Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:9]=[CH:10][C:11]3[C:16](=O)[NH:15][C:14]([CH2:18][O:19][CH3:20])=[N:13][C:12]=3[N:21]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.N1C(C)=CC=CC=1C.O=P(Cl)(Cl)[Cl:32]>C(Cl)(Cl)Cl>[Cl:32][C:16]1[C:11]2[CH:10]=[CH:9][C:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)=[N:21][C:12]=2[N:13]=[C:14]([CH2:18][O:19][CH3:20])[N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCc1nc2nc(-c3ncccc3Cl)ccc2c(=O)[nH]1
Solvent: ClC(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: COCc1nc(Cl)c2ccc(-c3ncccc3Cl)nc2n1

Procedure:
Reflux a mixture of 7-(3-chloro-pyridin-2-yl)-2-methoxymethyl-3H-pyrido[2,3-d]pyrimidin-4-one (0.25 g), 2,6-lutidine (0.44 g), and POCl3 (0.51 g) in CHCl3 (5 mL) for 20 hours. Cool the mixture and concentrate under reduced pressure. Partition the residue between EtOAc and saturated NaHCO3 solution. Wash the EtOAc portion with additional NaHCO3 and then dry (Na2SO4) and concentrate under reduced pressure. Filter the brown residue through 2 inches of silica gel (1:1 EtOAc/hexanes eluent) and concentrate under reduced pressure to give 4-chloro-7-(3-chloro-pyridin-2-yl)-2-methoxymethyl-pyrido[2,3-d]pyrimidine.
Reaction SMILES: [I-:1].[K+].C(O[CH2:6][CH2:7][CH2:8][CH:9]1[C:15]2[CH:16]=[C:17]([I:20])[CH:18]=[CH:19][C:14]=2[CH:13]=[CH:12][C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]1=2)C>>[I:1][CH2:6][CH2:7][CH2:8][CH:9]1[C:15]2[CH:16]=[C:17]([I:20])[CH:18]=[CH:19][C:14]=2[CH:13]=[CH:12][C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]1=2
Reactant: CCOCCCC1c2ccccc2C=Cc2ccc(I)cc21
Reactant: [I-]
Agent: [K+]
Product: ICCCC1c2ccccc2C=Cc2ccc(I)cc21
Temperature: 25 °C

Procedure:
Phosphorus pentoxide (1.28 g.) and concentrated (85%) phosphoric acid (2.7 ml.) are mixed well and cooled to room temperature. Potassium iodide (6.6 g., 0.04 mole), finely powdered, and 5-(3-ethoxypropyl)-3-iodo-5H-dibenzo[a,d]cycloheptene (4.0 g., 0.01 mole) are added and the mixture stirred and heated in an oil bath at 110° for 16 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(Cl)(C(Cl)=O)=O.[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:22][C:21]2[CH:23]=[CH:24][C:18]([F:17])=[C:19]([N+:25]([O-:27])=[O:26])[CH:20]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39592.9 %

Procedure:
To the solution of 4-chlorobenzoic acid (19) (9.36 g, 0.06 mmol) in DCM (150 mL) was added (COCl)2 (17.4 mL, 0.3 mol) dropwise and cat. amount of DMF at 0° C. The mixture was stirred at room temperature for 2 h and evaporated. The residue was again dissolved in DCM (150 mL) and added to a mixture of 4-fluoro-3-nitroaniline (6.24 g, 0.04 mol) and DIEA (20.9 mL, 0.12 mol) in CH2Cl2 (100 mL) at 0° C. The mixture was allowed to stir at room temperature overnight. The solvent was removed under vacuo and the residue was washed with sat. NaHCO3 aq. (50 mL) and brine (50 mL). The organic layer was separated, dried and purified by crystallization to give 20 (7 g, 60%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.Cl.[CH3:8][N:9]([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](O)=[O:14].[NH2:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH2:29][CH3:30])[N:24]=[CH:23][C:22]([C:31]#[N:32])=[C:21]2[NH:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[C:36]([Cl:48])[CH:35]=1.C(=O)(O)[O-].[Na+]>C(#N)C.CN1CCCC1=O.CN(C)C=O>[CH2:41]([O:40][C:37]1[CH:38]=[CH:39][C:34]([NH:33][C:21]2[C:20]3[C:25](=[CH:26][C:27]([O:28][CH2:29][CH3:30])=[C:18]([NH:17][C:13](=[O:14])/[CH:12]=[CH:11]/[CH2:10][N:9]([CH3:16])[CH3:8])[CH:19]=3)[N:24]=[CH:23][C:22]=2[C:31]#[N:32])=[CH:35][C:36]=1[Cl:48])[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: CN(C)C/C=C/C(=O)O
