Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:7][C:8]1[C:13]([CH2:14]Br)=[CH:12][CH:11]=[CH:10][N:9]=1.O>CN(C)C=O>[Br:7][C:8]1[C:13]([CH2:14][O:4][CH:1]([CH3:3])[CH3:2])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: CC(C)O
Reactant: BrCc1cccnc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)OCc1cccnc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
To a solution of isopropyl alcohol (7.31 mL, 95.65 mmol) in dimethylformamide (50 mL) at 0° C. is added sodium hydride (3.63 g, 90.87 mmol) and the mixture is stirred at room temperature for 30 minutes (this reaction is run using a shield as special protection). Then, 2-bromo-3-bromomethyl-pyridine (6 g, 23.91 mmol) in 10 mL of dimethylformamide is added via syringe and the mixture is stirred at room temperature for 1 h. Water is added and the mixture is extracted with ethyl acetate, washed with brine and water, dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure. The crude material is purified by normal phase Isco chromatography using ethyl acetate and hexane as eluent (gradient of 5 to 25% of ethyl acetate) to yield 3.67 g of the title compound. MS (m/z): 230, 232 (M+1, M+3)
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:8])=[N:4][N:5]([CH3:7])[CH:6]=1.C(N(CC)CC)C.[Cl:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21].[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[C:3]([NH:8][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][Cl:16])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: O=C(Cl)CCCCl
Reactant: Cn1cc(Br)c(N)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1cc(Br)c(NC(=O)CCCCl)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-1-methyl-1H-pyrazol-3-amine (310 mg) and triethylamine (0.37 mL) in THF (8.8 mL) was added 4-chlorobutanoyl chloride (0.22 mL) under ice-cooling, and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (456 mg).
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]([CH3:20])=[CH:6][C:7]1[CH:12]=[C:11]2[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:10]2=[CH:9][CH:8]=1)C.[OH-].[Na+]>CO>[N+:17]([C:15]1[CH:14]=[CH:13][C:11]2[C:10]([CH:16]=1)=[CH:9][CH:8]=[C:7]([CH:6]=[C:5]([CH3:20])[C:4]([OH:21])=[O:3])[CH:12]=2)([O-:19])=[O:18]
Reactant: CCOC(=O)C(C)=Cc1ccc2cc([N+](=O)[O-])ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=Cc1ccc2cc([N+](=O)[O-])ccc2c1)C(=O)O
Yield: 98.2 %

Procedure:
Into 130 ml of methanol, 5.48 g (19 mmol) of 3-(2-nitro-benzo[d]phenyl)-2-methyl-2-propenoic acid ethyl ester were dissolved; and, with 23 ml of a 2-N aqueous sodium hydroxide solution being added thereto, the resulting mixture was reacted at 40° C. for one night. After the completion of the reaction was confirmed by TLC, the reaction liquid was concentrated under a reduced pressure. The pH of the concentrated product was adjusted to 1 with 1-N hydrochloric acid being added thereto, and the precipitated crystal was filtered out. This crystal was washed with water and a small amount of methanol, and was dried, whereby 4.8 g of the aimed compound were obtained as a crystal (yield: 98%).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([N:25]5[CH:29]=[C:28]([Sn](CCCC)(CCCC)CCCC)[N:27]=[N:26]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([N:25]5[CH:29]=[C:28]([C:44]6[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=6)[N:27]=[N:26]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1ccccn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2ccc3ncn(-c4ccnc(N[C@@H](C)c5ccccc5)n4)c3c2)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C[C@H](Nc1nccc(-n2cnc3ccc(-n4cc(-c5ccccn5)nn4)cc32)n1)c1ccccc1
Reaction time: 16 h
Yield: 9.6 %

