Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:11]=[CH:12][N:13]2[C:18](=[O:19])[N:17]([CH2:20][S:21][CH3:22])[N:16]=[N:15][C:14]=12.[OH:23]OS([O-])=O.[K+]>CN(C=O)C.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:11]=[CH:12][N:13]2[C:18](=[O:19])[N:17]([CH2:20][S:21]([CH3:22])=[O:23])[N:16]=[N:15][C:14]=12
Reactant: O=S([O-])OO
Reactant: CSCn1nnc2c(-c3nc4ccccc4s3)ncn2c1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)Cn1nnc2c(-c3nc4ccccc4s3)ncn2c1=O
Temperature: 0 °C
Yield: 98 %

Procedure:
To a 0° C. solution of 8-(benzo[d]thiazol-2-yl)-3-(methylthiomethyl)imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one (0.23 mmol, 75 mg, 1 eq.) in DMF (4.5 mL) was added slowly drop wise Oxone™ (0.25 mmol, 77 mg, 1.1 eq.) dissolved in water (0.75 mL). The formed suspension was stirred at 0° C. and stepwise additions of Oxone™ in water were made until reaction completion. The reaction mixture was filtered and the obtained solid washed with water, acetonitrile, ethyl acetate and ether, and dried under vacuum to give the title compound. Yield: 98%. δH (DMSO-d6) 9.07 (1H, s), 8.22 (1H, m), 8.16 (1H, m), 7.60 (1H, m), 7.52 (1H, m), 5.63 (1H, d, J=13.2), 5.50 (1H, d, J=13.2), 2.79 (3H, s).
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][C:10]([NH:19][CH3:20])=[CH:9][N+:8]=2[O-:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]([O:26][C:27](=[O:35])[CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)([CH3:25])([CH3:24])[CH3:23]>>[C:1]1([C:7]2[C:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:11][C:10]([N:19]([CH2:33][CH2:32][CH2:31][CH2:30][O:29][CH2:28][C:27]([O:26][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:35])[CH3:20])=[CH:9][N+:8]=2[O-:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNc1c[n+]([O-])c(-c2ccccc2)c(-c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)COCCCCBr
Product: CN(CCCCOCC(=O)OC(C)(C)C)c1c[n+]([O-])c(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
In the same manner as in Example 22, except that 2,3-diphenyl-5-(methylamino)pyrazine 1-oxide was used in place of 5,6-diphenyl-2-(methylamino)pyrazine and 2-(4-bromobutyloxy)acetic acid tert-butyl ester was used in place of 2-(4-bromobutyloxy)acetic acid methyl ester, the desired compound was prepared as a pale yellow oily substance.
Reaction SMILES: CN(C=O)C.[OH:6][CH2:7][C:8]([N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9].Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[O:25][CH3:26]>O>[CH3:26][O:25][C:17]1[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[CH:21][C:16]=1[O:6][CH2:7][C:8]([N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9]
Reactant: O=C(CO)N1CCCC1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1OCC(=O)N1CCCC1
Reaction time: 18 h

Procedure:
To a stirred solution of DMF (20 mL) containing 2-hydroxy-1-(pyrrolidin-1-yl)ethanone (2.00 g, 15.5 mmol) under N2 was added 60% NaH/paraffin (640 mg, 16 mmol). Once gas evolution ceased, 2-chloro-5-nitroanisole (1.9 g, 10 mmol) was added. After stirring for 18 hr at 20°, the reaction was diluted with H2O prior to being extracted with EtOAc 3×. The organic layers were washed twice with aq. Na2CO3, brine and dried over Na2SO4 prior to concentration. Chromatography on silica gel using 25% EtOAc/CH2Cl2 eluted 2.06 g of 2-(2-methoxy-4-nitrophenoxy)-1-(pyrrolidin-1-yl)ethanone (52%). 