Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH2:7][O:8][C:9]([C:11]1[N:12]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[CH:13]=[C:14]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[CH3:27])=[O:18])[N:15]=1)=[O:10])=[O:4].[I-].[Na+].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.CS(C)=O>COCCOC>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:17]([NH:16][C:14]2[N:15]=[C:11]([C:9]([O:8][CH2:7][CH2:6][O:5][C:3](=[O:4])[CH2:2][N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[O:10])[N:12]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)[CH:13]=2)=[O:18])=[C:21]([CH3:27])[CH:22]=1
Reactant: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)OCCOC(=O)CBr)n1
Reactant: C1COCCN1
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CS(C)=O
Product: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)OCCOC(=O)CN2CCOCC2)n1

Procedure:
61.8 mg (0.1 mmol) of 2-[(2-bromoacetyl)oxy]ethyl 4-({[(4-chloro-2-methylphenyl)amino]carbonyl}amino)-1-[4-(trifluoromethyl)benzyl]-1H-imidazole-2-carboxylate (Example 24A) are dissolved in 0.4 ml of 1,2-dimethoxyethane under argon, and 15 mg (0.1 mmol) of sodium iodide and 43.6 mg (0.5 mmol) of morpholine are added. The reaction mixture is heated under reflux for 2 h and then mixed with 0.3 ml of DMSO, filtered and purified by preparative HPLC (Method 9).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][N:12](C(=O)C(F)(F)F)[NH:11][C:10]1=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.[Cl-].[Na+]>O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][NH:12][NH:11][C:10]1=[O:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(C(=O)C(F)(F)F)NC1=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CNNC1=O
Yield: 39.7 %

Procedure:
4-(S)-(t-butoxycarbonylamino)-1-(trifluoroacetyl)-3-oxo-1,2-diazolidine (2.97 g, 10 mmol) was suspended in water (30 ml), 1N sodium hydroxide solution (20 ml, 0.8 g, 20 mmol) was added to raise the pH of the solution to 12.2 and the resultant mixture was stirred for one hour at room temperature. The pH of the mixture was adjusted to 7.2 by the addition of 1N hydrochloric acid (10 ml). Sodium chloride (13 g) was added to the solution and the mixture was extracted with chloroform (50 ml, 8X). The chloroform extracts were combined, washed with saturated aqueous sodium chloride solution (75 ml), dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. Diethyl ether (100 ml) was added to the residue and then the ether was removed in vacuo to yield 0.798 g of a white solid of 4-(S)-(t-butoxycarbonylamino)-3-oxo-1,2-diazolidine: n.m.r. (300 MHz, DMSO-d6): δ 9.23 (s, 1), 7.04 (d, 1, J=9), 5.24 (br. s, 1,), 4.24 (m, 1), 3.41 (t, 1), 2.88 (t, 1), 1.38 (s, 9); specific rotation: [α]D25 =-74.16° (10.06 mg/ml in methanol); (the compound was dried overnight at 80° C. before analysis):
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[C:21]([OH:22])=[CH:20][C:10]2[CH2:11][C:12]3([O:19][C:9]=2[CH:8]=1)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)([CH3:6])([CH3:5])[CH3:4].[CH2:23](Cl)[C:24](=[CH2:26])[CH3:25]>CN(C)C=O>[C:3]([C:7]1[C:21]([O:22][CH2:25][C:24]([CH3:26])=[CH2:23])=[CH:20][C:10]2[CH2:11][C:12]3([O:19][C:9]=2[CH:8]=1)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)([CH3:6])([CH3:4])[CH3:5]
Reactant: C=C(C)CCl
Reactant: CC(C)(C)c1cc2c(cc1O)CC1(CCCCCC1)O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)COc1cc2c(cc1C(C)(C)C)OC1(CCCCCC1)C2

Procedure:
0.13 g of oily sodium hydride and 0.74 g of 6-t-butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-1′-cycloheptane synthesized in Example 7 were treated with 0.32 ml of methallyl chloride in dimethylformamide in the same manner as in Example 8-1) to give 0.89 g of 6-t-butyl-5-(2-methyl-2-propenyloxy)-2,3-dihydrobenzofuran-2-spiro-1′-cycloheptane as a colorless oil (quantitative).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[C:6](=[O:12])[NH:7][NH:8][C:9](=[O:11])[CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[N:7]1[NH:8][C:9](=[O:11])[CH:10]=[C:5]2[CH2:4][CH2:3][CH2:2][O:12][C:6]=12
Reactant: O=c1cc(CCCO)c(=O)[nH][nH]1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1cc2c(n[nH]1)OCCC2
Reaction time: 0.08 h
Yield: 79.2 %

