Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8](F)=[CH:7][C:6]=1[CH3:15])[CH3:3].[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:15][C:6]1[C:5]([O:4][CH:2]([CH3:3])[CH3:1])=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]([NH:16][CH:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1OC(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1OC(C)C
Temperature: 80 °C
Yield: 37.7 %

Procedure:
A solution of 4-fluoro-2-methyl-5-nitrophenyl 1-methylethyl ether (D73) (0.53 mmol, 115 mg) in dimethylformamide (3 mL) was treated with 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (0.53 mmol, 106 mg, 1 eq) and diisopropylethylamine (0.53 mmol, 68.5 mg, 1 eq) under argon at room temperature and then heated at 80° C. overnight. The mixture was then concentrated under reduced pressure, then treated with 10% aqueous sodium carbonate solution and extracted with ether/ethyl acetate. The organics were dried, concentrated under reduced pressure and purified by chromatography on silica (ethyl acetate/petrol ether) to give the title compound as a solid (0.2 mmol, 80 mg, 39% yield). M+H 338.1 for main fragment (loss of tert-butyl group).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1.[CH3:20]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH3:20])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2cc(Br)cnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cn(COCC[Si](C)(C)C)c2ncc(Br)cc12
Temperature: 90 °C
Yield: 2.9 %

Procedure:
A mixture of 5-bromo-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (1.05 g, 2.33 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (2.6 mL, 18.6 mmol), and potassium carbonate (0.97 g, 7.0 mmol) in 10% aqueous dioxane (19 mL) was sparged with Ar. Pd(PPh3)4 (134 mg, 0.12 mmol) was added and the reaction was sealed and heated to 90° C. for 6.5 h. The reaction was allowed to cool to rt and concentrated in vacuo. The remaining residue was dissolved in EtOAc (250 mL), washed sequentially with water (100 mL), aqueous 0.1 M HCl solution (150 mL), and brine (100 mL). The resulting solution was dried (Na2SO4) and concentrated. Purification by reverse phase HPLC yielded 23 mg of 5-bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine as the TFA salt: LCMS (m/z): 342.9 (MH+), tR=0.74 min
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[N:20]=[CH:19][C:18]([NH:21][C:22]([C:24]4[CH:25]=[CH:26][C:27]([C:34]5[C:39]([Cl:40])=[C:38]([O:41][CH3:42])[CH:37]=[C:36]([O:43][CH3:44])[C:35]=5[Cl:45])=[C:28]5[C:33]=4[N:32]=[CH:31][CH:30]=[CH:29]5)=[O:23])=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=CC=1>C(Cl)Cl.CO>[N:11]1([CH2:14][C:15]2[N:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[CH:25]=[CH:26][C:27]([C:34]4[C:39]([Cl:40])=[C:38]([O:41][CH3:42])[CH:37]=[C:36]([O:43][CH3:44])[C:35]=4[Cl:45])=[C:28]4[C:33]=3[N:32]=[CH:31][CH:30]=[CH:29]4)=[O:23])=[CH:17][CH:16]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COc1ccc(CN2CCN(Cc3ccc(NC(=O)c4ccc(-c5c(Cl)c(OC)cc(OC)c5Cl)c5cccnc45)cn3)CC2)cc1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCNCC4)nc3)c3ncccc23)c1Cl
Temperature: 120 °C
Reaction time: 1 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 105 but using 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (6-piperazin-1-ylmethyl-pyridin-3-yl)-amide (Example 170) and stirring the reaction mixture for 1 h at 120° C. Title compound: ESI-MS: 552.0 [M+H]+; tR=3.57 min (System 1); TLC: Rf=0.12 (DCM/MeOH, 9:1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:11]=[N:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=O)[O:5][C:6]=1[CH3:7].[NH3:18]>CO>[CH3:17][O:16][C:13]1[N:12]=[CH:11][C:10]([C:8]2[C:4]([OH:5])=[CH:3][C:2]([CH3:1])=[C:6]([CH3:7])[N:18]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(C(=O)c2cc(C)c(C)o2)cn1
Reactant: N
Solvent: CO
Product: COc1ccc(-c2nc(C)c(C)cc2O)cn1
Temperature: 160 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
(4,5-Dimethylfuran-2-yl)-(6-methoxypyridin-3-yl)-methanone (650 mg), methanol (6 ml), and a 28% aqueous ammonia solution (6 ml) were placed in a sealed tube and was stirred at 160° C. overnight. The reaction solution was cooled to room temperature, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-ethyl acetate to give 6′-methoxy-5,6-dimethyl-[2,3′]bipyridin-3-ol (109 mg, yield 86%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:33]=[CH:32][C:11]([CH2:12][N:13]2[C:21](=[O:22])[C:20]3[CH:19]=[CH:18][N:17]=[C:16]([C:23]([O:25]C4C=CC=CC=4)=O)[C:15]=3[CH2:14]2)=[CH:10][C:9]=1[CH3:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([NH2:37])[CH3:36]>>[CH2:35]([NH:37][C:23]([C:16]1[C:15]2[CH2:14][N:13]([CH2:12][C:11]3[CH:32]=[CH:33][C:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[C:9]([CH3:34])[CH:10]=3)[C:21](=[O:22])[C:20]=2[CH:19]=[CH:18][N:17]=1)=[O:25])[CH3:36]
Reactant: CCN
Reactant: Cc1cc(CN2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)ccc1C(=O)OC(C)(C)C
Product: CCNC(=O)c1nccc2c1CN(Cc1ccc(C(=O)OC(C)(C)C)c(C)c1)C2=O
Yield: 99 %

