Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27](C#N)[CH:26]=3)[C:10](=[O:33])[CH:9]=2)[CH2:3]1.BrCC1C=CC([N:42]2[CH:46]=[CH:45][CH:44]=[N:43]2)=CC=1>>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([N:42]4[CH:46]=[CH:45][CH:44]=[N:43]4)=[CH:29][CH:30]=3)[C:10](=[O:33])[CH:9]=2)[CH2:3]1
Reactant: N#Cc1cccc(Cn2c(=O)cc(N3CCC[C@@H](N)C3)n(Cc3ccccc3C#N)c2=O)c1
Reactant: BrCc1ccc(-n2cccn2)cc1
Product: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)cc(=O)n(Cc2ccc(-n3cccn3)cc2)c1=O

Procedure:
Title compound 21 was prepared by the methods used in the preparation of compound 17, except that 1-(4-bromomethyl-phenyl)-1H-pyrazole was used in the place of m-cyano-benzyl bromide. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1) δ 7.90 (d, J=2.5 Hz, 1 H), 7.71 (d, J=1.8 Hz, 1 H), 7.65 (d, J=7.6 Hz, 1 H), 7.51-7.58 (m, 3 H), 7.43-7.37 (m, 3 H), 7.22 (d, J=7.8 Hz, 1 H), 6.47 (t, J=2.1 Hz, 1 H), 5.43 (s, 1H), 5.14-5.30 (ABq, J=41.2, 16.4 Hz, 2 H), 5.05 (s, 2 H), 3.32-3.40 (m, 2H), 2.96 (m, 1 H), 2.89 (m, 1 H), 2.70 (m, 1 H), 2.10 (m, 1 H), 1.88 (m, 1 H), 1.66 (s, 2 H). MS (ES) [m+H] calc'd for C27H28N7O2, 482.2. found 482.2.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])=[CH:6][CH:5]=1.[ClH:17].[Cl:18]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.O>[Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[C:8]([Cl:17])[C:7]([NH:10][CH2:11][C:12]([N:14]([CH3:15])[CH3:16])=[O:13])=[C:6]([Cl:18])[CH:5]=1
Reactant: Cl
Reactant: CN(C)C(=O)CNc1ccc(CCBr)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CN(C)C(=O)CNc1c(Cl)cc(CCBr)cc1Cl
Reaction time: 1 h

Procedure:
To a stirred solution of 2-[[4-(2-bromoethyl)phenyl]-amino]-N,N-dimethylacetamide (1.13 g) in acetonitrile (11.3 ml) were added concentrated hydrochloric acid (331 μl) and N-chloro-succinimide (1.06 g) under ice-cooling, and the mixture was stirred for 1 hour. A solution of sodium thiosulfate (1.26 g) in water (20 ml) was added to the reaction mixture, and the resulting mixture was stirred for 30 minutes under ice-cooling. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane/ethyl acetate=2/1) gave 2-[[4-(2-bromoethyl)-2,6-dichlorophenyl]amino]-N,N-dimethylacetamide (795 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[CH2:20][CH2:21][CH2:22][CH3:23])=[C:13](Cl)[N:12]=2)=[CH:6][N:5]=1)[CH3:2].[CH2:25]([O:27]C1C=CC(NC2N=C3C(N(CCCC)C=N3)=C(Cl)N=2)=CN=1)C.C[O-].[Na+]>CO>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[CH2:20][CH2:21][CH2:22][CH3:23])=[C:13]([O:27][CH3:25])[N:12]=2)=[CH:6][N:5]=1)[CH3:2]
Reactant: CCCCn1cnc2nc(Nc3ccc(OCC)nc3)nc(Cl)c21
Reactant: CCCCn1cnc2c(Cl)nc(Nc3ccc(OCC)nc3)nc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCn1cnc2c(OC)nc(Nc3ccc(OCC)nc3)nc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of a 4:1 mixture of 2-[(2-Ethoxypyrid-5-yl)amino]-6-chloro-9-butyl-9H-purine and 2-[(2-Ethoxypyrid-5-yl)amino]-6-chloro-7-butyl-7H-purine (214 mg; 0.62 mmol) in methanol (15 mL) is treated with sodium methoxide (4 mL of a 25% wt. solution in methanol) and the mixture is stirred at room temperature for three days. The reaction mixture is concentrated in vacuo , the residue is treated with water (30 mL), neutralized with acetic acid, and extracted with ethyl acetate (3×40 mL). The combined organic extracts are washed with water (2×30 mL) and brine (1×30 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo . The residue is purified by preparative thin layer chromatography on silica gel by elution with ethyl acetate-hexane (3:1) to afford 2-[(2-Ethoxypyrid-5-yl)amino]-6-methoxy-9-butyl-9H-purine (94 mg), m.p. 174-176° C. (compound 1).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH3:24])[N:19]=3)[O:12]2)=[C:4]([NH:25][CH2:26][CH: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)[N:3]=1.[N:40]1([CH2:46][CH2:47][NH2:48])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1.CS(C)=[O:51]>>[CH:18]([OH:22])=[O:51].[C:34]1([CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][NH:25][C:4]2[N:3]=[C:2]([NH:48][CH2:47][CH2:46][N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[C@H:11]2[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH3:24])[N:19]=3)[O:12]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NCCN1CCCCC1
Reactant: CS(C)=O
Reactant: CCc1noc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1
Product: CCc1noc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)n1
Product: O=CO
Temperature: 80 °C