Procedure:
A suspension of 4-(3-hydroxypropyl)-1,2-dihydro-3,6-pyridazinedione (1.48 g, 8.7 mmol) in THF (105 ml) was held in an ultrasound bath for 5 minutes, then cooled under argon in an ice bath. Triphenylphosphine (3.67 g, 14 mmol) was added, followed by diisopropyl azodicarboxylate (2.76 ml, 14 mmol). After 30 minutes the solvent was evaporated and the residue kept under high vacuum overnight. Chromatography, eluting first with 2.5% methanol/dichloromethane until triphenylphosphine oxide was removed and then with 5% methanol/dichloromethane, gave the product as an off-white solid (1.049 g, 79%).
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.Br[CH2:23][C:24]1[CH:32]=[C:31]([CH3:33])[C:30]2[C:26](=[CH:27][N:28]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[N:29]=2)[CH:25]=1.[H-].[Na+]>CN(C)C=O>[CH3:33][C:31]1[C:30]2[C:26](=[CH:27][N:28]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:39])([CH3:41])[CH3:40])[N:29]=2)[CH:25]=[C:24]([CH2:23][O:1][CH2:2][C:3]2([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Reactant: Cc1cc(CBr)cc2cn(COCC[Si](C)(C)C)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(COCC2(c3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (102 mg, 0.350 mmol) and 5-(bromomethyl)-7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (113 mg, 0.318 mmol) in dimethylformamide (0.75 mL) at 0° C. was added sodium hydride (16.8 mg, 0.70 mmol). The resulting solution was stirred at at 0° C. for 30 min. The reaction was quenched by the cautious addition of saturated ammonium chloride and diluted with diethyl ether. The ethereal was washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (12%→25% EtOAc/Hex) gave 170 mg (94%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 7.99 (s, 1H), 7.31-7.40 (m, 4H), 7.25 (m, 1H), 7.21 (s, 1H), 6.79 (s, 1H), 5.70 (s, 2H), 4.37 (s, 2H), 3.73 (bs, 2H), 3.63 (m, 2H), 3.40 (s, 2H), 3.04 (m, 2H), 2.57 (s, 3H), 2.16 (m, 2H), 1.91 (m, 2H), 1.43 (s, 9H), 0.94 (m, 2H), −0.03 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 155.1, 149.2, 143.3, 132.5, 128.5, 128.1, 127.4, 126.3, 125.7, 122.9, 121.9, 116.1, 81.8, 79.3, 78.9, 73.8, 67.4, 41.8, 40.1 (br), 32.0, 28.6, 18.0, 17.2, −1.3.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH:19]([CH3:23])[CH2:20][O:21][CH3:22])=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:24][CH3:25])=[C:5]([CH3:26])[O:4][N:3]=1.[N:27]([CH2:30][CH2:31][O:32][CH3:33])=[C:28]=S>>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:24][CH3:25])=[CH:9][C:10]3[C:11]4[N:18]([CH:19]([CH3:23])[CH2:20][O:21][CH3:22])[C:28]([NH:27][CH2:30][CH2:31][O:32][CH3:33])=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: COCCN=C=S
Reactant: COCC(C)Nc1c(N)cnc2cc(-c3c(C)noc3C)c(OC)cc12
Product: COCCNc1nc2cnc3cc(-c4c(C)noc4C)c(OC)cc3c2n1C(C)COC
Yield: 47 %

Procedure:
From 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-(1-methoxypropan-2-yl)quinoline-3,4-diamine (for a preparation see Intermediate 19) (70 mg) and 1-isothiocyanato-2-(methyloxy)ethane (50 mg) to give the title compound as beige solid (41 mg, 47%). LCMS (formate) Rt 0.56 min, MH+ 440.
Reaction SMILES: N1C(N)=C2C(N=CN2)=NC=1.[CH:11]1[N:16]=[C:15]([NH2:17])[C:14]2[N:18]=[CH:19][N:20]([CH2:21][CH2:22][O:23]CP(O)(O)=O)[C:13]=2[N:12]=1.CC(C)[O-].[Mg+2].CC(C)[O-].C1(=O)OCCO1>CN(C=O)C.[OH-].[Na+].C1(C)C=CC=CC=1>[OH:23][CH2:22][CH2:21][N:20]1[CH:19]=[N:18][C:14]2[C:13]1=[N:12][CH:11]=[N:16][C:15]=2[NH2:17]
Reactant: Nc1ncnc2c1ncn2CCOCP(=O)(O)O
Agent: CC(C)[O-]
Agent: Nc1ncnc2nc[nH]c12
Agent: [Mg+2]
Solvent: O=C1OCCO1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Nc1ncnc2c1ncn2CCO
Temperature: 130 °C
Yield: 90 %