Procedure:
The title compound was prepared from 30.5 mg of 2-[(S)-1-phenylethylamino]-4-[6-(4-tributylstannyl-triazol-1-yl)benzimidazol-1-yl]pyrimidine, 36.3 mg 2-bromopyridine and 0.5 mg Pd(PPh3)4 using the procedure described in EXAMPLE 273 except that the the reaction mixture was stirred for 16 hours. The residue was purified by flash chromatography eluting with acetone in hexanes to give 2.0 mg of the title compound. 1H NMR (500 MHz, 1:1 CD3OD/CDCl3): δ 1.64 (d, J=6.8 Hz, 3H), 5.28 (m, 1H), 7.0-7.35 (m, 5H), 7.40 (br s, 6.4 Hz, 1H), 7.54 (t, J=7.1 Hz, 1H), 7.84 (m, 1H), 7.93 (d, J=8.4 Hz, 1H), 8.11 (t, J=7.5 Hz, 1H), 8.32 (d, J=8.3 Hz, 1H), 8.36 (m, 1H), 8.65 (d, J=4.6 Hz, 1H), 8.83-9.2 (m, 3H). Mass Spectrum (CH3CN-TFA-NH4HCO2-ESI): 460.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[C:12](=O)([O:18]C(C)(C)C)[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]>C1COCC1>[C:12]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][CH:3]=1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:18]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-aminobenzotrifluoride (100 g, 0.62 mol) and di-tert-butyl carbonate (150 g, 0.69 mol) in anhydrous THF (400 mL) is heated at reflux temperature for 6 hours and then cooled to room temperature. Most of the solvent is removed using a rotary evaporator and the non-volatile material that remains is triturated with water (1000 mL) to form a solid. The solid is isolated by filtration and washed with additional water (500 mL), then washed with hexanes (500 mL) to give 4-(BOC-amino)benzotrifluoride (m.p. 123–124° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[CH:23]=[CH:22][C:21]2[N:20]3[CH2:24][CH2:25][C@@H:19]3[CH2:18][O:17][C:16]=2[C:15]=1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>N1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[CH:23]=[CH:22][C:21]2[N:20]3[CH2:24][CH2:25][C@@H:19]3[CH2:18][O:17][C:16]=2[C:15]=1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])(=[O:11])=[O:10]
Reactant: CC(C)(C)OC(=O)c1c(N)ccc2c1OC[C@H]1CCN21
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OC[C@H]1CCN21
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.3 %

Procedure:
2-Bromo-4-fluorobenzenesulfonyl chloride (0.091 g) was added to a solution of tert-butyl (R)-6-amino-1,2,2a,3-tetrahydro-4-oxa-8b-azacyclobuta[a]naphthalene-5-carboxylate (Intermediate 44, 0.092 g) in pyridine (2 mL) and DCM (2 mL) and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and the residue was partitioned between DCM and 1M hydrochloric acid and filtered through a phase separator. 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 0-25% to give tert-butyl (R)-6-(2-bromo-4-fluorobenzenesulfonylamino)-1,2,2a,3-tetrahydro-4-oxa-8b-azacyclobuta-[a]naphthalene-5-carboxylate (0.062 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH2:11]Br)[C:9]=1[Cl:10])=[O:4].[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH2:11][N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]2)[C:9]=1[Cl:10])=[O:4]
Reactant: CN1CCNCC1
Reactant: COC(=O)c1scc(CBr)c1Cl
Solvent: ClCCl
Product: COC(=O)c1scc(CN2CCN(C)CC2)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.8 %

