Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]2[C:13]([O:18]C)=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.[Na+].[C:21]1([S:27]([O-:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:21]1([S:27]([C:2]2[CH:3]=[C:4]([C:12]3[C:13](=[O:18])[NH:14][CH:15]=[CH:16][CH:17]=3)[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ncccc1-c1cc(Br)cc(C(C)(C)C)c1
Reactant: O=S([O-])c1ccccc1
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)c1cc(-c2ccc[nH]c2=O)cc(S(=O)(=O)c2ccccc2)c1
Temperature: 120 °C

Procedure:
step 2—A mixture of 122 (150 mg, 0.469 mmol), benzene sulfinic acid sodium salt (94 mg, 0.573 mmol), Pd2(dba)3 (45 mg, 0.049 mmol), 4,5-bis-(diphenylphosphine)-9,9-dimethylxanthine (56 mg, 0.097 mmol, xantphos, CASRN 161265-03-8), tetrabutylammonium chloride (156 mg, 0.561 mmol), and Cs2CO3 (234 mg, 0.718 mmol) in a Schlenk flask was purged with argon 3 times before toluene (5 mL) was added. The reaction mixture was heated at 120° C. under an argon atmosphere overnight. The reaction mixture was cooled to RT, diluted with EtOAc and water. The organic layer was washed sequentially with water and brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 column chromatography eluting with an EtOAc/hexane gradient (10 to 20% EtOAc) to afford 0.119 g (67%) of I-107 as a light brown oil.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[H-].[Na+].F[C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29]>O1CCCC1>[N+:28]([C:19]1[CH:20]=[C:21]([S:24](=[O:26])(=[O:25])[NH2:27])[CH:22]=[CH:23][C:18]=1[O:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)([O-:30])=[O:29]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CO)C1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](COc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])C1
Reaction time: 0.25 h

Procedure:
To a solution of (S)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (0.300 g) in tetrahydrofuran (5 mL) was added sodium hydride (0.238 g). After stirring for 15 minutes, 4-fluoro-3-nitrobenzenesulfonamide (0.295 g) was added and reaction stirred at room temperature. After 1 hour, the reaction was partitioned between water (25 mL) and dichloromethane (50 mL) and the reaction quenched with 1N aqueous HCl (5.96 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (Reveleris 12 g) eluting with a gradient of 0.2% to 2% methanol/dichloromethane over 30 minutes (flow=36 m/minute) gave the title compound.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[N:11]=[C:10]([C:13]3[C:14](=[O:27])[NH:15][CH:16]=[CH:17][C:18]=3[NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.O1CCCC1.[Pt]=O>[NH2:1][C:4]1[C:12]2[N:11]=[C:10]([C:13]3[C:14](=[O:27])[NH:15][CH:16]=[CH:17][C:18]=3[NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=c1[nH]ccc(NCc2ccccn2)c1-c1nc2c([N+](=O)[O-])cccc2[nH]1
Agent: O=[Pt]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cccc2[nH]c(-c3c(NCc4ccccn4)cc[nH]c3=O)nc12
Temperature: 25 °C
Yield: 113 %

Procedure:
Platinum oxide (0.146 g, 0.65 mmol) was added to a stirred solution of 3-(4-nitro-1H-benzoimidazol-2-yl)-4-[(pyridin-2-ylmethyl)-amino]-1H-pyridin-2-one in methanol (12 ml) and tetrahydrofuran (12 ml). The reaction was purged with nitrogen three times and the atmosphere replaced with hydrogen and the reaction stirred at room temperature. After 72 hours the reaction was recharged with platinum oxide (0.146 g, 0.65 mmol) and hydrogen and stirred for a further 24 hours. The reaction was filtered through Celite and the filter cake washed with tetrahydrofuran and methanol. The solvent was concentrated under reduced pressure to give the desired crude aniline (0.610 g, 113%), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:28])[C:15]([O:18][C:19]1[C:24]([CH:25]=O)=[CH:23][C:22]([Cl:27])=[CH:21][N:20]=1)([CH3:17])[CH3:16].N1CCCC1>CO>[CH3:12][O:13][C:14](=[O:28])[C:15]([O:18][C:19]1[C:24](/[CH:25]=[C:6]2\[C:7](=[O:11])[NH:8][C:9]3[C:5]\2=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)=[CH:23][C:22]([Cl:27])=[CH:21][N:20]=1)([CH3:17])[CH3:16]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: COC(=O)C(C)(C)Oc1ncc(Cl)cc1C=O
Solvent: CO
Solvent: C1CCNC1
Product: COC(=O)C(C)(C)Oc1ncc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C
Yield: 78.9 %