Procedure:
Adenine to PMEA using Magnesium Isopropoxide. To a suspension of adenine (16.8 g, 0.124 mol) in DMF (41.9 ml) was added ethylene carbonate (12.1 g, 0.137 mol) and sodium hydroxide (0.100 g, 0.0025 mol). The mixture was heated at 130° C. overnight. The reaction was cooled to below 50° C. and toluene (62.1 ml) was added. The slurry was further cooled to 5° C. for 2 hours, filtered, and rinsed with toluene (2×). The wet solid was dried in vacuo at 65° C. to yield 20.0 g (90%) of 9-(2-hydroxyethyl)adenine as an off-white solid. Mp: 238-240° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:7](=[O:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].N([CH2:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[C:64]2[N:68]([C:69]([C:82]3[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=3)([C:76]3[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=3)[C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)[N:67]=[N:66][N:65]=2)=[CH:54][CH:53]=1)=[N+]=[N-]>>[C:69]([N:68]1[C:64]([C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][C:58]=2[C:55]2[CH:54]=[CH:53][C:52]([CH2:51][N:8]3[C:7](=[O:10])[N:6]([CH2:11][C:12]4[CH:13]=[CH:14][C:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=5[C:24]5[N:28]([C:29]([C:36]6[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=6)([C:30]6[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=6)[C:42]6[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=6)[N:27]=[N:26][N:25]=5)=[CH:16][CH:17]=4)[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9]3)=[CH:57][CH:56]=2)=[N:65][N:66]=[N:67]1)([C:82]1[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=1)([C:70]1[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=1)[C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: [N-]=[N+]=NCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCCc1nn(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 96 %

Procedure:
The alkylation of 5-n-butyl-2,4-dihydro-4-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]-3H-1,2,4-triazol-3-one (from Example 2, Step D) with 5-[4'-(bromomethyl)-biphenyl-2-yl]-N-trityltetrazole (see Example 2, Step B) was carried out as described in Example 3, Step A, except that only 3 equivalents of the alkylating agent was used. After work-up, the residue was flash chromatographed over silica gel (25 mL for 0.162 mmole, gradient elution using 0.25-1.0% MeOH/CH2Cl2) to give the desired material as a white foam in 96% yield, homogeneous by TLC in 2% MeOH/CH2Cl2, mass spectrum (FAB) 1094 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[N:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])=[CH:22][C:14]2=3)=[O:12])[CH:5]=[C:6]([Br:10])[C:7]=1[O:8]C.[Br-].[Li+].N1CCNCC1.Cl>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[N:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:30])([F:32])[F:31])=[CH:22][C:14]2=3)=[O:12])[CH:5]=[C:6]([Br:10])[C:7]=1[OH:8]
Reactant: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4ccccc4C(F)(F)F)cc32)cc1Br
Agent: C1CNCCN1
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cc(Br)c(O)c(Br)c1)N1CCOc2ncc(-c3ccccc3C(F)(F)F)cc21
Reaction time: 2 h
Yield: 69.4 %

Procedure:
In a 10 ml flask, (3,5-dibromo-4-methoxy-phenyl)-[7-(2-trifluoromethyl-phenyl)-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl]-methanone (46 mg, 0.08 mmol), lithium bromide (56 mg, 0.64 mmol) and piperazine (10 mg, 0.04 mmol) were dissolved in 3 ml of N,N-dimethyl formamide, and then stirred at 100□ for 2 hours. After completion of the reaction by adding water dropwise, the mixture was adjusted to weak acidic condition (pH=6) by using 1N hydrochloric acid. The formed solid was filtered and washed with distilled water. The resulting solid was recrystallized from methanol to obtain the target compound 46, i.e., (3,5-dibromo-4-hydroxy-phenyl)-[7-(2-trifluoromethyl-phenyl)-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl]-methanone (31 mg, 69%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br.[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([CH3:21])=[CH:16][N:15]=1>O1CCCC1.BrCCBr.C[Si](Cl)(C)C.[Zn].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>[Cl:13][C:14]1[N:19]=[C:18]([CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=2)[C:17]([CH3:21])=[CH:16][N:15]=1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: Cc1cnc(Cl)nc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: Cc1cnc(Cl)nc1Cc1cccc(C(F)(F)F)c1
Yield: 41.9 %

