Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](Br)([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=1>O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH:1]([CH3:3])[CH3:2])[C:21]#[N:22])=[CH:16][CH:15]=1
Reactant: CC(C)Br
Reactant: COc1ccc(CC#N)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C(C#N)C(C)C)cc1

Procedure:
A mixture comprising: isopropyl bromide, sodium hydroxide pels, and optionally the catalyst triethylamine (i.e., approximately 0.5 to 12 mol or weight percent) is stirred and heated to 50°-60° C. Over approximately a 30-minute period 4-methoxyphenylacetonitrile is added to the reaction mixture. Following this addition, the mixture is stirred and heated at reflux for several hours. After cooling, water is added to the reaction mixture which is then stirred briefly. The organic phase containing the product is then separated. This solution can be used in subsequent reaction steps or the product can be isolated by removal of the solvents.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:10]2)=[CH:5][CH:4]=1.CCN(CC)CC.[Cl:24][CH2:25][C:26](Cl)=[O:27].[OH-].[Na+]>C(Cl)Cl>[Cl:24][CH2:25][C:26]([N:13]([CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:10]1)[CH2:14][CH2:15][CH3:16])=[O:27]
Reactant: O=C(Cl)CCl
Reactant: CCCNC1CCc2ccc(OC)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(C(=O)CCl)C1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.4 %

Procedure:
Compound 32a (HCl salt, 5.0 g, 19.5 mmol) and Et3N (5.5 ml, 39.1 mmol) was stirred at 0° C. in CH2Cl2 (65 ml) for 15 min. Chloroacetyl chloride (1.9 ml, 23.5 mmol) was added dropwise and the resulting solution was stirred at room temperature for 20 min, at which time the reaction mixture was poured into a 1M solution of NaOH (50 ml) and the product was extracted with dichloromethane, dried (Na2SO4), filtered, and concentrated. The crude material was purified by column chromatography (Hex:EtOAc, 3:1) to give 5.5 g (95%) of 33a. 1H NMR (400 MHz, CDCl3) 0.90-0.98 (m, 3H), 1.64-1.72 (m, 2H), 3.19-3.27 (m, 2H), 4.00 (s, 3H), 6.61-6.62 (dd, 1H, J=1.6 Hz), 6.64-6.77 (m, 1H), 6.96-6.99 (d, 1H, J=8.8 Hz).
Reaction SMILES: [C:1]([CH2:4][N:5]([C:10]1[CH:15]=[C:14]([C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:17])[CH:13]=[C:12]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:30])[CH:11]=1)[CH2:6][C:7]([OH:9])=[O:8])([OH:3])=[O:2].[C:42]([O:48][CH2:49]Cl)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44].[I-].[Na+]>CC(C)=O>[CH3:44][C:43]([CH3:46])([CH3:45])[C:42](=[O:47])[O:48][CH2:49][O:2][C:1](=[O:3])[CH2:4][N:5]([C:10]1[CH:15]=[C:14]([C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:17])[CH:13]=[C:12]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:30])[CH:11]=1)[CH2:6][C:7]([O:9][CH2:49][O:48][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])=[O:8]
Reactant: CCCCCCCCCCNC(=O)c1cc(C(=O)NCCCCCCCCCC)cc(N(CC(=O)O)CC(=O)O)c1
Reactant: CC(C)(C)C(=O)OCCl
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCCCCCCNC(=O)c1cc(C(=O)NCCCCCCCCCC)cc(N(CC(=O)OCOC(=O)C(C)(C)C)CC(=O)OCOC(=O)C(C)(C)C)c1
Yield: 66.5 %

Procedure:
A mixture of 0.1023 g (0.174 mmol) of N-(carboxymethyl)-N-[3,5-bis[(decylamino)carbonyl]phenyl]glycine, 0.12 ml (0.84 mmol) of chloromethyl pivalate, 0.07 ml (0.49 mmol) of triethylamineand 0.04 1 g of sodium iodide in 3 ml of anhydrous acetone was stirred at reflux under argon for 17 hours. The solvent was removed, NaHCO3 solution was added to the residue and the product was extracted with ethylacetate. The dried extract was concentrated to an oil and purified by chromatography on 20 g of silica gel using 50% ethyl acetate-hexane to give 0.093 g (66% yield) of N-[3,5-bis[(decylamino)carbonyl]phenyl]-N-[2-[(2,2-dimethyl-1-oxopropoxy)methoxy]-2-oxoethyl]glycine (2,2-dimethyl-1-oxopropoxy)methyl ester as a waxy solid.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([OH:12])[CH2:8][CH2:9][C:10]#[CH:11].C(=O)(O)[O-].[Na+]>CC1C=CC(S(O)(=O)=O)=CC=1>[CH2:7]([O:12][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1)[CH2:8][CH2:9][C:10]#[CH:11]
Reactant: C#CCCCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: C#CCCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.2 %

