Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.Cl[C:9]1[N:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=1>>[CH3:1][NH:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:9]2[N:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=2)[CH2:4]1
Reactant: CN[C@H]1CCNC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Product: CN[C@H]1CCN(c2ncc([N+](=O)[O-])cn2)C1
Temperature: 110 °C

Procedure:
(S)—N-Methylpyrrolidin-3-amine (286 mg, 2.86 mmol) was added to 2-chloro-5-nitropyrimidine (415 mg, 2.60 mmol) slowly (CAUTION: extreme exotherm!!!). The resulting mixture was heated at 110° C. for 10 min. After cooling down to room temperature, another portion of amine (0.100 g) was added to the reaction mixture. The resulting mixture was heated at 110° C. for 10 min. After cooling down to room temperature, the obtained black solid product (Example 47A) was used for next step without further purification. LCMS (ES): m/z 252.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37]CBr)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>CN(C)C=O>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37][O:19][C:13]2[CH:12]=[C:11]3[C:16]([C:7]([O:6][C:5]4[CH:20]=[CH:21][C:2]([NH2:1])=[CH:3][CH:4]=4)=[CH:8][CH:9]=[N:10]3)=[CH:15][C:14]=2[C:17]#[N:18])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(CCBr)CC1
Reactant: N#Cc1cc2c(Oc3ccc(N)cc3)ccnc2cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COc2cc3nccc(Oc4ccc(N)cc4)c3cc2C#N)CC1

Procedure:
After treating 4-(4-aminophenoxy)-7-hydroxyquinoline-6-carbonitrile (0.32 g) with sodium hydride in dimethylformamide in the same manner as Production Example 713-2, it was reacted with 4-bromoethylpiperidine-1-carboxylic acid tert-butyl ester to obtain the title compound (225 mg) as a solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[ClH:7].[CH2:8]([NH:10][CH2:11][CH2:12][Cl:13])[CH3:9]>C(O)C>[ClH:13].[Cl-:7].[CH2:8]([NH:10][CH2:11][CH2:12][N+:4]1[CH:5]=[CH:6][N:2]([CH3:1])[CH:3]=1)[CH3:9]
Reactant: CCNCCCl
Reactant: Cn1ccnc1
Agent: Cl
Solvent: CCO
Product: CCNCC[n+]1ccn(C)c1
Product: [Cl-]
Reaction time: 36 h

Procedure:
4.0 g (60 mmol) of N-methylimidazole are added to 7.7 g (50 mmol) of 2-ethylaminoethyl chloride hydrochloride in 50 ml of absolute ethanol and the mixture is stirred for 36 hours at not more than 40° C. If higher temperatures are used, elimination takes place and the 1-methylimidazolium chloride thus formed can be removed only with difficulty. After the reaction is complete, the solution is concentrated under reduced pressure and the product is precipitated with ether. Washing a number of times with THF gives the product as a white hygroscopic powder. Yield: 9.3 g (83%).
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[C:4]([NH:6][CH:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[NH:14][CH:13]=3)[N:9]([CH3:23])[CH2:8]1)=[O:5])[CH3:2].B(F)(F)F.CCOCC.S(Cl)([Cl:38])(=O)=O>C(#N)C.C(Cl)Cl>[Cl:38][C:13]1[NH:14][C:15]2[C:22]3[C:12]=1[CH2:11][C@@H:10]1[C@@H:20]([C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:21][C@@H:7]([NH:6][C:4](=[O:5])[N:3]([CH2:1][CH3:2])[CH2:24][CH3:25])[CH2:8][N:9]1[CH3:23]
Reactant: CCN(CC)C(=O)NC1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Reactant: O=S(=O)(Cl)Cl
Agent: FB(F)F
Solvent: ClCCl
Solvent: CC#N
Solvent: CCOCC
Product: CCN(CC)C(=O)N[C@@H]1C[C@@H]2c3cccc4[nH]c(Cl)c(c34)C[C@H]2N(C)C1