Procedure:
To the mixture of 6-chlorooxindole (4.9 g, 29.3 mmol) and 2-(5-Chloro-3-formyl-pyridin-2-yloxy)-2-methyl-propionic acid methyl ester (7.2 g, 28 mmol) in methanol (50 mL) was added pyrrolidine (2.3 mL, 28 mmol) dropwise. The mixture was then heated at 70° C. for 1 h. After cooled to room temperature, the mixture was filtered and the precipitate was collected, dried to give title compound as a yellow solid (9 g).
Reaction SMILES: CN1C=CC=C1.[C:7]([C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)#[N:8].ClS(N=[C:20]=[O:21])(=O)=O.C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(#N)C.C1COCC1.O.CN(C)C=O>[C:7]([C:9]1[N:10]([CH3:14])[C:11]([CH:20]=[O:21])=[CH:12][CH:13]=1)#[N:8]
Reactant: Cn1cccc1C#N
Reactant: O=C=NS(=O)(=O)Cl
Agent: Cn1cccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: O
Product: Cn1c(C#N)ccc1C=O
Temperature: -20 °C
Reaction time: 0.75 h

Procedure:
1-methylpyrrole can be converted into 2-cyano-1-methylpyrrole by reaction with chlorosulfonyl isocyanate and dimethylformamide in acetonitrile (see, for example, C. E. Loader et al. Can. J. Chem. 59, (1981) 2673-6). Diisopropylamine (17.5 ml, 124.38 mmol) was introduced into THF (100 ml) under nitrogen. At -78° C., n-butyllithium solution in hexane (15% strength, 75.9 ml, 124.38 mmol) was added dropwise. The mixture was then stirred at -20° C. for 45 min and subsequently cooled to -78° C. again, at which temperature a solution of N-methylpyrrole-2-carbonitrile (12 g, 113.07 mmol) in THF (50 ml) was added dropwise. After stirring at -78° C. for 45 min, DMF (43.9 ml, 546.46 mmol) was added dropwise and stirring was continued at this temperature for 2 h. Addition of citric acid monohydrate (20.56 g) was followed by warming to room temperature and addition of water (112 ml). The THF was removed in a rotary evaporator, and the aqueous phase was saturated with sodium chloride and extracted with diethyl ether (3×200 ml). The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent was removed in a rotary evaporator, and the crude product was purified by flash chromatography (silica gel, dichloromethane). Yield: 8.25 g (54%). 1H-NMR (CDCl3) δ=4.1 (s, 3H), 6.8 (d, 1H), 6.9 (d, 1H), 9.7 (s, 1H).
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1C=CC=CC=1.CO.[NH:29]1[CH2:35][CH2:34][CH2:33][C@H:30]1[CH2:31][OH:32]>C(OCC)(=O)C>[C:1]([N:29]1[CH2:35][CH2:34][CH2:33][C@H:30]1[CH2:31][OH:32])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: OC[C@@H]1CCCN1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC(=O)N1CCC[C@H]1CO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of stearic acid (0.5 g 1.758 mmol) in 5 ml dry pyridine (kept over KOH) (0.399 g, 1.93 mmol) and NHS (0.223 g, 1.93 mmol) were added and dissolved in, stirred for 24 hr at room temperature. Reaction was followed by TLC 5% MeOH. Prolinol (0.197 g, 1.949 mmol) were added and the mixture was stirred at room temperature for three days was added to the mixture, and stirred at room temperature. Reaction controlled by TLC (100% Ethyl acetate). At the end of the reaction, volatiles were removed under reduced pressure and the mixture was dissolved in 30 ml DCM and DCU precipitate was filtrated off and the desired product was purified using column chromatography (ethyl acetate/DCM=1:1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][N:18]=2)[C:13](O)=[O:14])=[CH:4][C:3]=1[O:19][CH3:20].C(N(CC)CC)C.ClC(OCC)=O>C1COCC1>[Cl:1][C:2]1[C:3]([O:19][CH3:20])=[CH:4][C:5]([C:10]2[CH:11]=[C:12]([CH2:13][OH:14])[CH:16]=[CH:17][N:18]=2)=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1cc(-c2cc(C(=O)O)ccn2)cc(OC)c1Cl
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(-c2cc(CO)ccn2)cc(OC)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of 2-(4-chloro-3,5-dimethoxyphenyl)isonicotinic acid (7.20 g) and triethylamine (5.6 mL) in THF (70 mL) was added ethyl chloroformate (2.8 mL). The mixture was stirred at room temperature for 1 hour and filtered. To the filtrate was then added a solution of sodium borohydride (1.25 g) in water (4 mL). The mixture was stirred at room temperature for another hour and evaporated. Water was added to the residue and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was subjected to silica gel column chromatography using chloroform-methanol (20:1) and then chloroform-methanol (15:1) to give the title compound.
