Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[CH3:9][OH:10].[N-]=[C:12]=[O:13]>O1CCCC1>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:9]([O:13][CH3:12])=[O:10])[CH3:3]
Reactant: [N-]=C=O
Reactant: CCOC(=O)CN
Reactant: CO
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)OC
Temperature: 25 °C

Procedure:
Alternatively, glycine ethyl ester hydrochloride (40.1 g, 0.28 mole) suspended in dry tetrahydrofuran (200 ml) and phosgene were bubbled through the reaction mixture for 0.5 hrs, as the reaction mixture was refluxed. At the end of 0.5 hrs., the reaction was cooled to room temperature and toluene was added followed by the distillation of THF. The reaction mixture containing toluene was further refluxed for 1 hr. The unreacted glycine ethyl ester hydrochloride was filtered and the filtrate containing glycine ethyl ester isocyanate (IR 2250 cm-1) was reacted with excess (2-3 mole) anhydrous methanol and, when the isocyanate peak disappeared, the solvent was removed to isolate N-carbomethoxyglycine ethyl ester.
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][CH:23]=1>C(Cl)Cl>[NH2:28][C:26]([C:25]1[CH:29]=[CH:30][C:22]([NH:21][C:14]([C:10]2[CH:9]=[C:8]([N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:17][CH:18]3[CH2:20][CH2:19]3)[N:13]=[CH:12][N:11]=2)=[O:16])=[CH:23][CH:24]=1)=[O:27]
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Reactant: NC(=O)c1ccc(N)cc1
Solvent: ClCCl
Product: NC(=O)c1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Yield: 85 %

Procedure:
Following the general method as outlined in Example 1, starting from 6-[cyclohexyl(cyclopropylmethyl)amino]pyrimidine-4-carboxylic acid (Intermediate 13) and 4-aminobenzamide (Aldrich), the title compound was obtained as a brown solid in 85% yield after trituration in DCM.
Reaction SMILES: [CH3:1][CH:2]([CH:4]1[NH:8][CH2:7][C:6](=[O:9])[N:5]1[CH2:10][C:11]([NH2:13])=[O:12])[CH3:3].[O:14]1[CH2:24][CH:15]1[CH2:16][C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18]>C(O)CCCC>[C:11]([CH2:10][N:5]1[C:6](=[O:9])[CH2:7][N:8]([CH2:24][CH:15]([OH:14])[CH2:16][C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18])[CH:4]1[CH:2]([CH3:1])[CH3:3])(=[O:12])[NH2:13]
Reactant: CC(C)COC(=O)CC1CO1
Reactant: CC(C)C1NCC(=O)N1CC(N)=O
Solvent: CCCCCO
Product: CC(C)COC(=O)CC(O)CN1CC(=O)N(CC(N)=O)C1C(C)C
Yield: 49.1 %

Procedure:
A solution of 1.2 g (6.4 mmol) of 2-(1-methylethyl)-5-oxo-1-imidazolidineacetamide and 2 g of 2-methylpropyl 3,4-epoxybutanoate in 40 ml of anhydrous pentanol was stirred at 80° C. for 48 hours. The solvent was evaporated under reduced pressure. The residue was dissolved in 15 ml of 15% HCl, washed with 2×25 ml dichloromethane, basified with sodium carbonate with sodium carbonate and extracted with 3×35 ml dichloromethane. The organic layer was dried and evaporated to afford 1.08 g of the title compound as a colorless oil (mixture of two diastereoisomers, Rf 0.27 and 0.32 respectively (dichloromethane/methanol 9:1; silica gel plates). Mass spectrum (E.I., 70 eV, 1.5 mA), m/z=300 (M+ --C3H7). IR spectrum (neat): 3400, 3200, 1730 and 1690 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([OH:10])[CH:3]=1.[Na].[OH-].[Na+].[CH2:14](Br)[C:15]#[CH:16].C1(C)C=CC=CC=1>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH2:16][C:15]#[CH:14])[CH:3]=1
Reactant: C#CCBr
Reactant: O=Cc1ccc(Br)cc1O
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: C#CCOc1cc(Br)ccc1C=O

