Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1>C(O)(=O)C>[CH3:9][C:5]1[C:6]([NH2:8])=[N:7][C:2]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([N:14]3[CH2:13][CH2:12][N:11]([CH3:10])[CH2:16][CH2:15]3)=[CH:22][CH:21]=2)=[N:3][CH:4]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: Cc1cnc(Cl)nc1N
Solvent: CC(=O)O
Product: Cc1cnc(Nc2ccc(N3CCN(C)CC3)cc2)nc1N
Temperature: 100 °C

Procedure:
A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (1.0 g, 6.9 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (1.5 mL, 7.8 mmol) in acetic acid (15 mL) was heated at 100° C. for 2.5 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and the mixture was neutralized with 10% NaOH solution until solid precipitated. After filtration and washed with water, the title compound was obtained as a grey solid (1.3 g, 63%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=C(C)C=C(C)[C:3]=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[NH2:22].C(Cl)(=O)C(C)C>N1C=CC=CC=1>[Br:21][C:18]1[CH:19]=[CH:20][N:15]2[N:14]=[C:1]([CH:2]([CH3:7])[CH3:3])[N:22]=[C:16]2[CH:17]=1
Reactant: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Reactant: Nc1cc(Br)cc[n+]1N
Agent: CC(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)c1nc2cc(Br)ccn2n1
Temperature: 100 °C
Reaction time: 18 h
Yield: 30.6 %

Procedure:
A mixture of 1,2-diamino-4-bromopyridinium 2,4,6-trimethylbenzenesulfonate (2 g, 5.15 mmol) and isobutyryl chloride (809 μl, 7.73 mmol) in pyridine (12 ml) is stirred for 18 hours at 100° C. The solvent is evaporated and the orange residue triturated for 2 hrs with sat. aqueous sodium hydrogen carbonate solution. The solid is collected by filtration, washed several times with water and dried affording 7-bromo-2-isopropyl-[1,2,4]triazolo[1,5-a]pyridine (378 mg, 30.6%) as a light brown solid. MS: m/z=240; 242 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.[CH3:33][O:34][CH2:35][CH2:36][C:37](O)=O.Cl.CN(C)CCCN=C=NCC.ClCCl.C[CH2:56][O:57]CC>CN(C)C1C=CN=CC=1.CN(C=O)C.C(OCC)(=O)C>[CH3:33][O:34][CH2:35][CH2:36][CH2:37][C:56]([O:20][CH2:19][C@H:17]1[O:16][N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:21]4[CH2:25][C@H:24]([CH2:26][N:27]5[CH:31]=[CH:30][N:29]=[N:28]5)[O:23][C:22]4=[O:32])=[CH:3][C:2]=3[F:1])=[CH:9][N:10]=2)[CH2:18]1)=[O:57]
Reactant: CCOCC
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Reactant: COCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCCCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(5R)-3-(3-Fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1, 0.125 g, 0.29 mmol), 3-methoxypropionic acid (0.13 g, 1.1 mmol), 4-dimethylaminopyridine (0.003 g, 0.025 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.125 g, 0.65 mmol) were combined in DMF (2 ml). The suspension was allowed to stir for 1.5 hours at room temperature resulting in a clear solution. The mixture was then diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. The residue obtained upon filtration and evaporation was sonnicated with a solution of dichloromethane:ether (1:5) to give a solid which was dried collected and dried in vacuo. The title compound was obtained as a white solid (0.15 g), melting point: 154° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]CC(=O)CC([O-])=O)=[CH:4][CH:3]=1.[NH2:17]/[C:18](/[CH3:24])=[CH:19]\[C:20]([O:22][CH3:23])=[O:21].[N+:25]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH:31]=O)([O-:27])=[O:26]>CO>[CH3:24][C:18]1[NH:17][C:18]([CH3:24])=[C:19]([C:20]([O:22][CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)=[O:21])[CH:31]([C:30]2[CH:33]=[CH:34][CH:35]=[C:28]([N+:25]([O-:27])=[O:26])[CH:29]=2)[C:19]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)/C=C(/C)N
Reactant: O=C([O-])CC(=O)CCCc1ccc(O)cc1
Solvent: CO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCc2ccc(O)cc2)C1c1cccc([N+](=O)[O-])c1
Yield: 130.5 %