Reaction SMILES: [C:1]([Si:5]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[O:6][CH2:7][CH2:8][CH:9]1[NH:13][C:12](=[O:14])[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:10]1=[O:23])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:38](I)[CH2:39][CH3:40]>CN(C=O)C>[C:1]([Si:5]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[O:6][CH2:7][CH2:8][CH:9]1[N:13]([CH2:38][CH2:39][CH3:40])[C:12](=[O:14])[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:10]1=[O:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(CN2C(=O)NC(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2=O)cc1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1C(=O)N(Cc2ccc(C)cc2)C(=O)C1CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
A 0° C. solution of 5-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-3-(4-methyl-benzyl)-imidazolidine-2,4-dione (14.26 g, 29.3 mmol) in DMF (250 mL) was treated with sodium hydride (60% dispersion, 1.29 g, 32.2 mmol) and warmed to room temperature and stirred under N2 for 30 minutes. The resultant mixture was cooled to 0° C. and then treated with 1-propyl iodide (5.47 g, 32.2 mmol) and then warmed to room temperature and stirred for 3 h. The reaction was quenched with aqueous 1 N HCl (60 mL) and then worked up extractively with diethyl ether and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo to give crude product that was purified by flash chromatography using 6:1 hexanes:acetone to afford 14.8 g (96%) 5-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-3-(4-methyl-benzyl)-1-propyl-imidazolidine-2,4-dione. MS (ES+) Calc'd for C32H40N2O3Si (M+1) 529. Found m/z 529 (100%). 1H NMR.
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=O)=[C:9]([N:17]2[CH2:21][CH2:20][O:19][C:18]2=[O:22])[CH:8]=1.[OH-].[Na+].Cl.[CH3:27][C:28]1[C:29]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[N:30][CH:31]=[C:32]([CH3:34])[CH:33]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>O.CO>[CH3:27][C:28]1[C:29]([N:35]2[CH2:36][CH2:37][N:38]([C:11]([C:10]3[CH:15]=[CH:16][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:23])=[O:1])=[CH:8][C:9]=3[N:17]3[CH2:21][CH2:20][O:19][C:18]3=[O:22])=[O:13])[CH2:39][CH2:40]2)=[N:30][CH:31]=[C:32]([CH3:34])[CH:33]=1
Reactant: COC(=O)c1ccc(N2CCCS2(=O)=O)cc1N1CCOC1=O
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3N3CCOC3=O)CC2)c(C)c1
Temperature: 60 °C

Procedure:
To methyl 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-(2-oxooxazolidin-3-yl)benzoate (170 mg) described in Preparation Example 32 were added methanol (2.5 mL) and 1N aqueous sodium hydroxide solution (0.75 mL), and the mixture was stirred at 60° C. After completion of the reaction, the reaction mixture was neutralized with 1N hydrochloric acid (0.75 mL), 1-(3,5-dimethylpyridin-2-yl)piperazine (96 mg) described in Preparation Example 79 and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (138 mg) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol) to give 3-{2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-5-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl}oxazolidin-2-one. The obtained 3-{2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-5-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl}oxazolidin-2-one was dissolved in ethyl acetate, 4N hydrogen chloride/ethyl acetate (0.13 mL) was added, and the precipitate was collected by filtration to give the title compound (131 mg).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:15]1([NH2:18])[CH2:17][CH2:16]1>>[CH:15]1([NH:18][C:2]2[CH:10]=[CH:9][C:8]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:17][CH2:16]1
Reactant: NS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Reactant: NC1CC1
Product: NS(=O)(=O)c1ccc(NC2CC2)c(C(=O)O)c1

