Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.Cl.CN(C)[CH2:15][CH2:16]CN=C=N.O.ON1C2C=CC=CC=2N=N1.C(O)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([O:9][CH2:15][CH3:16])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: CN(C)CCCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.8 %

Procedure:
5-Chlorosalicylic acid (344 mg), 1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (420 mg), 1-hydroxybenzotriazole hydrate (337 mg), and ethanol (2 ml) were dissolved in N,N-dimethylformamide to prepare a solution which was then stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give ethyl 5-chlorosalicylate (147 mg, yield 37%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[OH:4].O=[C:13]([CH3:27])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:26][O:25][C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[Cl:11])[OH:4])[CH3:27])=[CH:21][CH:20]=1)=[O:24]
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Reactant: NCC(O)c1ccccc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2ccccc2Cl)cc1
Yield: 73.8 %

Procedure:
Following a procedure similar to that described in Example 6, but using 2 g of 2-amino-1-(2-chlorophenyl)ethanol (prepared as described in Preparation 11), 3.11 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 60 ml of benzene, 50 ml of absolute methanol and 2.3 g of sodium cyanoborohydride, 3.25 g of the title compound were obtained having an Rf=0.39 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12](F)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[NH2:20][CH:21]([C:23]1[CH:24]=[CH:25][C:26]([F:35])=[C:27]([NH:29][C:30]([CH:32]2[CH2:34][CH2:33]2)=[O:31])[CH:28]=1)[CH3:22].CCN(C(C)C)C(C)C>C(O)CCC>[C:14]([C:13]1[C:12]([NH:20][CH:21]([C:23]2[CH:24]=[CH:25][C:26]([F:35])=[C:27]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])[CH:28]=2)[CH3:22])=[N:11][C:10]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:8][N:7]=2)=[C:17]([F:18])[CH:16]=1)#[N:15]
Reactant: N#Cc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1F
Reactant: CC(N)c1ccc(F)c(NC(=O)C2CC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C#N)c1ccc(F)c(NC(=O)C2CC2)c1
Temperature: 150 °C