Procedure:
Conversion of 4-bromo-2-hydroxybenzaldehyde to its sodium salt was carried out as follows: A solution of 4-bromo-2-hydroxybenzaldehyde (3.0 g, 24.9 mmol) in MeOH (−150 mL) was treated with 1N aq. NaOH (15.7 mL, 1.05 equiv). The resulting pale yellow solution was concentrated under reduced pressure. EtOH (30 mL) was added to the residue and the solution was concentrated under reduced pressure. This was repeated with EtOH (30 mL) and then with heptane (50 mL). The resulting yellow, powdery sodium salt was dissolved in DMF (60 mL) with stirring and to it was added propargyl bromide in toluene (80 wt %, 2.33 mL, 1.4 equiv). The reaction mixture was stirred at ambient temperature for 22 h, after which time the volatiles were concentrated under reduced pressure. The residue was partitioned between EtOAc (70 mL) and water (40 mL). The organic layer was separated and treated with charcoal (˜1 g) then dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure. The residue obtained was crystallized from EtOAc and hexane (3:7). Crop I afforded 4-bromo-2-(prop-2-ynyloxy)benzaldehyde (893 mg) as colorless needles. The mother liquor was concentrated under reduced pressure and crystallized again from EtOAc and hexane (7:93) to obtain a further Crop II of 4-bromo-2-(prop-2-ynyloxy)benzaldehyde (1.902 g). The mother liquor was concentrated again and subjected to one more crystallization as described before. Crop III yielded additional 4-bromo-2-(prop-2-ynyloxy)benzaldehyde (344 mg). All the three crops were combined to give a total of 3.14 g (87% yield) of 4-bromo-2-(prop-2-ynyloxy)benzaldehyde as colorless needles. 1H NMR (500 MHz, CDCl3) δ 10.43 (s, 1 H), 7.74 (d, J=8.2 Hz, 1 H), 7.31 (d, J=1.5 Hz, 1 H), 7.24-7.28 (m, 1 H), 4.85 (d, J=2.4 Hz, 2H), 2.64 (t, J=2.4 Hz, 1H); LCMS (Method A) (ESI) m/e 239.0, 241.0 Br pattern [(M+H)+, calcd for C10H7BrO2 239.0]; SiO2 TLC (EtOAc:Hexane=1:9) indicated Rf of 0.32 compared with an Rf of 0.43 for starting material aldehyde.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[N:15]=[C:14]([NH:16][C@H:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH2:18][OH:19])[C:13]([N+:27]([O-])=O)=[CH:12][N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[C:30](O)(=O)C.C(N)=N>[Pd].CCO.CCOC(C)=O.CCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[N:15]=[C:14]4[C:13]([N:27]=[CH:30][N:16]4[C@H:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH2:18][OH:19])=[CH:12][N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1cnc(Nc2cc(C3CC3)[nH]n2)nc1N[C@@H](CO)c1ccc(F)cc1
Agent: [Pd]
Agent: N=CN
Solvent: CCO
Solvent: CCOC(C)=O
Product: OC[C@@H](c1ccc(F)cc1)n1cnc2cnc(Nc3cc(C4CC4)[nH]n3)nc21
Temperature: 70 °C
Yield: 61.3 %