Procedure:
The title compound is prepared in >99% yield (260 mg, pale brown solid) from phenyl 2-(4-(tert-butoxycarbonyl)-3-methylbenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (270 mg, 0.59 mmol, Step-2) and ethylamine (0.14 mL, 1.8 mmol, 70% aqueous solution) in a similar manner to Example-435 (Method-G).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[N:4][C:5]([C:9]([Cl:12])([Cl:11])[Cl:10])=[N:6][C:7]=1[CH3:8].[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=O.C(N(CC)CC)C>C(OCC)C>[Cl:1][C:2]1[C:3]([O:13][CH2:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[F:14])=[N:4][C:5]([C:9]([Cl:10])([Cl:11])[Cl:12])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(C(Cl)(Cl)Cl)nc(O)c1Cl
Reactant: O=C(Cl)c1ccccc1F
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1nc(C(Cl)(Cl)Cl)nc(OCc2ccccc2F)c1Cl
Yield: 113.5 %

Procedure:
A solution of 5.8 g (0.02 mole) 5-chloro-4-hydroxy-6-methyl-2-trichloromethylpyrimidine, 3.2 g (0.02 mole) 2-fluorobenzoyl chloride, and 2.0 g (0.02 mole) triethylamine in 100 ml diethyl ether was refluxed for 17 hours. After removal of triethylamine hydrochloride by filtration, the filtrate was concentrated in-vacuo to leave 8.4 g of residue, which, after recrystallization from ligroin, gave 4.6 g (59% yield) of pure product; m.p. 101° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([CH2:12][OH:13])[C:10]#[N:11].[OH:14][CH2:15][CH2:16]C#N>>[C:15]([O:13][CH2:12][CH:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Cl:1])[C:10]#[N:11])(=[O:14])[CH3:16]
Reactant: N#CC(CO)c1cc(Cl)ccc1Cl
Reactant: N#CCCO
Product: CC(=O)OCC(C#N)c1cc(Cl)ccc1Cl