Procedure:
To a 10-ml microwave reaction vessel was added 6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2,5-difluoronicotinonitrile (Method 32, 431 mg, 1.65 mmol), N-[5-(1-aminoethyl) -2-fluorophenyl]cyclopropanecarboxamide (Method 69, 550 mg, 2.5 mmol), and DIEA (1.15 ml, 6.6 mmol) in n-butanol (5 ml). The resulting suspension was set to microwave heating (CEM Discover System) at 150° C. for 3 hours. The reaction was concentrated in vacuo and purified by silica gel chromatography (Biotage Horizon System) using a gradient elution of 25-35% EtOAc (20% v/v MeOH) in hexanes to give 267 mg (35% isolated yield) of the title compound. 1H NMR: 11.99 (s, 1H) 9.91 (s, 1H) 9.42 (s, 1H) 7.88 (d, J=6.03 Hz, 1H) 7.59 (d, J=10.55 Hz, 1H) 6.95-7.20 (m, 3H) 5.99 (s, 1H) 5.02-5.21 (m, 1H) 1.89-2.03 (m, 1H) 1.76-1.89 (m, 1H) 1.45 (d, J=7.54 Hz, 3H) 0.87 (t, J=8.67 Hz, 2H) 0.75 (d, J=6.03 Hz, 4H) 0.54-0.66 (m, 2H). MS: Calcd.: 463. Found: [M+H]+ 464.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:24])[C@H:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:12][C:13](=[O:16])[CH2:14][NH2:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.ClC1C=C(Cl)C(Cl)=CC=1[O:34][C:35](=O)[CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].CN1CCOCC1>C(Cl)Cl>[CH2:2]([O:9][C:10](=[O:24])[C@H:11]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH:12][C:13](=[O:16])[CH2:14][NH:15][C:35](=[O:34])[CH2:36][NH:37][C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NCC(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)Oc1cc(Cl)c(Cl)cc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
A solution of 6.1 parts glycyl-L-phenylalanine benzyl ester hydrochloride, 7.0 parts N-t-butoxycarbonylglycine 2,4,5-trichlorophenyl ester and 1.8 parts N-methylmorpholine in 150 parts methylene chloride is stirred overnight at room temperature. The solvents are then removed by evaporation under reduced pressure to yield the crude tripeptide. Purification by low pressure column chromatography affords pure N-t-butoxycarbonylglycylglycyl-L-phenylalanine benzyl ester.
Reaction SMILES: C[O-].[Na+].ClC1C=CC=CC=1.CO[C:13](=[O:18])[C:14]([O:16][CH3:17])=[O:15].[CH3:19][C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21]>CO>[CH3:17][O:16][C:14](=[O:15])[C:13]([CH2:19][C:20](=[O:21])[C:22]([CH3:25])([CH3:24])[CH3:23])=[O:18]
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)C(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Clc1ccccc1
Product: COC(=O)C(=O)CC(=O)C(C)(C)C
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
198 g of methanolic sodium methyate solution (30% strength by weight) are added to 400 g of chlorobenzene. The methanol is distilled off at 65° C. in the course of 1 hour. The mixture is cooled to 10° C. and 118 g (1 mol) of molten oxalic acid dimethyl ester are introduced in the course of 1 hour. Thereafter, 100 g (1 mol) of pinacolin are allowed to run in and the mixture is subsequently stirred at room temperature for 15 minutes. It is heated, and the methanol formed in the reaction is distilled off in the course of 2 hours. Neutralisation with sulphuric acid, separation of the phases and distillation of the organic phase gives 165 g of pivaloylpyruvic acid methyl ester (87.8% of the theoretical yield). Purity: 99.0%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[CH2:8][CH:7]([NH:13][CH:14]([CH2:18][CH2:19][CH3:20])[C:15]([OH:17])=O)[CH2:6][CH2:5]2.[NH2:21][C:22]1[N:23]=[CH:24][N:25]([CH:27]2[CH2:30][CH:29]([OH:31])[CH2:28]2)[CH:26]=1>>[OH:31][CH:29]1[CH2:28][CH:27]([N:25]2[CH:26]=[C:22]([NH:21][C:15](=[O:17])[CH:14]([NH:13][CH:7]3[CH2:6][CH2:5][C:4]4[C:9](=[C:10]([F:12])[CH:11]=[C:2]([F:1])[CH:3]=4)[CH2:8]3)[CH2:18][CH2:19][CH3:20])[N:23]=[CH:24]2)[CH2:30]1
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Reactant: Nc1cn(C2CC(O)C2)cn1
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C2CC(O)C2)cn1

Procedure:
Following the procedure for Example 86, 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (diastereomer 2) was reacted with 3-(4-Amino-imidazol-1-yl)-cyclobutanol to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.1, 19.5, 28.2, 28.9, 29.7, 36.5, 40.2, 41.9, 43.4, 48.7, 52.9, 60.5, 60.9, 64.5, 100.8, 101.1, 101.3, 105.1, 105.3, 110.7, 110.9, 131.6, 131.9, 137.7, 139.8, 159.8, 162.3, 172.6; MS m/z 419.2 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[N:8][C:9]([C:14]([O:16]CC)=O)=[C:10]([OH:13])[C:11](=[O:12])[N:6]2[CH2:5][C:4](=[O:19])[N:3]1[CH3:20].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][C:23]=1[CH3:30]>>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:14]([C:9]2[N:8]=[C:7]3[N:6]([C:11](=[O:12])[C:10]=2[OH:13])[CH2:5][C:4](=[O:19])[N:3]([CH3:20])[N:2]3[CH3:1])=[O:16])=[CH:24][C:23]=1[CH3:30]
Reactant: Cc1cc(CN)ccc1F
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC(=O)N(C)N2C
Product: Cc1cc(CNC(=O)c2nc3n(c(=O)c2O)CC(=O)N(C)N3C)ccc1F
Yield: 79.8 %