Procedure:
3,4-Dihydro-2H-pyran (5.0 g) was added dropwise to an ice cooled mixture of 4-pentyn-1-ol (5.0 g) and 4-methylbenzenesulfonic acid (0.512 g). The resultant mixture was stirred at room temperature for 4 hours. Solid sodium bicarbonate (1.0 g) was added and the mixture was stirred for 10 minutes, then filtered and washed with diethyl ether. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-100% to give 2-(pent-4-ynyloxy)tetrahydropyran (7.72 g) as a clear oil.
Reaction SMILES: [H-].[Na+].C[CH2:4][CH:5](C(OCC)=O)[C:6](OC)=[O:7].Br[C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[N+:23]([O-])=O>CS(C)=O>[Br:22][C:19]1[CH:18]=[C:17]2[C:16]([CH:5]([CH3:4])[C:6](=[O:7])[NH:23]2)=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Reactant: CCOC(=O)C(CC)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1C(=O)Nc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Sodium hydride (3.9 g) was suspended in dimethyl sulfoxide (24 mL), and diethyl methyl malonate (16 mL) was added at 0° C., and then the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was heated to 100° C., and a solution of 2,5-dibromonitrobenzene (15.3 g) in dimethyl sulfoxide (17 mL) was added at 100° C., and then the reaction mixture was stirred at 100° C. for 5 hours. The reaction mixture was quenched with water, and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (75 mL), and tin (11.5 g) was added at room temperature. Concentrated hydrochloric acid (45 mL) was added at 0° C., and then the reaction mixture was heated at reflux for 2 hours. After cooling to room temperature, the reaction mixture was quenched with water, and extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (4.9 g) as a brown solid.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[C:8]([OH:10])=[O:9].[CH3:11][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[ClH:1].[CH3:11][O:9][C:8]([C@H:4]1[CH2:5][CH2:6][CH2:7][C@H:3]1[NH2:2])=[O:10]
Reactant: N[C@@H]1CCC[C@@H]1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)[C@H]1CCC[C@H]1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(1S,2R)-2-Amino-cyclopentanecarboxylic acid hydrochloride (126 mg, 0.76 mmol) was dissolved in a 1:1 mixture of benzene and methanol (8 mL). The mixture was cooled to 0° C. A 2.0 M solution of (trimethylsilyl)diazomethane in hexanes (0.57 mL, 1.14 mmol) was added and the reaction was stirred at 25° C. for 30 min. The mixture was concentrated and dried in vacuo. The crude product was directly used in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)=[CH:11]/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N+:26]([C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)([O-:28])=[O:27].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:26]([C:29]1[CH:34]=[CH:33][C:32]([O:15][C:14](=[O:16])/[CH:13]=[CH:12]/[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:31][CH:30]=1)([O-:28])=[O:27]
Reactant: O=C(O)/C=C/C=C(c1cccc([N+](=O)[O-])c1)c1cccc([N+](=O)[O-])c1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(/C=C/C=C(c1cccc([N+](=O)[O-])c1)c1cccc([N+](=O)[O-])c1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 95.5 %

Procedure:
As in Example 115, (E)-5,5-bis(3-nitrophenyl)-2,4-pentadienoic acid (0.78 g) and 4-nitrophenol (0.35 g) in dichloromethane (10 mL) was treated with 1,3-dicyclohexylcarbodiimide (0.47 g). The mixture was stirred at 0°-5° C. for 1 hour, then at room temperature for 1 hour. The usual work up furnished 1.01 g of crude (E)-5,5-bis(3-nitrophenyl)-2.4-pentadienoic acid 4-nitrophenyl ester. This intermediate was used without further purification.
Reaction SMILES: [O-]CC.[Na+].O=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]1[C:19]([O:21]C)=O.[O:23]1[C:27]([C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH2:37])=[NH:36])=[CH:30][CH:29]=2)=[CH:26][N:25]=[CH:24]1>C(O)C>[OH:21][C:19]1[C:7]2[CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11][C:6]=2[N:37]=[C:35]([NH:34][C:31]2[CH:32]=[CH:33][C:28]([C:27]3[O:23][CH:24]=[N:25][CH:26]=3)=[CH:29][CH:30]=2)[N:36]=1
Reactant: N=C(N)Nc1ccc(-c2cnco2)cc1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(O)c2C1
Temperature: 100 °C
Yield: 75.6 %

