Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCO.[NH2:4][N:5]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[C:6]1[C:12]#[N:13].C(O)(=O)C.[CH:18](N)=[NH:19].C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O>[NH2:13][C:12]1[C:6]2=[CH:7][C:8]([C:10]#[N:11])=[CH:9][N:5]2[N:4]=[CH:18][N:19]=1
Reactant: N#Cc1cc(C#N)n(N)c1
Reactant: N=CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: N#Cc1cc2c(N)ncnn2c1
Temperature: 80 °C
Yield: 75.3 %

Procedure:
To a solution of EtOH (50 mL) was added 1-amino-1H-pyrrole-2,4-dicarbonitrile (1.00 g, 7.57 mmol) followed by formamidine acetate (9.46 g, 90.8 mmol) and potassium carbonate (14.6 g, 106.0 mmol). The solution was heated to 80° C. for 2 h. Upon cooling to rt, the reaction mixture was diluted with EtOAc transferred to a separatory funnel and washed with water. The organic layer was collected, dried (MgSO4), filtered, and concentrated to dryness. The crude material was then triturated with EtOH-water. The solid was collected, washed with water, and dried under vacuum to afford 0.91 g of the above compound as a yellow-orange solid (5.70 mmol, yield 75%). 1H-NMR (DMSO-d6) δ 8.37 (d, J=1.8 Hz, 1H), 8.19 (d, J=17.4, 2H), 7.93 (s, 1H), 7.27 (d, J=1.8 Hz, 1H); LCMS RT=1.14 min.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([S:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=2)=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:48][CH2:49][C:50]([N:52]1[CH2:57][CH2:56][N:55]([C:58](=[O:69])[C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]([F:68])([F:67])[F:66])[CH2:54][CH2:53]1)=[O:51].C(O)(C(F)(F)F)=O>CN(C=O)C.O>[C:10]1([S:16]([C:18]2[CH:19]=[CH:20][C:21]([C:22]([NH:48][CH2:49][C:50](=[O:51])[N:52]3[CH2:53][CH2:54][N:55]([C:58](=[O:69])[C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=4[C:65]([F:66])([F:68])[F:67])[CH2:56][CH2:57]3)=[O:24])=[CH:25][CH:26]=2)=[O:17])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1ccc(S(=O)c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(S(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
DIPEA (0.084 mL, 0.49 mmol) was added drop wise to 4-benzenesulfinyl-benzoic acid (48 mg, 0.19 mmol) in DMF (4 mL). EDCI (78 mg, 0.41 mmol) and HOBT 26 mg, 0.19 mmol) were added consecutively and 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone in its TFA salt form (70 mg, 0.16 mmol) was added after a further 10 mins. The resulting mixture was allowed to stir at room temperature overnight. Water was then added and the product was extracted with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford a crude product. Purification by column chromatography (using silica gel with a mesh size of 60-120 and 100% EtOAc as eluent) afforded 45 mg (51% yield) of 4-benzenesulfinyl-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide. LC-MS purity: 91.93%. 1H NMR (DMSO-D6): δ 8.7 (t, 1H), 8 (m, 3H), 7.8 (m, 6H), 7.5 (m, 3H), 7.2 (m, 1H), 4.2 (d, 2H), 3.6 (m, 6H), 3.1 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:15]=[CH:14][N:13]=2)[C:7]([CH3:10])=[N:8][CH:9]=1)([O-])=O.O.NN>C(O)C.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:15]=[CH:14][N:13]=2)[C:7]([CH3:10])=[N:8][CH:9]=1
Reactant: Cc1ncc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1ncc(N)cc1Nc1nccc(-c2cccnc2)n1
Yield: 92.3 %

