride, washed with water (2 x), saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound, NMR (300 MHz, CDCl3) 8.30, 8.08, 6.66, 3.60, 3.41, 3.10, 2.89 and 1.93 δ.
Reaction SMILES: [F:1][CH:2]([F:8])[CH2:3][O:4]C(=O)C.[CH2:9]([NH2:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(NC(=O)C(F)F)CC>C(#N)C>[CH2:9]([NH:21][C:3](=[O:4])[CH:2]([F:1])[F:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCN
Reactant: CC(=O)OCC(F)F
Agent: CCCNC(=O)C(F)F
Solvent: CC#N
Product: CCCCCCCCCCCCNC(=O)C(F)F

Procedure:
One equivalent difluoroethylacetate and one equivalent dodecylamine stirred at room temperature in acetonitrile 16 hours. The solvent is removed to give a white wax, which is chromatographed on silica gel in CHCl3 /EtOAc (15:1), Rf =0.7. NMR (CDCl3, δ) 7.2 b-s (1H); 5.9 g (2H) J=26; 3.35 m (2H); 1.3 s (20H); 0.9 m (3H). Other compounds prepared this way, with similar NMR, acceptable Mass Spectra and TLC: N-propyl-difluoroacetamide.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[N:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[Br:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:17]2[CH:18]=[N:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[N:3][CH:4]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ncc(Br)cc2[N+](=O)[O-])cn1
Temperature: 90 °C
Reaction time: 19 h

Procedure:
A stirred mixture of 2,5-dibromo-3-nitropyridine (1.57 g, 5.57 mmol), 6-methoxypyridin-3-ylboronic acid (1.03 g, 6.73 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (0.2 g, 0.28 mmol), and 2.0M sodium carbonate (8.4 mL, 16.8 mmol) in 1,4-dioxane (27 mL) was heated to 90° C. After 19 h, the reaction was cooled to rt then diluted with water. After extraction with EtOAc, the organic extraction was dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified on silica gel (0-20% EtOAc in hexanes) to afford a light yellow solid as 5-bromo-6′-methoxy-3-nitro-2,3′-bipyridine. 1H NMR (400 MHz, CDCl3) δ ppm 8.92 (1H, d, J=2.2 Hz), 8.40 (1H, dd, J=2.5, 0.6 Hz), 8.32 (1H, d, J=2.2 Hz), 7.78 (1H, dd, J=8.6, 2.5 Hz), 6.85 (1H, dd, J=8.7, 0.7 Hz), 4.02 (3H, s).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[C:15]1[N:20]=[C:19]([O:21][CH:22]([CH3:24])[CH3:23])[C:18]([N+:25]([O-:27])=[O:26])=[CH:17][CH:16]=1.O>CS(C)=O>[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[CH:17][C:18]([N+:25]([O-:27])=[O:26])=[C:19]([O:21][CH:22]([CH3:24])[CH3:23])[N:20]=2)[CH2:10][CH2:9]1
Reactant: CC(C)Oc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)Oc1nc(N2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 105 °C
Yield: 73.4 %

Procedure:
463 mg of potassium carbonate and 224 mg of 1-methylpiperazine are added to a solution of 484 mg of 6-chloro-3-nitro-2-(propan-2-yloxy)pyridine in 4.45 ml of DMSO. The reaction medium is heated for 1 hour at 105° C. After cooling, the mixture is run into water and extracted with ethyl acetate. The organic phase is washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is taken up in diisopropyl ether and the insoluble material is filtered off and dried under vacuum, so as to give 460 mg of 1-methyl-4-[5-nitro-6-(propan-2-yloxy)pyridin-2-yl]piperazine in the form of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([SH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:12][C:13]([CH3:15])=O.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:13]([CH3:15])([CH3:12])[O:8][C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: O=C(O)c1cc(Cl)ccc1S
Reactant: CC(C)=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC1(C)OC(=O)c2cc(Cl)ccc2S1
Yield: 25.4 %