Procedure:
Sodium ethoxide (0.106 g, 1.55 mmol) was added to 1-tert-butyl 3-methyl 4-oxopiperidine-1,3-dicarboxylate (0.400 g, 1.55 mmol, Example 3c) and 1-(4-(oxazol-5-yl)phenyl)guanidine (obtained from Example 1e, 0.314 g, 1.55 mmol) in ethanol (4 mL) and heated in a microwave reactor at 100° C. for 15 minutes. The suspension was diluted with ethanol (5 mL) and the precipitated product was filtered off and washed with cold ethanol to give tert-butyl 4-hydroxy-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.480 g, 75%). No further purification. MS (ESI+)/(ESI−) M/Z 410/408
Reaction SMILES: [F:1][C:2]1[C:11]2[N:10]=[N:9][C:8]3[C:12](=[O:24])[N:13]([C:15]4[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=4)[NH:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:27])=O>>[F:1][C:2]1[C:11]2[N:10]=[N:9][C:8]3[C:12](=[O:24])[N:13]([C:15]4[CH:23]=[CH:22][C:18]([C:19]([Cl:27])=[O:20])=[CH:17][CH:16]=4)[NH:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(-n2[nH]c3c(nnc4c(F)cccc43)c2=O)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(-n2[nH]c3c(nnc4c(F)cccc43)c2=O)cc1
Temperature: 70 °C

Procedure:
Crude 4-(6-fluoro-3-oxo-1,3-dihydro-2H-pyrazolo[4,3-c]cinnolin-2-yl)-benzoic acid (1.45 g) from the previous stage was dissolved in thionyl chloride (50 ml). The mixture was heated to 70° C. for 2-3 h until no further gas evolution was observed. The mixture was cooled to room temperature and excess thionyl chloride was removed under vacuum. The residues were azeotroped with toluene (2×20 ml) to give a solid. The solid was collected by filtration, washed with toluene and dried under vacuum. The product was isolated as a yellow powder (670 mg, 1.95 mmol). LCMS: m/z [M+H]+ 339 (methyl ester resulting from sample make-up in methanol).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6]Cl.[CH3:8][C:9]([C:12]1[CH:13]=[C:14]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])[C:15]([O:17][CH3:18])=[O:16])([CH3:11])[CH3:10].C(N(C(C)C)CC)(C)C.[NH4+].[Cl-]>C(Cl)Cl>[CH3:11][C:9]([C:12]1[CH:13]=[C:14]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[O:22][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:15]([O:17][CH3:18])=[O:16])([CH3:8])[CH3:10]
Reactant: COCCOCCl
Reactant: COC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOc1c(C(C)(C)C)cc(C(=O)OC)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.6 %

Procedure:
2-Methoxyethoxy-methyl chloride (24.0 g, 192.7 mmol) is added dropwise to a 0° C. mixture of 25.0 g (94.6 mmol) of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoic acid, methyl ester and 27.5 g (212.4 mmol) of diisopropylethylamine in 50 ml of CH2Cl2 under a nitrogen atmosphere. The reaction is stirred at 25° C. for 24 hours and then poured onto saturated aqueous NH4Cl and the layers are separated. The aqueous layer is extracted with t-butylmethyl ether (2×150 ml). The combined organic extracts are washed with saturated aqueous NH4Cl, water and brine (2×), dried over Na2SO4, and concentrated in vacuo to give 33.2 g of the desired product as an orange oil. The product is pure enough to use in subsequent reactions. A sample can be purified by chromatography (flash, SiO2, 230-400 mesh, 29×6.5 cm, 15% t-butylmethylether-hexane) followed by Kugelrohr distillation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.ClC1C(Cl)=CC=CC=1N1CCN([CH2:29][CH2:30][CH:31]2[CH2:33][O:32]2)CC1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:29][CH2:30][CH:31]2[CH2:33][O:32]2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: Clc1cccc(N2CCN(CCC3CO3)CC2)c1Cl
Product: COc1ccccc1N1CCN(CCC2CO2)CC1
Yield: 87 %