Procedure:
This ester was prepared using the procedure described in Example 5, except 2-(2,5-dichlorophenyl)-3-hydroxypropanenitrile was used in place of 2-(2-chloro-5-(difluoromethoxy)phenyl)-3-hydroxypropanenitrile. The preparation of 2-2,5-dichlorophenyl)-3-hydroxypropanenitrile is described in Example 4. The recovered ester product was a white solid (92% yield), m.p. 79-80.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:19][OH:20])[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=[CH:4][CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:19][O:20][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1c2ccccc2CCC1(CO)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1(c2ccc(Cl)cc2)CCc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 0.99 g of the title compound of Step C and 0.6 ml of methanesulfonyl chloride in 20 ml of THF at 0° C. was added 1.05 ml of triethylamine. The reaction was stirred overnight at room temperature, partitioned between 5% aqueous sodium bicarbonate and chloroform, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel with 30% ethyl acetate/hexane to afford 1.1 g of the title compound as a viscous yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:18]([NH:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH2:30][CH2:31][CH2:32][N:33]1C(=O)C3=CC=CC=C3C1=O)[CH:25]=[CH:24]2)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:18]([NH:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH2:30][CH2:31][CH2:32][NH2:33])[CH:25]=[CH:24]2)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc2c(ccn2CCCN2C(=O)c3ccccc3C2=O)c1)c1nc2ccc(Cl)cc2n1Cc1ccccc1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCn1ccc2cc(NC(=O)c3nc4ccc(Cl)cc4n3Cc3ccccc3)ccc21
Temperature: 25 °C
Yield: 82.2 %

Procedure:
To 5 g of 1-benzyl-6-chloro-2-[1-(3-phthalimidopropyl)indol-5-ylaminocarbonyl]benzimidazole was added 100 ml of ethanol and stirred, then 0.5 ml of hydrazine hydrate was added thereto, the mixture was refluxed overnight. After cooled the reaction mixture to room temperature, then white crystals were removed by filtration. Water was added to the filtrate, and made alkaline with 10% aqueous solution of potassium hydroxide. This mixture was extracted with dichloromethane, the extract was washed with water, an aqueous solution saturated with sodium chloride then was dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was crystallized from ethyl acetate-n-hexane, there was obtained 3.2 g of 1-benzyl-6-chloro-2-[1-(3-aminopropyl)indol-5-ylaminocarbonyl]-benzimidazole as in the form of yellow granular crystals. Melting point: 106-108° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].C(CN)O.OCCN1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][CH:27]=[C:20]3[C:21]=2[C:16](=[CH:17][CH:18]=[CH:19]3)[C:15]1=[O:28]>>[OH:6][CH2:5][CH2:4][CH2:3][CH2:2][N:1]1[C:15](=[O:28])[C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:21]=2[C:22](=[CH:25][CH:26]=[CH:27]3)[C:23]1=[O:24]
Reactant: NCCCCO
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCO
Solvent: NCCO
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCO

Procedure:
Following the procedure of example 1(a) and (b) but substituting 4-aminobutanol for the ethanolamine in part (a) one obtains 2-(4-hydroxybutyl)-1H-benz[de]isoquinoline-1,3(2H)-dione, 4-methylbenzenesulfonate ester.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:14][C:13]2[C:12]([F:15])=[C:11]([NH:16][C@H:17]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:18]([NH2:20])=[O:19])[N:10]=[C:9]([C:25]3[O:26][CH:27]=[CH:28][CH:29]=3)[C:8]=2[C:7]1=[O:30]>C(O)(C(F)(F)F)=O>[F:15][C:12]1[C:13]2[CH2:14][NH:6][C:7](=[O:30])[C:8]=2[C:9]([C:25]2[O:26][CH:27]=[CH:28][CH:29]=2)=[N:10][C:11]=1[NH:16][C@H:17]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:18]([NH2:20])=[O:19]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@H](CC(C)C)C(N)=O)nc(-c4ccco4)c3C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@@H](Nc1nc(-c2ccco2)c2c(c1F)CNC2=O)C(N)=O

Procedure:
A solution of (R)-2-(2-(2,4-dimethoxybenzyl)-7-fluoro-4-(furan-2-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)-4-methylpentanamide (93.1 mg, 0.188 mmol) in TFA (5 mL) was heated to 65° C. for 3 h. The solvent was removed and the resulting residue was diluted in MeOH/DCM (10 mL) and was purified via preparative HPLC eluting with water (0.05% TFA) and ACN (30%, 0.035% TFA). The collected fractions were stripped to dryness via rotary evaporation to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.79-0.97 (m, 6H), 1.52-1.87 (m, 3H), 4.38 (s, 2H), 4.66-4.85 (m, 1H), 6.61 (dd, J=3.54, 1.77 Hz, 1H), 6.92-7.07 (m, 2H), 7.36 (br s, 1H), 7.79 (dd, J=1.64, 0.63 Hz, 1H), 8.04 (dd, J=3.54, 0.51 Hz, 1H), 8.32 (s, 1H). [M+H] calc'd for C17H19FN4O3, 347. found, 347.
Reaction SMILES: [OH-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[C:8]1([S:14]([N:3]2[CH:7]=[CH:6][CH:5]=[CH:4]2)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: c1cc[nH]c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1cccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 5998.8 %