1H NMR (DMSO-d6) δ 1.73-1.79 (m, 2H), 1.86-1.92 (m, 2H), 3.29-3.32 (m, 2H), 3.43-3.46 (m, 2H), 3.04 (s, 3H), 4.93 (s, 2H), 7.02 (d, J=8.80 Hz, 1H), 7.73 (d, J=2.74 Hz, 1H), 7.84 (dd, J=8.80 Hz, 2.20 Hz, 1H); 13C NMR (DMSO-d6) δ 23.22, 25.35, 44.27, 45.30, 55.76, 66.23, 106.35, 111.93, 116.99, 140.51, 148.25, 153.28, 164.33; HPLC a) column: Phenomenex C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.2% H3PO4 to 90% MeOH/10% H2O/0.2% H3PO4; 1 min hold, 4 mL/min UV detection at 220 nm, 2.24 min retention time, (100%); HPLC b) column: Phenomenex C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold; 4 mL/min, UV detection at 220 nm, 2.29 min retention time; MS (ES): m/z 281 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)C.N[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1S.CC(OC(C)=O)=O>C1C=CC=CC=1>[NH:2]1[C:1]2[C:12](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:11]=[CH:4]1
Reactant: Nc1ccccc1S
Reactant: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: c1ccc2[nH]ccc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
A dry DMF solution of the compound (A-2) (0.01 mole) was added o-aminothiophenol (0.013 mole) and Ac2O (0.5ml) at room temperature. The mixture was stirred at 60° C. for 3 h. The reaction mixture was poured into stirred benzene and the precipitated solid was collected by filtration. The crude solid was washed with MeOH and recrystallized from benzene to afford target compound (A) (32% yield). 1H-NMR spectrum is shown in FIG. 3. Photoluminescence spectrum is shown in FIG. 4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[C:10]([CH:19]=C)=[N:9]2)[CH:5]=[N:6][CH:7]=1.I([O-])(=O)(=O)=[O:22].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[C:10]([CH:19]=[O:22])=[N:9]2)[CH:5]=[N:6][CH:7]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1nn(-c2cncc(F)c2)cc1NC(=O)C(C)C
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cn(-c2cncc(F)c2)nc1C=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.2 %

Procedure:
To a solution of N-(1-(5-fluoropyridin-3-yl)-3-vinyl-1H-pyrazol-4-yl)isobutyramide (0.706 g, 2.57 mmol) in tetrahydrofuran (12.87 ml) and water (12.87 ml) was added osmium tetroxide (0.164 ml, 0.026 mmol). After 10 minutes at room temperature, sodium periodate (1.101 g, 5.15 mmol) was added in portions over 3 minutes and the resulting solution was stirred at room temperature. After 18 hours, the solution was poured into 10 mL water and was extracted with 3×10 mL dichloromethane. The combined organic layers were dried, concentrated and chromatographed (0-100% ethyl acetate/hexanes) to give N-(1-(5-fluoropyridin-3-yl)-3-formyl-1H-pyrazol-4-yl)isobutyramide (626 mg, 2.266 mmol, 88% yield) as a yellow solid: mp 140.0-142.0° C.; 1H NMR (300 MHz, CDCl3) δ 10.12 (s, 1H), 9.14 (s, 1H), 8.90 (d, J=2.0 Hz, 1H), 8.82 (s, 1H), 8.51 (d, J=2.5 Hz, 1H), 7.92 (dt, J=9.2, 2.4 Hz, 1H), 2.65 (dt, J=13.8, 6.9 Hz, 1H), 1.31 (d, J=6.9 Hz, 6H); ESIMS m/z 277 ([M+H]+).