Procedure:
Prepared from 24 and 1-(2-methoxyphenyl)piperazine in a similar fashion as described above for 28a. Yield: 87%, 1H NMR (CDCl3): δ 2.60 (m, 2H), 2.67 (s, 4H), 2.78 (dd, J 4.9, 4.0), 3.00 (m, 1H), 3.10 (s, 4H), 3.86 (s, 3H), 6.86 (dd, J 7.8, 1.3, 1H), 6.88-7.03 (m, 3H). 13C NMR (CDCl3): δ 30.2, 47.2, 50.7, 51.0, 53.5, 55.2, 55.4, 111.2, 118.3, 121.1, 123.0, 141.4, 152.3.
Reaction SMILES: [NH2:1][CH:2]1[N:7]=[C:6](Br)[C:5]([C:9]#[N:10])=[C:4]([CH3:11])[N:3]1[SH:12].[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[NH2:1][CH:2]1[N:7]=[C:6]([N:23]2[CH2:22][CH2:21][N:20]([C:17]3[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=3)[CH2:25][CH2:24]2)[C:5]([C:9]#[N:10])=[C:4]([CH3:11])[N:3]1[SH:12]
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CC1=C(C#N)C(Br)=NC(N)N1S
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC1=C(C#N)C(N2CCN(c3ccc(F)cc3)CC2)=NC(N)N1S

Procedure:
In analogy to the procedure described in example 20b, 2-amino-4-bromo-6-methyl-sulfanyl-pyrimidine-5-carbonitrile (see example 69) was treated with 1-(4-fluorophenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at room temperature during 36 hours to yield 2-amino-4-[4-(4-fluoro-phenyl)-piperazin-1-yl]-6-methyl-sulfanyl-pyrimidine-5-carbonitrile as a yellow powder; MS: [M+H]+=345.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[Br:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>O1CCCC1>[Br:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][CH:5]=[O:7]
Reactant: Nc1ccccc1Br
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: O=CO
Product: O=CNc1ccccc1Br
Temperature: 25 °C
Yield: 83.8 %

Procedure:
To acetic anhydride (74.2 g, 727 mmol) was added formic acid (32.9 mL, 872 mmol) under a nitrogen atmosphere while stirring at room temperature, followed by stirring at 70° C. for 3 hours. The reaction mixture was allowed to cool down to room temperature, and tetrahydrofuran (50 mL) was added. To the solution was added a solution of 2-bromoaniline (50.0 g, 291 mmol) in tetrahydrofuran (50 mL) at room temperature, followed by stirring at the same temperature for 1 hour, and concentration was carried out. To the resultant crude crystals was added ethanol (200 mL), followed by heating and stirring at 60° C. After the crystals dissolved, the mixture was allowed to cool down to room temperature, then water (400 mL) was added, followed by stirring for 3 hours. The precipitated crystals were collected by filtration to give 48.8 g of the title compound as white crystals.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])(=[O:3])[CH3:2].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].CC(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([N:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C(C)=O)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 57 %

Procedure:
3.48 g (10 mmol) of Compound 27 obtained in Example 27 was dissolved in 100 ml of dimethylformamide under argon atmosphere, 1.32 ml of ethyl bromoacetate and 1.23 g of potassium tert-butoxide were added under ice-cooling and the mixture was stirred at room temperature for 25 minutes. The reaction solution was cooled on ice, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was triturated with ethyl acetate to give 3.20 g (57%) of 2-[4-(N-acetyl-N-ethoxycarbonylmethylamino)-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([S:11][CH3:12])=[N:10][C:3]=12.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=1.[H-].[Na+].O>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=4[C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=3)[C:9]([S:11][CH3:12])=[N:10][C:3]=12
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CSc1nc2c(C)ccnc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1-c1ccc(Cn2c(SC)nc3c(C)ccnc32)cc1
Reaction time: 0.5 h

Procedure:
200 mg of 7-methyl-2-methylthio-3H-imidazo[4,5-b]pyridine and 370 mg of methyl 2-(4-bromomethylphenyl)benzoate was dissolved in dimethylformamide, and 48 mg of sodium hydride was added at room temperature to the solution under stirring. The reaction was allowed to proceed for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and the solvent was distilled off in vacuo. The residue was purified by silica gel chromatography (benzene:ethyl acetate=10:1→3:2) to prepare the intended product as a colorless oleaginous substance. The yield was 60 mg.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N+:29]([O-])=O)=[C:14]([CH2:16][CH2:17][CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:27]([O:26][C:24]([CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][CH2:16][C:14]1[CH:15]=[C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:11]=[CH:12][C:13]=1[NH2:29])=[O:25])[CH3:28]
Reactant: [H][H]
Reactant: CCOC(=O)C(CCc1cc(CNC(=O)OC(C)(C)C)ccc1[N+](=O)[O-])C(=O)OCC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CCc1cc(CNC(=O)OC(C)(C)C)ccc1N)C(=O)OCC
Yield: 93.9 %