Procedure:
To a well-agitated suspension of sodium hydroxide (4.46 g, 111 mmol) in methylene chloride (26 mL) at 0° C. is added pyrrole (2.5 g, 0.37 mmol), and the reaction mixture is stirred for 10 min, following which a solution of benzenesulfonyl chloride (7.86 g, 0.44 mmol) in methylene chloride (5.15 mL) is slowly added, allowed to warm to room temperature and stirred overnight. The reaction is quenched by pouring into water (100 mL). The organic layer is separated, and the aqueous layer is extracted with methylene chloride three times. The combined organic extracts are water, dried with sodium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (10% ethyl acetate-hexane) provides 4.6 g (60%) of the title compound as a white solid. 1H NMR (CDCl3): δ 7.80 (m, 2H), 7.50 (m, 3H), 7.25 (m, 2H), 6.30 (m, 2H).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:15])[CH:5]=[C:6]([C:12]([OH:14])=[O:13])[NH:7]2.Br[C:17]1C=C(C)C=C2[C:18]=1C(=O)C=C(C(O)=O)N2>>[CH2:17]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:15])[CH:5]=[C:6]([C:12]([OH:14])=[O:13])[NH:7]2)[CH3:18]
Reactant: Cc1cc(Br)c2c(=O)cc(C(=O)O)[nH]c2c1
Reactant: O=C(O)c1cc(=O)c2c(I)cccc2[nH]1
Product: CCc1cccc2[nH]c(C(=O)O)cc(=O)c12

Procedure:
5-iodo-4-oxo-1,4-dihydroquinoline-2-carboxylic acid; 5-bromo-7-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid;
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:32]=[CH:31][CH:30]=[CH:29][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:34]([C:37]1[CH:45]=[CH:44][C:40]([C:41]([OH:43])=[O:42])=[C:39]([OH:46])[CH:38]=1)(=[O:36])=[O:35]>>[CH2:1]([C:8]1[O:9][C:10]2[CH:32]=[CH:31][CH:30]=[CH:29][C:11]=2[C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][S:34]([C:37]3[CH:45]=[CH:44][C:40]([C:41]([OH:43])=[O:42])=[C:39]([OH:46])[CH:38]=3)(=[O:36])=[O:35])=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=2)=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)ccc1O
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Product: O=C(O)c1ccc(S(=O)(=O)Oc2ccc(-c3ccc(-c4c(Cc5ccccc5)oc5ccccc45)cc3)cc2[N+](=O)[O-])cc1O

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzofuran-3-yl)-3-nitro-biphenyl-4-ol and 4-chlorosulfonyl-2-hydroxy-benzoic acid, in substantially the same manner, as described in Example 1 step g, and was obtained as a yellow solid, mp 200° C.; MS m/e 620 (M−H)+;
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:8]=1[O:9][CH3:10])=[O:2].[C:24]1([CH2:30][CH2:31][CH2:32][C:33](Cl)=[O:34])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH:1]([C:3]1[CH:4]=[C:5]([S:20]([NH:23][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:22])=[O:21])[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:8]=1[O:9][CH3:10])=[O:2]
Reactant: O=C(Cl)CCCc1ccccc1
Reactant: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1cccc([N+](=O)[O-])c1
Product: COc1c(C=O)cc(S(=O)(=O)NC(=O)CCCc2ccccc2)cc1-c1cccc([N+](=O)[O-])c1