Procedure:
A mixture of Intermediate 4 (0.034 g, 0.062 mmol), 2-piperidinoethylamine (0.044 ml, 0.311 mmol) and DMSO (0.03 ml), in a sealed vial (e.g. Reacti-vial™) was heated at 80° C. for 28 h. Purification by Autoprep. HPLC afforded the title compound after freeze drying as a white solid (0.010 g). LC/MS system A Rt=3.72 mins, m/z=640MH+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[CH3:13][O:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24](Cl)[C:25]3[C:30]([CH3:31])=[CH:29][S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1>>[CH3:13][O:14][C:15](=[O:33])[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:23]=[C:24]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:25]3[C:30]([CH3:31])=[CH:29][S:28][C:26]=3[N:27]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c(C)csc3n2)cc1
Reactant: COc1ccc(CN)cc1OC
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(OC)c(OC)c3)c3c(C)csc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-dimethoxy-benzylamine is reacted with 4-(4-chloro-5-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-dimethoxybenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].C(Cl)(=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CCCC)CCCC)CCC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC(C)=CC=1>[C:1](#[N:4])[CH:2]=[CH:3][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccc(C)cc1
Solvent: CCCCN(CCCC)CCCC
Product: N#CC=Cc1ccccc1
Yield: 540 %

Procedure:
The procedure described in Example 1 is repeated, except that 3.31 g (0.0625 mol) of acrylonitrile, 7.02 g (0.05 mol) of benzoyl chloride, 11.6 g (0.0625 mol) of tri-n-butylamine, 100 ml of p-xylene and 0.1122 g (0.0005 mol) of palladium acetate are used. After a reaction time of 2 hours at 120° C., 3.47 g (0.27 mol) of cinnamonitrile are obtained, corresponding to a yield of 54% of theory. Boiling point=134°-136° C./17×102Pa.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10].N1C=CC=CC=1.Cl[C:18]([O:20][CH:21]=[CH2:22])=[O:19]>C(Cl)(Cl)Cl>[CH:21]([O:20][C:18]([O:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10])=[O:19])=[CH2:22]
Reactant: O=C1CCC(=O)N1CCO
Reactant: C=COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: C=COC(=O)OCCN1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.2 %