Procedure:
The title compound is prepared from 2-fluoro-5-sulfamoylbenzoic acid and cyclopropylamine in substantially the same manner as in Reference Example 87.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][CH2:13][CH2:14][NH2:15])[CH:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH2:5]2.[C:24]([C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1)#[N:25]>>[C:24]([C:26]1[CH:27]=[C:28]([NH:32][C:33]([NH:15][CH2:14][CH2:13][CH2:12][N:7]2[CH:6]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)=[O:34])[CH:29]=[CH:30][CH:31]=1)#[N:25]
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: NCCCN1Cc2ccc(F)cc2CC1Cc1ccc(F)cc1
Product: N#Cc1cccc(NC(=O)NCCCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)c1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 238-b) as a starting material, and using 3-cyanophenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([NH:12][CH:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[CH2:14][O:15][CH2:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[O:11])[S:7][C:6]=2[CH:30]=1.[CH3:31][C:32]([CH3:34])=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([NH:12][CH:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[CH2:14][O:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([CH:32]([CH3:34])[CH3:31])[CH2:19][CH2:18]3)=[O:11])[S:7][C:6]=2[CH:30]=1
Reactant: CC(C)=O
Reactant: O=C(NC(COCC1CCNCC1)c1ccccc1Cl)c1cc2ccc(Cl)cc2s1
Product: CC(C)N1CCC(COCC(NC(=O)c2cc3ccc(Cl)cc3s2)c2ccccc2Cl)CC1

Procedure:
Using alkylation method A, 6-chloro-N-[1-(2-chloro-phenyl)-2-(piperidin-4-ylmethoxy)ethyl]benzo[b]thiophene-2-carboxamide (255 mg, 0.55 mmol) and acetone (2.0 mL, 27 mmol) afforded, after purification (SiO2: 4:4:1 hexane EtOAc:isopropylamine), 150 mg (54%) of the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].Cl.[CH3:15][O:16][C:17](=[O:20])[CH2:18][NH2:19].C([O-])([O-])=O.[K+].[K+]>CO>[CH3:15][O:16][C:17](=[O:20])[CH2:18][NH:19][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: COC(=O)CN
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)CNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
A mixture of 1-fluoro-2,4-dinitrobenzene (1) (15 g, 0.81 mmol), glycine methyl ester hydrochloride (11.5 g, 0.92 mmol), K2CO3 (22.3 g, 0.162 mmol) and methanol (300 mL) was heated at 60° C. for 30 minutes. After cooling in an ice bath, the resulting yellow precipitate was collected by filtration, washed with water and methanol and dried in vacuo. Yield 10.5 g (51%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9](I)[CH:8]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.[CH3:19][O:20][CH2:21][C:22]1[CH:26]=[CH:25][O:24][C:23]=1[Sn](C)(C)C>>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([C:23]3[O:24][CH:25]=[CH:26][C:22]=3[CH2:21][O:20][CH3:19])[CH:8]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1
Reactant: Cc1ccc(-n2c(N)nc3ccccc32)cc1I
Reactant: COCc1ccoc1[Sn](C)(C)C
Product: COCc1ccoc1-c1cc(-n2c(N)nc3ccccc32)ccc1C

Procedure:
2-Amino-1-[3-(3-methoxymetyl-2-furyl)-4-methylphenyl]benzimidazole was prepared from 4-(2-amino-1-benzimidazolyl)-2-iodotoluene and 3-methoxymethyl-2-trimethylstannylfuran according to method C. mp 174°-176° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:23][C:24]([CH3:36])([CH3:35])[CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[NH2:27][CH2:26][CH2:25][C:24]([NH:23][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[NH:18][CH:19]=1)=[O:22])([CH3:35])[CH3:36]
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)CCNC(=O)OC(C)(C)C)c3n2)c2ccc(F)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)CCN)c3n2)c2ccc(F)cc21
Reaction time: 1 h
Yield: 30.9 %

