Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:15][CH:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=3)[C:4]=2[C:5]([N:8]=CN(C)C)=[N:6][CH:7]=1.[Cl:37][CH2:38][CH2:39][CH2:40][N:41]=[C:42]=[O:43]>>[NH2:8][C:5]1[C:4]2[C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=3)=[CH:14][S:15][C:3]=2[C:2]([NH:1][C:42]([NH:41][CH2:40][CH2:39][CH2:38][Cl:37])=[O:43])=[CH:7][N:6]=1
Reactant: COc1cc(-c2csc3c(N)cnc(N=CN(C)C)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: O=C=NCCCCl
Product: COc1cc(-c2csc3c(NC(=O)NCCCCl)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using N-[4-(7-amino-4-{[(dimethylamino)methylene]amino}thieno[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-indole-2-carboxamide and 3-chloropropyl isocyanate using General Procedure N followed by General Procedure M. 1H NMR (DMSO-d6, 400 MHz) δ 9.50 (s, 1H), 8.69 (s, 1H), 8.19 (br, 1H), 8.13 (d, 1H), 7.94 (s, 1H), 7.71 (d, 1H), 7.60 (d, 1H), 7.35 (m, 1H), 7.29 (s, 1H), 7.16 (m, 2H), 6.08 (m, 2H), 4.04 (s, 3H), 3.93 (s, 3H), 3.71 (t, 2H), 3.25 (m, 2H), 1.93 (m, 2H); MS: (MH)+ 563.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH2:7])[CH2:5][CH3:6].C([O-])([O-])=O.[K+].[K+].[C:14](Cl)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>O1CCOCC1>[CH2:17]([O:16][C:14](=[O:15])[NH:7][CH:4]([CH2:3][O:2][CH3:1])[CH2:5][CH3:6])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCC(N)COC
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCC(COC)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of 1-methoxymethyl-propylamine (2.50 g, 24.3 mmol, 1.0 eq.) in dioxane (15 mL) was added an aqueous solution of K2CO3 (15 g in 15 mL of H2O) and the mixture was cooled to 0° C. CBZ-Cl (4.16 mL, 1.2 eq.) was then introduced and, the resulting mixture was warmed to room temperature and stirred for 3 h, extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (hexanes to 40% EtOAc/hexanes) to give (1-methoxymethyl-propyl)-carbamic acid benzyl ester (4.4 g, 76%) as a white solid.
Reaction SMILES: C[N:2](C)C=O.FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.[CH3:27][C:28]([O:31][C:32]([NH:34][C@@H:35]([C:40]([OH:42])=[O:41])[CH2:36]C(N)=O)=[O:33])([CH3:30])[CH3:29].N1C=CC=CC=1>O>[CH3:30][C:28]([O:31][C:32]([NH:34][CH:35]([C:40]([OH:42])=[O:41])[CH2:36][NH2:2])=[O:33])([CH3:27])[CH3:29]
Reactant: CC(C)(C)OC(=O)N[C@H](CC(N)=O)C(=O)O
Reactant: CN(C)C=O
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)NC(CN)C(=O)O
Yield: 25 %

Procedure:
To a 1:1 dimethylformamide:water solution (170 ml) of [bis(trifluoroacetoxy)iodo]benzene (12.89 g, 32.29 mmol, 1.5 equiv) was added N-α-BOC-D-asparagine (5 g, 21.53 mmol, 1 equiv). This solution stirred at room temperature for 0.5 h before pyridine (3.4 g, 43.06 mmol, 2 equiv) was added. After 18 h the reaction was concentrated in vacuo and the residue was redissolved in water before being washed with diethyl ether (2×, 50 ml). The aqueous layer was concentrated in vacuo and the crude product was recrystallized from hot acetonitrile to give E7-1 (1.10 g, 25% yield).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([N:16]([OH:31])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]#[CH:28])=[C:21]([O:29][CH3:30])[CH:20]=2)=[O:15])=[CH:9][CH:8]=1.CCN(CC)CC>C(Cl)Cl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C:14]([N:16]([O:31][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]#[CH:28])=[C:21]([O:29][CH3:30])[CH:20]=2)=[O:15])=[CH:11][CH:12]=1
Reactant: C#CCOc1ccc(CCN(O)C(=O)Cc2ccc(Cl)cc2)cc1OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCOc1ccc(CCN(OS(C)(=O)=O)C(=O)Cc2ccc(Cl)cc2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (0.022 ml, 0.286 mmol) is added dropwise to a solution of 2-(4-chloro-phenyl)-N-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-acetamide (0.1 g, 0.26 mmol), and Et3N (0.036 ml, 0.26 mmol) in 1 ml CH2Cl2 at 0° C. The reaction mixture is allowed to warm to room temperature and stirred for another 2 hours. The reaction mixture is then washed with water, 1N HCl, and brine and dried over Na2SO4. After rotary evaporation, the product is purified by flash chromatography (ethyl acetate:hexane, 1:2) to yield 2-(4-chloro-phenyl)-N-mesyloxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-acetamide as a solid, mp. 91-93° C.
Reaction SMILES: [C:1]([Si:5]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[O:6][CH2:7][C:8]([NH:12][C:13]([C:15]1[N:19]2[CH:20]=[CH:21][CH:22]=[C:23]([O:24][CH2:25][C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])[C:18]2=[N:17][C:16]=1[CH3:34])=[O:14])([C:10]#[N:11])[CH3:9])([CH3:4])([CH3:3])[CH3:2].C[Sn]([N:51]=[N+:52]=[N-:53])(C)C.Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.CO>[C:1]([Si:5]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[O:6][CH2:7][C:8]([NH:12][C:13]([C:15]1[N:19]2[CH:20]=[CH:21][CH:22]=[C:23]([O:24][CH2:25][C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])[C:18]2=[N:17][C:16]=1[CH3:34])=[O:14])([C:10]1[N:51]=[N:52][NH:53][N:11]=1)[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(C)(C#N)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1nn[nH]n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.2 %