Procedure:
To 2-methoxycarbonyl-3-chloro-4-(bromomethyl)thiophene (0.20 g, 0.74 mmol) in methylene chloride (7.5 mL) was added 1-methylpiperazine (0.095 mL, 0.86 mmol) and the mixture was stirred at ambient temperature. After 16 hours, the mixture was poured onto methylene chloride (20 mL) and washed with dilute aqueous NaHCO3, water and brine, dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 0.085 g (40% yield) of 2-methoxycarbonyl-3-chloro-4-((4-methylpiperazin-1-yl)methyl)thiophene as a tan solid; NMR (CDCl3) 7.4 (s, 1), 3.9 (s, 3), 3.5 (s, 2), 2.3-2.7 (br m, 8), 2.2 (s, 3) ppm.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[NH:14][C:13](=[O:15])[O:12][C:11]([CH3:17])([CH3:16])[C:10]=2[CH:18]=1.[Cl:19][C:20]1[CH:21]=[C:22]([SH:27])[CH:23]=[CH:24][C:25]=1[Cl:26]>>[Cl:19][C:20]1[CH:21]=[C:22]([S:27][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[NH:14][C:13](=[O:15])[O:12][C:11]([CH3:17])([CH3:16])[C:10]=3[CH:18]=2)[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCl)cc21
Reactant: Sc1ccc(Cl)c(Cl)c1
Product: CC1(C)OC(=O)Nc2ccc(OCCCSc3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(3-chloropropoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 3,4-dichloro-thiophenol.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22](I)=[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][N:16]3[N:15]=2)=[CH:10][CH:9]=1.CC1(C)C(C)(C)OB([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([NH:38][C:39](=[O:42])[CH2:40][CH3:41])[CH:33]=2)O1.C(OCC)(=O)C>O1CCOCC1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([NH:38][C:39](=[O:42])[CH2:40][CH3:41])[CH:33]=3)=[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][N:16]3[N:15]=2)=[CH:10][CH:9]=1
Reactant: CCC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: Fc1ccc(-c2nn3c(c2I)CCCC3)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCC(=O)Nc1cc(-c2c(-c3ccc(F)cc3)nn3c2CCCC3)ccn1
Temperature: 120 °C
Yield: 79.3 %

Procedure:
Under argon, 1.39 ml of a 2M aqueous Na2CO3 solution are added dropwise to a solution of 200 mg (0.55 mmol) of 2-(4-fluorophenyl)-3-iodo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine, 168 g (0.61 mmol) of N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]propanamide in 2 ml of dioxane, and 32 mg (0.04 mmol) of Pd(PCy3)2Cl2 are added. In a microwave reactor, the reaction mixture is heated at 120° C. for 15 min. After cooling, 50 ml of ethyl acetate are added, the reaction mixture is filtered through kieselguhr and the filtrate is extracted with ethyl acetate. The combined organic phases are washed with water, dried over MgSO4 and freed from the solvent under reduced pressure. Purification by column chromatography on silica gel (cyclohexane/ethyl acetate) gives 159 mg (78%) of the desired product; log P(HCOOH): 1.97; 1H-NMR (MeCN-d3): 8.54 (br.s, 1H), 8.11 (d. 1H), 8.02 (s, 1H), 7.42 (dd, 2H), 7.04 (dd, 2H), 6.77 (d, 1H), 4.16 (dd, 2H), 2.81 (dd, 2H), 2.40 (q, 2H), 1.77 (m, 2H), 1.11 (t, 3H).
Reaction SMILES: [CH2:1]([C@@H:7]1[CH2:10][N:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]1=[O:19])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[OH2:20].[OH-].[Li+].O.Cl>C1COCC1.O.CO>[CH2:12]([O:11][NH:9][CH2:10][C@@H:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6])[C:8]([OH:19])=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O
Reactant: C=CCCCC[C@@H]1CN(OCc2ccccc2)C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=CCCCC[C@H](CNOCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (3R)-3-(5-hexen-1-yl)-N-benzoxy-2-azetidinone (0.39 g, 1.52 mmol) in a mixture of THF—H2O-MeOH (15 mL, 3:1:1 v/v) was added lithium hydroxide monohydrate (1.64 g, 15.2 mmol). After stirring at room temperature overnight, water (15 mL) was added to the mixture. The solution was acidified to pH 4 with 3N aqueous HCl solution. It was extracted with EtOAc (30 mL×2). The combined organic layers were dried over MgSO4. Removal of the solvent under vacuum provided the title compound. MH+278.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][N:15]([C:18]4[C:23]([CH3:24])=[CH:22][C:21]([N+:25]([O-])=O)=[CH:20][N:19]=4)[CH2:14][CH2:13]3)[C:9]2=[O:28])[CH2:4][CH2:3]1>CO.[Pd]>[NH2:25][C:21]1[CH:22]=[C:23]([CH3:24])[C:18]([N:15]2[CH2:16][CH2:17][C:10]3([C:9](=[O:28])[N:8]([C@H:5]4[CH2:4][CH2:3][C@@H:2]([OH:1])[CH2:7][CH2:6]4)[CH2:12][CH2:11]3)[CH2:13][CH2:14]2)=[N:19][CH:20]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1N1CCC2(CC1)CCN([C@H]1CC[C@@H](O)CC1)C2=O
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N)cnc1N1CCC2(CC1)CCN([C@H]1CC[C@@H](O)CC1)C2=O
Reaction time: 2 h