Procedure:
Reaction of intermediate 22, ethyl 1,2-dimethyl-7-hydroxy-3,6-dioxo-2,3,4,6-tetrahydro-1H-pyrimido[2,1-c][1,2,4]triazine-8-carboxylate, (0.050 g, 0.177 mmol) with 4-fluoro-3-methylbenzylamine (0.10 g, 0.72 mmol) as described in the preparation of example 1 gave 0.053 g (79% yield) of the title amide as white crystals. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.31 (3H, s, CH3), 3.27 (3H, s, NCH3), 3.30 (3H, s, NCH3), 4.56 (2H, d, J=5.9 Hz, NCH2), 4.67 (2H, s, CH2), 7.02 (1H, m, aromatic), 7.14 (1H, m, aromatic), 7.17 (1H, m, aromatic), 7.71 (1H, broad t, NH), 12.02 (1H, s, OH). MS (ESI+) m/z 376 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH:13]([NH2:15])[CH3:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.[C:16]([O:20][C@@H:21]([C@H:23]1[CH2:27][O:26][C:25](=[O:28])[N:24]1[C:29]1[CH:34]=[CH:33][N:32]=[C:31](F)[N:30]=1)[CH3:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)C(C)C)C>CS(C)=O.CCOC(C)=O>[C:16]([O:20][C@@H:21]([C@H:23]1[CH2:27][O:26][C:25](=[O:28])[N:24]1[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([NH:15][CH:13]([C:11]2[O:10][N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH:12]=2)[CH3:14])[N:30]=1)[CH3:22])([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(N)c1cc(-c2ccc(Cl)cc2)no1
Reactant: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1c1ccnc(F)n1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1nccc(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)n1)c1cc(-c2ccc(Cl)cc2)no1
Temperature: 120 °C
Yield: 37.6 %

Procedure:
To a solution of 1-(3-(4-chlorophenyl)isoxazol-5-yl)ethanamine (610 mg, 2.74 mmol) and (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (774 mg, 2.74 mmol) in DMSO (5 ml) was added N-ethyl-N-isopropylpropan-2-amine (2 eq, 0.96 mL, 5.48 mmol) and heated in a microwave at 120° C. for 2 hours. Dilute with EtOAc (50 ml), wash with water (50 ml), brine (50 ml), concentrate in vacuo. Flash column chromatography (silica, 40 g) eluting w/0-25% EtOAc/DCM afforded 500 mg of white solid: 1H NMR (400 MHz, CDCl3) b 8.24 (dd, J=5.8, 1.6 Hz, 1H), 7.80-7.65 (m, 2H), 7.58 (dd, J=5.8, 1.6 Hz, 1H), 7.49-7.37 (m, 2H), 6.48-6.35 (m, 1H), 5.66-5.44 (m, 1H), 4.71 (dddd, J=9.8, 8.5, 4.6, 3.0 Hz, 1H), 4.63 (ddd, J=9.4, 3.1, 2.1 Hz, 1H), 4.50-4.26 (m, 2H), 1.71 (s, 1H), 1.25 (s, 5H), 1.15 (s, 5H), 1.03 (dd, J=22.4, 6.4 Hz, 3H), 5.44-5.13 (m, 1H). HRMS(B) tR=3.36 min; m/z 485.1830
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][N:7]=1.[C:14]([N:16]=[C:17](SC)[S:18][CH3:19])#[N:15]>C(O)C>[C:14]([NH:16][C:17](=[N:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][N:7]=1)[S:18][CH3:19])#[N:15]
Reactant: COc1cccnc1CSCCN
Reactant: CSC(=NC#N)SC
Solvent: CCO
Product: COc1cccnc1CSCCN=C(NC#N)SC
Reaction time: 8 h
Yield: 72.4 %