Procedure:
In the same was as described in Example 7, 340 mg of 1,1-diethyl-3(6-methylergolinyl)urea (1 millimole) was dissolved in 19 ml of anhydrous acetonitrile and 0.3 ml of boron trifluoride etherate in 5 ml of anhydrous methylene chloride and reacted with 0.09 ml of freshly distilled sulfuryl chloride, dissolved in 10 ml of anhydrous methylene chloride. The product was worked up and chromatographed as described in Example 7, thus obtaining 270 mg of 3-(2-chloro-6-methyl-8β-ergolinyl)-1,1-diethylurea.
Reaction SMILES: [CH2:1]([CH:9]1[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]1)[CH:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.[C:16]([OH:20])(=O)[CH2:17][OH:18]>C(O)(C)C.C(O)C>[CH2:1]([CH:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:16](=[O:20])[CH2:17][OH:18])[CH2:6][CH2:7]1)[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:17](=[O:18])[CH2:16][OH:20])[CH2:11][CH2:10]1
Reactant: NC1CCC(CC2CCC(N)CC2)CC1
Reactant: O=C(O)CO
Solvent: CCO
Solvent: CC(C)O
Product: O=C(CO)NC1CCC(CC2CCC(NC(=O)CO)CC2)CC1

Procedure:
4,4'-Methylenebis(cyclohexylamine) (56.5 g, 0.27 mole) was dissolved in hot isopropanol (500 ml) and glycolic acid (40.9 g, 0.54 mole) added portion-wise with stirring. Upon cooling, a white gummy solid separated which was isolated by decantation and redissolved in a small volume of ethanol. Crystallization produced a white crystalline, deliquescent solid; m.p. 96°-102° C. Thorough drying under vacuum increased the melting point (m.p. 149°-151° C.) and reduced the deliquescence.
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[S:3]([CH2:6][C:7](OC)=[O:8])(=[O:5])=[O:4].[NH2:25][OH:26]>>[OH:26][NH:25][C:7](=[O:8])[CH2:6][S:3]([N:2]([CH3:1])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)(=[O:5])=[O:4]
Reactant: COC(=O)CS(=O)(=O)N(C)CCc1ccc(-c2ccccc2)cc1
Reactant: NO
Product: CN(CCc1ccc(-c2ccccc2)cc1)S(=O)(=O)CC(=O)NO

Procedure:
In a manner similar to Example 1 (b), methyl 2-({methyl-[2-(biphen-4-yl)ethyl]amino}sulfonyl)acetate was reacted with hydroxylamine to give the title compound as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:15])[NH:4][C:5](=[O:14])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[NH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1>C1COCC1>[Cl-:1].[NH2:16][C:17]1[CH:18]=[N+:19]([C:2]2[C:3](=[O:15])[NH:4][C:5](=[O:14])[C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: O=C1NC(=O)C(c2ccc(Cl)cc2)=C1Cl
Reactant: Nc1cccnc1
Solvent: C1CCOC1
Product: Nc1ccc[n+](C2=C(c3ccc(Cl)cc3)C(=O)NC2=O)c1
Product: [Cl-]
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 3-chloro-4-(4-chlorophenyl)-1H-pyrrole-2,5-dione (100 mg, 0.41 mmol) and 3-aminopyridine (42.7 mg, 0.45 mmol) in dry THF (2.5 mL) was heated at 50° C. for 2 hours then stirred at room temperature overnight. The resulting suspension was filtered and the solid washed with dichloromethane (20 mL), then hexane (10 mL) to give the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.Cl.[CH2:13]([O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN(CC)CC.O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:25][C:24]2[CH:23]=[CH:22][C:21]([O:20][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:27][CH:26]=2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=[N+]([O-])c1cnc(Cl)cc1Nc1ccc(OCc2ccccc2)cc1
Temperature: 60 °C
Yield: 92.1 %

Procedure:
The product of Example 1, Step 3 (15.2 g, 78.7 mmol), 4-benzyloxyaniline HCl (15.6 g, 78.7 mmol) and Et3N (27 mL, 196.9 mmol) were combined in DMF (125 mL) and heated to 60° C. for 1 h. The reaction mixture was cooled and H2O (200 mL) was added dropwise over 1 h. The resulting yellow/orange precipitate was filtered and washed with Et2O to provide the title compound as a yellow powder (25.8 g, 92%). MS (ES+) m/e 356 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]#N.S(=O)(=O)(O)O.[CH2:18]([O:20]CC)[CH3:19].[OH2:23]>C(O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]([O:20][CH2:18][CH3:19])=[O:23]
Reactant: CCOCC
Reactant: N#CCc1c(F)ccc(F)c1F
Reactant: O
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)Cc1c(F)ccc(F)c1F
Temperature: 125 °C