Procedure:
To a 500 mL 3-neck round bottom flask fitted with a mechanical stirrer, condenser, nitrogen blanket, dropping funnel, ice-saltwater bath, and thermometer were added 5.0 (35.0 mmol) of N-(2-hydroxyethyl) succinimide, 2.8 g (35.0 mmol) of pyridine, and 100 mL chloroform. To the reaction mixture was added 3.7 g (35.0 mmol) of vinyl chloroformate so that the temperature remained below 10° C. After stirring at room temperature for 18 hours the reaction mixture was washed with 100 mL 2N HCl and 100 mL 2N NaOH. The organic phase was dried over magnesium sulfate. The solvent was removed on a rotary evaporator and the resulting red liquid chromatographed (silica gel, chloroform). The recovered oil totaled 3.0 g (14.1 mmol, 40.2% yield). FTIR (neat, capillary) 1755.10, 1694.90, 1648.77, 1427.00, 1396.38, 1366.15, 1329.97, 1298.34, 1239.58, 1185.85, 1152.26, 1111.20, 1085.92, 1024.25, 1005.00, 946.53, 894.87, 882.46, 848.52, 818.51, 778.99, 700.00, 661.32. NMR (CDCl3) 6.50-6.83 (1H,q), 4.13- 4.66 (2H,m), 3.93-4.13 (2H,m), 3.33-3.66 (2H,m), 2.41 (4H,S). ##STR17##
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:9][C:10]1[CH:14]=[CH:13][NH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:9][C:10]1[CH:14]=[CH:13][N:12]([C:2]2[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=2)[N:11]=1
Reactant: Clc1cccnc1Cl
Reactant: Brc1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cccnc1-n1ccc(Br)n1
Temperature: 125 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 2,3-dichloropyridine (27.4 g, 185 mmol) and 3-bromopyrazole (i.e. the product of Step B) (25.4 g, 176 mmol) in dry N,N-dimethylformamide (88 mL) was added potassium carbonate (48.6 g, 352 mmol), and the reaction mixture was heated to 125° C. for 18 hours. The reaction mixture was cooled to room temperature and poured into ice water (800 mL). A precipitate formed. The precipitated solids were stirred for 1.5 hrs, filtered and washed with water (2×100 mL). The solid filter cake was taken up in methylene chloride and washed sequentially with water, 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and brine. The organic extracts were then dried over magnesium sulfate and concentrated to afford 39.9 g of a pink solid. The crude solid was suspended in hexane and stirred vigorously for 1 hr. The solids were filtered, washed with hexane and dried to afford the title product as an off-white powder (30.4 g) determined to be >94% pure by NMR. This material was used without fbrther purification in Step D.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:12]=[CH:11][C:9](N)=[CH:8][CH:7]=2)[N:3]=[N:4][CH:5]=1.[ClH:13].N([O-])=O.[Na+].[S:18](=[O:20])=[O:19].C(O)(=O)C>C(#N)C.C(O)(=O)C.O.O.[Cu](Cl)Cl>[N:1]1[N:2]([C:6]2[CH:12]=[CH:11][C:9]([S:18]([Cl:13])(=[O:20])=[O:19])=[CH:8][CH:7]=2)[N:3]=[N:4][CH:5]=1
Reactant: Nc1ccc(-n2ncnn2)cc1
Reactant: Cl
Reactant: O=S=O
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O
Product: O=S(=O)(Cl)c1ccc(-n2ncnn2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-(2H-tetrazol-2-yl)aniline (2 g, 12.41 mmol) and hydrochloric acid (3.52 mL, 42.8 mmol) in acetonitrile (124 mL) and acetic acid (7 mL) stirred at −10° C., sodium nitrite (2.349 mL, 14.89 mmol) was added dropwise. The resulting mixture was stirred at 0° C. for 10 minutes, after which sulfur dioxide/acetic acid (saturated) (44 mL, 12.41 mmol) was added dropwise to the resulting mixture at a rate such that the reaction temperature is maintained below 5° C. Following the addition of SO2, a solution of copper(II) chloride dihydrate (3.61 mL, 15.51 mmol) was added dropwise. The reaction mixture was allowed to react at 0° C. for 30 minutes and then was warmed to room temperature and stirred at room temperature for 3 hours. The mixture was poured onto 400 g of ice and stirred until all the ice melted. The solid was collected by filtration and washed with water and air-dried to afford the title compound. 1H NMR (400 MHz, acetone-d6): δ 9.15 (s, 1H), 8.62 (d, 2H), 8.48 (d, 2H).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[CH3:16][C:17]([CH3:23])([CH3:22])[CH2:18][C:19](Cl)=[O:20].[CH2:24]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)[CH2:25][CH3:26]>>[CH3:16][C:17]([CH3:23])([CH3:22])[CH2:18][C:19]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:31]([C:30]3[CH:32]=[CH:33][C:27]([CH2:24][CH2:25][CH3:26])=[CH:28][CH:29]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)=[O:20]
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CCCc1ccc(N)cc1
Product: CCCc1ccc(N2CCC3(CCN(C(=O)CC(C)(C)C)CC3)C2=O)cc1