Procedure:
A mixture of 5-chloro-2-mercapto-benzoic acid (2.5 g, 13.25 mmol) (commercial available from Biogene Organics), acetone (7.9 g, 136 mmol), (+/−) camphor sulfonic acid (1.54 g, 6.63 mmol) and 4A moleculare sieves (1.5 g) in CHCl3 was heated to reflux for 3 days. Reaction mixture was diluted with CH2Cl2 (100 mL) and then washed with saturated NaHCO3 aqueous solution (2×50 mL). Organic layer was washed with brine, dried over MgSO4, filtered and concentrated. Crude residue was passed through a pad of silica gel and eluted with CH2Cl2. Filtrate was concentrated to provide the title compound (769 mg). 1H NMR (200 MHz, CDCl3): δ (ppm)=8.15 (d, J=2.4 Hz, 1H), 7.44 (dd, J=8.3, 2.0 Hz, 1H), 7.21 (d, J=8.3 Hz, 1H), 1.83 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[CH2:5][C:6]2=[O:11].[N+:13]([O-])([OH:15])=[O:14]>CCOCC>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[CH:5]([N+:13]([O-:15])=[O:14])[C:6]2=[O:11]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc2c1C(=O)CC2=O
Solvent: CCOCC
Product: Cc1cccc2c1C(=O)C([N+](=O)[O-])C2=O
Reaction time: 0.17 h

Procedure:
To a stirred suspension of 4-methyl-1,3-indane-dione (1.02 g. 0.006 mole) in anhydrous ether (5 ml) at ca 10°C was added dropwise and with stirring fuming nitric acid (2.0 ml). After 10 mins. a clear, dark solution formed followed by precipitation of a bright yellow N The mass was filtered and washed with 5N. hydrochloric acid. Recrystallization from water/hydrochloric acid afforded the title compound, m.p. 108°-9°C. (Found; C, 56.16; H, 3.74; N, 6.32; C10H7NO4.1 /2H2O requires; C, 56.07; H, 3.76; N, 6.54%).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[S:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.O1CCCC1.Cl>O.CO>[CH3:3][C:4]1[S:8][C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][OH:22])=[CH:23][CH:24]=1
Reactant: Cc1sc(-c2ccccc2)nc1COc1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
Sodium borohydride (0.38 g) was added to a mixture of 4-(5-methyl-2-phenyl-4-thiazolylmethoxy)benzaldehyde (6.00 g), tetrahydrofuran (30 ml) and methanol (20 ml) under ice-cooling, which was stirred at room temperature for 30 minutes. The reaction mixture was neutralized with dilute hydrochloric acid and water to give a precipitate, which was collected by filtration and air-dried to obtain crystals of 4-(5-methyl-2-phenyl-4-thiazolylmethoxy)benzyl alcohol (5.68 g, yield 94%). This was recrystallized from ethyl acetate-hexane to obtain colorless prisms. Melting point: 94–95° C.
Reaction SMILES: C1(C)C=CC=CC=1.[OH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=O)[CH:16]2[CH:14]([CH2:15]2)[C:13]1=O.O>C(OCC)C>[CH:14]12[CH2:15][CH:16]1[CH2:17][N:12]([CH2:11][CH2:10][CH2:9][OH:8])[CH2:13]2
Reactant: O=C1C2CC2C(=O)N1CCCO
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: OCCCN1CC2CC2C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 82.4 %