Procedure:
A mixture of 4.3 g of 2-(4-hydroxyphenyl)-ethylacetoacetate (10), 2.3 g of methyl β-aminocrotonate, 2.9 g of 3-nitrobenzaldehyde and 70 ml of methanol was heated at reflux for 12 hours. The solvent was removed under reduced pressure and the residue purified by silica gel chromatography using 50:50 ethyl acetate-hexane to yield 5.9 g of 2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-[2-(4-hydroxyphenyl)ethoxycarbonyl]-1,4-dihydropyridine (11), as an amorphous solid. Calculated for C24H24N2O7.1.5H2O: C-60.12, H-5.68, N-5.84. Found: C-60.55, H-5.33, N-6.03.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH2:14]Br.C[N+]([O-:20])(C)C>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH:14]=[O:20]
Reactant: C[N+](C)(C)[O-]
Reactant: BrCc1cc(-c2ncccn2)ccc1Br
Solvent: CS(C)=O
Product: O=Cc1cc(-c2ncccn2)ccc1Br
Temperature: 55 °C
Reaction time: 12 h

Procedure:
To a solution of 1.75 g of the crude title compound of Step D in 6 mL of anhydrous dimethylsulfoxide ("DMSO") under argon, 3.0 g of anhydrous trimethylamine N-oxide (prepared as described in Soderquist et al., Tet. Letters., 27, 3961 (1986); this compound is also commercially available) were added and the mixture stirred at 55° C. for 12 hrs. The mixture was then cooled and added to 100 mL of ice/water and extracted with 3×50 mL of EtOAc. The combined organic extracts were washed once with 100 mL of brine and dried and evaporated. The residue was chromatographed on 100 mL of silica gel using Hexanes/EtOAc 6:1 to afford 0.86 g (81.5% for two steps) of the title compound of this step as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[C:17]([CH2:29][CH2:30][CH3:31])=[N:18][C:19]3[C:24]([C:25]=2[C:26]([OH:28])=[O:27])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:11][CH:10]=1)#[N:2].C([Sn]([N:45]=[N+:46]=[N-:47])(CCCC)CCCC)CCC.CO>CC1C=CC=CC=1C>[CH2:29]([C:17]1[C:16]([O:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[N:45]=[N:46][NH:47][N:2]=3)=[CH:14][CH:13]=2)=[C:25]([C:26]([OH:28])=[O:27])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)[CH2:30][CH3:31]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCCc1nc2ccccc2c(C(=O)O)c1Oc1ccc(-c2ccccc2C#N)cc1
Solvent: Cc1ccccc1C
Solvent: CO
Product: CCCc1nc2ccccc2c(C(=O)O)c1Oc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 253.3 %

Procedure:
A solution of the title E compound of Example 1, 3-[(2'-cyano[1,1'-biphenyl]-4-yl)oxy]-2-propyl-4-quinolinecarboxylic acid (3.9 g, 9.6 mmol) and tri-n-butyltin azide (9.6 g, 28.9 mmol) in o-xylene (3.9 mL) was heated to 108° C. for 48 hours. After cooling to room temperature, methanol (15 mL) was added and the dark brown solution was stirred for 20 minutes. The methanol was removed under vacuum, more methanol was added (15 mL), the reaction mixture was stirred briefly and concentrated again. The residue was dissolved in ethyl acetate (500 mL), washed three times with 1.0M trisodium citrate solution, brine, dried over sodium sulfate, and concentrated to yield a brown, viscous oil (10.98 g). Flash chromatography on silica gel (659 g), eluting with 70:25:5 toluene:acetone:acetic acid yielded the title compound as a light yellow solid 2.14 g).
Reaction SMILES: Br[C:2]1[CH:17]=[N:16][C:5]2=[C:6]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:7]=[N:8][CH:9]=[C:4]2[CH:3]=1.[CH:18]1([NH:21][C:22](=[O:39])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:24]=2)[CH2:20][CH2:19]1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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.CCO>[CH:18]1([NH:21][C:22](=[O:39])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([C:2]3[CH:17]=[N:16][C:5]4=[C:6]([N:10]5[CH2:15][CH2:14][O:13][CH2:12][CH2:11]5)[N:7]=[N:8][CH:9]=[C:4]4[CH:3]=3)[CH:24]=2)[CH2:19][CH2:20]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1cnc2c(N3CCOCC3)nncc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1cnc2c(N3CCOCC3)nncc2c1
Temperature: 25 °C