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([C:16](=[O:26])[N:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[N:13]=[C:12]1[C:27]1[CH:35]=[CH:34][C:33]([C:36]([O:38][CH3:39])=[O:37])=[CH:32][C:28]=1[C:29](O)=[O:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:40]([O:47][CH2:48][C@@H:49]1[CH2:58][C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH2:51][NH:50]1)([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]>>[Si:1]([O:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([C:16](=[O:26])[N:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[N:13]=[C:12]1[C:27]1[CH:35]=[CH:34][C:33]([C:36]([O:38][CH3:39])=[O:37])=[CH:32][C:28]=1[C:29]([N:50]1[C@H:49]([CH2:48][O:47][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:41])[CH3:42])[CH2:58][C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH2:51]1)=[O:30])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1Cc2ccccc2CN1
Reactant: CCCCN(CCCC)C(=O)c1cn(CCO[Si](C)(C)C(C)(C)C)c(-c2ccc(C(=O)OC)cc2C(=O)O)n1
Product: CCCCN(CCCC)C(=O)c1cn(CCO[Si](C)(C)C(C)(C)C)c(-c2ccc(C(=O)OC)cc2C(=O)N2Cc3ccccc3C[C@H]2CO[Si](C)(C)C(C)(C)C)n1
Yield: 85.4 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 271H, 2-(1-(2-(tert-butyldimethylsilyloxy)ethyl)-4-(dibutylcarbamoyl)-1H-imidazol-2-yl)-5-(methoxycarbonyl)benzoic acid (105 mg, 0.19 mmol) and (S)-3-((tert-butyldimethylsilyloxy)methyl)-1,2,3,4-tetrahydroisoquinoline (62 mg, 0.22 mmol) were converted to the title compound (133 mg, 87%). MS(ESI+) m/z 820.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](O)=[CH:4][CH:3]=1.OCC(=O)C.[NH3:24].[OH-].[Na+]>O>[NH2:24][C:5]1[C:6]2[C:7](=[O:17])[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14](=[O:16])[C:15]=2[C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: N
Reactant: O=C1c2ccccc2C(=O)c2c(O)ccc(O)c21
Agent: CC(=O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(O)c2c1C(=O)c1ccccc1C2=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
70 ml of water, 26.5 g of 1,4-dihydroxyanthraquinone, 1.2 g of hydroxyacetone, 80 g of 25% strength by weight aqueous ammonia solution and 20 g of 50% strength by weight sodium hydroxide solution were introduced into a pressure-resistant apparatus. The apparatus was then sealed pressure-tight and its contents were heated to 100° C., giving rise to an autogenous pressure of 2.7 bar. The reaction mixture was held under these conditions for 3 h, then cooled down and depressurized. The precipitate found was filtered off with suction, washed salt-free with water and dried to leave 15.8 g of 1-amino-4-hydroxyanthraquinone (purity according to GC: 71.1%).
Reaction SMILES: [F:1][C:2]1([F:20])[CH2:8][O:7][CH2:6][C:5]([NH2:9])=[N:4][C@@:3]21[C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=1)[CH2:12][CH2:11][CH2:10]2.[C:21]([C:23]1[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1)#[N:22]>>[NH2:9][C:5]1[CH2:6][O:7][CH2:8][C:2]([F:1])([F:20])[C@@:3]2([C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:29](=[O:30])[C:26]4[CH:25]=[CH:24][C:23]([C:21]#[N:22])=[CH:28][N:27]=4)[CH:17]=3)[CH2:12][CH2:11][CH2:10]2)[N:4]=1
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: NC1=N[C@@]2(CCCc3ccc(N)cc32)C(F)(F)COC1
Product: N#Cc1ccc(C(=O)Nc2ccc3c(c2)[C@@]2(CCC3)N=C(N)COCC2(F)F)nc1
Yield: 37 %

Procedure:
The condensation of (R)-6′,6′-difluoro-3,4,6′,7′-tetrahydro-2H,2′H-spiro[naphthalene-1,5′-[1,4]oxazepine]-3′,7-diamine (intermediate C4.1) and 5-cyanopicolinic acid yielded the title compound (37% yield) as an off-white solid. MS (ISP): m/z=412.2 [M+H]+.