Procedure:
To a suspension of zinc dust (2.5 g, 38 mmol) stirred in 25 mL of tetrahydrofuran were added 2 drops of 1,2-dibromoethane and the mixture was heated to reflux. The suspension was then cooled and 2 drops of trimethylsilyl chloride were added followed by portionwise addition of 3-(trifluoromethyl)benzyl bromide (6.0 g, 25 mmol) with heating. When the reaction temperature reached 55° C., a strong exotherm occurred and the reaction mixture was allowed to heat at reflux. The cooled reaction solution was decanted into a solution of 2,4dichloro-5-methylpyrimidine (3.3 g, 20 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.44 g, 0.63 mmol) stirring in 15 mL of tetrahydrofuran. Upon heating, the reaction mixture exothermed strongly again at 55° C. and was then heated to reflux. The reaction mixture was allowed to cool and partitioned between diethyl ether and water. The organic layer was separated, washed with 1 N aqueous hydrochloric acid and brine, dried over magnesium chloride and concentrated under reduced pressure to give a crude oil. Purification by flash chromatography on silica gel (15 to 25% ethyl acetate in hexane) yielded 2.4 g of the title compound of Step A as an oil. 1H NMR (CDCl3): δ8.35 (s, 1H), 7.60-7.35 (m, 4H), 4.15 (s, 2H), 2.25 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])/[C:5](/[C:14]#[N:15])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)[CH3:2].Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25]>>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:14]#[N:15])[CH:6]([C:7]1[CH:8]=[CH:9][C:10]([Br:13])=[CH:11][CH:12]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25])[CH3:2]
Reactant: CCOC(=O)/C(C#N)=C/c1ccc(Br)cc1
Reactant: FC(F)(F)c1ccccc1Br
Product: CCOC(=O)C(C#N)C(c1ccc(Br)cc1)c1ccccc1C(F)(F)F

Procedure:
In analogy to example 74, step 2, from (E)-3-(4-bromo-phenyl)-2-cyano-acrylic acid ethyl ester and 2-bromobenzotrifluoride (CAS RN: [392-83-6]) was prepared the title compound as a brown oil, MS (ESI−): m/z=424.0 ([M−H]−, 1Br).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][C:10]=2[C:11]#[N:12])=[C:4]([N+:20]([O-])=O)[CH:3]=1.[Sn](Cl)Cl>C(O)C.Cl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][C:10]=3[C:11]([NH2:12])=[N:20][C:4]=2[CH:3]=1
Reactant: CC(C)c1ccc(Nc2ccc(Cl)cc2[N+](=O)[O-])c(C#N)c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: CC(C)c1ccc2c(c1)C(N)=Nc1cc(Cl)ccc1N2
Reaction time: 16 h
Yield: 198 %

Procedure:
Heat a solution of 2-(4-chloro-2-nitro-phenylamino)-5-isopropyl-benzonitrile (0.313 g, 0.99 mmol) in ethanol (6 ml) to 60° C. To this is add a solution of tin (II) chloride (0.752 g, 3.96 mmol) in 5.0 N hydrochloric acid (6 ml) and heat the resulting mixture to reflux for 16 hours. Cool the reaction to room temperature and place in a freezer for 16 hours. Collect by filtration the precipitated product s from the solution and to obtain 0.316 g of the title compound (0.98 mmol, 99% yield) as a yellow amorphous solid: Mass Spectrum (m/e): 286(M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][O:10][C:11]3[C:16]([C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:15][CH:14]=[C:13]([OH:26])[CH:12]=3)=[CH:4][CH:3]=1>C(O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:16]3[C:11](=[CH:12][C:13]([OH:26])=[CH:14][CH:15]=3)[O:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)COc3cc(O)ccc32)cc1
Solvent: CCO
Product: COc1ccc(C2c3ccc(O)cc3OCC2c2ccc(O)cc2)cc1
Yield: 46.3 %