Procedure:
This title compound by heating a mixture of 3-bromo-8-morpholinopyrido[2,3-d]pyridazine (0.033 g, 0.11 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.048 g, 0.16 mmol), sodium carbonate (0.049 g, 0.46 mmol) and trans-dichlorobis(triphenyl-phosphine)palladium (II) (0.011 g, 0.016 mmol) in DME (2.1 mL)/H2O (0.9 mL)/EtOH (0.6 mL) at 80° C. The mixture was cooled to RT, evaporated onto silica gel and purified flash chromatography eluting with 2M NH3 in MeOH:CH2Cl2 (0:1→1:19) to give the title compound as a tan amorphous solid. MS m/z: 390.2 [M+1].
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:13]([NH2:14])=[N:12][C:11]([NH2:15])=[C:10]([Cl:16])[N:9]=1)=[O:7].[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH2:28])=[O:27]>CN(C=O)C>[Br-:18].[C:26]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][N+:2]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:13]([NH2:14])=[N:12][C:11]([NH2:15])=[C:10]([Cl:16])[N:9]=1)=[O:7])([CH3:17])[CH3:1])(=[O:27])[NH2:28]
Reactant: CN(C)CCNC(=O)c1nc(Cl)c(N)nc1N
Reactant: NC(=O)CCCCCCCBr
Solvent: CN(C)C=O
Product: C[N+](C)(CCCCCCCC(N)=O)CCNC(=O)c1nc(Cl)c(N)nc1N
Product: [Br-]

Procedure:
A solution of 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid (2-dimethylamino-ethyl)-amide (Intermediate H) (100 mg, 0.39 mmol) and 8-Bromo-octanoic acid amide (Intermediate P) (130 mg, 0.6 mmol) in DMF (3 mL) is heated at 70° C. for 3 days. After this time, the solvent is removed in vacuo to yield an orange oil, which is triturated with acetone (2×10 mL) to afford the title compound. M+ 400.
Reaction SMILES: Cl.[N:2]1([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.O[N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[N:21]1.CN1CC[O:33][CH2:32][CH2:31]1.Cl.CN(C)CCCN=C=N>CN(C=O)C>[NH:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:31][C:32]([N:5]3[CH2:6][CH2:7][N:2]([C:8]([O:10][CH2:11][C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=4)=[O:9])[CH2:3][CH2:4]3)=[O:33])=[CH:28][C:23]=2[N:22]=[N:21]1
Reactant: On1nnc2ccccc21
Reactant: O=C(OCc1ccc(Cl)cc1)N1CCNCC1
Reactant: CN1CCOCC1
Agent: CN(C)CCCN=C=N
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(Cc1ccc2[nH]nnc2c1)N1CCN(C(=O)OCc2ccc(Cl)cc2)CC1

Procedure:
7.3 220 mg (1.24 mmol) of 23, 362 mg (1.24 mmol) of 4-chlorobenzyl piperazine-1-carboxylate hydrochloride, 168 mg (1.24 mmol) of 1-hydroxybenzotriazole (HOBt), 143 mg (1.24 mmol) of N-methylmorpholine and 238 mg (1.24 mmol) of 3-dimethylaminopropylcarbodiimide hydrochloride (DAPECI) are stirred at RT for 48 h in 10 ml of DMF.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].[CH:22]1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[CH:6][C:5]([CH3:22])=[CH:4][N:3]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Cc1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1