Procedure:
To a solution of 300 mg of N-(1-{[tert-butyl (diphenyl)silyl]oxy}-2-cyanopropan-2-yl)-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide in 6 ml of toluene was added 240 mg of trimethyltin azide, followed by stirring for 4 hours under heating to reflux. The reaction mixture was left to be cooled to room temperature, and 10 ml of methanol and 10 ml of 1 M hydrochloric acid were then added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was neutralized by the addition of 1 M sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 292 mg of N-[1-{[tert-butyl (diphenyl)silyl]oxy}-2-(2H-tetrazol-5-yl)propan-2-yl]-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([C:21]([O:23]C)=O)=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[N:26]1([CH2:31][CH2:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:30][CH2:29][CH2:28][CH2:27]1.C[Al](C)C>ClCCCl>[NH3:13].[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[O:20][C:19]([C:21]([N:36]3[CH2:35][CH2:34][CH:33]([CH2:32][CH2:31][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[CH2:38][CH2:37]3)=[O:23])=[N:18][N:17]=2)(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1
Reactant: COC(=O)c1nnc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)o1
Reactant: C1CCN(CCC2CCNCC2)C1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N3CCC(CCN4CCCC4)CC3)o2)c(C)c1
Product: N

Procedure:
The title compound was prepared according to general procedure AT using methyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3,4-oxadiazole-2-carboxylate (30 mg, 0.08 mmol), 4-[2-(pyrrolidin-1-yl)ethyl]piperidine (29 mg, 0.16 mmol) and trimethylaluminium (2 M in toluene, 0.08 mL) in DCE (5 mL). The crude product was purified twice using FCC, eluting with 95:4.5:0.5 and 98:2:0.5 DCM:MeOH:NH3, to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])=O.F.[C:12]1([CH3:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:18][C:12]1[CH:17]=[CH:16][C:15]([C:3]([C:15]2[CH:16]=[CH:17][C:12]([CH3:18])=[CH:13][CH:14]=2)([C:5]([F:8])([F:7])[F:6])[C:2]([F:10])([F:9])[F:1])=[CH:14][CH:13]=1
Reactant: Cc1ccccc1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: F
Product: Cc1ccc(C(c2ccc(C)cc2)(C(F)(F)F)C(F)(F)F)cc1

Procedure:
It has been disclosed in U.S. Pat. No. 3,310,573 to react toluene with hexafluoroacetone in the presence of hydrofluoric acid to give 2,2-bis-(4-methylphenyl)hexafluoropropane (2). This is oxidized to the dicarboxylic acid (3) using chromium(III) oxide, which is subsequently converted into the 2,2-bis-(4-aminophenyl)hexafluoropropane (4) by a Schmidt reaction using sodium azide/sulfuric acid. In the next reaction steps, this compound is acetylated using acetic anhydride and then nitrated in the 3-position using 70% strength nitric acid in concentrated sulfuric acid. The elimination of the acetyl group then takes place, for which the nitrated substance is dissolved in concentrated sulfuric acid and water added until the 2,2-bis-(3-nitro-4-aminophenyl)hexafluoropropane (5) precipitates from the solution.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23])([O-:15])=[O:14]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH:12][S:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N+:13]([O-:15])=[O:14])(=[O:23])=[O:24])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: Nc1cc(F)cc2cccnc12
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1cc(F)cc2cccnc12
Yield: 76 %