Procedure:
Pd/C (15 mg) was added to a solution of 2-(cis-4-hydroxycyclohexyl)-8-(3-methyl-5-nitropyridin-2-yl)-2,8-diazaspiro[4.5]decan-1-one in methanol (5.0 mL) under an atmosphere of nitrogen. The mixture was stirred under an atmosphere of hydrogen for 2 hrs, and filtered. The filtrate was concentrated to give 8-(5-amino-3-methylpyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,8-diazaspiro[4.5]decan-1-one.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[CH:14]=[CH:13][NH:12][CH:11]=2)=O)=[CH:6][CH:5]=[C:4]([Cl:15])[N:3]=1.O.[NH2:17][NH2:18]>C(O)C>[Cl:15][C:4]1[N:3]=[C:2]2[NH:17][N:18]=[C:8]([C:10]3[CH:14]=[CH:13][NH:12][CH:11]=3)[C:7]2=[CH:6][CH:5]=1
Reactant: NN
Reactant: O=C(c1cc[nH]c1)c1ccc(Cl)nc1Cl
Solvent: CCO
Solvent: O
Product: Clc1ccc2c(-c3cc[nH]c3)n[nH]c2n1
Temperature: 90 °C

Procedure:
A mixture of (2,6-dichloro-pyridin-3-yl)-(1H-pyrrol-3-yl)-methanone (300 mg) and hydrazine hydrate (0.2 mL) in ethanol (10 mL) was heated at 90° C. for 20 hours. The reaction was concentrated to 6 mL, diluted with water (2 mL) and cooled. The precipitate was collected and dried to give 160 mg of the titled compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7](=[O:9])[O:6][C:4](=[O:5])[CH2:3]1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>O1CCOCC1>[CH3:1][CH:2]([CH2:3][C:4]([N:14]1[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]1)=[O:5])[CH2:8][C:7]([OH:6])=[O:9]
Reactant: CC1CC(=O)OC(=O)C1
Reactant: CN1CCNCC1
Solvent: C1COCCO1
Product: CC(CC(=O)O)CC(=O)N1CCN(C)CC1
Reaction time: 4 h

Procedure:
1.6 g of 3-methylglutaric anhydride and then 1.48 cm3 of N-methylpiperazine are added to 20 cm3 of dioxane. After stirring for 4 hours, an additional 320 mg of 3-methylglutaric anhydride are added. The stirring is continued at 20° C. for 18 hours. The solvent is evaporated under reduced pressure (2.7 kPa), at 50° C. The resulting oil is dried at 50° C. (90 Pa) to give 3.1 g of (3RS)-3-methyl-5-(4-methylpiperazin-1-yl)-5-oxopentanoic acid in the form of a yellow lacquer which is used as it is.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([N+:24]([O-:26])=[O:25])=[C:19]([CH:23]=1)[C:20]([OH:22])=[O:21]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([N+:24]([O-:26])=[O:25])=[C:19]([CH:23]=1)[C:20]([OH:22])=[O:21])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: Nc1ccc([N+](=O)[O-])c(C(=O)O)c1
Product: CC(C)(C)OC(=O)NCCC(=O)Nc1ccc([N+](=O)[O-])c(C(=O)O)c1

Procedure:
For the preparation of the ester starting material, MS: 468 (18, M+NH4), 451 (100, M+H), N-(t-butoxycarbonyl)-β-alanine and 5-amino-2-nitrobenzoic acid are reacted to give 5-[3-(1-t-butoxyformamido)propionamido]-2-nitrobenzoic acid, MS: 354 (17, M+H), the latter is reacted with β-alanine t-butyl ester to give N-[5-[3-(1-t-butoxyformamido)propionamido]-2-nitrobenzoyl]-β-alanine t-butyl ester and this is hydrogenated on Pd/C in ethanol.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:15])=[CH:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1)=O.[BH4-].[Na+]>CO>[OH:2][CH2:3][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:15])=[CH:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc2c(Cl)ccnc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc2c(Cl)ccnc2c1
Temperature: 0 °C
Yield: 30.4 %