Procedure:
Under an argon atmosphere, 2.50 g (19.6 mmol) of 2-methyl-5-chloropyridine and 4.38 g (23.5 mmol) of N-(tert-butyloxycarbonyl)-piperazine are dissolved in 50 ml of absolute toluene. Then, 2.26 g (23.5 mmol) of sodium-tert-butylate, 0.37 g (0.59 mmol) of BINAP, and 0.36 g (0.39 mmol) of tris(dibenzylideneacetone)-dipalladium are added, and it is heated for 12 hours to 70° C. After cooling, the reaction mixture is mixed with diethyl ether, washed three times with saturated sodium chloride solution, dried on sodium sulfate, and solvent is removed in a vacuum. The residue is purified by flash chromatography (cyclohexane/ethyl acetate 9:1).
Reaction SMILES: C([Li])CCC.CCCCCC.[C:12]([C:16]1[CH:46]=[C:45]([C:47]([CH3:50])([CH3:49])[CH3:48])[CH:44]=[C:18]([CH:19]=[N:20][C@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]2[N:27]=[CH:28][C:29]2[C:30](=[C:32]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:33]=[C:34]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:35]=2)[OH:31])[C:17]=1[OH:51])([CH3:15])([CH3:14])[CH3:13].[Cl:52][Ti:53](Cl)(Cl)Cl>C(OCC)C>[C:40]([C:32]1[CH:33]=[C:34]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:35]=[C:29]([CH:28]=[N:27][C@H:22]2[CH2:23][CH2:24][CH2:25][CH2:26][C@@H:21]2[N:20]=[CH:19][C:18]2[C:17](=[C:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:46]=[C:45]([C:47]([CH3:48])([CH3:49])[CH3:50])[CH:44]=2)[OH:51])[C:30]=1[OH:31])([CH3:41])([CH3:42])[CH3:43].[Cl-:52].[Cl-:52].[Ti+4:53]
Reactant: Cl[Ti](Cl)(Cl)Cl
Agent: CC(C)(C)c1cc(C=N[C@H]2CCCC[C@@H]2N=Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: [Cl-]
Product: [Ti+4]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1.4 ml of a solution of n-butyllithium in hexane (3.6 mmol. 2.5M) was slowly added at room temperature to a solution of 1 g (1.8 mmol) of (S,S)-(+)-N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-diaminocyclohexane in 70 ml of diethyl ether. The yellow solution was stirred at room temperature for 1.5 hours and subsequently admixed with 0.34 g (1.8 mmol) of TiCl4. The reaction mixture was stirred at room temperature for 18 hours, subsequently filtered and the solvent was removed in an oil pump vacuum. This gave 0.85 g of (1) as a red, free-flowing powder.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([CH2:11][Cl:12])=[C:6]([CH3:13])[C:5]=1[CH3:14].[C:17]1([P:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[Cl-:12].[F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([CH2:11][P+:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:6]([CH3:13])[C:5]=1[CH3:14]
Reactant: Cc1cc(OC(F)(F)F)c(C)c(C)c1CCl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Cc1cc(OC(F)(F)F)c(C)c(C)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]
Reaction time: 2 h

Procedure:
The crude (4-trifluoromethoxy-2,3,6-trimethylphenyl)methyl chloride, 27.5 g (0.104 mol) of triphenylphosphine and 250 ml of acetonitrile were heated to reflux for 20 hours. The solvent was removed on a rotary evaporator at room temperature and the residue was triturated with 300 ml of ethyl acetate. The resulting solid was filtered, dissolved in 250 ml of hot acetonitrile and treated with 1 liter of ethyl acetate. The mixture was allowed to stand 2 hours; 38 g of (4-trifluoromethoxy-2,3,6-trimethylphenyl)methyltriphenylphosphonium chloride was collected; mp 272°-274° C. In a similar manner, the mother liquor afforded an additional 10.5 g of product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18](I)[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(N[CH2:25][CH3:26])C.[CH3:27][N:28]([CH3:31])[CH:29]=O>>[CH2:27]([N:28]([CH3:31])[CH2:29][C:25]#[C:26][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][N:12]=[C:11]2[NH:10][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Ic1ccc2ncnc(Nc3ccc4[nH]ccc4c3)c2c1
Reactant: CCNCC
Reactant: CN(C)C=O
Product: CN(CC#Cc1ccc2ncnc(Nc3ccc4[nH]ccc4c3)c2c1)Cc1ccccc1