Reactant: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccc4)c(Cl)c3)c2cc1N
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccc4)c(Cl)c3)c2cc1NC(=O)/C=C/CN(C)C
Reaction time: 0.33 h
Yield: 53.2 %

Procedure:
A 1.74 ml (2.54 g, 0.02 moles) portion of oxalyl chloride was added to 3.31 grams (0.02 moles) of (E)-4-(dimethylamino)-2-butenoic acid hydrochloride in 75 ml of acetonitrile. To this was added a small drop of dimethylformamide. The reaction was heated and stirred in an oil bath at 63° for 20 minutes, giving an orange solution. This solution as concentrated in vacuo without the application of heat to about half its original volume. This solution was cooled in an ice bath and a solution of 4.45 g (0.01 moles) of the 6-amino-4-[4-(benzyloxy)-3-chloroanilino]-7-ethoxy-3-quinolinecarbonitrile in 50 ml of N-methylpyrrolidone was added in a stream. The reaction was cooled and stirred for 2 hours. The reaction was poured onto 100 ml of saturated aqueous sodium bicarbonate in ice. On standing the resulting gum solidified and the solid was filtered. This solid was chromatographed on silica gel. The column was washed with 3 liters of 1:19 methanol-ethyl acetate, then the product was eluted with 3 liters of 1:5:94 triethylamine-methanol-ethyl acetate. Concentration of the eluate gave a solid, which was filtered to give 2.96 grams of the title compound. From the filtrate was obtained an additional 1.0 grams of product. Total: 3.96 g.
Reaction SMILES: [CH2:1]([N:8]([CH3:30])[C:9](=O)[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Cl:21])[CH:19]=2)[N:14](C2C=CC(F)=CC=2)[CH:13]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:8]([CH2:9][CH2:10][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Cl:21])[CH:19]=2)[NH:14][CH:13]=1)[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)C(=O)C(=O)c1cn(-c2ccc(F)cc2)c2ccc(Cl)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN(CCc1c[nH]c2ccc(Cl)cc12)Cc1ccccc1
Temperature: 0 °C
Yield: 92.3 %

Procedure:
To a solution of 5-chloroindole (20 g, 0.13 mol) in dry diethyl ether (200 mL) was added a solution of oxalylchloride (20 g, 0.16 mol) in dry diehtyl ether (200 mL) at 0°-5° C. After stirring for 0.5 h at 0°-5° C. was added a solution of benzylmethylamine (24 g, 0.20 mol) in dry diethyl ether at 0°-5° C. and triethylamine was slowly added to pH at 8-9. Water and ethyl acetate (500 mL) was added and the organic phase was washed with brine and dried (Na2SO4). Evaporation of the solvents afforded the crude N-benzyl-N-methyl-2-(5-chloro-1-(4-fluorophenyl)-3-1H-indolyl)-2-oxoacetamide (19.1 g) as an oil. A solution of the crude N-benzyl-N-methyl-2-(5-chloro-1-(4-fluorophenyl)-3-1H-indolyl)-2-oxoacetamide (20.1 g, 0.058 mol) in dry tetrahydrofuran (200 mL) was added to a suspension of lithium aluminium hydride (5.4 g, 0.14 mol) in tetrahydrofuran (100 mL). After heating at reflux for 2.5 h the reaction mixture was cooled to 0° C. and treated with water (6 mL) and 4N aqueous NaOH (6 mL). The precipitate was filtered off and extracted with dichloromethane (3×200 mL). The combined organic phases were dried (Na2SO4) and the solvents were evaporated. The remaining oil was purified by column chromatography (eluted with ethyl acetate) affording N-benzyl-N-methyl-2-(5-chloro-3-1H-indolyl)ethylamine (16 g) as an oil: 1H NMR (CDCl3) δ 2.30 (s, 3 H), 2.65-2.80 (m, 2 H), 2.85-3.00 (m, 2 H), 3.60 (s, 2 H), 6.95 (broad s, 1 H), 7.05-7.20 (m, 2 H), 7.15-7.35 (m, 5), 7.45 (broad s,1 H), 8.35 (broad s,1 H).