Procedure:
To a stirred solution of N-(5-nitro-2-methylpyrid-3-yl)-4-(pyrid-3-yl)-2-pyrimidinamine (18.0 g) and hydrazine hydrate (9 mL) in ethanol (180 mL) was added activated nickel (0. g). The mixture was refluxed for 3 hours, filtrated and the filtrate was concentrated in vacuo to give solid, which was put in the fridge (0° C.) overnight. The residue was filtrated off and the filtrate was concentrated in vacuo to give N-(5-amino-2-methylpyrid-3-yl)-4-(pyrid-3-yl)-2-pyrimidinamine (15 g).
Reaction SMILES: [F:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=O.Cl.[CH3:22][O:23][NH2:24]>S(Cl)(Cl)=O>[F:18][C:17]([F:20])([F:19])[S:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([C:2]([F:1])([CH3:6])[C:3]([NH:24][O:23][CH3:22])=[O:5])=[CH:8][CH:9]=1)(=[O:16])=[O:15]
Reactant: CON
Reactant: CC(F)(C(=O)O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CONC(=O)C(C)(F)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
A suspension of 1 (0.5 gr, 1.6 mmol) in thionyl chloride (5 mL) was refluxed for 3 h. After cooling at room temperature, thionyl chloride was evaporated under vacuum and the crude acyl chloride was diluted in dry CH2Cl2 (5 mL) and cooled at T=0° C. by ice-water bath. Methoxyamine hydrochloride (0.27 g, 3.2 mmol) was added portionwise. The ice-water bath was removed and the reaction mixture was left stirring at room temperature. After complete disappearance of the starting material (TLC) a buffer solution (pH=2.0) (V=10 ml) was added, the two phases trasferred into a separator funnel and separated and the organic one was washed with brine (3×10 mL), dried over Na2SO4 and evaporated under vacuum to give pure 11 as pale yellow oil (0.47 gr, yield 85%). 1H-NMR (CDCl3) δ 9.05 (bs, 1H, CONH), 7.70 (d, 2H, J=7 Hz), 7.30 (d, 2H, J=7 Hz), 3.80 (s, 3H), 1.95 (d, 3H, J=23 Hz).
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[N:16]1([C:2]2[CH:15]=[CH:14][C:5]([C:6]([C:8]3[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=3)=[O:7])=[CH:4][CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C1CCNCC1
Reactant: O=C(c1ccncc1)c1ccc(F)cc1
Product: O=C(c1ccncc1)c1ccc(N2CCCCC2)cc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture consisting of 4.76 g of 4-(4-fluorobenzoyl)pyridine and 9.8 ml of piperidine was stirred at 100° C. for 24 hours and the reaction mixture was then worked up in the same manner as Example 3 to give 5.3 g of the title compound as yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[O:9])[CH:4]=[C:3]1[C:22](O)=[O:23].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[N:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH3:1][N:2]1[C:3]([C:22]([N:56]2[CH2:57][CH2:58][N:53]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][N:47]=3)[CH2:54][CH2:55]2)=[O:23])=[CH:4][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]([F:20])([F:21])[F:19])=[CH:15][CH:16]=2)=[O:9])=[CH:6]1
Reactant: Cn1cc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)cc1C(=O)O
Reactant: c1ccc(N2CCNCC2)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cn1cc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)cc1C(=O)N1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.15 mmol) of 1-methyl-4[({[4-(trifluoromethoxy)phenyl]amino}carbonyl)amino]-1H-pyrrole-2-carboxylic acid (Example 5A) are initially charged in 1 ml of DMF, and 56 mg (0.18 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) and 8.9 mg (0.07 mmol) of 4-(dimethylamino)pyridine (DMAP) are added. 29 mg (0.18 mmol) of 1-(2-pyridyl)piperazine are then added, and the mixture is stirred at RT for 8 h. The reaction solution is purified by RP-HPLC (acetonitrile/water). This gives a solid.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[N:14]=[C:13]([C:15]([NH:17][C:18]3[NH:22][C:21]4[CH:23]=[CH:24][CH:25]=[C:26]([C:27](O)=[O:28])[C:20]=4[N:19]=3)=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[CH3:64][S:65]([C:68]1[CH:75]=[CH:74][C:71]([CH2:72][NH2:73])=[CH:70][CH:69]=1)(=[O:67])=[O:66]>CN(C=O)C>[CH3:64][S:65]([C:68]1[CH:75]=[CH:74][C:71]([CH2:72][NH:73][C:27]([C:26]2[C:20]3[N:19]=[C:18]([NH:17][C:15]([C:13]4[CH:12]=[CH:11][CH:10]=[C:9]([C:8]#[C:7][C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:14]=4)=[O:16])[NH:22][C:21]=3[CH:23]=[CH:24][CH:25]=2)=[O:28])=[CH:70][CH:69]=1)(=[O:66])=[O:67]
Reactant: O=C(Nc1nc2c(C(=O)O)cccc2[nH]1)c1cccc(C#Cc2ccccc2)n1
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(CNC(=O)c2cccc3[nH]c(NC(=O)c4cccc(C#Cc5ccccc5)n4)nc23)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.6 %