Reaction SMILES: [NH2-:1].[Na+].N.[Na].[CH2:5]([C:8]([CH2:12][CH2:13][CH3:14])(Cl)[C:9]#[CH:10])[CH2:6][CH3:7]>C(OCC)C>[CH2:5]([C:8]([NH2:1])([CH2:12][CH2:13][CH3:14])[C:9]#[CH:10])[CH2:6][CH3:7]
Reactant: C#CC(Cl)(CCC)CCC
Reactant: [NH2-]
Agent: N
Agent: [Na+]
Agent: [Na]
Solvent: CCOCC
Product: C#CC(N)(CCC)CCC
Reaction time: 1 h

Procedure:
To a suspension of sodium amide in liquid ammonia, prepared from 6.9 g of sodium and 250 ml of liquid ammonia, were added 17 g of 1,1-di-n-propyl-1-chloro-2-propyne in 50 ml of anhydrous ethyl ether. The operation of adding the chlorinated derivative lasted one hour. Stirring of the mixture was maintained for 2 hours and then 300 ml of anhydrous ethyl ether were added.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][CH2:7][CH2:8][O:9][N:10]1[CH:14]=[C:13]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])[CH:12]=[N:11]1.O.S(=O)(=O)(O)O>O1CCCC1>[O:1]=[CH:2][CH2:6][CH2:7][CH2:8][O:9][N:10]1[CH:14]=[C:13]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])[CH:12]=[N:11]1
Reactant: O=C(c1cnn(OCCCC2OCCO2)c1)N1CCCCC1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: O=CCCCOn1cc(C(=O)N2CCCCC2)cn1
Yield: 96.2 %

Procedure:
40 g of 1-[3-(2-dioxolanyl)-propoxy]-4-(N-piperidinylcarbonyl)-pyrazole in a mixture of 150 ml of tetrahydrofuran, 200 ml of water and 4 ml of concentrated sulfuric acid are refluxed for 8 hours. The mixture is cooled and then saturated with sodium chloride, the phases are separated and the aqueous phase is extracted again with tetrahydrofuran. The combined organic phases are evaporated down, the residue is taken up with methylene chloride, the solution is washed with water and the solvent is evaporated off to give 33 g of the title compound in the form of a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].C(N(C(C)C)CC)(C)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1)[C:26](Cl)=[O:27]>ClCCl>[C:9]([C:3]1[CH:4]=[C:5]([NH:8][C:26](=[O:27])[C:25]2[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=[C:23]([O:22][CH3:21])[CH:24]=2)[CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:11])[CH3:10]
Reactant: CC(=O)c1cc(N)ccc1Cl
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC)cc(C(=O)Nc2ccc(Cl)c(C(C)=O)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a magnetically stirred solution of 2′-chloro-5′-amino-acetophenone (0.72 g, 4.2 mmol) in 20 ml of dichloromethane was added diisopropylethylamine (2.2 ml, 12.6 mmol). 3,5-dimethoxybenzoyl chloride (1.39 g, 6.9 mmol) in a single portion. The reaction was stirred for 2 h at room temperature, and a second portion of 3,5-dimethoxybenzoyl chloride (1.26 g, 6.3 mmol) was added, followed by diisopropylethylamine (1.0 ml, 5.7 mmol). The resulting solution was stirred an additional 3 h, and then quenched by the addition of 30 ml 1N HCl. The layers were separated and the aqueous layer was extracted with EtOAc (3×30 ml). The combined organics were washed with saturated NaHCO3 (1×20 ml), dried with solid anhydrous MgSO4, then concentrated. The crude product was purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (0:1 to 2:5) to afford the desired N-(3-acetyl-4-chlorophenyl)-3,5-dimethoxybenzamide.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](I)[CH3:26]>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:25][CH3:26])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:3]=1
Reactant: CCI
Reactant: Clc1cccc(Nc2nc(Cl)nc3nc[nH]c23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1cnc2c(Nc3cccc(Cl)c3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