Procedure:
To a 25 ml round bottom flask was added palladium on activated carbon (10%, 104 mg, 0.098 mmol) and stirring bar. The flask was sealed, evacuated and refilled with hydrogen using balloon. A solution of (2R)-2-({2-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-5-nitropyrimidin-4-yl}amino)-2-(4-fluorophenyl)ethanol (Method 1, 196 mg, 0.49 mmol) in EtOH/EtOAc (6 ml/1 ml) via syringe. The reaction mixture was stirred at room temperature for 19 hours and was filtered through paper. The filtrate was concentrated to give a pink solid. The solid was then dissolved in EtOH (4 ml) and to the mixture was added formamidine acetate (100 mg, 0.96 mmol). The reaction mixture was heated on heating block (70° C.) for 4 hours. Removal of solvent followed by flash chromatography on silica gel (10-15% MeOH in EtOAc) gave the desired product as a solid (114 mg, 61% for two steps). NMR: 0.63 (m, 2H), 0.93 (m, 2H), 1.86 (m, 1H), 4.04 (m, 1H), 4.38 (m, 1H), 5.34 (m, 1H), 5.70 (m, 1H), 6.20 (m, 1H), 7.18 (m, 2H), 7.45 (m, 2H), 8.45 (s, 1H), 8.73 (s, 1H), 9.48 (br s, 1H), 11.85 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:22]([O:24]CC)=[O:23])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[OH-].[Li+].O.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:22]([OH:24])=[O:23])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)c(-c2cccc(C#N)c2)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2oc(C(=O)O)cc2-c2cc(F)cc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.05 g (2.84 mmol) of the compound from Example 11A are provided in 30 ml of tetrahydrofuran, and 0.68 g (28.4 mmol) of lithium hydroxide and 10 ml of water are added at room temperature. The mixture is stirred at room temperature overnight, a 1N aqueous HCl solution is then added until an acidic pH is established, the mixture is extracted with ethyl acetate and the organic phase is washed with water, dried over sodium sulfate, filtered and concentrated. The crude product is purified by preparative HPLC (RP18 column; eluent: acetonitrile/water gradient). 0.60 g (62% of theory) of the title compound are obtained.
Reaction SMILES: C[C:2]([CH3:5])([O-])C.[K+].[CH2:7](I)[CH3:8].[C:10]([CH2:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)#[N:11]>C1COCC1>[C:10]([C:12]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)([CH2:2][CH3:5])[CH2:7][CH3:8])#[N:11]
Reactant: CCI
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1ccc(CC#N)cc1
Agent: [K+]
Solvent: C1CCOC1
Product: CCC(C#N)(CC)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of potassium tert-butoxide (4.81 g) in THF (15 mL) at −30° C. was added a solution of ethyl iodide (4.11 mL) and methyl 4-(cyanomethyl)benzoate (3 g) THF (15 mL) under nitrogen atmosphere over 20 min. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched by the addition of water (10 mL) and ethyl acetate was added. The organic layer was washed successively with water, brine and dried over anhydrous sodium sulfate. The organic solvent was removed to obtain a residue, which was purified by column chromatography (silicagel, 20% ethyl acetate in petroleum ether) to obtain a crude solid. The crude solid was crystallized using chloroform in petroleum ether to afford the title compound.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH:28]([CH3:30])[CH3:29])[N:25]=[CH:26][CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].C1COCC1.[CH3:37][N:38]1[CH2:43][CH2:42][N:41]([C:44]2[CH:49]=[CH:48][C:47]([NH2:50])=[CH:46][CH:45]=2)[CH2:40][CH2:39]1>CCOC(C)=O.CCCCCC>[CH3:37][N:38]1[CH2:39][CH2:40][N:41]([C:44]2[CH:49]=[CH:48][C:47]([NH:50][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([CH:28]([CH3:29])[CH3:30])[N:25]=[CH:26][CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:46][CH:45]=2)[CH2:42][CH2:43]1
Reactant: CC(C)n1nccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)n1nccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(N3CCN(C)CC3)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
A small screw cap test tube was charged with 2-Isopropyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 138 mg, 0.3314 mmol) and THF (3.3 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (63.3 mg, 0.331 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and diluted with EtOAc (˜5 mL) and Hexane (˜40 mL). The precipitate that formed was collected by filtration and washed with 0° C. iPrOH (˜10 mL) to afford the title compound in 65% yield (0.127 g, 0.215 mmol).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][C:6]([C:7]([C:9]2[N:13]([CH3:14])[C:12]([CH2:15][C:16]([O:18]CC)=[O:17])=[CH:11][C:10]=2[CH3:21])=[O:8])=[CH:5][CH:4]=1.C(I)CCCCC>>[CH2:15]([C:12]1[N:13]([CH3:14])[C:9]([C:7](=[O:8])[C:6]2[CH:22]=[CH:23][C:3]([C:2]([F:24])([F:25])[F:1])=[CH:4][CH:5]=2)=[C:10]([CH3:21])[CH:11]=1)[CH3:16].[CH2:12]([CH2:15][C:16]([O-:18])=[O:17])[CH2:11][CH2:10][CH2:9][CH2:7][CH3:6]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(C(F)(F)F)cc2)n1C
Solvent: CCCCCCI
Product: CCCCCCCC(=O)[O-]
Product: CCc1cc(C)c(C(=O)c2ccc(C(F)(F)F)cc2)n1C