Procedure:
To a cold (0° C.) solution of sodium dihydro-bis(2-methoxyethoxy)aluminate in toluene (70% in mass, 2.43 mL, 4.5 eq.) was added 3-(3-hydroxy-propyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (example 5, step 1, 320 mg, 1.0 eq.) in diethyl ether (5 mL). The mixture was stirred 40 min at 0° C. and 4 h at reflux. Water was carefully added to and the white mixture was filtered on a dicalite pad. The filtrate was extracted with diethyl ether and the combined organic layers were dried over sodium sulfate, filtered and evaporated in vacuo, yielding 220 mg (78%) of the desired product as a purple liquid which was used without additional purification. MS (m/e): 143.1 (MH+, 100%).
Reaction SMILES: CO[CH:3]=[C:4]1[C:9](=[O:10])[O:8][C:7]([CH3:12])([CH3:11])[O:6][C:5]1=[O:13].[NH2:14][C:15]1[CH2:20][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:18][C:17](=[O:27])[CH:16]=1>C(#N)C>[CH3:12][C:7]1([CH3:11])[O:6][C:5](=[O:13])[C:4](=[CH:3][NH:14][C:15]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:18][C:17](=[O:27])[CH:16]=2)[C:9](=[O:10])[O:8]1
Reactant: NC1=CC(=O)CC(c2ccccc2)C1
Reactant: COC=C1C(=O)OC(C)(C)OC1=O
Solvent: CC#N
Product: CC1(C)OC(=O)C(=CNC2=CC(=O)CC(c3ccccc3)C2)C(=O)O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.4 %

Procedure:
To a solution of 5-methoxymethylene-2,2-dimethyl-[1,3]dioxane-4,6-dione (1.8 g) in acetonitrile (15 ml) was added 1-amino-5-phenylcyclohexen-3-one (2.0 g), and the mixture was stirred at room temperature for 24 hours. The resulting crystals were filtered and washed with acetonitrile to give crystals of 2,2-dimethyl-5-[(3-oxo-5-phenyl-1-cyclohexenylamino)methylene]-[1,3]dioxane-4,6-dione (1.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([OH:25])=O.O.Cl.Cl.[NH2:40][CH2:41][C:42]1[NH:43][C:44]2[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=2[N:46]=1>>[NH:43]1[C:44]2[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=2[N:46]=[C:42]1[CH2:41][NH:40][C:23](=[O:25])[CH:22]([N:8]1[CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[CH:7]1[CH2:6][C:5]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: NCc1nc2ccccc2[nH]1
Agent: Cl
Solvent: O
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCc2nc3ccccc3[nH]2)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 2-aminomethyl-benzimidazole dihydrochloride hydrate.
Reaction SMILES: [C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[C:21]([CH3:30])[C:20]=1[CH:31]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:47]CCCl>>[Cl:47][N:22]1[C:21]([CH2:30][N:14]2[CH2:13][CH2:12][C:11]3([N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:8][NH:9][C:10]3=[O:17])[CH2:16][CH2:15]2)=[C:20]([CH3:31])[CH2:19][N:23]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: ClCCCl
Reactant: Cc1nn(-c2ccccc2)c(Cl)c1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC1=C(CN2CCC3(CC2)C(=O)NCN3c2ccccc2)N(Cl)N(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Phenyl-1,3,8-triazaspiro[4.5]decan-4-one (0.050 g, 0.216 mmol), 5-chloro-3-methyl-1-phenylpyrazole-4-carboxaldehyde (0.042 g, 0.216 mmol), and sodium triacetoxyborohydride (0.039 g, 0.216 mmol) were combined in dry 1,2-dichloroethane (10 mL). The reaction was stirred overnight at room temperature. The mixture was concentrated to about 1 mL and the residue was purified by preparative thin layer chromatography to yield the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18][CH3:19])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N(CC)CC)C.Cl.[NH2:28][C@@H:29]1[CH2:34][CH2:33][C@H:32]([OH:35])[CH2:31][CH2:30]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[NH3:4].[F:1][C:2]1[CH:3]=[N:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18][CH3:19])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH:28][C@H:29]1[CH2:34][CH2:33][C@@H:32]([OH:35])[CH2:31][CH2:30]1)=[O:9]
Reactant: N[C@H]1CC[C@@H](O)CC1
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](O)CC2)c1
Product: N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-Fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (100 mg, 0.358 mmol) was dissolved in dimethylformamide (2 ml) and triethylamine (150 mg, 1.07 mmol) was added followed by cis-4-aminocyclohexanol hydrochloride (54 mg, 0.358 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (76 mg, 0.394 mmol) and 1-hydroxybenzotriazole (53 mg, 0.394 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (2×10 ml). The combined organic extracts were washed with water (2×3 ml), brine (3 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:concentrated aqueous ammonia (98:2:0.2, by volume) to give 5-fluoro-N-(cis-4-hydroxy-cyclohexyl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide (110 mg) as a white foam.
Reaction SMILES: C([O:3][C:4](=[O:14])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH2:13][CH:12]=1)C.[CH:15]([NH2:18])([CH3:17])[CH3:16]>CCOCC>[CH:15]([NH2:18])([CH3:17])[CH3:16].[C:11]1([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:14])=[O:3])[CH2:12][CH:13]=1
Reactant: CCOC(=O)CCCCCCC1=CC1
Solvent: CC(C)N
Solvent: CCOCC
Product: O=C(O)CCCCCCC1=CC1