Procedure:
Off-white solid. MS (ESI): 371.26 (MH+). This example was prepared in analogy to example 7 step A) to B) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 3,3-dimethyl-butyryl chloride and 4-propyl-aniline.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:26])[C:5]2[N:11]3[C:12]([CH2:15]Br)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=3)[C:6]=2[CH:25]=1.[CH3:27][NH:28][CH3:29].[I-].[Na+]>>[CH3:27][N:28]([CH2:15][C:12]1[N:11]2[C:5]3[C:4]([CH3:26])=[CH:3][C:2]([CH3:1])=[CH:25][C:6]=3[C:7]([C:17]3[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=3)=[N:8][CH2:9][C:10]2=[N:14][N:13]=1)[CH3:29]
Reactant: CSc1ccc(C2=NCc3nnc(CBr)n3-c3c(C)cc(C)cc32)cc1
Reactant: CNC
Agent: [I-]
Agent: [Na+]
Product: CSc1ccc(C2=NCc3nnc(CN(C)C)n3-c3c(C)cc(C)cc32)cc1

Procedure:
In the manner given in Example 1, 8,10-dimethyl-1-(bromomethyl)-6-[p-(methylthio)phenyl]-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine was reacted with dimethylamine in the presence of sodium iodide to give 1-[(dimethylamino)methyl]-8,10-dimethyl-6-[p-(methylthio)phenyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[O:12])[O:11][C:7]=2[CH:6]=1)=[O:4].[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:21][CH2:20][N:19]([CH2:2][CH:3]([C:5]2[CH:14]=[CH:13][C:8]3[NH:9][C:10](=[O:12])[O:11][C:7]=3[CH:6]=2)[OH:4])[CH2:18][CH2:17]1
Reactant: O=C(CCl)c1ccc2[nH]c(=O)oc2c1
Reactant: OC1(c2ccccc2)CCNCC1
Product: O=c1[nH]c2ccc(C(O)CN3CCC(O)(c4ccccc4)CC3)cc2o1
Yield: 25 %