Procedure:
The alkylation procedure of Example 77A is performed upon ethyl 5-(p-trifluoromethylbenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example 89), using an equivalent quantity of n-hexyl iodide instead of methyl iodide used in Example 77A to yield ethyl 5-(p-trifluoromethylbenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetate.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([N:11]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[C:12]([C:14]2[CH:15]=[N:16][C:17]([C:20]3[CH:21]=[N:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=3)=[N:18][CH:19]=2)=[O:13])[CH2:10][CH2:9]1.C(N(C(C)C)C(C)C)C.Cl[C:45]1[N:50]=[CH:49][C:48]([CH2:51][CH3:52])=[CH:47][N:46]=1>CN(C)C=O>[CH:8]1([N:11]([CH:29]2[CH2:30][CH2:31][N:32]([C:45]3[N:50]=[CH:49][C:48]([CH2:51][CH3:52])=[CH:47][N:46]=3)[CH2:33][CH2:34]2)[C:12]([C:14]2[CH:19]=[N:18][C:17]([C:20]3[CH:21]=[N:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=3)=[N:16][CH:15]=2)=[O:13])[CH2:9][CH2:10]1
Reactant: CCOc1ccc(-c2ncc(C(=O)N(C3CCNCC3)C3CC3)cn2)cn1
Reactant: CCc1cnc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2ncc(C(=O)N(C3CC3)C3CCN(c4ncc(CC)cn4)CC3)cn2)cn1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of 2-(6-ethoxy-pyridin-3-yl)-pyrimidine-5-carboxylic acid cyclopropyl-piperidin-4-yl-amide trifluoroacetic acid salt (48 mg), ethyldiisopropylamine (52 μL), and 2-chloro-5-ethylpyrimidine (14 mg) in N,N-dimethylformamide (2.0 mL) is stirred at 120° C. for 4 h. After cooling to room temperature, the reaction mixture is purified by HPLC (H2O/MeOH/TFA) to give the title compound. LC (method 3): tR=2.10 min; Mass spectrum (ESI+): m/z=474 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[Br:16][CH2:17][CH2:18][CH2:19]Br.C(OCC)(=O)C>CS(C)=O.O>[Br:16][CH2:17][CH2:18][CH2:19][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(OCCCBr)cc1
Reaction time: 0.08 h

Procedure:
In 50 ml of dimethyl sulfoxide was dissolved 10 g of 4-cyanophenol, followed by adding thereto 23 g of potassium carbonate at room temperature. The resulting mixture was stirred at the same temperature for 5 minutes and then 64 ml of 1,3-dibromopropane was added thereto, followed by stirring at room temperature for 12 hours. Subsequently, the reaction mixture was added to a mixed solvent of 200 ml of ethyl acetate and 100 ml of water, after which the organic layer was separated and the aqueous layer was extracted with 50 ml of ethyl acetate. The combined organic layer was washed successively with a 1N aqueous sodium hydroxide solution, water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent; hexane: ethyl acetate=5:1) to obtain 5.1 g of 1-bromo-3-(4-cyanophenoxy)-propane as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]=1[OH:13].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:21]([CH3:23])[CH3:22]>CC(C)=O>[CH:21]([O:13][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][CH2:9]2)([CH3:23])[CH3:22]
Reactant: CC(C)Br
Reactant: COc1ccc2c(c1O)CCCC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COc1ccc2c(c1OC(C)C)CCCC2
Yield: 92.6 %