Procedure:
2-(2,3,6-Trifluorophenyl)acetonitrile (13.3 g) is dissolved in ethanol (20 ml), and thereto is carefully added conc. sulfuric acid (8.5 ml), and the mixture is refluxed at 125° C. for 7 hours. After cooling, the reaction mixture is fractionated with diethyl ether and water. The ether layer is washed with aqueous saturated sodium chloride and dried over magnesium sulfate and then concentrated under reduced pressure to give ethyl 2-(2,3,6-trifluorophenyl)acetate (16.3 g), as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)=O.Cl.[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])(=O)C.[Na+]>C(O)CCC>[C:18]1([NH:24][N:25]=[C:4]([CH:6]2[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[F:1])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN1CCC(C(=O)c2ccccc2F)CC1
Reactant: NNc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: CN1CCC(C(=NNc2ccccc2)c2ccccc2F)CC1
Yield: 82.7 %

Procedure:
A mixture of 14.6 g of 4-(2-fluorobenzoyl)-1-methylpiperidine, 12.0 g of phenylhydrazine hydrochloride and 16.0 g of sodium acetate in 280 ml of n-butanol was heated under reflux for 3.5 hrs. The reaction mixture was cooled, filtered and concentrated. The residue was washed with ether to yield 17 g (83%) of 4-(2-fluorobenzoyl)-1-methylpiperidine phenylhydrazone, mp 131°-134° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.N[C:14]1[CH:21]=[CH:20][CH:19]=[C:16]2[CH2:17][CH2:18][C:15]=12.[N+:22](C1C=CC=C2CCC=12)([O-])=O.O>C(O)(=O)C>[CH:18]1[C:15]2[CH:14]=[CH:21][C:20]([N:22]3[C:9](=[O:10])[C:4]4=[CH:3][C:2]([Br:1])=[CH:12][CH:11]=[C:5]4[C:6]3=[O:8])=[CH:19][C:16]=2[CH:17]=1
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Reactant: O=[N+]([O-])c1cccc2c1CC2
Reactant: Nc1cccc2c1CC2
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccc(Br)cc2C(=O)N1c1ccc2c(c1)C=C2
Temperature: 25 °C

Procedure:
A mixture of 4-bromophthalic anhydride (12.4 g, 54.6 mmoles) and 4-amino-benzocyclobutene (6.5 g., 54.5 mmoles), freshly prepared from the catalytic hydrogenation of 4-nitro-benzocyclobutene, were gently refluxed in glacial acetic acid (120 ml) under nitrogen atmosphere for about 17 hrs. The resultant dark but homogeneous reaction mixture was allowed to cool to room temperature under N2 and then poured into approximately 750 ml of H2O. Precipitation of gray solid immediately took place. Then, about 200 ml of CH2Cl2 was added to the mixture to deliver a two-phase, homogeneous solution. Subsequently, the CH2Cl2 layer was separated and the aqueous layer was extracted further with CH2Cl2 (2×50 ml). The combined CH2Cl2 extract was first concentracted to about 100 ml and then passed through a chromotography column (internal diameter, 2 cm., approximately 110 g silica gel, saturated with hexane). Elution of the column with hexane led to the isolations of the desired product, which crystallized out as beige microcrystals upon rotary evaporation. The product was collected, washed with hexane and dried in vacuo at 75° C. overnight. Yield: 11.7 g (65.4%, based on 4-aminobenzocyclobutene). M.P.=167°-168° C. Calculate for C16H10BrNO2 : 58.56% C; 3.07% H; 4.27% N; 24.35% Br. Found: 58.03% C; 3.20% H; 4.20% N; 24.26% Br. Mass spectroscopy: 327,329 (31.24%, 35.51%, M+). Proton nmr (δ values in ppm): 3.24 (singlet; benzocyclobutenyl aliphatic protons, 4); 7.17, 8.06 (complex; aromatic protons, 6H). IR (KBr; in cm-1) 2990 vw, 2975 w (aliphatic C--H stretches); 1775 m, 1718 vs (imide linkage stretches).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:24][NH2:25]>>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:9]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([NH:25][CH3:24])[N:7]3[N:8]=2)=[CH:18][CH:19]=1
Reactant: CN
Reactant: Fc1ccc(-c2nn3c(Cl)cccc3c2-c2ccncc2)cc1
Product: CNc1cccc2c(-c3ccncc3)c(-c3ccc(F)cc3)nn12
Yield: 77.3 %