Procedure:
By the procedures of Examples 8 and 2, 6-(2-chloroacetyl)-2(1H)-benzoxazolone and 4-hydroxy-4-phenylpiperidine were converted to present title product in 25% yield after recrystallization from ethanol/ether; m.p. 175°-177° C. NMR (methanol-d4) 7.51 (dd, J=1.5, 8.5 Hz, 2H), 7.35-7.29 (m, 3H), 7.24-7.19 (m, 2H), 7.05 (d, J=8 Hz, 1H), 4.94-4.90 (m, 1H--becomes dd J=3, 8.5 Hz with D2O wash), 2.96-2.90 (m, 2H), 2.80-2.57 (m, 4H), 2.19 (dq, J=4.5, 13 Hz, 2H), 1.74 (br d, J=14.5 Hz, 2H). IR(KBr) 3320, 3115, 2920, 2830, 1785, 1750.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH:25]=[O:26])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][Mg]Br>C1COCC1>[C:1]([N:20]1[CH:24]=[C:23]([CH:25]([OH:26])[CH3:27])[N:22]=[CH:21]1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: C1CCOC1
Product: CC(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
To a solution of 1-trityl-1H-imidazole-4-carbaldehyde (10.0 g, 0.03 mol) in anhydrous THF (100 mL) was added dropwise methyl magnesium bromide (1.4 M in hexane, 52.8 mL, 0.075 mol) at 0° C. After the addition, the mixture was stirred at RT overnight. The reaction was quenched with sat. aq. NH4Cl (50 mL) and the mixture extracted with CH2Cl2 (3×50 mL). The organic layers were combined, washed with 1 N aq. NaOH (3×20 mL), water (3×20 mL) and brine (100 mL), dried over MgSO4 and evaporated. The residue was purified via column chromatography (silica gel, EtOAc/Petroleum ether 1:5) to yield the title compound (8.0 g, 75.0%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:27])[C@H:13]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH2:14])([CH3:4])([CH3:3])[CH3:2].Br[CH:30]1[CH2:35][CH:34]([CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[O:33][C:31]1=[O:32].C(N(CC)CC)C.O>C(#N)C>[C:1]([O:5][C:6](=[O:28])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:27])[C@H:13]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:14][CH:30]1[CH2:35][CH:34]([CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[O:33][C:31]1=[O:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reactant: CCCCCC1CC(Br)C(=O)O1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CCCCCC1CC(N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)OC(C)(C)C)C(=O)O1
Temperature: 70 °C
Reaction time: 40 h
Yield: 72.2 %

Procedure:
Dissolved in 50 ml of acetonitrile were 2.00 g of Nε -t-butoxycarbonyl-L-lysyl-L-proline t-butyl ester and 3.53 g of 2-bromo-4-pentyl-γ-butyrolactone. After a dropwise addition of 0.76 g of triethylamine, the resultant mixture was heated and stirred at 70° C. for 40 hours. The reaction mixture was poured into chilled water, followed by extraction with ethyl acetate. The extract was washed successively with water, a 2% aqueous solution of sodium hydrogencarbonate, and water. After drying the extract over anhydrous sodium sulfate, it was distilled under reduced pressure. The residue was isolated and purified by chromatography on a silica gel column (chloroform:ethyl acetate=10:1-5:1), thereby obtaining as a colorless syrupy substance 2.00 g of Nα -(2-oxo-5-pentyl-3-tetrahydrofuranyl)-Nε -t-butoxycarbonyl-L-lysyl-L-proline t-butyl ester [in the formula (I), R1 =--(CH2)4CH3, R2 =H, R3 =--(CH2)4NHCOO-t-Bu, R4 and R5 =--(CH2)3 --, R6 = t-Bu (Compound 27)]. Upon analysis of Compound 27 by high-performance liquid chromatography, it was found to be a mixture of 4 types of diastereomers.
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:5][N:4]([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12](O)=[O:13])=[N:10][CH:11]=2)[CH2:3]1.[NH2:22][C:23]1([CH2:29][C:30]([NH2:32])=[O:31])[CH2:26][S:25](=[O:28])(=[O:27])[CH2:24]1>>[NH2:32][C:30](=[O:31])[CH2:29][C:23]1([NH:22][C:12]([C:9]2[CH:8]=[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:6]([N:4]3[CH2:5][C:2]([F:21])([F:1])[CH2:3]3)=[CH:11][N:10]=2)=[O:13])[CH2:24][S:25](=[O:27])(=[O:28])[CH2:26]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(N2CC(F)(F)C2)cn1
Reactant: NC(=O)CC1(N)CS(=O)(=O)C1
Product: NC(=O)CC1(NC(=O)c2cc(OCC(F)(F)F)c(N3CC(F)(F)C3)cn2)CS(=O)(=O)C1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (example 223b) and 2-(3-amino-1,1-dioxo-thietan-3-yl)acetamide (example 160d) as starting materials and isolated (20 mg, 27%); MS (ESI, m/z): 473.3 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.[CH2:14](N)C(C)C.[Cl:19][C:20]1[CH:57]=[CH:56][C:23]([C:24]2[C:29]([C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[C:35]([C:40]5N(CC)C6C=C[C:49](C(O)=O)=[CH:50][C:42]=6[N:41]=5)[CH:36]=4)[N:31]=3)=[CH:28][C:27]([O:54][CH3:55])=[CH:26][CH:25]=2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]2[C:29]([C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[C:35]([C:40]5[N:41]([CH2:42][CH:50]([CH3:14])[CH3:49])[C:2]6[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=6[N:11]=5)[CH:36]=4)[N:31]=3)=[CH:28][C:27]([O:54][CH3:55])=[CH:26][CH:25]=2)=[CH:56][CH:57]=1
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCn1c(-c2ccc3nc(-c4cc(OC)ccc4-c4ccc(Cl)cc4)ccc3c2)nc2cc(C(=O)O)ccc21
Reactant: CC(C)CN
Product: COc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4CC(C)C)ccc3n2)c1