Procedure:
7-Methoxycarbonyl-4-chloroquinoline(3.75 g, 0.017 mol) was dissolved in methanol (200 ml), added under ice-cooling with sodium borohydride (12.9 g, 0.34 mol) and stirred for an hour. The reaction mixture was poured into ice water. The resulting precipitates were collected by filtration, dried over phosphorus pentoxide and recrystallized from chloroform (20 ml) to obtain 1.0 g (30%) of 7-hydroxymethyl-4-chloroquinoline.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[C:6]2[S:11][CH:10]=[CH:9][C:7]=2[N:8]=1.C([N-]C(C)C)(C)C.[Li+].[Br:24]N1C(=O)CCC1=O>O1CCCC1>[Br:24][C:10]1[S:11][C:6]2[C:5](=[O:12])[N:4]([CH2:13][CH2:14][CH3:15])[C:3]([S:2][CH3:1])=[N:8][C:7]=2[CH:9]=1
Reactant: CCCn1c(SC)nc2ccsc2c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCn1c(SC)nc2cc(Br)sc2c1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 29.8 %

Procedure:
In a sulfonation flask, 9.6 g (0.04 mol) of 2-methylsulfanyl-3-propyl-3H-thieno[3.2-d]-pyrimidin-4-one are added to 200 ml of absolute tetrahydrofuran. Subsequently, 4.07 g (0.042 mol) of lithium diisopropylamide, dissolved in 50 ml of absolute tetrahydrofuran, are added dropwise under N2 such that the internal temperature remains constant at about −78° C. The mixture is stirred for 1 hour at −78° C. and then a solution of 8.5 g (0.048 mol) of N-bromosuccinimide in 40 ml of absolute tetrahydrofuran is added dropwise such that the internal temperature remains constant at about −78° C. The condenser is then removed and the mixture is slowly warmed to room temperature. The tetrahydrofuran is removed in a water-jet vacuum and the residue is dissolved in ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and the ethyl acetate is then removed in the water-jet vacuum. The crude product is purified by column chromatography over silica gel (eluant: ethyl acetate/hexane=1:5), giving 3.8 g of 6-bromo-2-methylsulfanyl-3-propyl-3H-thieno[3.2-d]pyrimidin-4-one in the form of a yellow powder having a melting point of 138-141° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[N:7][C:6]([CH3:9])=[CH:5][N:4]=1.C(N(CC)CC)C.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>C1C=CC=CC=1>[C:17]([O:1][CH2:2][C:3]1[CH:8]=[N:7][C:6]([CH3:9])=[CH:5][N:4]=1)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cnc(CO)cn1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1cnc(COC(=O)C(C)(C)C)cn1
Reaction time: 7 h
Yield: 71.5 %

Procedure:
To a solution of 2-hydroxymethyl-5-methylpyrazine (6.2 g) and triethylamine (6.4 ml) in anhydrous benzene (150 ml) dropwise addition was made of a solution of pivaloyl chloride (6.15 ml) in anhydrous benzene (50 ml). The solution was maintained at boiling for 7 hours, the solvent was then evaporated and the residue treated with acetone. After filtration of the insoluble solid, the filtrate was evaporated to dryness and the residue re-dissolved in chloroform. The chloroform solution was first dehydrated and then evaporated to dryness, obtaining 7 g (71.5%) of 5-methyl-2-pyrazinylmethyl pivalate, b.p.=74° C./0.1 mmHg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][NH:16]C(=O)OC(C)(C)C)[CH:12]=[CH:11][C:10]=1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:34])[N:31]([CH3:33])[CH3:32])[CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[ClH:41]>>[ClH:41].[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][NH2:16])[CH:12]=[CH:11][C:10]=1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:34])[N:31]([CH3:32])[CH3:33])[CH:25]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)c1cccc(-c2ccc(CNC(=O)OC(C)(C)C)cc2OCc2ccccc2)c1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)C(=O)c1cccc(-c2ccc(CN)cc2OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl N-(2-benzyloxy-3′-dimethylcarbamoyl-biphenyl-4-ylmethyl)carbamate (0.7 g) was suspended in 4 mol/L hydrogen chloride-1,4-dioxane solution (7.0 mL), and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (0.55 g).
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:18])([CH3:17])[CH2:9][NH:8]2)[CH2:5][CH:4]=[CH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:25][C:26]1[CH:27]=[C:28]([CH2:33][C:34](Cl)=[O:35])[CH:29]=[CH:30][C:31]=1[Cl:32].Cl.C(OCC)C>C(Cl)(Cl)Cl.C(OCC)(=O)C>[ClH:25].[N:1]1([CH2:6][C:7]2([C:34](=[O:35])[CH2:33][C:28]3[CH:29]=[CH:30][C:31]([Cl:32])=[C:26]([Cl:25])[CH:27]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:18])([CH3:17])[CH2:9][NH:8]2)[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: O=C(Cl)Cc1ccc(Cl)c(Cl)c1
Reactant: CC1(C)CNC(CN2CC=CC2)c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC1(C)CNC(CN2CC=CC2)(C(=O)Cc2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 59.4 %