Procedure:
In a similar fashion using route 14 general procedure 26, 6-fluoroquinolin-8-ylamine (Intermediate 48) (320 mg, 1.97 mmol), 2-nitro-benzenesulfonyl chloride (523 mg, 2.37 mmol), pyridine (2 ml) for 16 h gave the title compound (520 mg, 76%) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:10](=[O:11])[O:9][CH2:8]2.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19].C1(P(=CC(OC)=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)Cl>[OH:11][CH:10]1[C:12]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=2[CH2:8][O:9]1.[OH:19][CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([O:14][CH3:13])[C:16]=1/[CH:3]=[CH:12]/[C:10]([O:9][CH3:8])=[O:11]
Reactant: COc1cccc2c1C(=O)OC2
Reactant: COc1cccc(C=O)c1
Agent: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)/C=C/c1c(CO)cccc1OC
Product: COc1cccc2c1C(O)OC2
Temperature: 50 °C
Reaction time: 0.67 h

Procedure:
1-Hydroxy-7-methoxy-1,3-dihydrobenzo[c]furan (1.08 g), which was prepared with using 7-methoxyphthalide which was synthesized with using 3-methoxybenzaldehyde by the method described in Journal of Organic Chemistry, 1980, 45, 1835-1838, was dissolved in chloroform (20 ml). Methyl (triphenylphosphoranylidene)acetate (2.68 g) was added to the solution. The mixture was stirred for 40 min. at 50° C. A temperature of the reaction mixture was down to room temperature. The reaction solution was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give the title compound (1.25 g) having the following physical data.
Reaction SMILES: [CH3:1][O:2][C:3]([O:32][CH3:33])([C:28]([F:31])([F:30])[F:29])[CH2:4][CH2:5][C:6]1[CH:27]=[CH:26][C:9]([O:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:8][CH:7]=1.[CH:34](N(C(C)C)CC)([CH3:36])[CH3:35].ICCC>C(O)(C)C.C(OCC)(=O)C>[CH2:35]([N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:12][CH2:11][O:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])([O:32][CH3:33])[C:28]([F:30])([F:31])[F:29])=[CH:27][CH:26]=1)[CH2:34][CH3:36]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCCCCCCCCCCCNCCOc1ccc(CCC(OC)(OC)C(F)(F)F)cc1
Solvent: CCOC(C)=O
Solvent: CCCI
Solvent: CC(C)O
Product: CCCCCCCCCCCCN(CCC)CCOc1ccc(CCC(OC)(OC)C(F)(F)F)cc1
Temperature: 25 °C
Yield: 96.8 %

Procedure:
A solution of N-[2-[4-(3,3-dimethoxy-4,4,4-trifluorobut-1-yl)phenoxy]ethyl]dodecylamine (500 mg, 1.05 mmol), diisopropyl ethylamine (0.35 ml, 2.1 mmol) and 1-iodopropane (0.26 ml, 2.66 mmol) in isopropanol was heated to reflux for 21 h. After cooling to r.t., the mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated in vacuo, and the residue was chromatographed on silica gel (dichloromethane/methanol 98:2 to 95:5) to afford the title compound (0.526 g, 73%) as a colorless oil.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][NH:5][C:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)=[O:7].O.[NH2:20][NH2:21].O>CCO>[NH:20]([C:3](=[O:2])[CH2:4][NH:5][C:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)=[O:7])[NH2:21]
Reactant: NN
Reactant: COC(=O)CNC(=O)c1cccc2ccccc12
Solvent: CCO
Solvent: O
Product: NNC(=O)CNC(=O)c1cccc2ccccc12
Temperature: 25 °C
Yield: 81.6 %