Procedure:
The title compound was prepared from Resin 534a and isobutylamine according to the procedure described in the preparation of Compound 534.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C[N:10](C)[CH:11]=[O:12]>>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]([NH2:10])=[O:12]
Reactant: CN(C)C=O
Reactant: C1CCNCC1
Agent: [H-]
Agent: [Na+]
Product: NC(=O)c1ccccn1
Reaction time: 2 h

Procedure:
Meanwhile sodium hydride (150 mg of a 60% dispersion in mineral oil) is added to a solution of N-(3,5-dichloro-1-oxido-4-pyridinio)acetamide (663 mg) in dimethylformamide (20 mL) and the mixture stirred for 2 hours. The mixture is then added to the solution of the acid chloride and stirring continued for 3 hours. Piperidine (0.26 mL) is added and stirring continued for a further 4 hours. After concentrating in vacuo the residue is dissolved in dichloromethane, the mixture filtered, the filtrate treated with decolourizing charcoal and refiltered. Evaporation in vacuo gives a brown oil which is purified by reverse phase high pressure liquid chromatography (methanol/water 4:1 v/v) to give (±)-N-(3,5-dichloro-1-oxido-4-pyridinio)-5-methoxy-4-(tricyclo[2.2.1.0.2.6]hept-2-yloxy)pyridine-2-carboxamide (60 mg) as a solid, m.p. 235-6° C. [Elemental analysis: C, 54.16; H, 4.21; N, 10.58% calculated: C, 56.04; H, 4.06; N, 9.95%].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH:19]=[O:20].O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH:19]=[O:20]
Reactant: COc1ccc(C=O)c(O)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1
Product: COc1ccc(C=O)c(Oc2ccnc3cc(OC)c(OC)cc23)c1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
4-Chloro-6,7-dimethoxyquinoline (111 mg), 2-hydroxy-4-methoxybenzaldehyde (304 mg), and 4-dimethylaminopyridine (244 mg) were suspended in monochlorobenzene (2 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give 2-[(6,7-dimethoxy-4-quinolyl)oxy]-4-methoxybenzaldehyde.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[C:4]2[N:5]([C:19]([C:22]#[C:23][Si](C)(C)C)=[CH:20][N:21]=2)[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:8]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO.CC(OC)(C)C>[C:22]([C:19]1[N:5]2[CH:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[CH:8]=[C:3]([C:2]([F:1])([F:29])[F:28])[C:4]2=[N:21][CH:20]=1)#[CH:23]
Reactant: C[Si](C)(C)C#Cc1cnc2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: C#Cc1cnc2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cn12
Temperature: 0 °C
Reaction time: 6 h
Yield: 65.5 %

Procedure:
To a solution of 8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-3-trimethylsilanylethynyl-imidazo[1,2-a]pyridine (10.5 g, 25 mmol) in THF (100 mL) and MeOH (250 mL) at 0° C. was added K2CO3 (340 mg, 10 mol %) and the mixture was stirred at 0° C. for 6 h. Diluted with TBME and ice water, separated, washed with brine, dried over Na2SO4, totally evaporated. Purified by column chromatography (heptane/AcOEt) and trituration with heptane and filtration gave the product as an off-white solid (5.8 g, 66%). MS (ISP) 355.0 [(M+H)+].