Procedure:
To a solution of 30 mg (0.07 mmol) of above 2-[(6-Phenylethynyl-pyridine-2-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid in DMF (1 mL) was added 40 mg (0.1 mmol) of HBTU and DIEA (0.1 mL), the resulting mixture was stirred at room temperature for 10 min, then 40 mg (0.1 mmol) of 4-methanesulfonyl-benzylamine HCl salt was added. After usual work up as described in general procedure A, 21 mg (48%) of 2-[(6-phenylethynyl-pyridine-2-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid 4-methanesulfonyl-benzylamide was obtained after column chromatography purification eluting with DCM/EtOAc (v/v from 5:1 to 1:1). LCMS: 550 (M+1)+.
Reaction SMILES: [Na+:1].[NH2:2][C:3]1[S:4][CH:5]=[C:6](/[C:8](=[N:26]/[O:27][CH2:28][C:29]([O:31]CC2C=CC([N+]([O-])=O)=CC=2)=[O:30])/[C:9]([NH:11][C@H:12]2[C@@H:15]([CH2:16][O:17][C:18](=[O:20])[NH2:19])[N:14]([S:21]([O-:24])(=[O:23])=[O:22])[C:13]2=[O:25])=[O:10])[N:7]=1>CO.[Pd]>[Na+:1].[NH2:2][C:3]1[S:4][CH:5]=[C:6](/[C:8](=[N:26]/[O:27][CH2:28][C:29]([OH:31])=[O:30])/[C:9]([NH:11][C@H:12]2[C@@H:15]([CH2:16][O:17][C:18](=[O:20])[NH2:19])[N:14]([S:21]([O-:24])(=[O:22])=[O:23])[C:13]2=[O:25])=[O:10])[N:7]=1
Reactant: NC(=O)OC[C@@H]1[C@H](NC(=O)/C(=N\OCC(=O)OCc2ccc([N+](=O)[O-])cc2)c2csc(N)n2)C(=O)N1S(=O)(=O)[O-]
Agent: [Pd]
Agent: [Na+]
Solvent: CO
Product: NC(=O)OC[C@@H]1[C@H](NC(=O)/C(=N\OCC(=O)O)c2csc(N)n2)C(=O)N1S(=O)(=O)[O-]
Yield: 54.8 %