Procedure:
The above compound 2a (3.3 g, 13.1 mmol) was heated at 60° C. with hydrazine hydrate (3.5 mL, 65 mmol) in EtOH (30 mL) for 2 hours. After cooling at room temperature, water (10 mL) was added. The resulting white precipitate was filtered and dried under vacuum to give hydrazide derivative 3a (2.6 g, 79%). 1H NMR (acetone-d6) δ 3.91 (d, J=5.9 Hz, 2H, CH2), 7.55-7.58 (m, 3H, Ar), 7.68 (dd, J=1.1 and 7.0 Hz, 1H, Ar), 7.98 (d, J=8.0 Hz, 1H, Ar), 8.02 (d, J=8.3 Hz, 2H, Ar), 8.35 (m, 1H, NH), 8.74 (t, J=6.3 Hz, 1H, NH), 9.31 (bs, 1H, NH); 13C NMR (acetone-d6) δ 41.08 (CH2), 124.88, 124.92, 125.13, 125.72, 126.12, 126.56, 128.07, 129.67, 129.80, 129.83, 133.08, 134.46, 168.34 (CO), 168.91 (CO).
Reaction SMILES: B(Br)(Br)Br.[NH2:5][C:6]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:9]([CH2:17][C:18]2[CH:19]=[C:20]([CH2:26][C:27]([OH:29])=[O:28])[CH:21]=[CH:22][C:23]=2[O:24]C)=[C:8]([CH3:30])[N:7]=1.[CH3:31]O.Cl>C(Cl)Cl.O1CCOCC1>[NH2:5][C:6]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:9]([CH2:17][C:18]2[CH:19]=[C:20]([CH2:26][C:27]([O:29][CH3:31])=[O:28])[CH:21]=[CH:22][C:23]=2[OH:24])=[C:8]([CH3:30])[N:7]=1
Reactant: CO
Reactant: CCCCNc1nc(N)nc(C)c1Cc1cc(CC(=O)O)ccc1OC
Agent: BrB(Br)Br
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCNc1nc(N)nc(C)c1Cc1cc(CC(=O)OC)ccc1O
Reaction time: 3 h

Procedure:
A solution of boron tribromide (2.51 ml, 1M in DCM) was added portionwise over 30 min to a stirred suspension of the product from example 83 step (iv) (300 mg) in DCM (5 mL) at 0° C. The suspension was allowed to warn to rt and stirred for 3 h. A further portion of boron tribromide (1.674 ml, 1M in DCM) was added and the mixture stirred at rt for a further 2 h. MeOH (2 mL) and 4M HCl in dioxane (2 mL) were added and the mixture stirred for 1 h. The solvent was evaporated under reduced pressure and the residue purified by RPHPLC, to give the title compound as a white solid, 27 mg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2Cl.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>CN1CCCC1=O.CCOC(C)=O>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[N:8]=[CH:7][N:6]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: Clc1ncnc2ccc(Br)cc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3ccc(Br)cc23)CC1
Temperature: 80 °C

Procedure:
A solution of the crude product from Step 1 (1.5 g), piperazine-1-carboxylic acid tert-butyl ester (2.29 g, 12.3 mmol) and triethylamine (2.15 mL, 15.4 mmol) in N-methylpyrrolidinone (50 mL) was stirred and heated at 80° C. for 2 hours. The solution was cooled to room temperature, diluted with EtOAc (200 mL), washed with water (3×200 mL) and dried over Na2SO4. The mixture was purified by silica gel column chromatography (50% EtOAc/hexanes) to give 4-(6-bromo-quinazolin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester as a colorless oil (1.5 g, 3.8 mmol, 85% from Step 1.) MS (APCI+) [M+H]+ 394.9 and 392.9. 1H NMR (CDCl3, 400 MHz) δ 8.76 (1H, s), 8.02 (1H, s), 7.84-7.78 (2H, m), 3.74 (4H, s), 3.66 (4H, s), 1.51 (9H, s.)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]([CH:20]=[CH2:21])=[CH2:19]>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:12](=[CH:13][CH:14]=1)[O:15][C:18]([O:17][CH3:16])([CH3:19])[CH2:20][CH2:21]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=C)OC
Reactant: Oc1ccc(OCc2ccccc2)cc1
Solvent: c1ccccc1
Product: COC1(C)CCc2cc(OCc3ccccc3)ccc2O1

Procedure:
A mixture of 40 g. of p-(benzyloxy)phenol, 33.6 g. of 2-methoxybutadiene, and 30 ml. of benzene was sealed in a glass tube under N2. The tube was heated at 160°-165° for 20 hours, cooled and opened. The yellow solution was chromatographed on silica gel with 97.5:2.5 benzene-ethyl acetate to give (±)-6-benzyloxy-2-methoxy-2-methylchroman, identical with the material prepared as described in Example 44, as 34.5 g. of pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[C:8]([CH:13]=1)[C:9]([O:11]C)=O)([O-])=O.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1.C[Mg]Br>C1COCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([NH:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[C:8]([CH:13]=1)[C:9]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:11]
Reactant: Nc1ccc(Cl)cn1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1NCC1CCN(c2ccncc2)CC1
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: Nc1ccc(NCC2CCN(c3ccncc3)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Reaction time: 3 h