Procedure:
A solution of 2-[2-aminoethylthiomethyl]-3-methoxypyridine (2.1 g) in ethanol (15 ml) was added over one hour to a stirred solution of dimethyl N-cyanodithioimidocarbonate (1.5 g) in ethanol (15 ml). The mixture was allowed to stand overnight and nitrogen was bubbled through for one hour. The crystalline precipitate was recrystallised from ethanol/ether to yield N-cyano-N'-[2-((3-methoxy-2-pyridyl)methylthio)ethyl]-S-methylisothiourea (2.2 g), m.p. 102°-103°.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH2:16][C:17]([OH:19])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH3:15][O:14][C:12]1[CH:11]=[CH:10][C:9]2[CH2:16][C:17](=[O:19])[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[CH2:1][C:8]=2[CH:13]=1
Reactant: COc1ccc(CC(=O)O)c(Cc2ccccc2)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2c(c1)Cc1ccccc1C(=O)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
A solution of 2-benzyl-4-methoxyphenylacetic acid (215 g of crude material that contained 204.6 g (0.80 mole) of pure material) in CH2Cl2 (1 L) was stirred under argon at ambient temperature, and DMF (1 mL) was added, followed by oxalyl chloride (400 mL, 4.59 mole). The oxalyl chloride was added over 1 hr, dropwise initially to control the vigorous gas evolution. The solution was stirred for 16 h at ambient temperature and then was concentrated to give the crude acid chloride (207.7 g, 0.756 mol, 95%) as a yellow liquid. This liquid was dissolved in CH2Cl2 to a total volume of 500 mL, and the solution and AlCl3 (100.8 g, 0.756 mol) were added concurrently over 1 hr to CH2Cl2 (3.7 L) with stirring under argon at ambient temperature. The temperature was 28° C. at the completion of the addition. The reaction mixture was stirred for 16 h at ambient temperature, during which time a solid precipitated. H2O (1 L) was added, initially dropwise, over a period of 30 min. The mixture was then separated and the organic phase was washed sequentially with H2O (1 L) and 5% aqueous NaHCO3 (1 L). The CH2Cl2 solution was then concentrated to give a yellow solid (175.3 g). Recrystallization from EtOAc/hexane gave the title compound (128 g, 71%): mp 107-109° C.
Reaction SMILES: [CH3:1][N:2]([CH3:45])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:44])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:29]=[C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[C:27]4[C:22](=[CH:23][C:24]([C:36]5[O:40][C:39]([C:41](O)=[O:42])=[CH:38][CH:37]=5)=[CH:25][CH:26]=4)[N:21]=3)=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)=[O:4].[CH3:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][N:2]([CH3:45])[C:3](=[O:4])[C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:29]=[C:28]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)[C:27]4[C:22](=[CH:23][C:24]([C:36]5[O:40][C:39]([C:41]([N:50]6[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]6)=[O:42])=[CH:38][CH:37]=5)=[CH:25][CH:26]=4)[N:21]=3)=[CH:16][CH:15]=2)=[O:44])=[CH:9][CH:10]=1
Reactant: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)c4ccc(-c5ccc(C(=O)O)o5)cc4n3)cc2)cc1
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2ccc(-c3ccc4c(N5CCOCC5)nc(-c5ccc(NC(=O)Nc6ccc(C(=O)N(C)C)cc6)cc5)nc4c3)o2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 9.1 %