676 mg (2.413 mmol) of 2-chloro-6-(3-chloro-phenyl-amino)-purine are dissolved in 10 ml of abs. DMF by means of gentle heating. 375 mg (2.713 mmol) of potassium carbonate, followed by 0.97 ml (12.01 mmol) of ethyl iodide are added at room temperature. The reaction mixture is stirred at room temperature for 2 hours. When the reaction is complete, the reaction mixture is poured onto ice/water (60 ml) and stirred for 10 minutes. The inhomogeneous mixture is extracted three times with ethyl acetate. The combined organic extracts are washed twice with water and once with saturated sodium chloride solution and dried over magnesium sulfate. After filtration, the filtrate is concentrated under reduced pressure at 35° C. and dried under an HV. The resulting crude product (crystalline oil) is purified by crystallization from diethyl ether/hexane. 2-Chloro-6-(3-chloro-phenyl-amino)-9-ethyl-9H-purine is obtained; Rf=0.55 (ethyl acetate:hexane=3:1); APCI-MS: (M+H)+=308; HPLC: tret(grad 20/1)=12.40 minutes; m.p. 127–128° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[N:4]=1.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:55]([N:62]([CH3:66])[CH2:63][CH2:64][NH2:65])([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56]>C(Cl)Cl>[CH3:66][N:62]([CH2:63][CH2:64][NH:65][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([C:5]2[N:4]=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=2)=[CH:16][CH:15]=1)[C:55](=[O:56])[O:57][C:58]([CH3:61])([CH3:59])[CH3:60]
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(-c2noc(C(F)(F)F)n2)cc1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCNC(=O)c1ccc(-c2noc(C(F)(F)F)n2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a suspension of 4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid (1 g, 3.87 mmol) in DCM (10 ml) was added COMU (1.825 g, 4.26 mmol) and DIPEA (0.812 ml, 4.65 mmol). The yellow solution was stirred for 2 min at rt and turned red. N-Boc-N-methyl-ethylenediamine (0.810 g, 4.65 mmol) was added and the reaction mixture was stirred at reflux for 1 hr, allowed to cool to rt and washed with water, saturated aqueous NH4Cl, and extracted with EtOAc. The organic layer was dried over Na2SO4 and the solvent was removed in vacuum. The final product was purified according to Method B in Examples 124-156 general method.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=1)[N:27]1[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]1)[CH3:7]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)C(Br)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Product: CCOC(=O)C(c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)N1CCN(C)CC1

Procedure:
The compound was synthesized as in Example 17 from Intermediate 11 (2.3 g, 6.2 mmol) and N-methylpiperazine (1.60 g, 16 mmol). This gave 1.1 g (46%) of pure product.
Reaction SMILES: CON(C)[C:4](=[O:17])[C@H:5]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1)[CH2:6][CH:7]=[CH2:8].[CH3:19][Li]>O1CCCC1>[Cl:16][C:11]1[CH:10]=[C:9]([C@H:5]([CH2:6][CH:7]=[CH2:8])[C:4](=[O:17])[CH3:19])[CH:14]=[CH:13][C:12]=1[Cl:15]
Reactant: [Li]C
Reactant: C=CC[C@H](C(=O)N(C)OC)c1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Product: C=CC[C@H](C(C)=O)c1ccc(Cl)c(Cl)c1
Reaction time: 3 h
Yield: 92.9 %

Procedure:
A solution of 319 mg (1.11 mmoL) of N-methoxy-N-methyl-2-(S)-(3,4-dichlorophenyl)-4-pentenamide (from Step 1 above) in 10 mL of dry tetrahydrofuran was cooled to -70° C. and treated with 1.0 mL (1.40 mmol) of methyllithium and stirred between -70° C. to -40° C. After 3 hours, the reaction was quenched with 5 mL of water, and diluted with 10 mL of ethyl acetate. The layers were separated and the organic layer was washed with water (3×10 mL). The aqueous layers were extracted with 10 mL of ethyl acetate. The combined organic layers were washed with 10 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography on 44 g of silica gel using 1:3 v/v ethyl acetate/hexane as the eluant afforded 250 mg (93%) of the title compound as a clear oil.