Procedure:
The title compound was synthesized according to the method of Example 2 using (1H-indol-5-yl)-(6-iodo-quinazolin-4-yl)-amine (200 mg, 0.517 mmol), N-Methyl-n-proparglylbenzylamine (246 mg, 1.596 mmol) and diethyl amine (189 gm, 2.59 mmol) in 2 mL, of dimethylformamide (DMF).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17](CCC(O)=O)=[CH:16][CH:15]=3)[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=2)=[C:4](OCC2CCCC2)[CH:3]=1.ClC1C=CC(C2NC3C=C(F)C(F)=CC=3N=2)=C([N+:56]([O-:58])=[O:57])C=1.BrCC1CCCCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=2)=[C:4]([N+:56]([O-:58])=[O:57])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2[nH]1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Agent: BrCC1CCCCC1
Product: O=[N+]([O-])c1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(4-Chloro-2-nitro-phenyl)-5,6-difluoro-1H-benzoimidazole and bromomethyl-cyclohexane (CAS Reg. No. 2550-36-9). Off-white powder (43%). MS (Turbo Spray): m/z=406.3 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:15]([O:17][C@H:18]4[C@H:22]5[O:23][CH2:24][C@@H:25]([OH:26])[C@H:21]5[O:20][CH2:19]4)=[N:16][C:11]3=[CH:10][C:9]=2[Cl:35])=[CH:4][CH:3]=1.[NH:36]1[CH2:41][CH2:40][CH:39]([NH:42][C:43](=[O:48])[O:44][CH:45]([CH3:47])[CH3:46])[CH2:38][CH2:37]1>>[Cl:35][C:9]1[CH:10]=[C:11]2[N:16]=[C:15]([O:17][C@@H:18]3[CH2:19][O:20][C@@H:21]4[C@H:25]([OH:26])[CH2:24][O:23][C@H:22]34)[N:14]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:12]2=[N:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([N:36]2[CH2:37][CH2:38][CH:39]([NH:42][C:43](=[O:48])[O:44][CH:45]([CH3:46])[CH3:47])[CH2:40][CH2:41]2)=[CH:3][CH:4]=1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(-c3ccc(Br)cc3)nc21
Reactant: CC(C)OC(=O)NC1CCNCC1
Product: CC(C)OC(=O)NC1CCN(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)CC1

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(5-(4-bromophenyl)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and isopropyl piperidin-4-ylcarbamate following a procedure analogous to that described for Intermediate 23. LC (method 1): tR=1.04 min; Mass spectrum (ESI+): m/z=688 [M+H]+.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[C:18]([CH3:30])[CH:17]=3)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[N+:31]([O-:33])=[O:32].CS(C)=O>O>[CH3:1][O:2][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[C:18]([CH3:30])[CH:17]=3)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[N+:31]([O-:33])=[O:32]
Reactant: C[O-]
Reactant: Cc1cc(Nc2ncnc3cc(Cl)c([N+](=O)[O-])cc23)ccc1OCc1ccccn1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(C)c3)c2cc1[N+](=O)[O-]
Temperature: 18 °C
Yield: 83.4 %

Procedure:
After appropriate repetition of the previous steps, sodium methoxide (11 g) was added portionwise to a stirred mixture of 7-chloro-4-[3-methyl-4-(2-pyridylmethoxy)anilino]-6-nitroquinazoline (20 g) and DMSO (200 ml) which was cooled in a water bath to approximately 18° C. The resultant mixture was stirred at ambient temperature for 4 hours. The mixture was poured slowly onto a mixture of ice and water. The precipitate was isolated to give 7-methoxy-4-[3-methyl-4-(2-pyridylmethoxy)anilino]-6-nitroquinazoline (16.5 g) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[N:5]=[C:4]([NH2:14])[CH:3]=1.N1C=CC=CC=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30](Cl)=[O:31])[CH:26]=[CH:27][CH:28]=1.O>C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH2:10][CH:11]([CH3:12])[CH3:13])[N:5]=[C:4]([NH:14][C:30](=[O:31])[CH2:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=2)[CH:3]=1
Reactant: COc1cccc(CC(=O)Cl)c1
Reactant: CC(C)Cc1nc(N)cc(N)c1C#N
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc(CC(=O)Nc2cc(N)c(C#N)c(CC(C)C)n2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.5 %