Procedure:
7-Chloro-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-α]pyridine (25 mg, 0.077 mmol) and excess of methylamine in alcohol (1 mL) in sealed tube was heated at 120° C. for overnight. The mixture was evaporated to dryness and purified by preparative thin layer chromatography to give 2-(4-fluorophenyl)-N-methyl-3-(4-pyridinyl)pyrazolo[1,5-α]pyridin-7-amine a peach solid in 77.3% yield. 1H NMR (CDCl3): δ 8.59 (d, 2H, J=5.4 Hz), 7.58–7.62 (m, 2H), 7.28–7.30 (m, 3H), 7.07–7.14 (m, 3H), 6.11 (bs, 1H), 6.00 (d, 1H, J=7.4 Hz), 3.16 (d, 3H, J=5.0 Hz); MS (ES+ve): 320 (18, M+2), 319 (20, M+1), 318 (100, M+).
Reaction SMILES: CO.C[O:4][C:5]1[C:10]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]3)[C:15]([CH3:32])=[C:14]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:13]=2)=[CH:9][CH:8]=[CH:7][N:6]=1.Cl>O1CCOCC1>[CH3:32][C:15]1[C:14]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[N:13][C:12]([NH:11][C:10]2[C:5](=[O:4])[NH:6][CH:7]=[CH:8][CH:9]=2)=[N:17][C:16]=1[NH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]1
Reactant: COc1ncccc1Nc1nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c(C)c(N2CCOCC2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1c(N[C@@H]2CCCNC2)nc(Nc2ccc[nH]c2=O)nc1N1CCOCC1
Temperature: 40 °C
Reaction time: 3 h
Yield: 50.7 %

Procedure:
Methanol was added to a stirred mixture of (R)-tert-butyl 3-(2-(2-methoxypyridin-3-ylamino)-5-methyl-6-morpholinopyrimidin-4-ylamino)piperidine-1-carboxylate (Preparation 26a, 0.212 g, 0.42 mmol) and 4N solution of hydrogen chloride in 1,4-dioxane (4 mL) in a sealed tube at ambient temperature until a clear solution was formed. After stirring for an additional 3 hours, further 4N hydrogen chloride solution in 1,4-dioxane (3 mL) was added and the resulting mixture was stirred and heated at 40° C. overnight. The solvents were evaporated under reduced pressure and the residue was partitioned between ethyl acetate and an saturated aqueous solution of sodium hydrogencarbonate. The organic layer was separated and the aqueous phase was washed with ethyl acetate (×2). The combined organic extracts were dried (Na2SO4) and the solvent evaporated under reduced pressure to give the title compound (0.082 g, 37%) as an orange foam that was used in the next synthetic step without further purification.
Reaction SMILES: [C:1]([C:8]1[C:9]([NH2:19])=[C:10]([C:14](=O)[C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[NH2:21][OH:22]>>[C:1]([C:8]1[C:9]([NH2:19])=[C:10]([C:14](=[N:21][OH:22])[C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)c1cccc(C(=O)C(=O)O)c1N
Reactant: NO
Agent: Cl
Product: CC(C)(C)OC(=O)c1cccc(C(=NO)C(=O)O)c1N