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[C:16]3[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=3)[CH:10]([C:18]3[C:19]([OH:27])=[CH:20][C:21]4[O:25][CH2:24][CH2:23][C:22]=4[CH:26]=3)[C:9]2=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:29]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=3)[C:10]3([CH2:35][O:27][C:19]4[CH:20]=[C:21]5[C:22](=[CH:26][C:18]3=4)[CH2:23][CH2:24][O:25]5)[C:9]2=[O:28])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1C(c2cc3c(cc2O)OCC3)c2cc(F)ccc2N1C(c1ccccc1)c1ccccc1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccc(F)cc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-5-fluoro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-5′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1H)-one was obtained (71%) as a colorless solid: mp 228-229° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.39-7.25 (m, 10H), 7.06 (s, 1H), 6.90-6.87 (m, 1H), 6.72-6.65 (m, 1H), 6.42-6.38 (m, 3H), 4.83 (ABq, 2H), 4.53 (t, J=9.0 Hz, 2H), 3.02-2.97 (m, 2H); MS (ES+) m/z 464.1 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:40])[C@H:10]([CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)[NH:11][C:12](=[O:29])[CH:13]([C:20]1[CH:25]=[CH:24][C:23]2[O:26][CH2:27][O:28][C:22]=2[CH:21]=1)[CH:14]([OH:19])[CH2:15][CH2:16][CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:47](OC(=O)C)(=[O:49])[CH3:48]>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9](=[O:40])[C@H:10]([CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)[NH:11][C:12](=[O:29])[CH:13]([C:20]1[CH:25]=[CH:24][C:23]2[O:26][CH2:27][O:28][C:22]=2[CH:21]=1)[CH:14]([O:19][C:47](=[O:49])[CH3:48])[CH2:15][CH2:16][CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(O)C(C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1)c1ccc2c(c1)OCO2
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCCC(OC(C)=O)C(C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of Nα-[(2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-tryptophan benzyl ester (255 mg) in dichloromethane (5 ml) were added pyridine (74 mg), acetic anhydride (72 mg) and 4-(dimethylamino)pyridine (11 mg) at 5° C. and the mixture was stirred at ambient temperature for 18 hours. The mixture was diluted with ethyl acetate (20 ml) and the solution was washed with 0.5N hydrochloric acid (20 ml×2), saturated sodium bicarbonate aqueous solution (20 ml×2) and brine (20 ml) successively and the organic layer was dried over magnesium sulfate. The solution was filtered and concentrated in vacuo to give Nα-[(2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-acetoxyheptanoyl]-L-tryptophan benzyl ester as an oil.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:18][CH:19]=1.[CH3:24][S:25]SC>C1COCC1.O>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[C:15]=1[S:25][CH3:24]
Reactant: CSSC
Reactant: Fc1cccc(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CSc1c(F)cccc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Under an atmosphere of inert gas, 32.8 ml (1.6 M in hexane, 52.5 mmol) of n-butyllithium were added dropwise to a solution, cooled to 0° C., of 7.77 ml (55 mmol) of diisopropylamine in 100 ml of anhydrous THF, and after 10 minutes of stirring the solution was cooled to −78° C. 8.21 g (50 mmol) of 3-fluorobenzotrifluoride were added at this temperature, and the reaction mixture was stirred at this temperature for 1 h. 4.21 ml (55 mmol) of dimethyl disulfide were then added dropwise. Within about 3 h, the reaction mixture had warmed to room temperature (RT), and it was then once more cooled to 0° C. At this temperature, 10 ml of water were added dropwise, and the reaction mixture was concentrated to about ¼ of its volume. The residue was taken up in water and dichloromethane, the phases were separated and the organic phase was washed successively with water, 10 percent strength hydrochloric acid, water, saturated aqueous NaHCO3 solution, water and saturated aqueous NaCl solution and dried over sodium sulfate and filtered. The solvent was removed and the residue was rectified under reduced pressure. This gave 8 g of 1-fluoro-2-methylthio-3-(trifluoromethyl)benzene of a boiling point of 68° C. at 6 mm Hg.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[N:18]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:17]([CH3:23])=[N:16][C:10]=3[C:11]([NH2:15])=[N:12][C:13]=2[CH:14]=1.[N:24]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C(Cl)(Cl)Cl>[NH2:15][C:11]1[C:10]2[N:16]=[C:17]([CH3:23])[N:18]([CH2:19][CH:20]([CH3:21])[CH3:22])[C:9]=2[C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][NH:1][C:30]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:31])=[CH:14][C:13]=2[N:12]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Cc1nc2c(N)nc3cc(OCCN)ccc3c2n1CC(C)C
Solvent: ClC(Cl)Cl
Product: Cc1nc2c(N)nc3cc(OCCNC(=O)N4CCOCC4)ccc3c2n1CC(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 37.3 %

Procedure:
A suspension of 7-(2-aminoethoxy)-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.300 g, 0.958 mmol) in chloroform (10 mL) was cooled to 0° C. 4-Morpholinecarbonyl chloride (0.110 mL, 0.942 mmol) was added dropwise, and the reaction was stirred for five minutes at 0° C. The reaction was then allowed to warm to ambient temperature over a period of 15 minutes, and the solvent was removed under reduced pressure. The resulting off-white solid was dissolved in dichloromethane. The solution was washed sequentially with 10% aqueous sodium hydroxide, water, and brine; dried over magnesium sulfate; filtered; and concentrated under reduced pressure. The residue was recrystallized from acetonitrile to provide 0.150 g of N-(2-{[4-amino-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)morpholine-4-carboxamide as a white powder, mp 215-219° C. (decomposition).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([CH3:25])([CH3:24])[CH2:11][O:12][C:13]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28]1[CH:43]=[CH:42][C:31]([C:32]([NH:34][C:35]2[C:36]([NH2:41])=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:33])=[CH:30][CH:29]=1>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([CH3:25])([CH3:24])[CH2:11][O:12][C:13]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15]([NH:41][C:36]1[C:35]([NH:34][C:32](=[O:33])[C:31]2[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[CH:43][CH:42]=2)=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: COc1ccc(C(=O)O)c(OCC(C)(C)CNC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(OC)cc2OCC(C)(C)CNC(=O)OC(C)(C)C)cc1
Yield: 73.4 %

Procedure:
In a manner substantially equivalent to Example 101-D, 2-(3-tert-butoxycarbonylamino-2,2-dimethylpropoxy)-4-methoxybenzoic acid (2.92 g, 8.25 mmol) and N1-(4-methoxybenzoyl)-1,2-benzenediamine (2.00 g, 8.25 mmol) were coupled. The crude material was dissolved in dichloromethane, and aminomethylated polystyrene was added to remove the unreacted acid chloride. The resin was filtered, the solution added directly to a SCX column (Varian, 60 cc/10 g, prewashed with MeOH), and the product washed through the column with 9:1 CHCl3:MeOH. Concentration of the wash in vacuo gave 3.50 g (73.4%) of a white foam.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1.[I-].[K+].[Cl:10][C:11]1[CH:12]=[C:13]([S:18][C:19]2[NH:23][C:22]([CH2:24][O:25]CC3C=CC(OC)=CC=3)=[N:21][C:20]=2[CH:35]([CH3:37])[CH3:36])[CH:14]=[C:15]([Cl:17])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O.C(O)C>[ClH:1].[Cl:17][C:15]1[CH:14]=[C:13]([S:18][C:19]2[N:23]([CH2:2][C:3]3[CH:7]=[CH:6][S:5][CH:4]=3)[C:22]([CH2:24][OH:25])=[N:21][C:20]=2[CH:35]([CH3:37])[CH3:36])[CH:12]=[C:11]([Cl:10])[CH:16]=1
Reactant: ClCc1ccsc1
Reactant: COc1ccc(COCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)[nH]2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: CC(C)c1nc(CO)n(Cc2ccsc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97 %

Procedure:
In dimethylformamide was added 67 mg of 3-(chloromethyl)thiophene and 152 mg of potassium iodide under ice-cooling, the mixture was allowed to warm up to room temperature and stirred for 20 minutes. Then, 200 mg of 5-(3,5-dichlorophenylthio)-4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (101b)was added, followed by addition of 126 mg of potassium carbonate. Then the mixture was warmed up to 50° C. and allowed to react for 6 hours. After completion of the reaction, the mixture was diluted with water, extracted with diethyl ether, the extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. To thus-obtained oil was added 5 ml of ethanol and 10 ml of 36% hydrochloric acid, and the mixture was stirred at 90° C. for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The crystals were washed with diethyl ether, filtered, and 200 mg of Compound I-127 was obtained (yield 97%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:9]1([CH2:14][C:15]([N:17]2[CH2:21][C@H:20]([NH2:22])[CH2:19][C@H:18]2[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)=[O:24])=[O:16])[CH:13]=[N:12][CH:11]=[N:10]1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[N:9]1([CH2:14][C:15]([N:17]2[CH2:21][C@H:20]([NH:22][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:19][C@H:18]2[C:23]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[CH:30][CH:31]=2)=[O:24])=[O:16])[CH:13]=[N:12][CH:11]=[N:10]1
Reactant: BrCc1ccccc1
Reactant: N[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2cncn2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](NCc2ccccc2)CN1C(=O)Cn1cncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.4 %

Procedure:
Benzyl bromide (0.111 mL, 0.934 mmol) was added to a flask charged with (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-amino-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (0.330 g, 0.778 mmol), DMF (3 mL) and potassium carbonate (0.429 g, 3.11 mmol). The reaction mixture was stirred at ambient temperature for 1 hour and then diluted with methanol (2 mL). Product was purified by reverse phase HPLC to give Compound 179, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(benzylamino)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (97 mg, 0.19 mmol, 24%) as an off-white solid. 1H-NMR (400 MHz, DMSO-d6): 10.08 (s, 1H), 8.44 (s, 1H), 7.95 (s, 1H), 7.57 (d, J=9.6 Hz, 2H), 7.38-7.30 (m, 4H), 7.26-7.16 (m, 3H), 7.03-6.93 (m, 4H), 5.24-5.21 (m, 2H), 4.53-4.48 (m, 1H), 3.85-3.79 (m, 1H), 3.75 (s, 2H), 3.51-3.45 (m, 2H), 3.17 (d, J=6.0 Hz, 1H), 2.15-2.00 (m, 2H). MS (EI) for C28H27FN6O3. found 515.2 (MH+).