Procedure:
To a 50 mL round bottom flask, 5-(2-(4-(3-(4-(dimethylcarbamoyl)phenyl)ureido)phenyl)-4-morpholino-quinazolin-7-yl)furan-2-carboxylic acid (0.1 g, 0.00016 mol; Example 10) and N-methyl piperazine (0.024 g, 0.00024 mol) in DMF (5 mL) was added. To the flask, HATU (0.153 g, 0.0004 and TEA (0.067 mL, 0.00048 mol) were added. The reaction mass was stirred at room temperature for 12 h. To the reaction mass, ice cold water was added to provide the solid. The obtained solid was collected by filtration. The crude product was purified by column chromatography using 60-120 silica gel and 5% MeOH in chloroform. The solid was washed with MeOH and filtered to yield the desired product [0.01 g, 9%]. 1H NMR (300 MHz, DMSO-d6): δ 9.11 (s, 1H), 9.05 (s, 1H), 8.43 (d, J=8.4 Hz, 2H), 8.14 (s, 1H), 8.07 (d, J=9.0 Hz, 1H), 7.81 (s, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.1 Hz, 2H), 7.43 (d, J=3.3 Hz, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.16 (d, J=3.3 Hz, 1H), 3.82-3.54 (m, 16H), 2.94 (s, 6H), 2.39 (s, 3H). LC-MS (ESI): Calculated mass: 688.3; Observed mass: 689.3 (RT: 0.10 min).
Reaction SMILES: [OH:1][CH:2]([C@@H:5]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:7][CH2:8][CH3:9])[C:3]#N.Cl.S([O-])(O)(=O)=[O:20].[K+].[O:25]1[CH2:30]COCC1>>[OH:1][CH:2]([C@@H:5]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:30]([OH:25])=[O:20]
Reactant: O=S(=O)([O-])O
Reactant: C1COCCO1
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(O)C#N
Agent: Cl
Agent: [K+]
Product: CCCC[C@H](NC(=O)OC(C)(C)C)C(O)CC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
Subsequently, to 260 ml of dioxane solution of 38.7 g (160 mmol) of the (2RS,3S)-2-hydroxy-3-[N-(2-methyl-2-propyloxycarbonyl)amino]heptanenitrile, 133 ml of concentrated hydrochloric acid was added thereto and was stirred under the reflux condition. After 3 hours, the reaction solution was concentrated under reduced pressure. 100 ml of distilled water and 100 ml of dioxane were added to the residue. 100 ml of dioxane of 70 g (319 mmol) of di-tert-butyl carboxylate was added dropwise to the above-prepared reaction mixture under 0° C. After completion of dropping, the reaction solution was warmed to the room temperature and then stirred overnight. The reaction solution was concentrated under reduced pressure. The residue thus obtained was washed with ether in addition to distilled water. The organic layer was extracted with aqueous solution of 1N sodium hydroxide and this water layer thus obtained was mixed with the water layer previously obtained. The mixed water layers was adjusted to be acid (pH 2 degree) with the addition of potassium hydrogensulfate and was extracted with ethyl acetate. The organic layer was washed with 50% brine and dried over anhydrous magnesium sulfate and concentrated under reduced pressure, whereby 36.2 g of (2RS,3S)-2-hydroxy-3-[N-(2-methyl-2-propyloxy-carbonyl)amino]heptanecarboxylic acid was obtained.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].BrC[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=O.O.CN(C)[CH:40]=[O:41]>>[CH2:35]([O:34][C:32](=[C:40]=[O:41])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][N:11]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:9]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:8]=[C:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:36]
Reactant: CCOC(=O)CCCCCCBr
Reactant: c1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)cc1
Reactant: CN(C)C=O
Agent: [H-]
Solvent: O
Product: CCOC(=C=O)CCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 41 %

Procedure:
2,4,5-Triphenylimidazole (1.3 g) was added to a suspension of sodinto hydride (0.23 g) (50% dispersion in oil, washed with hexane) in dry dimethylformamide (40 ml ) under nitrogen. The reaction was stirred at 45° C. for 1.5 h, cooled and ethyl 7-bromoheptanoate (1.1 g) in dry dimethylformamide (10 ml) was added. The reaction was stirred at 50° C. for 5 h, cooled and water was carefully added. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (100 ml). The organic solution was washed with saturated sodium chloride solution (150 ml), water (100 ml), dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. The residue was chromatographed on silica gel eluted with a dichloro-methane:ethanol gradient to give 1-(6-ethoxy-carbonylhexyl)-2,4,5-triphenylimidazole (0.81 g, 41%) as an oil. Found: C, 79.74; H, 7.32; N, 6.12%; C30H32N2O2 requires: C, 79.61; H, 7.13; N, 6.19%.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]([OH:14])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[N:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:19]O>>[CH3:19][O:13][C:12](=[O:14])[CH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][N:3]=[CH:4]2
Reactant: CO
Reactant: O=C(O)Cc1ccc2ncncc2c1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc2ncncc2c1
Temperature: 25 °C