Procedure:
A solution of 7-cycloprop-1-enyl-heptanoic acid ethyl ester in 5 ml of ether was treated with 0.1 g of isopropyl amine at room temperature. The solvent was stripped to give 40 mg of 7-cycloprop-1-enyl-heptanoic acid isopropylamine salt.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16]([C:17]([O:19]CC)=[O:18])=[C:15]([S:22][CH:23]3[CH2:28][CH2:27][CH:26]([CH2:29][C:30]([O:32]CC)=[O:31])[CH2:25][CH2:24]3)[N:14]=[C:13]2[CH2:35][CH2:36][CH3:37])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.O1CCCC1>C(O)C>[C:30]([CH2:29][CH:26]1[CH2:25][CH2:24][CH:23]([S:22][C:15]2[N:14]=[C:13]([CH2:35][CH2:36][CH3:37])[N:12]([CH2:11][C:3]3[C:2]([Cl:1])=[CH:10][C:6]4[O:7][CH2:8][O:9][C:5]=4[CH:4]=3)[C:16]=2[C:17]([OH:19])=[O:18])[CH2:28][CH2:27]1)([OH:32])=[O:31]
Reactant: CCCc1nc(SC2CCC(CC(=O)OCC)CC2)c(C(=O)OCC)n1Cc1cc2c(cc1Cl)OCO2
Solvent: CCO
Solvent: C1CCOC1
Product: CCCc1nc(SC2CCC(CC(=O)O)CC2)c(C(=O)O)n1Cc1cc2c(cc1Cl)OCO2
Reaction time: 24 h
Yield: 71.8 %