Procedure:
3-(4-hydroxyphenyl)-4-(4-methoxyphenyl)-2H-chromen-7-ol 25.5 g (70 mmoles), 10% Pd/Al2O3 3.95 g and 200 ml of ethanol were combined in a 2-neck 500 ml round bottom flask. The reaction was hydrogenated at low pressure using standard conditions for 3 hours. The reaction was filtered through Celite to remove the catalyst, rinsed through with ethanol (300 ml). The filtrate was concentrated to ˜50 ml before being poured into chilled, stirred water (1.4 L). A pale orange precipitate formed which then formed a brown oil. The mixture was then extracted with diethyl ether, the combined organic layers washed with water (3×1 L), brine (1×500 ml), dried over anhydrous magnesium sulphate and filtered. The solvent was removed in vacuo to give red/brown oil. The product was recrystallised from diethyl ether (˜100 ml), to give brown solid which was rinsed with chilled diethyl ether to give off-white crystals 11.3 g. The 1H NMR spectrum and numbering scheme being shown below.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([Br:19])=[C:12]([CH2:17]Br)[CH:13]=2)[N:8]([CH2:20][C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])[CH:7]=1)=[O:5])[CH3:2].[CH3:29][NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(OCC)(=O)C.O>CCN(C(C)C)C(C)C.CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([Br:19])=[C:12]([CH2:17][N:30]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH3:29])[CH:13]=2)[N:8]([CH2:20][C:21]2[C:22]([F:28])=[CH:23][CH:24]=[CH:25][C:26]=2[F:27])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CNCc1ccccc1
Reactant: CCOC(=O)c1cn(Cc2c(F)cccc2F)c2cc(Br)c(CBr)cc2c1=O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2c(F)cccc2F)c2cc(Br)c(CN(C)Cc3ccccc3)cc2c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 7-bromo-6-bromomethyl-1-(2,6-difluorobenzyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (110 mg, 0.21 mmol), methylbenzylamine (31 mg, 0.26 mmol) in DIPEA (0.045 mL) and DMF (15 mL) was stirred at room temperature for 16 h. Ethyl acetate and water were added. The organic phase was separated and washed with water, dried with MgSO4. The solvent was evaporated and the residue dried under vacuum to yield the product as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N+:12]([O-:19])=[C:11]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N+:12]([O-:19])=[C:11]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[O:31])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][n+]1c(CCCCCCCCCCCO)cc(OCc2ccccc2)c2ccccc21
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CCCCCCCCCCCc1cc(OCc2ccccc2)c2ccccc2[n+]1[O-]
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.2 %

Procedure:
In this example, 5 m moles of 4-benzyloxy-2-(11-hydroxyundecyl) quinoline-N-oxide is dissolved in dichloromethane, and 15 m moles of pyridinium chlorochromate is added thereto. Then, the mixture is stirred at room temperature for 2.5 hours. The reaction solution is washed with water and dried over anhydrous sodium sulfate, and the solvent is removed therefrom by distillation. The residue is purified by silica gel column procedure, whereby the captioned compound is obtained as a colorless oily substance (yield: 79.2%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32](=[O:37])[C:33]([F:35])([F:36])[F:34])[CH:26]=4)[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCCC(=O)C1
Reactant: O=C(Nc1cccc(I)c1)C(F)(F)F
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#Cc3cccc(NC(=O)C(F)(F)F)c3)CCCC(=O)C2)cc1OC1CCCC1
Temperature: 80 °C
Yield: 77.6 %

Procedure:
To a solution of the compound from Example 3 (E1) (0.5 g. 1.6 mmol) and 1-iodo-3-trifluoroacetamidobenzene (0.5 g, 1.6 mmol) in triethylamine (10 mL) under an argon atmosphere was added a small amount of tetrakis(triphenylphosphine)palladium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C. for 0.2 h, was cooled to room temperature and was concentrated in vacuo. The residue was purified by flash chromatography, eluting with 3:1 hexanes/ethyl acetate, to give the title compound as a pale yellow solid (0.62 g, 78%), m.p. 63-65° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24](O)=[O:25])[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[CH:27]1([NH2:30])[CH2:29][CH2:28]1.ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH:27]1([NH:30][C:24]([C:21]2[CH:22]=[CH:23][C:18]3[N:19]([C:15]([CH2:14][O:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[N:16][N:17]=3)[CH:20]=2)=[O:25])[CH2:29][CH2:28]1
Reactant: NC1CC1
Reactant: COc1ccc2c(OCc3nnc4ccc(C(=O)O)cn34)ccnc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(OCc3nnc4ccc(C(=O)NC5CC5)cn34)ccnc2c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
3-((7-Methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (0.047 g, 0.13 mmol), cyclopropanamine (0.011 ml, 0.16 mmol), 1-hydroxy-7-azabenzotriazole (0.018 g, 0.13 mmol), and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride, (0.039 g, 0.20 mmol) were added to a reaction flask then suspended in DMF (1 mL). N-Ethyldiisopropylamine (0.070 ml, 0.40 mmol) was added to the reaction mixture. The clear reaction mixture was stirred at 20° C. overnight. The reaction mixture was concentrated under vacuum then triturated with water. The solid was collected on a glass frit, washing with water. The sample was purified by preparative TLC eluting with 8% 7N ammonia in methanol/dichloromethane to afford N-cyclopropyl-3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide (0.023 g, 44% yield) as a tan solid.