Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([S:13][CH3:14])[N:5]=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[NH2:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([F:22])[CH:21]=1.CCN(C(C)C)C(C)C.CCOC(C)=O>CN(C=O)C>[F:22][C:20]1[CH:21]=[C:16]([NH:15][C:2]2[N:3]=[C:4]([S:13][CH3:14])[N:5]=[N:6][C:7]=2[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:17]=[N:18][CH:19]=1
Reactant: CCOC(=O)c1nnc(SC)nc1Cl
Reactant: Nc1cncc(F)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nnc(SC)nc1Nc1cncc(F)c1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
Ethyl 5-chloro-3-(methylthio)-1,2,4-triazine-6-carboxylate (300 mg, 1.29 mmol) was dissolved in 10 mL dry DMF. To it was added 3-amino-5-fluoropyridine (728 mg, 6.50 mmol) and then DIEA (0.45 mL, 2.60 mmol). The mixture was stirred at 100° C. for 1.5 h. To the mixture were poured 200 mL EtOAc. The mixture was washed with brine twice and water twice, dried in MgSO4, and concentrated in vacuo to afford crude ethyl 5-((5-fluoropyridin-3-yl)amino)-3-(methylthio)-1,2,4-triazine-6-carboxylate. It was stirred in 30 mL “7.0 N ammonia in methanol” (Acros, #133710010) as a slurry for overnight. The solid was isolated by filtration, washed with hexane and dried in vacuum oven. It was very pure 5-((5-fluoropyridin-3-yl)amino)-3-(methylthio)-1,2,4-triazine-6-carboxamide. Yield was 189 mg (52% for 2 steps).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[N:15]=[CH:16][NH:17][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([I:25])C(=O)C1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2[N:17]=[C:16]([I:25])[NH:15][C:12]=2[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)N1CCc2nc[nH]c2CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2nc(I)[nH]c2CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.6 %

Procedure:
To a solution of 4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepine-6-carboxylic acid tert-butyl ester (Preparation 27, 4.8 g, 20.23 mmol) in THF (60 mL) was added NIS (4.78 g, 21.24 mmol). The reaction was stirred at room temperature for 18 hours and the solvent was then removed in vacuo. The residue was dissolved in EtOAc (200 mL) and the resulting solution was washed with sodium thiosulfate solution (150 mL). The aqueous layer was re-extracted with EtOAc (150 mL) and the combined organic layers were washed with brine (150 mL), dried over MgSO4 and concentrated in vacuo to give the title compound as a tan solid (6.14 g) in an 84% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:26](=[O:29])[NH:27][CH3:28])[CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH2:10][CH:9]1[CH2:30][CH2:31][O:32][Si](C(C)(C)C)(C)C)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:26](=[O:29])[NH:27][CH3:28])[CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH2:10][CH:9]1[CH2:30][CH2:31][OH:32])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)OC(C)(C)C)C(CCO[Si](C)(C)C(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)OC(C)(C)C)C(CCO)C1

Procedure:
A solution of 2-[2-(tert-butyldimethylsilanyloxy)ethyl]4-(1-methylcarbamoyl-2-naphthalen-2-ylethyl)-piperazine-1-carboxylic acid tert-butyl ester, 59, (15.9 g, 23.5 mmol) and 1 M tetrabutylammonium fluoride (40 mL) is stirred for 24 hours. The reaction solution is filtered through a pad of silica gel, the filtrate is concentrated in vacuo, and the resulting crude product purified over silica gel (EtOAc/hexane 1:2, 1:1, then 5% methanol in EtOAc) to afford the desired product.
Reaction SMILES: Cl.[N:2]1([CH2:7][CH2:8][C:9]2[CH2:18][CH2:17][C:16]3[CH:15]=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[CH:13]=[CH:12][C:11]=3[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.CCN=C=NCCCN(C)C.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45]C(C(O)=O)=[CH:43][CH:42]=2)=[CH:37][CH:36]=1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.CN(C)C=O>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][C:21]([C:20]([NH:19][C:14]3[CH:13]=[CH:12][C:11]4[CH:10]=[C:9]([CH2:8][CH2:7][N:2]5[CH2:6][CH2:5][CH2:4][CH2:3]5)[CH2:18][CH2:17][C:16]=4[CH:15]=3)=[O:22])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1
Reactant: CC(=O)Nc1ccc2c(c1)CCC(CCN1CCCC1)=C2
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2c(c1)CCC(CCN1CCCC1)=C2)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 52.6 %