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)[N:17]=2)[N:10]([C:25](=[O:35])[CH:26]([NH:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]([CH3:29])[CH3:28])[CH2:9]1)=O)(C)(C)C.Cl.C(N(C(C)C)CC)(C)C.C(Cl)(=O)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>ClCCl>[CH3:34][O:33][C:31](=[O:32])[NH:30][CH:26]([C:25]([N:10]1[CH:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)[N:17]=2)[CH2:12][N:8]([C:6](=[O:5])[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:9]1)=[O:35])[CH:27]([CH3:29])[CH3:28]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)NC(C(=O)N1CN(C(=O)OC(C)(C)C)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NC(C(=O)N1CN(C(=O)c2ccccc2)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-(4-Bromo-phenyl)-3′-(2-methoxycarbonylamino-3-methyl-butyryl)-2′,3′,4′,5′-tetrahydro-1H-[2,4]biimidazolyl-1′-carboxylic acid tert-butyl ester (55.6 mg, 0.101 mmol) was dissolved in dichloromethane (0.5 mL) and HCl (4M dioxane, 0.5 mL) was added. The resultant suspension was stirred at room temperature for 20 minutes, after which all volatiles were removed in vacuo. The crude material was dissolved in THF (1 mL) and diisopropyl ethylamine (26.0 mg, 0.202 mmol) was added, followed by benzoyl chloride (15.6 mg, 0.11 mmol). The reaction was stirred at room temperature. After 10 minutes, all starting material was consumed. All volatiles were removed in vacuo and the crude brown solid {1-[1′-Benzoyl-4-(4-bromo-phenyl)-1′,2′,4′,5′-tetrahydro-1H-[2,4]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester was used in the coupling reaction without further analysis or purification: LCMS-ESI+: calc'd for C26H28BrN5O4: 554.4 (M+). Found: 554.3/556.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[Br:20][C:21](=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:22]=O>>[Br:20][C:21](=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:22][N:17]1[CH2:18][CH2:19][CH:14]([NH:13][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=3)[O:8][C:7](=[O:12])[CH:6]=2)[CH2:15][CH2:16]1
Reactant: O=c1cc(NC2CCNCC2)c2cc(Cl)ccc2o1
Reactant: O=CC(Br)=Cc1ccccc1
Product: O=c1cc(NC2CCN(CC(Br)=Cc3ccccc3)CC2)c2cc(Cl)ccc2o1
Yield: 25.1 %

Procedure:
According to Procedure A above, 6-chloro-4-(piperidin-4-ylamino)-chromen-2-one and 2-bromo-3-phenyl-propenal (0.046 g, 0.216 mmol) were allowed to react to give the title compound (0.0088 g, 25.1%, mono-TFA salt) as a off-white solid. 1H NMR (400 MHz, MeOH) δ ppm 8.15 (d, J=4, 1H), 7.72 (dd, J=4, 8, 1H), 7.60 (dd, J=4, 8, 1H), 7.39-7.49 (m, 4H), 7.33 (d, J=8, 2H), 5.47 (s, 1H), 4.40 (s, 2H), 3.86-3.97 (m, 1H), 3.64-3.78 (m, 2H), 3.27-3.41 (partially buried m, 2H), 2.30-2.44 (m, 2H), 2.01-2.18 (m, 2H); MS (ESI+Q1MS) m/z 475 [M+H]+
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:5]=[CH:4][C:3]=1[CH2:19][C:20]([CH3:28])([CH3:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:48]1([C:54]#[CH:55])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CCN(CC)CC.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:27][C:20]([CH3:28])([CH2:19][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:7][C:2]=1[C:55]#[C:54][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: C#Cc1ccccc1
Reactant: CCOC(=O)CC(C)(C)Cc1ccc(OCCCNc2ccccn2)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(C)(C)Cc1ccc(OCCCNc2ccccn2)cc1C#Cc1ccccc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Ethyl 4-{2-bromo-4-[3-(pyridin-2-ylamino)propoxy]phenyl}-3,3-dimethylbutanoate (500 mg) was dissolved in Et3N (5 ml) followed by the addition of phenylylacetylene (250 μL), Cul (11 mg), triphenylphosphine (85 mg), and Pd(Ph3P)2Cl2 (42 mg). The reaction mixture was heated to 80° C. under a nitrogen atmosphere for 24 hours. Further phenylacetylene (125 μL) and triethylamine (5 mL) were added and heating was continued for a further 24 h. The mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and filtered through a pad of celite. The solvent was evaporated and the residue was chromatographed on silica gel eluting with hexane/ethyl acetate (3:2). This gave the product (516 mg) as an oil. The NMR spectrum was consistent for the proposed structure.