Procedure:
270 mg (0.43 mmol) of (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(p-nitrobenzyloxycarbonyl)methoxyimino]acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid sodium salt are dissolved in 30 ml of methanol and hydrogenated over 5% palladium on infusorial earth (150 mg). The catalyst is filtered off and the solvent is evaporated. The residue is taken up in 2.5 ml of water and washed twice with ethyl acetate. The aqueous phase is chromatographed (reverse-phase, water as the elution agent). There are obtained 115 mg (54%) of (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(carboxymethoxy)imino]acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid sodium salt.
Reaction SMILES: [S:1]1[C:5]([NH:6][S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][N:19](C(=O)C(F)(F)F)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[N:4][CH:3]=[N:2]1.[OH-].[Na+].Cl>O>[NH:19]1[CH2:18][CH2:17][CH:16]([C:13]2[CH:14]=[CH:15][C:10]([S:7]([NH:6][C:5]3[S:1][N:2]=[CH:3][N:4]=3)(=[O:9])=[O:8])=[CH:11][CH:12]=2)[CH2:21][CH2:20]1
Reactant: O=C(N1CCC(c2ccc(S(=O)(=O)Nc3ncns3)cc2)CC1)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(Nc1ncns1)c1ccc(C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Prepared using general procedure 16. A mixture of N-(1,2,4-thiadiazol-5-yl)-4-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzenesulfonamide (2.0 g, 4.8 mmol), NaOH (1.92 g, 48.0 mmol), and H2O (25 mL) was stirred at RT for 30 minutes. An aqueous 1.0 N HCl solution was added (48.0 mL, 48 mmol), and the mixture was azeotroped with MeOH (3×100 mL). A 9:1 solution of CH2Cl2 and MeOH (100 mL) was added, and the mixture was filtered to remove NaCl. The filtrate was concentrated under reduced pressure to give 4-(piperidin-4-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide as a clear oil which solidified upon standing (1.5 g, 96%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=325.3; tR=0.99 min.
Reaction SMILES: O=[C:2]1[NH:7][N:6]=[C:5]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH2:10][CH2:11][CH2:12][C:4]2=[CH:3]1.O(Cl)[Cl:18].[P+3]>>[Cl:18][C:2]1[N:7]=[N:6][C:5]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH2:10][CH2:11][CH2:12][C:4]=2[CH:3]=1
Reactant: ClOCl
Reactant: O=c1cc2c(n[nH]1)-c1ccccc1CCC2
Agent: [P+3]
Product: Clc1cc2c(nn1)-c1ccccc1CCC2

Procedure:
Alternatively, 3-Oxo-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine was heated with 20 mL of phosphorus (III) oxychloride at 100° C. for 4.75 h. The solvent was removed under vacuum. The residue was treated with ice and saturated sodium bicarbonate solution. The solid which formed was filtered off, washed well with water and air-dried to yield the corresponding 3-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (1.6 g); 1H NMR (CDCl3, 300 MHz) 7.82 (m, 1H), 7.44 (m, 2H), 7.39 (s, 1H), 7.27 (m, 1H), 2.55 (m, 4H), 2.32 (m, 2H) ppm; MS (ES) 231/233 (M+H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[F:20]>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])=[CH:15][C:14]=1[F:20]
Reactant: Oc1ccc(Cl)c(F)c1
Reactant: N#Cc1cc(C=O)ccc1F
Product: N#Cc1cc(C=O)ccc1Oc1ccc(Cl)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 4-chloro-3-fluorophenol.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[O:5].Cl.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>>[N:23]1[CH:24]=[CH:25][C:20]([C:19]([NH:1][C:2]2[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=2[C:4]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[O:5])=[O:26])=[CH:21][CH:22]=1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Product: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cc1)c1ccncc1
Yield: 90.7 %

Procedure:
Using the procedure described in Example 93, Part A, 2-amino-N-(4-chlorophenyl)benzamide (5 g, 20.3 mmol) and isonicotinoyl chloride hydrochloride (3.97 g, 22.3 mmol) yielded 6.48 g (91%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1>[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(/C=C/c2ccc(F)cc2)cc1
Agent: [Pd]
Product: Nc1ccc(CCc2ccc(F)cc2)cc1