Procedure:
Prepared as Example No. 1 from 1.4 g (5.78 mmoles) of 1-(3-pyrrolin-1-yl)methyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline, 1.6 g (11.59 moles) of anhydrous potassium carbonate and 1.5 g (6.71 moles) of 3,4-dichlorophenylacetyl chloride in 50 ml of dry chloroform. The work-up of the reaction mixture afforded 1.9 g of the crude product which was dissolved in 60 ml of ethyl acetate and the solution brought to acidic pH with HCl/diethyl ether. The precipitate was filtered, washed and dried, to yield 1.6 g of the title compound. C24H26Cl2N2O.HCl M.P.=254°-257° C. M.W.=465.843 Elemental analysis: Calcd. C,61.87; H,5.84; N,6.01; Cl,22.83; Found C,61.94; H,5.88; N,5.99; C1,22.75. I.R. (KBr): 3450; 2960; 2540; 1630; 1440 cm-1N.M.R. (CDCl3): δ12.5 (s, broad, 1H); 6.9-7.5 (m, 7H); (80 MHz) 6.1 (dd, 1H); 5.8 (s, 2H); 3.9-5.1 (m, 4H);
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([C:10]3[S:11][C:12]([C:16]([OH:18])=O)=[C:13]([CH3:15])[N:14]=3)[CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.O.O[N:23]1[C:27]2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.C(Cl)CCl.CN>C(Cl)Cl>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([C:10]3[S:11][C:12]([C:16]([NH:23][CH3:27])=[O:18])=[C:13]([CH3:15])[N:14]=3)[CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: Cc1nc(N2CCOc3cc(Br)ccc32)sc1C(=O)O
Agent: CN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1sc(N2CCOc3cc(Br)ccc32)nc1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 543.1 %

Procedure:
To a stirred solution of Example 28 (0.35 g, 0.99 mmol) in DCM (10 mL) were added 1-hydroxybenzotriazole hydrate (0.015 g, 0.11 mmol), DIPEA (0.175 mL, 1.00 mmol) and EDC (210 mg, 1.08 mmol). The reaction mixture was stirred at r.t. for 5 minutes. Methylamine (0.185 mL, 33% wt. solution in EtOH, 1.97 mmol) was added and stirring was continued at r.t. for 20 h. The reaction mixture was then diluted with DCM (100 mL) and then washed with sat. aqueous NaHCO3 solution (100 mL), then water (100 mL) and brine (100 mL). The organic fraction was dried (NaSO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 0-10% MeOH/DCM) gave the title compound (0.22 g, 61%) as a white solid. δH (DMSO-d6) 8.07 (1H, d, J 8.5 Hz), 7.83-7.75 (1H, m), 7.19-7.12 (2H, m), 4.34-4.27 (2H, m), 4.04-3.97 (2H, m), 2.70 (3H, d, J 4.5 Hz), 2.47 (3H, s). LCMS (ES+) 368.1 and 370.1 (M+H)+, RT 3.50 minutes (Method 7).