Procedure:
Proceeding as in Reference 21, but substituting 5-formyl-6-methoxy-3′-nitro-biphenyl-3-sulfonamide and 4-phenylbutyryl chloride, gave 5-formyl-6-methoxy-3′-nitro-N-(4-phenylbutyryl)-biphenyl-3-sulfonamide.
Reaction SMILES: [C:1]([NH:4][C:5]([NH2:7])=[S:6])(=[NH:3])[NH2:2].Cl[CH2:9][C:10](=O)[CH3:11]>CC(C)=O>[CH3:11][C:10]1[N:7]=[C:5]([NH:4][C:1]([NH2:2])=[NH:3])[S:6][CH:9]=1
Reactant: N=C(N)NC(N)=S
Reactant: CC(=O)CCl
Solvent: CC(C)=O
Product: Cc1csc(NC(=N)N)n1
Temperature: 25 °C
Yield: 83 %

Procedure:
A mixture of amidinothiourea (2.0 g, 16.9 mmol), chloroacetone (1.56 g, 16.9 mmol) was heated at reflux in acetone (12 mL) for 4 h. The mixture was cooled to room temperature and removed half of the solvent. The precipitate was filtered, washed with dry acetone, and dried to give N-(4-methyl-1,3-thiazol-2-yl)guanidine (2.19 g, 83%).
Reaction SMILES: C(ON=O)CC(C)C.[Cl:9][C:10]1[N:11]=[C:12]([N+:18]([O-:20])=[O:19])[C:13](N)=[N:14][C:15]=1[Cl:16].C(Br)(Br)[Br:22]>>[Br:22][C:13]1[C:12]([N+:18]([O-:20])=[O:19])=[N:11][C:10]([Cl:9])=[C:15]([Cl:16])[N:14]=1
Reactant: Nc1nc(Cl)c(Cl)nc1[N+](=O)[O-]
Reactant: BrC(Br)Br
Agent: CC(C)CCON=O
Product: O=[N+]([O-])c1nc(Cl)c(Cl)nc1Br

Procedure:
To 4.8 g isoamylnitrite in 150 ml bromoform heated to 95°-100° is added portionwise 5.0 g 5,6-dichloro-3-nitro-pyrazinamine. The reaction mixture is heated at reflux for 18 hours. After cooling, the bromoform is removed in vacuo to give an oil which is chromatographed on silica gel. The initial component to elute is 5,6-dichloro-2-bromonitropyrazine, which is obtained (2.6 g) as a viscous oil.
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:17][CH2:16][CH2:15][C:14]3[CH:18]=[CH:19][C:20]([C:22](=[O:31])[CH2:23][CH2:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[CH:21][C:13]=3[CH2:12]2)=[CH:6][CH:5]=1.[Cl:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35]Cl.[I-].[K+]>>[ClH:32].[ClH:1].[Cl:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][N:28]1[CH2:27][CH2:26][CH:25]([CH2:24][CH2:23][C:22]([C:20]2[CH:19]=[CH:18][C:14]3[CH2:15][CH2:16][CH2:17][N:11]([CH2:10][C:7]4[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=4)[CH2:12][C:13]=3[CH:21]=2)=[O:31])[CH2:30][CH2:29]1
Reactant: O=C(CCC1CCNCC1)c1ccc2c(c1)CN(Cc1ccc(F)cc1)CCC2
Reactant: ClCc1ccccc1Cl
Agent: Cl
Agent: [I-]
Agent: [K+]
Product: O=C(CCC1CCN(Cc2ccccc2Cl)CC1)c1ccc2c(c1)CN(Cc1ccc(F)cc1)CCC2

Procedure:
Using 1-[2-[(4-fluorophenyl)methyl]-2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl]-3-(4-piperidinyl)-1-propanone(free base) obtained in Example 211, 2-chlorobenzylchloride, and potassium iodide, the procedure of Example 51-3 was otherewise repeated to provide the title compound as colorless amorphous powders.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=1.I[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]#[C:28][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:25][CH:26]=1
Reactant: Ic1ccccc1
Reactant: C#Cc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Product: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(C#Cc4ccccc4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The compound was obtained starting from 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene and iodobenzene.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]([NH:8][C:9]([C:11]2[NH:12][C:13]([CH2:17][CH3:18])=[C:14]([Cl:16])[N:15]=2)=[O:10])[CH2:6][CH2:5][N:4]([C:19]2[S:20][C:21]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:3]1.[CH3:33][CH:34]([CH3:37])[CH:35]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:16][C:14]1[N:15]=[C:11]([C:9]([NH:8][C@H:7]2[CH2:6][CH2:5][N:4]([C:19]3[S:20][C:21]4[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)[CH2:3][C@H:2]2[NH:1][CH2:33][CH:34]([CH3:37])[CH3:35])=[O:10])[NH:12][C:13]=1[CH2:17][CH3:18]
Reactant: CC(C)C=O
Reactant: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](N)C3)sc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](NCC(C)C)C3)sc12
Yield: 88 %