Procedure:
Concentrated hydrochloric acid (2 ml) was added to N-[6-[2-(1-pyrrolidinyl)ethyl]-7,8-dihydro-2-naphthalenyl]acetamide (98.0 mg, 0.345 mmol) obtained in Reference Example 103, which was stirred at 100° C. for 16 hours. The solvent was distilled out under reduced pressure. Ethyl acetate was added to the residue, which was washed with aqueous potassium carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. WSC (62.5 mg, 0.326 mmol) was added to a dimethylformamide solution (1.5 ml) of the resulting oily substance (79.0 mg, 0.326 mmol), 4′-chloro-[1,1′-biphenyl]-4-carboxylic acid (64.6 mg, 0.326 mmol) and DMAP (39.8 mg, 0.326 mmol) under ice-cooling, which was stirred at room temperature for 1 day. Ethyl acetate was added to the reaction mixture, which was washed with aqueous potassium carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. The resulting residue was purified by aluminum column chromatography (development solvent; ethyl acetate), powdered with ethyl acetate-isopropyl ether (1:5), to give the titled compound (78.4 mg).
Reaction SMILES: IC.[Cl:3][C:4]1[CH:25]=[CH:24][C:7]([CH2:8][NH:9][C:10]([C:12]2[C:13](=[O:23])[C:14]3[CH:21]=[C:20]([I:22])[CH:19]=[N:18][C:15]=3[NH:16][N:17]=2)=[O:11])=[CH:6][CH:5]=1.[CH2:26](N(CC)CC)C>C(#N)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C:12]2[C:13](=[O:23])[C:14]3[CH:21]=[C:20]([I:22])[CH:19]=[N:18][C:15]=3[N:16]([CH3:26])[N:17]=2)=[O:11])=[CH:24][CH:25]=1
Reactant: CCN(CC)CC
Reactant: O=C(NCc1ccc(Cl)cc1)c1n[nH]c2ncc(I)cc2c1=O
Solvent: CI
Solvent: CC#N
Product: Cn1nc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)cnc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Iodomethane (0.6 mL) is added to a mixture of N-(4-chlorobenzyl)-6-iodo-4-oxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxamide (Preparation 22, 0.196 g) and triethyl-amine (70 μL) in acetonitrile (10 mL) and the mixture is stirred at room temperature for 48 h. The reaction mixture is concentrated, and the residue is dissolved in chloroform and water. The organic phase is dried (Na2SO4) and concentrated in vacuo. The crude product is purified by flash chromatography on silica gel (240-400 mesh, 7 g) eluting with 2% methanol/chloroform. The product fractions are pooled and concentrated in vacuo to give 0.16 g of the title compound as a yellow solid. Physical characteristics: mp 207-208° C.; 1H NMR (400 MHz, CDCl3) δ4.39, 4.70, 7.33, 9.0, 9.1, 10.0; IR (drift) 1676, 1608, 1574, 1550, 1493, 1470, 1397, 1393, 1370, 1320, 1267, 1257, 812, 673, 666 cm−1; MS (EI) m/z 454 (M+, 61); HRMS (FAB) m/z 454.9767 (C16H12ClIN4O2+H). Anal. Found: C, 42.10; H, 2.61; N, 12.22.
Reaction SMILES: C(CC1C=CC(C[CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C@@H:19]2[CH2:28][CH2:27][C:26]3[CH:25]=[C:24]([O:29]C(=O)C(C)(C)C)[CH:23]=[CH:22][C:21]=3[CH2:20]2)=CC=1)(O)=O.[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH2:11]([N:12]([CH2:25][C:26]1[CH:27]=[CH:28][C:19]([CH2:14][CH2:13][N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:20][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C@@H:19]1[CH2:28][CH2:27][C:26]2[CH:25]=[C:24]([OH:29])[CH:23]=[CH:22][C:21]=2[CH2:20]1)[CH3:10]
Reactant: CC(C)(C)C(=O)Oc1ccc2c(c1)CC[C@@H](c1ccccc1NCCCc1ccc(CC(=O)O)cc1)C2
Reactant: C1CCNC1
Product: CCN(Cc1ccc(CCN2CCCC2)cc1)c1ccccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 86.3 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]phenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (28 mg) and pyrrolidine (20 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (11 mg) was obtained.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH2:11]([O:18][C:19]([C:21]1([C:24](=[O:41])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][N:36]=[C:35]([NH2:39])[CH:34]=3)=[CH:28][C:27]=2[F:40])[CH2:23][CH2:22]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.ClC(OC1C=CC=CC=1)=O.C(#N)C.C(OC(C1(C(=O)NC2C=CC(OC3C=CN=C(N)C=3)=CC=2F)CC1)=O)C1C=CC=CC=1.O1CCCC1>C(#N)C.O1CCCC1.O.O1CCCC1.N1C=CC=CC=1.N1C=CC=CC=1>[CH2:11]([O:18][C:19]([C:21]1([C:24](=[O:41])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][N:36]=[C:35]([NH:39][C:2]([O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[O:3])[CH:34]=3)=[CH:28][C:27]=2[F:40])[CH2:22][CH2:23]1)=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc(NC(=O)C3(C(=O)OCc4ccccc4)CC3)c(F)c2)ccn1
Solvent: O
Solvent: CC#N
Solvent: C1CCOC1
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)OCc4ccccc4)CC3)c(F)c2)ccn1)Oc1ccccc1
Temperature: 10 °C
Yield: 99.1 %