Procedure:
33 (4.55 g, 25.5 mmol) was charged in a 250 mL round bottom flask, equipped with a reflux condenser, under nitrogen gas. 50 mL of anhydrous acetone was added followed by cesium carbonate (66.55 g, 204.3 mmol). 2-bromopropane (23.94 mL, 255.0 mmol) was added and the reaction mixture was refluxed for 12 h. The solvent was filtered and evaporated in vacuo and purified by flash column chromatography (slilica gel, 1:99 EtOAc:Hexanes) to afford 5.2 g (93%) of 5-isopropoxy-6-methoxy-1,2,3,4-tetrahydronaphtalene (34). Rf value: 0.615 (15:85 EtOAc:Hexanes).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]([OH:13])=O)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][N:34]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C>ClCCl.CN(C=O)C>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:11]([C:8]3[S:7][C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=4[CH:9]=3)=[O:13])=[CH:35][N:34]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cn2)CC1
Reactant: O=C(O)c1cc2c(Cl)cccc2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3cc4c(Cl)cccc4s3)cn2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 4-chloro-benzo[b]thiophene-2-carboxylic acid (98 mg, 0.462 mmol), CH2Cl2 (5 mL), and a catalytic amount of DMF was stirred under Ar, and oxalyl chloride (2M in dichloromethane, 600 μL, 1.20 mmol) was dripped into the mixture over 5 min. The mixture was stirred at room temperature and after 1.0 hr the reaction was concentrated to dryness. Benzene was added and the solution was evaporated to dryness again. The white-yellow solid was re-dissolved in 5 mL of CH2Cl2 and dripped, under Ar, into a solution of 4-(5-amino-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (134 mg, 0.462 mmol), and triethylamine (102 μL, 1.0 mmol) in 5 mL of dichloromethane. The reaction was stirred at room temperature for 0.5 hr and then concentrated and the residue was taken up in 50 mL of EtOAc and washed with 50 mL of saturated ammonium chloride, brine and dried over anhydrous sodium sulfate. The EtOAc solvent was removed and the product was triturated with diethyl ether and hexanes (1:1 ratio), followed by filtration, to afford the product, 4-{5-[(4-chloro-benzo[b]thiophene-2-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester, as a pale green solid (80 mg, 38% yield). LCMS for C23H25ClN4O3S calcd. (m/e) 472, observed 471 (M−H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)(Cl)=O.[CH3:10][C:11]1[S:12][C:13]([C:17](O)=[O:18])=[C:14]([CH3:16])[N:15]=1>O1CCCC1>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:17]([C:13]1[S:12][C:11]([CH3:10])=[N:15][C:14]=1[CH3:16])=[O:18]
Reactant: Cc1nc(C)c(C(=O)O)s1
Reactant: c1c[nH]cn1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1nc(C)c(C(=O)c2ncc[nH]2)s1
Reaction time: 0.5 h

Procedure:
To a solution of imidazole (2.72 g; 40 mmol) in dry tetrahydrofuran (60 ml) was added dropwise thionyl chloride (1.20 g; 10 mmol) under ice-cooling while stirring. After the resultant mixture was turned to room temperature, 2,4-dimethyl-5-thiazolecarboxylic acid (1.57 g; 10 mmol) was added thereto at once, and stirring was continued for 30 minutes, whereby 5-imidazolylcarbonyl-2,4-dimethylthiazole was produced. To the mixture was added dropwise a solution of 2-(2-furyl)aminoacetonitrile (1.46 g; 12 mmol) in dry tetrahydrofuran under ice-cooling, and the resultant mixture was stirred at room temperature for 1 hour. After completion of the reaction, tetrahydrofuran was removed under reduced pressure to separate the residue. Water was added to the residue, which was extracted with ethyl acetate. The ethyl acetate layer was washed twice with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crude crystals. Recrystallization from ethanol gave 2.0 g of 2-(2,4-dimethylthiazole-5-carboxamido)-2-(2-furyl)acetonitrile as colorless crystals. m.p., 108° -109° C. Yield, 74%.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.C(Cl)Cl.Cl.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:33]=1>CN(C)C1C=CN=CC=1.CN(C)C=O>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH:14]=[CH:15][C:16]([C:17]#[N:18])=[CH:19][CH:20]=3)=[CH:9][N:10]2[S:38]([C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)(=[O:40])=[O:39])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N#Cc1ccc(-c2c[nH]c3cc([N+](=O)[O-])ccc23)cc1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2cn(S(=O)(=O)c3cccnc3)c3cc([N+](=O)[O-])ccc23)cc1
Reaction time: 8 h
Yield: 56 %