Procedure:
11.7 g of 2-(3-BOC-aminophenyl)-glyoxylic acid are reacted with 5 g of hydroxylamine hydrochloride in the manner described in Example 4. 2-(3-BOC-Aminophenyl)-2-hydroxyiminoacetic acid is obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N+:11]([O-])=O)[C:6](=[O:10])[NH:7][C:8]=1[CH3:9])[CH3:2].[H][H]>CO.O1CCCC1.[Pd]>[NH2:11][C:5]1[C:6](=[O:10])[NH:7][C:8]([CH3:9])=[C:3]([CH2:1][CH3:2])[CH:4]=1
Reactant: CCc1cc([N+](=O)[O-])c(=O)[nH]c1C
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc(N)c(=O)[nH]c1C

Procedure:
A yellow solution of the 5-ethyl-6-methyl-3-nitro-2(1H)-pyridinone (10 g, 55 mmol) in a mixture of methanol and tetrahydrofuran (100 mL, 1:1 v/v) was reduced catalytically in the presence of 7% palladium on charcoal (0.7 g) under and atmosphere of hydrogen (50 psi) at room temperature over a period of 3.5 hours. The resultant mixture was filtered through a small pad of Celite. The filtrate was concentrated under reduced pressure (15 torr) to provide the corresponding aminopyridone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5](Cl)=[N:6][CH:7]=1.[O-:20][CH2:21][CH3:22].[Na+].C(=O)(O)[O-].[Na+].Cl>>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5]([O:20][CH2:21][CH3:22])=[N:6][CH:7]=1
Reactant: O=S(=O)(Nc1cc(Br)cnc1Cl)c1ccc(O)cc1
Reactant: CC[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOc1ncc(Br)cc1NS(=O)(=O)c1ccc(O)cc1
Yield: 94 %

Procedure:
N-(5-Bromo-2-chloropyridin-3-yl)-4-hydroxybenzenesulfonamide (264 mg, 0.55 mmol) and sodium ethoxide (21% in ethanol, 10 ml, 27 mmol) were stirred at 120° C. for 90 min under microwave conditions. The reaction mixture was poured into sodium bicarbonate saturated solution, neutralized with concentrated chlorhydric acid and extracted with ethyl acetate (×3). The organic phase was dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure to obtain 211 mg (94% yield, 91% purity) of the title compound, which was used in the next synthetic step without further purification.
Reaction SMILES: C1C=CC=CC=1.[Cl:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[CH:15]([CH3:17])[CH3:16])[NH2:11].[CH3:18][C:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1>C(N(CC)CC)C>[Cl:7][C:8]1[CH:9]=[C:10]([NH:11][C:22]([C:19]2([CH3:18])[CH2:21][CH2:20]2)=[O:23])[CH:12]=[CH:13][C:14]=1[CH:15]([CH3:17])[CH3:16]
Reactant: CC1(C(=O)Cl)CC1
Reactant: CC(C)c1ccc(N)cc1Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)c1ccc(NC(=O)C2(C)CC2)cc1Cl
Reaction time: 1 h
Yield: 0 %

Procedure:
To 90 ml of benzene were added 1.0 g (5.9/1000 mole) of 3-chloro-4-isopropylaniline, 0.7 g of triethylamine, and 0.8 g (6.8/1000 mole) of 1-methylcyclopropanecarboxylic acid chloride. The mixture was stirred for 1 hour at 5° to 10° C. The precipitated crystals were separated by filtration, and the filtrate was washed with a saturated aqueous solution of sodium hydrogen carbonate and dried over anhydrous sodium sulfate. The resulting dried filtrate was concentrated by an evaporator. The resulting oily product was isolated and purified by silica gel column chromatography [eluent: benzene/ethyl acetate=40/1 (v/v)] to give 1.3 g of N-(3-chloro-4-isopropylphenyl)-1-methylcyclopropanecarboxamide as an oil in a yield of 87.6 % based on 3-chloro-4-isopropylaniline. On standing for a long period of time, the oil crystallized.
Reaction SMILES: [C:1]1([O:11][C:12](=[O:63])[C@H:13]([CH2:36][CH2:37][CH2:38][N:39](C(OCC2C=CC=CC=2)=O)[C:40](=[NH:52])[NH:41]C(OCC2C=CC=CC=2)=O)[NH:14][C:15](=[O:35])[C@H:16]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[NH:17]C(OCC2C=CC=CC=2)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[ClH:64].O1CCOCC1.[H][H]>CN(C=O)C.[C].[Pd]>[ClH:64].[ClH:64].[C:1]1([O:11][C:12](=[O:63])[C@H:13]([CH2:36][CH2:37][CH2:38][NH:39][C:40](=[NH:41])[NH2:52])[NH:14][C:15](=[O:35])[C@H:16]([CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH2:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: N=C(NC(=O)OCc1ccccc1)N(CCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)Oc1cccc2ccccc12)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)Oc1cccc2ccccc12
Reaction time: 4 h
Yield: 78 %