Procedure:
Pyridine (50 ml) was mixed with tetrahydrofuran (40 ml) and cooled to 10° C. A solution of phenyl chloroformate (4.83 g) in acetonitrile (50 ml) and a solution of 1-[4-(2-aminopyridin-4-yloxy)-2-fluorophenylcarbamoyl]cyclopropanecarboxylic acid benzyl ester (10.00 g) in tetrahydrofuran (80 ml) were added dropwise to the tetrahydrofuran-pyridine solution over a period of 2 hours at 10° C. At this time, the amounts of the phenyl chloroformate-acetonitrile solution and the 1-[4-(2-aminopyridin-4-yloxy)-2-fluorophenylcarbamoyl]cyclopropanecarboxylic acid benzyl ester/tetrahydrofuran solution added dropwise were adjusted to the constant rate so that each solution was added dropwise over a period of 2 hours. The crystals were precipitated while the solutions were added dropwise. After completing the dropwise addition, the completion of reaction was confirmed using an HPLC apparatus. Subsequently, a mixed solution of water (10 ml) and acetonitrile (50 ml) was added to the reaction mixture. The crystals were collected by filtration and washed with a mixed solution of tetrahydrofuran (15 ml)-acetonitrile (15 ml) and dried under reduced pressure to give the title compound (12.74 g). Apparent yield 98.0%, purity 94.6% (HPLC area percentage).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:37])[C@H:10]([CH:34]([CH3:36])[CH3:35])[N:11]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]#[N:32])=[CH:21][C:20]=1[Br:33])[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn]([N:51]=[N+:52]=[N-:53])(CCCC)CCCC)CCC>C1(C)C(C)=CC=CC=1>[CH2:1]([O:8][C:9](=[O:37])[C@H:10]([CH:34]([CH3:36])[CH3:35])[N:11]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[NH:53][N:52]=[N:51][N:32]=2)=[CH:21][C:20]=1[Br:33])[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1Br)[C@H](C(=O)OCc1ccccc1)C(C)C
Solvent: Cc1ccccc1C
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1Br)[C@H](C(=O)OCc1ccccc1)C(C)C