Procedure:
A solution of methyl 5-nitro-2-[1-(4-pyridinyl)piperidin-4-ylmethylamino]benzoate (400 mg, 1.08 mmol) was treated with the magnesium salt of 2-amino-5-chloropyridine [freshly prepared by the addition of methyl magnesium bromide (2.16 mmol) to a solution of 2-amino-5-chloropyridine (2.16 mmol) in THF (11 mL)] and the mixture was heated at reflux. After 3 h, the mixture was cooled, sonicated, and the resulting solid (645 mg) collected by filtration. Using a similar procedure to that described in Example 2-B, the crude material was reduced to yield 370 mg of the titled compound; which was used without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])=[CH:6][CH:5]=1.CN(C)C=O.[F:20][CH2:21][CH2:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.O>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:14])([CH3:13])[CH2:11][O:12][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([O:23][CH2:22][CH2:21][F:20])=[CH:31][CH:30]=2)=[CH:6][CH:5]=1
Reactant: FCCOc1ccc(CCl)cc1
Reactant: Cc1ccc(C(C)(C)CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(C)(C)COCc2ccc(OCCF)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.5 %

Procedure:
Sodium hydride (0.9 g; 60% in oil) was added to 20 ml of toluene, and with heating, a solution of 2.5 g of 2-(4-methylphenyl)-2-methylpropyl alcohol in 10 ml of a mixture of 25% dimethylformamide and toluene was added dropwise over the course of 15 minutes. The mixture was stirred for 10 minutes, and then a solution of 2.9 g of 4-(2-fluoroethoxy)benzyl chloride in 10 ml of toluene was added dropwise over the course of 20 minutes. The mixture was further heated under reflux for 1 hour. The reaction mixture was cooled to room temperature, poured into water, and then extracted with toluene. The toluene layer was washed with water and dried over anhydrous sodium sulfate. Toluene was evaporated under reduced pressure. The resulting crude ether was purified by silica gel (100 g) column chromatography (developing solvent: a 2:1 mixture of toluene and n-hexane) to give 3.3 g of the desired 4-(2-fluoroethoxy)benzyl 2-(4-methylphenyl)-2-methylpropyl ether.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[ClH:28].[Cl:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][NH:20][C:16]1[N:15]=[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=[CH:18][N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccnc(NCc3cccc(Cl)c3)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: Clc1cccc(CNc2nccc(N3CCNCC3)n2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-[2-(3-chloro-benzylamino)-pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (I-3a) (48.5 mg, 0.12 mmol) in CH2Cl2 (1 mL) was added trifluoroacetic acid (139 μL, 1.8 mmol). After stirring at room temperature for 3 h, the mixture was poured into 1N NaOH (10 mL) and extracted with CH2Cl2 (1×35 mL). The organic layer was washed with brine, dried and concentrated to afford the title compound as a free amine. The free amine in CH2Cl2 (1 mL) was added to 1M HCl in ether (0.10 mL, 0.10 mmol). After stirring for 10 min at room temperature, the solution was concentrated in vacuo to yield the hydrochloride salt (3-A) (32.4 mg) as a yellow solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Br)[CH:6]=1)[CH:2]=[CH2:3].C([Li])(C)(C)C.[CH2:17]([N:24]([CH2:37][C:38]1[CH:49]=[CH:48][C:41]([C:42](N(OC)C)=[O:43])=[CH:40][CH:39]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:26]=1[CH3:36])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[C:42]([C:41]1[CH:40]=[CH:39][C:38]([CH2:37][N:24]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:25]2[C:26]([CH3:36])=[C:27]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:28]=[CH:29][CH:30]=2)=[CH:49][CH:48]=1)=[O:43])[CH:2]=[CH2:3]
Reactant: CON(C)C(=O)c1ccc(CN(Cc2ccccc2)c2cccc(NS(C)(=O)=O)c2C)cc1
Reactant: C=CCOc1cccc(Br)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C=CCOc1cccc(C(=O)c2ccc(CN(Cc3ccccc3)c3cccc(NS(C)(=O)=O)c3C)cc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
The product from Example 88C (0.983 g, 3.80 mmoles) in anhydrous THF (10 mL) at −78° C. was treated dropwise with 1.7 M t-butyllithium (4.46 mL, 7.59 mmoles). Reaction stirred 30 minutes at −78° C. and was then treated with the product from Example 88B (1.00 g, 1.90 mmoles. Reaction stirred 15 minutes at −78° C. and then allowed to warm to 0° C. Reaction quenched with saturated NH4Cl and warmed to room temperature. The mixture was diluted with ethyl acetate, washed with H2O, brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by chromatography on a pre-packed Biotage silica gel column (30% ethyl acetate:hexanes) to provide the title compound (0.369 g, 36%). MS (ESI−) m/z 539 (M−H)−.