Procedure:
To a solution of 20 mg (0.11 mmol) of 4,6-diamino-2-isobutyl-nicotinonitrile in 1 mL of CH2Cl2 was added 40 μL (0.49 mmol) of pyridine, then 30 μL (0.19 mmol) of (3-methoxyphenyl)acetyl chloride. The solution was stirred at ambient temperature for 10 minutes then 0.5 mL of water was added. The mixture was concentrated under reduced pressure, then the residue was taken up in 5 mL of ethyl acetate and extracted with water (2×2 mL), saturated NaHCO3(aq.), and brine (1×2 mL), dried over MgSO4, filtered, and concentrated to an oil. The product was partially purified via silica gel chromatography, eluting with 30% ethyl acetate:hexanes to provide a solid. This was recrystallized from methanol to provide 8 mg (23%) of a white solid. 1H NMR (300 MHz, d6-DMSO) δ 10.48 (s, 1H), 7.37 (s, 1H), 7.22 (t, 1H, J=7.8 Hz), 6.84 (m, 5H), 3.73 (s, 3H), 3.66 (s, 2H), 2.54 (d, 2H, J=7.1 Hz), 2.09 (m, 1H), 0.92 (d, 6H, J=6.1 Hz); MS (ESI) m/e 339 (M+H)+, 337 (M−H)−.
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.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24].[CH3:27][N:28]1[CH:36]=[C:35]2[C:30]([CH:31]=[CH:32][C:33]([NH2:37])=[CH:34]2)=[N:29]1>>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:37]([C:33]3[CH:32]=[CH:31][C:30]4[C:35](=[CH:36][N:28]([CH3:27])[N:29]=4)[CH:34]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)(=[O:25])=[O:24]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: Cn1cc2cc(N)ccc2n1
Product: Cn1cc2cc(N3CCC4(CCN(S(=O)(=O)c5ccccc5Cl)CC4)C3=O)ccc2n1

Procedure:
Off-white crystalline solid. MS (ESI): 459.3 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-chlorobenzenesulfonyl chloride and 2-methyl-2H-indazol-5-ylamine (synthesis: Boyer, et al; Journal of Chemical Research, Miniprint; English; 11; 1990; 2601).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:24])[CH:7]=[C:8]([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)[O:9]2)=[CH:4][CH:3]=1.Br[C:26]([Br:29])([CH3:28])C.[C:30](=O)([O-])[O-].[K+].[K+].[K+].[Br-]>CN(C)C=O>[Br:29][CH2:26][CH2:28][CH2:30][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:24])[CH:7]=[C:8]([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)[O:9]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(-c2cc(=O)c3ccc(O)cc3o2)cc(OC)c1OC
Reactant: CC(C)(Br)Br
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(-c2cc(=O)c3ccc(OCCCBr)cc3o2)cc(OC)c1OC

Procedure:
This compound (59) was prepared from 7-hydroxy-3′,4′,5′-trimethoxy-flavone, 25 (3.3 g, 10 mmol), dibromo propane (3 mL, 30 mmol) and potassium carbonate (2.7 g, 20 mmol) in dry dimethyl formamide (120 mL) using the identical procedure as described for 56. Yield 3.1 g (69%); mp 156-157° C.; MS (FAB) 449/451 (M++1); IR (KBr) 1629; 1H NMR (200 MHz, CDCl3) δ 8.13 (d, J=9.4 Hz, 1H), 7.11 (s, 2H), 7.01-6.97 (m, 2H), 6.70 (s, 1H), 4.25 (t, J=5.8 Hz, 2H), 3.96 (s, 6H), 3.93 (s, 3H), 3.64 (t, J=6.3 Hz, 2H), 2.39 (q, J=6.1 Hz, 2H).