Procedure:
Method N Combine 4-(6-nitro-1H-indol-3-yl)-benzonitrile, 9, (290 mg, 1.1 mmol), 4-dimethylaminopyridine (14 mg, 0.11 mmol), triethyl amine (740 μL, 5.3 mmol), methylene chloride (7.0 mL) and dimethylformamide (2.5 mL) in a 25 mL flask. Add 3-pyridine sulfonyl chloride hydrochloride (283 mg, 1.32 mmol). Let the solution stir overnight. Isolate the precipitate by filtration and wash the precipitate 3× with methylene chloride to yield 251 mg, 0.62 mmol, 56% of the title compound. LRMS (API ES+)=405.0 (M+H).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([O:19][CH3:20])[CH:11]=2)[CH2:6][CH2:5]1)[CH3:3]>CCO>[CH3:3][CH:2]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([O:19][CH3:20])[CH:11]=2)[CH2:8][CH2:9]1)[CH3:1]
Reactant: COc1cc(N2CCN(C(C)C)CC2)ccc1[N+](=O)[O-]
Solvent: CCO
Product: COc1cc(N2CCN(C(C)C)CC2)ccc1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 101 %

Procedure:
In a pressure vessel was placed a solution of 1-(1-methylethyl)-4-[3-(methyloxy)-4-nitrophenyl]piperazine (4.0 g, 14.3 mmol) in EtOH (100 mL). The solution was purged with N2 for 15 min before the addition of 10% Pd/C (0.5 g). The reaction was stirred at RT for 5 h under 60 psi H2. After releasing H2 pressure, filtration removed the solid resin, and the filtrate was concentrated and purified with silica gel chromatography (0-5% 2 M NH3 in MeOH/DCM) to furnish 4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)aniline (3.6 g, 99% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.09 (d, J=6.6 Hz, 6 H), 2.66-2.75 (m, 5 H), 3.05-3.10 (m, 4 H), 3.47 (s, 3 H), 3.83 (s, 2 H), 6.42 (dd, J=8.2, 2.4 Hz, 1 H), 6.52 (d, J=2.2 Hz, 1 H), 6.64 (d, J=8.4 Hz, 1 H).
Reaction SMILES: OC(C1C=CC2C(=CC=CC=2)C=1)[C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[S:5][C:4]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[N:11]1[CH:10]=[CH:9][C:8]([C:6]2[S:5][C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:3][CH:7]=2)=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1sc(-c2ccncc2)cc1C(O)c1ccc2ccccc2c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(-c2ccncc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 121.7 %

Procedure:
Ethyl 3-[hydroxy(2-naphthyl)methyl]-5-pyridin-4-ylthiophene-2-carboxylate (118.0 mg, 0.3030 mmol), methylene chloride (2.4 mL), trifluoroacetic acid (140.0 uL, 1.818 mmol), and triethylsilane (84.7 uL, 0.530 mmol) were combined in a round bottomed flask equipped with a stirbar. The reaction was stirred overnight at room temperature under an atmosphere of nitrogen. An aliquot was taken from the reaction, quenched into water, basified with sodium carbonate, and extracted with ethyl acetate. TLC analysis (2:1 ethyl acetate:DCM) indicated that the starting ester was ˜50% converted to a slightly higher Rf product. Additional trifluoroacetic acid (300 uL, 4 mmol) and triethylsilane (200 uL, 1 mmol) were added and the reaction was stirred at room temperature under an atmosphere of nitrogen for another 4 hours. LCMS analysis showed one major peak with correct ES+ for product with a small amount of SM remaining. The reaction was quenched into water, basified, and extracted into ethyl acetate. The extract was washed with saline, dried over sodium sulfate, filtered, and evaporated to leave crude product as an oil. The crude product was dissolved in minimal DCM then was purified by column chromatography on silica gel (gradient 100% DCM to 50% ethyl acetate) to afford product 86 mg (76% yield) as a white solid. LC/MS (FA) ES+ 374. 1H NMR (400 MHz, DMSO) δ 8.64-8.55 (m, 2H), 7.90-7.80 (m, 4H), 7.80-7.75 (s, 1H), 7.73-7.66 (m, 2H), 7.52-7.40 (m, 3H), 4.57-4.49 (s, 2H), 4.39-4.27 (q, J=7.1 Hz, 2H), 1.35-1.25 (t, J=7.1 Hz, 3H).