Procedure:
A solution of ethyl 4-(5-tert-butoxycarbonylaminomethyl-2-nitrophenyl)-2-ethoxycarbonylbutanoate (3.2 g, 7.3 mmol) in ethyl acetate (30 mL) was hydrogenated over palladium/charcoal (500 mg) under atmospheric pressure of hydrogen at room temperature for 2.5 h. The mixture was passed through celite and the filtrate was concentrated to give 2.8 g of the title compound (94%).
Reaction SMILES: [F:1][C:2]1[CH:52]=[CH:51][C:5]([C:6]([N:8]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:49]=[CH:48][C:25]4[N:26]([C:29]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:27]=[N:28][C:24]=4[CH:23]=3)[CH:19]=[CH:18][C:17]=2[F:50])[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1.[CH:53](I)([CH3:55])[CH3:54].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:49]=[CH:48][C:25]4[N:26]([C:29]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:27]=[N:28][C:24]=4[CH:23]=3)[CH:19]=[CH:18][C:17]=2[F:50])[CH:9]2[CH2:14][CH2:13][N:12]([CH:53]([CH3:55])[CH3:54])[CH2:11][CH2:10]2)=[O:7])=[CH:51][CH:52]=1
Reactant: CC(C)I
Reactant: O=C(c1ccc(F)cc1)N(Cc1cc(-c2ccc3c(c2)nnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)ccc1F)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N1CCC(N(Cc2cc(-c3ccc4c(c3)nnn4C(c3ccccc3)(c3ccccc3)c3ccccc3)ccc2F)C(=O)c2ccc(F)cc2)CC1
Reaction time: 240 h
Yield: 61.5 %

Procedure:
A mixture of 4-Fluoro-N-[2-fluoro-5-(1-trityl-1H-benzotriazol-5-yl)-benzyl]-N-piperidin-4-yl-benzamide (25 mg, 0.04 mmol), isopropyl iodide (34 mg, 0.2 mmol) and potassium carbonate (28 mg, 0.2 mmol) in 2 mL of DMF was heated at 40° C. for 3 h when additional isopropyl iodide (34 mg, 0.2 mmol) was added. The mixture was heated for an additional 2 h and then left at ambient temperature for 10 days. The mixture was diluted with water and the product extracted into ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated to leave the crude product. Chromatography (elution with methanol/dichloromethane) provided 18 mg of product.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=2)[CH:4]=[CH:3][N:2]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:47][C@@H:48]([CH2:62][C:63]1[CH:68]=[C:67]([F:69])[CH:66]=[C:65]([F:70])[CH:64]=1)[C@H:49]([OH:61])[CH2:50][NH:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][CH3:60])[CH:54]=1>C(Cl)Cl>[F:69][C:67]1[CH:68]=[C:63]([CH:64]=[C:65]([F:70])[CH:66]=1)[CH2:62][C@H:48]([NH:47][C:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH:4]=[CH:3][N:2]=[CH:1]2)=[CH:6][CH:7]=1)=[O:13])[C@H:49]([OH:61])[CH2:50][NH:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][CH3:60])[CH:54]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: O=C(O)c1ccc2ccncc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2ccc3ccncc3c2)c1
Reaction time: 18 h
Yield: 17.8 %

Procedure:
To a stirred solution of isoquinoline-7-carboxylic acid (200 mg, 1.15 mmol) and N,N-diisopropyl ethylamine (1.20 mL, 6.88 mmol) in methylene chloride (14.0 mL) was added HBTU (438 mg, 1.15 mmol) and the reaction stirred for 0.5 h. (2R,3S)-3-Amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (470 mg, 1.15 mmol) was added in one portion and the reaction mixture was stirred under nitrogen for 18 h. The reaction mixture was then diluted with additional methylene chloride and washed with saturated sodium bicarbonate, saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 0–5% methanol/methylene chloride) gave N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}isoquinoline-7-carboxamide (100 mg) which was characterized as its bis-HCl salt: mp 142–143° C.; ESI MS m/z 490 [M+H]+