Procedure:
In an analogous manner to that described in Example 36b), the hydrogenation of (E)-1-fluoro-4-[2-(4-nitrophenyl)ethenyl]-benzene [Example 39a)] using palladium on carbon (10%) as the catalyst yields the 4-[2-(4-fluoro-phenyl)-ethyl]-phenylamine as a light red solid; MS: m/e=216 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O.C(OCC)(=O)C>[CH:36]([C:33]1[CH:34]=[CH:35][C:27]2[C:26]([NH:25][C:17]3[CH:18]=[C:19]([C:20]([N:39]4[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]4)=[O:22])[CH:23]=[CH:24][C:16]=3[S:15][C:12]3[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:10][CH:11]=3)=[N:31][CH:30]=[N:29][C:28]=2[N:32]=1)([CH3:38])[CH3:37]
Reactant: C1CNCCN1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)c1ccc2c(Nc3cc(C(=O)N4CCNCC4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Temperature: 25 °C
Yield: 133 %

Procedure:
To a solution of the product from Example 1E (100 mg, 0.188 mmol) in DMSO (2.0 mL) were added piperazine (16 mg, 0.188 mmol), HATU (79 mg, 0.207 mmol) and Hunigs base (100 μL, 0.564 mmol) and the mixture was stirred at room temperature until the starting material was consumed. Additional product from Example 1E (100 mg, 0.188 mmol), HATU (79 mg, 0.212 mmol), and Hunigs base (100 μL, 0.564 mmol), were added and the reaction was stirred for 2 hours. The reaction was diluted with ethyl acetate and washed water. Dried over Na2SO4, filtered and evaporated. Purification by chromatography on silica gel eluting with (10% methanol in dichloromethane) gave the title compound (150 mg) as a yellow solid.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6].[CH3:16]O>>[OH:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[C:5]([CH2:7][CH2:8][C:9]([O:11][CH3:16])=[O:10])=[O:6]
Reactant: CO
Reactant: O=C(O)CCC(=O)c1ccccc1O
Agent: Cl
Product: COC(=O)CCC(=O)c1ccccc1O
Temperature: 0 °C
Yield: 98 %

Procedure:
Hydrogen chloride was bubbled into a gently boiling solution of the known 3-(2-hydroxybenzoyl)propionic acid (10 g, 0.05 mole) in dry methanol (20 ml) until esterification was complete. The solution was poured into ice-water and the ester extracted into dichloromethane. The organic solution was washed with water and evaporated to give methyl 3-(2-hydroxybenzoyl)propionate (10.55 g, 98%) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:10]2)=[CH:5][CH:4]=1.CCN(CC)CC.[Cl:24][CH2:25][C:26](Cl)=[O:27].[OH-].[Na+]>C(Cl)Cl>[Cl:24][CH2:25][C:26]([N:13]([CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:10]1)[CH2:14][CH2:15][CH3:16])=[O:27]
Reactant: O=C(Cl)CCl
Reactant: CCCNC1CCc2ccc(OC)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(C(=O)CCl)C1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.4 %