Procedure:
760 mg of the product of Example 1 is introduced into 20 ml of tetrahydrofuran, 50 ml of ethanol and 25 ml of 2N soda are added and the whole is left for 24 hours at ambient temperature. The tetrahydrofuran and the ethanol are evaporated off then the reaction medium is acidified to pH 1. After extraction with ethyl acetate and evaporating to dryness, the residue is recrystallized from ethanol. 490 mg of expected product is obtained. M.p.=166° C.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[C:17]([CH:19]2[C:28]3[C:27](=[O:29])[CH2:26][CH:25]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:24][C:23]=3[NH:22][C:21]([CH3:36])=[C:20]2[C:37]#[N:38])[CH:16]=[C:15]([O:39][CH3:40])[C:3]=1[O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](O)=[O:10].CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[S:61]1[CH:65]=[CH:64][CH:63]=[C:62]1[CH2:66][NH2:67]>ClCCl>[Br:1][C:2]1[CH:18]=[C:17]([CH:19]2[C:28]3[C:27](=[O:29])[CH2:26][CH:25]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:24][C:23]=3[NH:22][C:21]([CH3:36])=[C:20]2[C:37]#[N:38])[CH:16]=[C:15]([O:39][CH3:40])[C:3]=1[O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:67][CH2:66][C:62]1[S:61][CH:65]=[CH:64][CH:63]=1)=[O:10]
Reactant: NCc1cccs1
Reactant: COc1cc(C2C(C#N)=C(C)NC3=C2C(=O)CC(c2ccccc2)C3)cc(Br)c1OCc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C2C(C#N)=C(C)NC3=C2C(=O)CC(c2ccccc2)C3)cc(Br)c1OCc1cccc(C(=O)NCc2cccs2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the product of step b (20 mg) in 2 mL of dichloromethane were added EDCI (7.0 mg), DIPEA (7 μL) and 2-thiophenemethylamine (4.1 μL) and the reaction mixture was stirred for 3 h. at room temperature. The reaction mixture was concentrated and the title compound was obtained after flash column chromatography (silica gel, heptane/ethyl acetate (1/4, v/v), Rf=0.78).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:11])=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[NH2:12][C:13]1[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16].[ClH:23].Cl.[C:25](=N)(OCC)[CH2:26][C:27](=N)OCC.C(O)(=O)C>Cl>[ClH:23].[ClH:23].[NH2:10][C:6]1[C:5]2[N:11]=[C:25]([CH2:26][C:27]3[NH:22][C:21]4[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([OH:17])=[O:16])[C:13]=4[N:12]=3)[NH:1][C:4]=2[CH:9]=[CH:8][CH:7]=1
Reactant: Nc1cccc([N+](=O)[O-])c1N
Reactant: CCOC(=N)CC(=N)OCC
Reactant: Nc1cccc(C(=O)O)c1N
Agent: Cl
Solvent: CC(=O)O
Product: Nc1cccc2[nH]c(Cc3nc4c(C(=O)O)cccc4[nH]3)nc12
Yield: 15 %

Procedure:
The following components were reacted according to General Procedure 1, above: 3-nitro-1,2-phenylenediamine (0.50 g; 3.26 mmoles) 2,3-diaminobenzoic acid (0.40 g; 3.26 mmoles), diethyl malonimidate dihydrochloride (1.1 eq.; 0.83 g; 3.60 mmoles) and acetic acid (25 mL). The crude mixture of three compounds was then reduced according to General Procedure 2, above. The crude solid was taken up in 10 mL of dilute HCl, purified by preparative HPLC (2 to 40% acetonitrile (with 0.1% TFA) over 60 minutes) and converted to the HCl salt by three freeze drying cycles with dilute HCl. This procedure gave 0.103 g of pure 2-[(4-amino-1H-benzimidazol-2-yl)methyl]-1H-benzimidazole-4-carboxylic acid dihydrochloride in 8% yield. It had MS: m/z=308.2 [M+1] amu and gave one peak on HPLC at both 210 and 280 nm (10.20 minutes using the JWTFACN gradient).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=4)=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[CH:34]1([CH2:37][NH2:38])[CH2:36][CH2:35]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.CO>[CH:34]1([CH2:37][NH:38][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([C:21]3[CH:20]=[CH:19][C:18]4[N:14]([C:10]5[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:32])([F:33])[F:1])=[O:6])[CH:9]=5)[CH:15]=[N:16][C:17]=4[CH:22]=3)=[CH:24][CH:25]=2)[CH2:36][CH2:35]1
Reactant: NCC1CC1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4ccc(C(=O)O)cc4)ccc32)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4ccc(C(=O)NCC5CC5)cc4)ccc32)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]-1H-benzimidazol-5-yl}benzoic acid (20.0 mg, 0.0440 mmol) and cyclopropylmethylamine (6.3 mg, 0.088 mmol, Aldrich, Cat. No. 359521) in N,N-dimethylformamide (1 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (23 mg, 0.053 mmol, Adv. ChemTech. Cat. No. RC8105) and N,N-diisopropylethylamine (23 μL, 0.13 mmol). The reaction mixture was stirred at r.t. for 2 h, then diluted with MeOH, and purified by RP-HPLC (pH=10) to afford the desired compound. LCMS (M+H)+: m/z=508.2.