Procedure:
A solution of 4.5 g (8 mmol) of N-[(3-bromo-2'-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine benzyl ester and 3.4 g (10.4 mmol) of tributyltin azide in 50 ml of xylene is heated to boiling under reflux for 20 hours. Working-up analogously to Example 54 and "flash"-chromatographic purification (toluene-methanol 4:1) gives the title compound as a colourless foam (Rf 0.57, system A2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][S:25]3(=[O:30])=[O:29])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:31])[CH3:9])=[CH:4][CH:3]=1.[CH3:32][C:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[CH:35][N:34]=1>>[CH3:32][C:33]1[CH:38]=[C:37]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@:13]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)([CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][S:25]4(=[O:30])=[O:29])[O:12][C:11]3=[O:31])[CH3:9])=[CH:4][CH:3]=2)[CH:36]=[CH:35][N:34]=1
Reactant: Cc1cc(B(O)O)ccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCN2CCCS2(=O)=O)(c2ccccc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@@](CCN4CCCS4(=O)=O)(c4ccccc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(1,1-dioxo-isothiazolidin-2-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one and 2-methylpyridine-4-boronic acid following a procedure analogous to that described in Example 1 Step 2.
Reaction SMILES: CN1CCOCC1.[F:8][C:9]([F:18])([F:17])[C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12].[O:19]=[C:20]1[CH2:37][CH2:36][C@@:35]2([CH3:38])[C:22]([CH2:23][CH2:24][C@@H:25]3[C@@H:34]2[CH2:33][CH2:32][C@@:30]2([CH3:31])[C@H:26]3[CH2:27][CH2:28][C@@H:29]2[C:39](Cl)=[O:40])=[CH:21]1>C(Cl)Cl>[O:19]=[C:20]1[CH2:37][CH2:36][C@@:35]2([CH3:38])[C:22]([CH2:23][CH2:24][C@@H:25]3[C@@H:34]2[CH2:33][CH2:32][C@@:30]2([CH3:31])[C@H:26]3[CH2:27][CH2:28][C@@H:29]2[C:39]([NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]([F:17])([F:18])[F:8])=[O:40])=[CH:21]1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Cl
Reactant: Nc1ccccc1C(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Nc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-methylmorpholine (0.28 g, 2.8 mmol) and 2-(trifluoromethyl)aniline (0.5 g, 3.1 mmol) in anhydrous CH2Cl2 (3.0 mL) at 0° C. under a nitrogen atmosphere was added a solution of 3-oxoandrost-4-ene-17β-carbonyl chloride from Step A (2.56 mmol) in anhydrous CH2Cl2 (8.1 mL) dropwise. The ice bath was removed and the mixture stirred at room temperature overnight. The reaction was then concentrated and the residue was purified by flash chromatography on silica gel eluting with 0 to 50% EtOAc-hexanes to afford the desired product as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:13]Br.S([O-])(O)=O.[Na+]>[Fe](Cl)(Cl)Cl.O>[Br:13][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)c1ccc([N+](=O)[O-])cc1
Reactant: BrBr
Agent: Cl[Fe](Cl)Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)c1ccc([N+](=O)[O-])cc1Br
Yield: 101.1 %

Procedure:
A solution of p-nitrocumene (X) (50 g, 0.300 mol, GC purity: 99.1%) and iron(III) chloride was heated to 40° C. and bromine (59.92 g, 0.375 mol) was added dropwise over a period of 3 hours. The reaction mixture was poured into 120 ml of water, sodium hydrogensulphite (40% strength in water, 20.81 g, 0.078 mol) was added dropwise and the mixture was extracted with 100 ml of chlorobenzene. After phase separation, the chlorobenzene phase was washed with 100 ml of 5% strength aqueous HCl. Removal of the chlorobenzene under reduced pressure gave 2-bromo-1-isopropyl-4-nitrobenzene (74.05 g, 96.9 GC-% by area, 98% of theory) as a yellow oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].C(=O)([O-])[O-].[K+].[K+].[C:17]([C:24](OCC)=[O:25])#[C:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].Cl>C(O)C.O>[CH2:22]([O:21][C:19]([C:18]1[CH:17]=[C:24]([OH:25])[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[Cl:2])[N:10]=1)=[O:20])[CH3:23]
Reactant: NNc1ccccc1Cl
Reactant: CCOC(=O)C#CC(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(O)n(-c2ccccc2Cl)n1