Procedure:
The same operation as in Example (77d) was performed using ethyl cis(±)-2-(3-amino-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-benzothiazole-7-carboxylate obtained by the method described in Example (81e) (30 mg, 0.063 mmol), 2-methylpropanal (7 μL, 0.077 mmol) and sodium (triacetoxy)borohydride (60 mg, 0.28 mmol), to obtain 29.6 mg of the title compound as a white solid (88%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH2:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[C:23]([F:24])=[C:22]([F:25])[CH:21]=[CH:20][C:12]=1[C:13]([NH:15][O:16][CH2:17][CH2:18][OH:19])=[O:14]>O1CCCC1.[Pd].CO>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[C:23]([F:24])=[C:22]([F:25])[CH:21]=[CH:20][C:12]=1[C:13]([NH:15][O:16][CH2:17][CH2:18][OH:19])=[O:14]
Reactant: C=Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(Cl)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(Cl)c1
Reaction time: 6 h

Procedure:
A solution of the product of Example 2, Step D, 2-(2-chloro-4-vinyl-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide (0.291 g, 0.789 mmol) in tetrahydrofuran (16 mL) was hydrogenated over 10% palladium on carbon (0.08 g) at 6900 psig at room temperature for 17 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to afford a crystalline solid. The solid was dissolved in methanol and concentrated to near dryness. Ether (10 mL) was added and the mixture was allowed to stand at ambient temperature for 6 hours. during which crystallization ensued. The white crystals were filtered, washed with a small volume of ether, and dried in vacuo at 60° C. overnight yielding 2-(2-chloro-4-ethyl-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide (222 mg): m.p. 142.5–145° C.; 1H NMR (400 MHz, DMSO-d6) δ 11.94 (br s, 1 H), 8.85 (br s, 1 H), 7.44 (br t, J=6.4 Hz, 1 H), 7.30 (d, J=2.0 Hz, 1 H), 7.22–7.15 (m, 1 H), 7.05 (dd, J=8.3, 2.0 Hz, 1 H), 6.75 (dd, J=8.3, 6.3 Hz, 1 H), 4.71 (br s, 1 H), 3.89 (br s, 2 H), 3.59 (br s, 2 H), 2.54 (q, J=7.6 Hz, 2 H), 1.15 (t, J=7.6 Hz, 3 H); 19F NMR (376 MHz, DMSO-d6) δ −132.7, −142.0; MS (APCI+)=371.0. Anal. Calcd/found for C17H17ClF2N2O3: C, 55.07/55.14; H, 4.62/4.51; N, 7.56/7.38; F, 10.25/9.98.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)=[CH:9][N:10]=2)[CH:5]=[CH:6][N:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(C(C)C)CC)(C)C>CC(O)C>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:2]2[C:3]3[N:4]([C:8]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=4)=[CH:9][N:10]=3)[CH:5]=[CH:6][N:7]=2)[CH2:22][CH2:21]1
Reactant: CN1CCNCC1
Reactant: CSc1nccc(-c2cnc3c(Cl)nccn23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CSc1nccc(-c2cnc3c(N4CCN(C)CC4)nccn23)n1

Procedure:
To a solution of 8-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazine (from Example 44 supra) (1.36 g, 4.91 mmol) in iPrOH (100 mL) was added 1-methylpiperazine (0.64 g, 6.38 mmol) followed by diisopropylethylamine (0.82 g, 6.38 mmol). The reaction mixture was stirred at reflux for 15 hours and the solvent was removed under reduced pressure. The residue was extracted with dichloromethane (150 mL) and washed with water (3×25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 8-(4-methyl-piperazin-1-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazine. (Yield 1.4 g, 83.7%). LC-MS: [M+H]+ 342.