Procedure:
In DMF was dissolved 935 mg of the above ester, and to the resulting solution were added 0.5 g of 10% palladium-carbon (Pd-C) and 0.98 ml of a 2 N hydrochloric acid-dioxane solution, after which hydrogen gas was passed through the resulting mixture with ice-cooling and with stirring for 4 hrs. After the reaction, the Pd-C was removed by filtration, and 300 ml of anhydrous diethyl ether was added dropwise to the filtrate, upon which a powder was precipitated. The powder was collected by filtration to obtain 450 mg (yield 78%) of L-phenylalanyl-L-arginine 1-naphthyl ester dihydrochloride, m.p. 215° C. (decomp.).
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+].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24]Br>C(O)C>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][CH2:2][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]
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(NC(=O)CCc1ccc(Cl)c(Cl)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diethyl acetamidomalonate (48.2 g) was dissolved in ethanol (250 ml) containing sodium ethoxide (10.2 g) and stirred at room temperature for 0.5 hours before adding 3,4-dichlorobenzyl bromide and heating at reflux for 3.5 hours. After cooling, the title compound was collected by filtration and dried under reduced pressure (36.73 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:23]=[O:24].O>C(OCC)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[N:10]=[CH:11][C:12]([CH:23]=[O:24])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(OCc2ccccc2)nc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(OCc2ccccc2)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of 2-benzyloxy-5-bromopyridine described in Manufacturing Example 231-1-1 (53.0 g, 201 mmol) in diethyl ether (500 mL) was added n-butyl lithium (82.8 mL, 2.67 M n-hexane solution, 221 mmol) was added dropwise on a dry ice-ethanol bath (−78° C.) under nitrogen atmosphere, which was stirred for 30 minutes at −78° C. While cooling at the same temperature, N,N-dimethylformamide (17.6 g, 241 mmol) was added to this reaction mixture, which was stirred for 30 minutes. Water and ethyl acetate were added to the reaction mixture, which was stirred for 10 minutes at room temperature, the organic layer was then separated. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:5 then 1:4) to obtain the title compound (36.8 g, 86%).
Reaction SMILES: [CH2:1]([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2B2OC(C)(C)C(C)(C)O2)[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:36]1[CH:37]=[N:38][C:39]([O:46][CH3:47])=[C:40]([CH:45]=1)[C:41]([NH:43][CH3:44])=[O:42]>>[CH2:28]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:36]2[CH:37]=[N:38][C:39]([O:46][CH3:47])=[C:40]([CH:45]=2)[C:41]([NH:43][CH3:44])=[O:42])[O:11][CH2:10]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC1(C)OB(c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)OC1(C)C
Reactant: CNC(=O)c1cc(Br)cnc1OC
Product: CNC(=O)c1cc(-c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)cnc1OC
Yield: 66 %

Procedure:
The title compound was synthesized as described for Intermediate I-28 in 66% yield starting from (3S)-N,N-dibenzyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman -3-amine and 5-bromo-2-methoxy-N-methylnicotinamide; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.33 (q, 1 H), 8.29 (d, 1 H), 8.06 (d, 1 H), 7.24-7.32 (m, 8 H), 7.11-7.21 (m, 3 H), 6.71-6.82 (m, 2 H), 4.26-4.38 (m, 1 H), 4.04 (s, 3 H), 4.01-4.11 (m, 1 H), 3.57-3.73 (m, 4 H), 2.87-3.09 (m, 2 H), 2.84 (d, 3 H), 2.46-2.54 (m, 1 H, obscured by DMSO); MS (ESI) m/z 494[M+H+].