Procedure:
To a stirred solution of 2-chlorophenylhydrazine hydrochloride (22.4 g) and potassium carbonate (34.5 g) in ethanol (250 ml) was added diethyl acetylenedicarboxylate (20 ml) and the resulting mixture was heated at reflux for 18 hours. The reaction mixture was cooled, 6 N hydrochloric acid (75 ml) and water (500 ml) were added sequentially. The reaction mixture was extracted with ethyl acetate, the organic layer washed with water, brine, dried (Na2SO4) and concentrated in vacuo. The resulting gum was stirred with isopropyl ether (250 ml) to afford the title compound (I-1a) as a tan solid, (23 g) after filtering and drying in vacuo.
Reaction SMILES: [NH2:1]/[C:2](=[N:16]\[OH:17])/[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[CH3:18][CH2:19]N(C(C)C)C(C)C.C(Cl)(=O)C>C(#N)C>[CH3:18][C:19]1[O:17][N:16]=[C:2]([CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[N:1]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1/C(N)=N/O
Reactant: CCN(C(C)C)C(C)C
Solvent: CC(=O)Cl
Solvent: CC#N
Product: Cc1nc(C2CCCCN2C(=O)OC(C)(C)C)no1
Temperature: 0 °C
Yield: 33.2 %

Procedure:
In a 16 mL vial, tert-butyl 2-[(Z)-amino(hydroxyimino)methyl]piperidine-1-carboxylate (150 mg, 0.62 mmol; which may be prepared as described in Step 1) was dissolved in acetonitrile (6.2 mL) and cooled at 0° C. under nitrogen. DIPEA (324 μL, 1.86 mmol) and acetyl chloride (88 μL, 1.24 mmol) were added dropwise and the reaction mixture was allowed to warm to room temperature then heated to 100° C. for 4 h, cooled and concentrated. The residue was taken up in EtOAc and water. The two layers were separated and the aqueous phase extracted with EtOAc. The combined organics were dried on Na2SO4 and concentrated. The residue was taken up in o-xylene (7 mL) and heated to 150° C. for 3 h then concentrated. The crude mixture was purified on column chromatography (eluent: Pentane/EtOAc 7/3) to give the product (55 mg, 33%) as a yellow oil.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].Cl[C:6]1[C:7]2[CH:14]=[CH:13][NH:12][C:8]=2[N:9]=[CH:10][N:11]=1>CO>[CH3:1][O:2][C:6]1[C:7]2[CH:14]=[CH:13][NH:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: C[O-]
Reactant: Clc1ncnc2[nH]ccc12
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1ncnc2[nH]ccc12
Temperature: 65 °C
Reaction time: 16 h

Procedure:
To a solution of sodium methoxide prepared by adding portion wise the sodium (2 g) in methanol (100 mL) under an inert atmosphere, was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (Reference: Gerster, John F.; Hinshaw, Barbara C.; Robins, Roland K.; Townsend, Leroy B. Study of electrophylic substitution in the pyrrolo[2,3-d]pyrimidine ring. J. Heterocycl. Chem. (1969), -(2), 207-13.) (3.5 g). The solution was stirred at 65° C. for 16 hours and then partitioned between ethyl acetate and brine. The organic phase was separated, then dried over magnesium sulfate and then evaporated under reduced pressure. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane (50:50, v/v) to give the title compound (1.2 g) as an amorphous solid. MS: 150 [MH]+. LCMS (Method B) RT=2.39 minutes.
Reaction SMILES: [N:1]1([C:6]2[CH:33]=[CH:32][C:9]([O:10][CH2:11][CH2:12][N:13](CC3C=CC=CC=3)[CH2:14][CH:15]([OH:24])[CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>CO.[Pd]>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][NH:13][CH2:14][CH:15]([OH:24])[CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:32][CH:33]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: OC(COc1ccccc1)CN(CCOc1ccc(-n2ccnc2)cc1)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: OC(CNCCOc1ccc(-n2ccnc2)cc1)COc1ccccc1