Procedure:
A solution of quinazolin-6-yl-acetic acid (0.025 g, 0.133 mmol), thionyl chloride (0.1 mL) and methanol (2 mL) was heated to 60° C. for 6 hours. The reaction was cooled to room temperature and evaporated several times with dichloromethane to give quinazolin-6-yl-acetic acid methyl ester. This was dissolved in a solution of methanol (2 mL) and hydrazine (0.061 mL) and stirred at room temperature for several hours. The reaction was evaporated in vacuo to give quinazolin-6-yl-acetic acid hydrazide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7](=[O:10])[O:8][CH2:9][C:2]=12.[N:11]1[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][CH:12]=1.C[O-].[Na+].N#N>CO.C(OCC)(=O)CC.O>[N:11]1[CH:16]=[CH:15][C:14]([CH:17]2[C:9](=[O:8])[C:2]3[N:1]=[CH:6][CH:5]=[CH:4][C:3]=3[C:7]2=[O:10])=[CH:13][CH:12]=1
Reactant: O=Cc1ccncc1
Reactant: O=C1OCc2ncccc21
Agent: C[O-]
Agent: N#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(=O)CC
Solvent: O
Product: O=C1c2cccnc2C(=O)C1c1ccncc1

Procedure:
To a suspension of 20.27 g (150 mmol) furo[3,4-b]pyridin-5(7H)-one (for preparation see Synthesis 1997, 113) and 14.13 ml (150 mmol) 4-pyridinecarbaldehyde in 120 ml methanol and 75 ml ethyl propionate, 27.8 ml (150 mmol) of a 5.4 M solution of sodium methylate in methanol is added dropwise under ice cooling (and N2 atmosphere). The mixture is heated for 15 min to RT and then for 2 h to reflux temperature. The suspension temporarily goes into solution before a solid forms again. After cooling, 120 ml water is added, before stirring, filtering and washing the product with water. Further product is obtainable from the filtrate by acidification with acetic acid: FAB MS (M+H)+=225.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].C1C(=O)N([Br:20])C(=O)C1.[C:21]1([P:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Br-:20].[C:7]([C:6]1[CH:9]=[C:2]([CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11])[CH2:1][P+:27]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)#[N:8]
Reactant: Cc1ccc([N+](=O)[O-])c(C#N)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Product: N#Cc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)ccc1[N+](=O)[O-]
Product: [Br-]

Procedure:
Benzylic bromination of 5-methyl-2-nitrobenzonitrile by NBS by the standard procedure followed by treatment of the resultant product (3b) with triphenylphosphine gave 3-cyano-4-nitrobenzyltriphenylphosphonium bromide in good yield.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[CH2:19][C:20](=O)[CH2:21][C:22](OC)=[O:23]>>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[CH2:19][C:20]1[CH:21]=[C:22]([OH:23])[N:1]([C:3]2[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: COC(=O)CC(=O)Cc1ccc(F)cc1F
Reactant: N#Cc1ccnc(NN)c1
Product: N#Cc1ccnc(-n2nc(Cc3ccc(F)cc3F)cc2O)c1

Procedure:
The title compound was prepared from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and methyl 4-(2,4-difluorophenyl)-3-oxobutanoate according to the procedure for the preparation of Example 158, part A.
Reaction SMILES: [C:1]([N:4]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)[CH2:5][CH2:6][NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])(=[O:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([N:4]([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[CH2:5][CH2:6][NH:7][C:8](=[O:13])[C:9]([F:11])([F:12])[F:10])(=[O:3])[CH3:2]
Reactant: CC(=O)N(CCNC(=O)C(F)(F)F)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(=O)N(CCNC(=O)C(F)(F)F)c1ccc(N)cc1

Procedure:
0.7 g (2.1 mmol) of 4-[N-acetyl-N-(2-trifluoroacetylamino-ethyl)-amino]-nitrobenzene are dissolved in 20 ml of methanol and after the addition of 100 mg of 10% palladium on activated charcoal hydrogenated with hydrogen for 3 hours. Then the catalyst is filtered off and evaporated down.