Procedure:
To a stirred solution of tert-butyl 3-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)-3-methylbutylcarbamate (110 mg, 0.22 mmol) in 6 mL of dichloromethane was added trifluoroacetic acid (3 mL) in one portion at room temperature and the solution stirred for one hour. The solvent was evaporated at 40° C. under reduced pressure and the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 20% acetonitrile/80% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 50% acetonitrile/50% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give N-(4-amino-2-methylbutan-2-yl)-2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide 2,2,2-trifluoroacetate (35 mg, 30.9%) as a yellow solid. MS: (M+H)+=396; 1H NMR (300 MHz, DMSO): δ 12.94 (s, 1H), 9.11 (s, 1H), 8.50-8.43 (m, 2H), 7.89 (s, 1H), 7.74-7.70 (m, 3H), 7.70-7.21 (m, 1H), 4.18 (s, 3H), 2.90 (brs, 2H), 2.31-2.26 (m, 2H), 1.53 (s, 6H).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[O-]CC.[Na+].Br[CH2:21][CH2:22][CH2:23][S:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].Cl.C(O)C>C(O)C>[C:1]([NH:4][C:5]([CH2:21][CH2:22][CH2:23][S:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CCCCCCCCCCCCSCCCBr
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCSCCCC(NC(C)=O)(C(=O)OCC)C(=O)OCC

Procedure:
Diethyl acetamidomalonate (1.6 g) was dissolved in 30 ml of dehydrated ethanol and 505 mg of sodium ethoxide and 2 g of 3-bromopropyldodecyl sulfide were added thereto. The mixture was refluxed under a nitrogen atmosphere overnight. The reaction mixture was neutralized with concentrated hydrochloric acid-ethanol (1:11) and concentrated. The concentrate was purified by silica gel column chromatography using hexane-ethyl acetate (5:1→5:2) as an eluent to give 1.722 g of colorless, powdery diethyl 2-acetamido-2-(3-dodecylthiopropyl)malonate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([NH:9][CH2:10][CH2:11][OH:12])[C:3]=1[N+:13]([O-:15])=[O:14].[CH3:16][O-:17].[Na+]>CO>[NH2:1][C:2]1[CH:7]=[C:6]([O:17][CH3:16])[CH:5]=[C:4]([NH:9][CH2:10][CH2:11][OH:12])[C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: Nc1cc(Cl)cc(NCCO)c1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(N)c([N+](=O)[O-])c(NCCO)c1

Procedure:
0.172 mole (40 g) of 2-amino-6-(β-hydroxyethyl)amino-4-chloronitrobenzene in 160 ml of a 30% solution of sodium methylate in methanol was heated for 21/2 hours over a boiling water bath. The desired product precipitated out after dilution with 350 ml of ice water. After recrystallizing from boiling isopropanol to eliminate an insoluble impurity, the desired product melted at 148° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)=[O:5])[CH3:2].[H-].[Na+].[CH3:16][S:17](Cl)(=[O:19])=[O:18].O>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([S:17]([CH3:16])(=[O:19])=[O:18])[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c[nH]1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc([N+](=O)[O-])cn1S(C)(=O)=O
Temperature: 25 °C
Yield: 84.3 %

Procedure:
To a solution of 4-nitro-1H-pyrrole-2-carboxylic acid ethyl ester (2.0 g, 10.86 mmol) in anhydrous THF (54 mL) was added NaH (650 mg, 60% dispersion, 16.25 mmol) at room temperature. The suspension was stirred at room temperature for 30 minutes before the addition of methanesulfonyl chloride (1.87 g, 16.32 mmol). The reaction mixture was stirred at room temperature over night. Water was carefully added to the reaction solution, and the resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with aqueous NaHCO3 solution and brine, dried over MgSO4, filtered, and evaporated under reduced pressure to give a white solid (2.4 g, 84%). The crude product was used directly without purification. 1H NMR (500 MHz, DMSO-d6) δ8.36 (s, 1H), 7.60 (s, 1H), 4.33 (q, 2H), 4.02 (s, 3H), 2.51 (DMSO), 1.35 (t, 3H) ppm. MS (ES−): m/e=183.1 (M−Ms); LC/Method A/3.64 min.