Procedure:
To a solution of 5.5 g (12.4 mmol) 1-[[2-[4-(1H-imidazol-1-yl)phenoxy]ethyl](phenylmethyl)amino]-3-phenoxy-2-propanol in 25 mL methanol is suspended 1.0 g 10% palladium on carbon. The reaction mixture is hydrogenated at 50 psi in a Parr Hydrogenator. Follow the progress of the reaction by thin-layer chromatography on silica gel (methylene chloride:methanol, 9:1). At the completion of the reaction, thecatalyst is filtered and the solvents are removed in vacuo. The isolated oil is taken up in methylene chloride, dried over anhydrous Na2SO4, filtered and the solvents are removed to give the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:10][C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:13]=1.[C-:26]#[N:27].[Na+].O>CS(C)=O>[C:26]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:10][C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:13]=1)#[N:27]
Reactant: BrCCCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCCCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 50 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
2-(7-Bromoheptyl)-4,5-diphenyloxazole (13.8 g) in dimethylsulphoxide (80 ml) was added over 45 minutes to a mixture of sodium cyanide (1.87 g) in dimethylsulphoxide (80 ml). The reaction was stirred at 50° C. for 2 h, cooled and poured into water (500 ml). The aqueous was extracted with diethyl ether (4×250 ml). The ether extracts were combined, washed with water (250 ml), dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Column chromatography on silica gel eluted with a hexane: dichloromethane gradient gave 2-(7-cyanoheptyl)-4,5-diphenyloxazole (4.89 g, 41%) as an oil. Found: C, 80.20; H, 7.02; N, 8.13%; C23H24N2O requires: C, 80.31; H, 7.18; n, 8.16%;
Reaction SMILES: O1CCCC1.[O:6]=[C:7]([CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8]P(=O)(OC)OC.[H-].[Na+].[CH:25]([C@@H:27]1[C@@H:35]2[C@@H:30]([S:31][C@@H:32]([CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH2:33][CH2:34]2)[CH2:29][C@H:28]1[O:43][CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][O:45]1)=O>C(OCC)(=O)C.C(O)(=O)C>[O:6]=[C:7]([CH2:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)/[CH:8]=[CH:25]/[C@@H:27]1[C@@H:35]2[C@@H:30]([S:31][C@@H:32]([CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH2:33][CH2:34]2)[CH2:29][C@H:28]1[O:43][CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][O:45]1
Reactant: COP(=O)(CC(=O)COc1ccccc1)OC
Reactant: COC(=O)CCC[C@H]1CC[C@@H]2[C@@H](C=O)[C@H](OC3CCCCO3)C[C@@H]2S1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)CCC[C@H]1CC[C@@H]2[C@@H](/C=C/C(=O)COc3ccccc3)[C@H](OC3CCCCO3)C[C@@H]2S1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.1 %

Procedure:
To an anhydrous tetrahydrofuran (2.7 mL) solution of dimethyl (2-oxo-3-phenoxypropyl)phosphonate (194 mg) was added sodium hydride (24.8 mg) in an ice bath, and the mixture was stirred at room temperature for 1.5 hours. Thereto was added dropwise an anhydrous tetrahydrofuran (2 mL) solution of the compound 11 (200 mg), and the mixture was reacted at room temperature for 4.5 hours. Acetic acid was added in a small amount, and the reaction liquid was then diluted with ethyl acetate. This solution was washed with water and a saturated saline, dried with anhydrous magnesium sulfate, and then concentrated to obtain a titled compound (250 mg) having the following physical property values.