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[O:30][CH2:29]2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:37]1([S:40]([NH2:43])(=[O:42])=[O:41])[CH2:39][CH2:38]1>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:43][S:40]([CH:37]3[CH2:39][CH2:38]3)(=[O:42])=[O:41])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:24][CH2:25][C:26]2([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[O:30][CH2:29]2)[CH2:27][CH2:28]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Product: O=C(NS(=O)(=O)C1CC1)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Yield: 46.3 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-(2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.105 g, 0.217 mmol) obtained in Example 125, step 2 and cyclopropanesulfonamide (0.131 g, 1.09 mmol), the title compound (0.059 g, 47%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][S:5]([NH:8][C:9]1[C:10](=[O:20])[N:11]([CH2:16][C:17](O)=[O:18])[C:12]([CH3:15])=[CH:13][CH:14]=1)(=[O:7])=[O:6].Cl.Cl.[N:28]1[NH:29][CH:30]=[C:31]2[C:36]=1[CH2:35][CH2:34][CH:33]([CH2:37][NH2:38])[CH2:32]2>>[Cl:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][S:5]([NH:8][C:9]1[C:10](=[O:20])[N:11]([CH2:16][C:17]([NH:38][CH2:37][CH:33]2[CH2:34][CH2:35][C:36]3[C:31](=[CH:30][NH:29][N:28]=3)[CH2:32]2)=[O:18])[C:12]([CH3:15])=[CH:13][CH:14]=1)(=[O:7])=[O:6]
Reactant: NCC1CCc2n[nH]cc2C1
Reactant: Cc1ccc(NS(=O)(=O)Cc2ccc(F)cc2Cl)c(=O)n1CC(=O)O
Agent: Cl
Product: Cc1ccc(NS(=O)(=O)Cc2ccc(F)cc2Cl)c(=O)n1CC(=O)NCC1CCc2n[nH]cc2C1

Procedure:
The title compound was prepared from 2-[3-{[(2-chloro-4-fluorobenzyl)sulfonyl]amino}-6-methyl-2-oxo-1(2H)pyridinyl]acetic acid and 4,5,6,7-tetrahydro-2H-indazol-5-ylmethanamine dihydrochloride using the procedure of EXAMPLE 1 (STEP 6), and was obtained as a white solid compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:31])=[C:8]([CH:30]=1)[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:11]=1)(O)=[O:2].[C:32]([C:36]1[CH:37]=[C:38]([S:45]([CH3:47])=[O:46])[C:39]([O:43][CH3:44])=[C:40]([CH:42]=1)[NH2:41])([CH3:35])([CH3:34])[CH3:33].C(N(CC)CC)C>C(OCC)(=O)C.O1CCCC1>[C:32]([C:36]1[CH:37]=[C:38]([S:45]([CH3:47])=[O:46])[C:39]([O:43][CH3:44])=[C:40]([NH:41][C:1]([C:4]2[CH:5]=[CH:6][C:7]([CH3:31])=[C:8]([CH:30]=2)[O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][CH:17]3[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:21][CH2:22]3)[CH:11]=2)=[O:2])[CH:42]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: Cc1ccc(C(=O)O)cc1Oc1ccnc(CC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: COc1c(N)cc(C(C)(C)C)cc1S(C)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1c(NC(=O)c2ccc(C)c(Oc3ccnc(CC4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)cc(C(C)(C)C)cc1S(C)=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
At ambient temperature 560 μl of a 50% solution of propanephosphoric acid cycloanhydride in ethyl acetate are added to a solution of 120 mg tert-butyl 4-[4-(5-carboxy-2-methyl-phenoxy)-pyridin-2-ylmethyl]-piperidine-1-carboxylate, 68 mg 5-tert-butyl-3-methanesulphinyl-2-methoxy-aniline and 145 μl triethylamine in 4 ml of tetrahydrofuran. The solution is heated to 80° C. and stirred overnight at this temperature. Then the solution is evaporated to dryness and the residue is combined with saturated aqueous NaHCO3 solution and ethyl acetate. The organic phase is separated off and washed with water and saturated aqueous saline solution and dried (Na2SO4). The solvent is evaporated off, and the residue is chromatographed on silica gel with dichloromethane/10% methanolic ammonia solution (99:1→90:10) as eluant.