Procedure:
Compound 32a (HCl salt, 5.0 g, 19.5 mmol) and Et3N (5.5 ml, 39.1 mmol) was stirred at 0° C. in CH2Cl2 (65 ml) for 15 min. Chloroacetyl chloride (1.9 ml, 23.5 mmol) was added dropwise and the resulting solution was stirred at room temperature for 20 min, at which time the reaction mixture was poured into a 1M solution of NaOH (50 ml) and the product was extracted with dichloromethane, dried (Na2SO4), filtered, and concentrated. The crude material was purified by column chromatography (Hex:EtOAc, 3:1) to give 5.5 g (95%) of 33a. 1H NMR (400 MHz, CDCl3) 0.90-0.98 (m, 3H), 1.64-1.72 (m, 2H), 3.19-3.27 (m, 2H), 4.00 (s, 3H), 6.61-6.62 (dd, 1H, J=1.6 Hz), 6.64-6.77 (m, 1H), 6.96-6.99 (d, 1H, J=8.8 Hz).
Reaction SMILES: [CH:1]1([N:4]2[CH:8]=[CH:7][N:6]=[CH:5]2)[CH2:3][CH2:2]1.[Br:9]N1C(C)(C)C(=O)N(Br)C1=O>C(Cl)Cl>[Br:9][C:8]1[N:4]([CH:1]2[CH2:3][CH2:2]2)[CH:5]=[N:6][CH:7]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: c1cn(C2CC2)cn1
Solvent: ClCCl
Product: Brc1cncn1C1CC1
Temperature: 7.5 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
Cyclopropyl-1H-imidazole (1.18 g, 10.9 mmol) was dissolved in methylene chloride (0.1 M), cooled to 5-10° C., and 1,3-dibromo-5,5-dimethylhydantoin (1.59 g, 5.57 mmol) was added. The temperature was maintained between 5-10° C. and the reaction was stirred for 2 hours. Solvent was removed from the reaction mixture under reduced pressure, and the residue was purified by column chromatography (eluting with 1%-7% methanol in methylene chloride, 5% methanol/methylene chloride) to afford 620 mg (37% yield) of 5-bromo-1-cyclopropyl-1H-imidazole.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:5]2=[C:4]([N+]([O-])=O)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[OH:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH:31]=[CH:32][CH:33]=[C:34]2[C:39]([OH:41])=[O:40].Cl>CS(C)=O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:5]2=[C:4]([O:28][C:29]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:30]=2[CH:31]=[CH:32][CH:33]=[C:34]3[C:39]([OH:41])=[O:40])[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c([N+](=O)[O-])cc(Cl)nc21
Reactant: O=C(O)c1cccc2c(O)cccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[Si](C)(C)CCOCn1ccc2c(Oc3cccc4c(C(=O)O)cccc34)cc(Cl)nc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
To a solution of 6-chloro-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (400 mg, 1.22 mmol) in DMSO (4 mL) were added K2CO3 (507 mg, 3.67 mmol) and 5-hydroxy-1-naphthoic acid (230 mg, 1.22 mmol). The reaction mixture was stirred for overnight at 100° C. after which, It was cooled to room temperature. To the reaction mixture was added 1N HCl solution to reach pH=5. The produced solid was filtered and dried nitrogen gas flow. The title compound (380 mg, 66% yield) was used next reaction without further purification. MS m/z: 469 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([OH:25])=O)=[CH:14][C:12]=2[N:13]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[F:56][C:57]([F:67])([F:66])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[CH2:64][NH2:65]>C1COCC1.CN(C=O)C>[Cl:26][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([NH:65][CH2:64][C:59]3[CH:60]=[CH:61][CH:62]=[CH:63][C:58]=3[C:57]([F:56])([F:66])[F:67])=[O:25])=[CH:14][C:12]=2[N:13]=1
Reactant: NCc1ccccc1C(F)(F)F
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC1(C)Cc2c(c(C(=O)NCc3ccccc3C(F)(F)F)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Yield: 21.5 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-3, 0.050 g, 0.127 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.082 g, 0.255 mmol), N-methyl morpholine (0.5 mL), DMF (1.0 mL), THF (5.0 mL) and 1-[2-(trifluoromethyl)phenyl]methanamine (Intermediate-4, 0.027 g, 0.154 mmol) to afford 0.015 g of the desired product. 1HNMR (DMSO-d6): δ 1.21 (s, 3H), 1.48 (s, 3H), 3.01 (s, 2H), 4.68 (m, 2H), 7.19 (s, 1H), 7.46-7.51 (m, 2H), 7.62 (d, J=7.8 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 8.27 (m, 1H), 8.41 (s, 2H), 10.89 (s, 1H), 11.42 (s, 1H); MS [M+H]+: 550.31.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH2:19])[CH:13]([CH3:15])[CH3:14]>>[CH2:12]([O:16][C:17](=[O:21])[CH:18]([CH3:20])[NH:19][C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)COC(=O)[C@H](C)N
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Product: CC(C)COC(=O)C(C)NC(=O)Cc1ccccc1

Procedure:
Following General Procedure BA above and using phenylacetyl chloride (Aldrich) and D, L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.