Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:16]#[C:17][Si](C)(C)C)=[CH:15][C:10]3=[N:9][C:8]=2[C:22]2[CH:27]=[CH:26][C:25]([C:28]3([NH2:32])[CH2:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(N(CC)CC)C>C1COCC1>[C:16]([C:14]1[CH:13]=[CH:12][N:11]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:8]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4([NH2:32])[CH2:29][CH2:30][CH2:31]4)=[CH:24][CH:23]=3)[N:9]=[C:10]2[CH:15]=1)#[CH:17]
Reactant: C[Si](C)(C)C#Cc1ccn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#Cc1ccn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.2 %

Procedure:
To a solution of 1-[4-(3-phenyl-7-trimethylsilanylethynyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine (31 mg, 0.07 mmol) in THF (0.5 mL) was added a 1 M solution of tetra-n-butylammonium fluoride in THF (0.2 mL, 0.2 mmol, 3.0 equiv). The resulting solution was stirred at room temperature for 18 h, then was separated between water (15 mL) and EtOAc (15 mL). The aqueous layer was extracted with EtOAc (2×15 mL). The combined organic phases were washed with water (15 mL), dried (Na2SO4 anh) and concentrated under reduced pressure. The remaining material was treated with triethylamine (0.03 mL, 0.21 mmol, 3.0 equiv) and the resulting material was purified using MPLC (Biotage Isolera Flash NH2 Snap 10 reverse phase column; 100% CH2Cl2 for 8.5 min., gradient to 95% CH2Cl2: 5% MeOH over 7 min.; 95% CH2Cl2: 5% MeOH for 9 min.) to give 1-[4-(7-ethynyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine (12 mg, 39%).
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[CH:25][CH:26]=1.BrC1C=C(C=CC=1)OC1CCCCO1>C1COCC1>[OH:1][CH:2]([C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([O:20][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][O:14]2)[CH:26]=1)[CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Br[Mg]c1cccc(OC2CCCCO2)c1
Reactant: O=CCCc1ccccc1C(=O)O
Agent: Brc1cccc(OC2CCCCO2)c1
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1CCC(O)c1cccc(OC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At -10° C., a solution of the aldehyde of Step 2 (5.045 g, 28.3 mmol) in 50 mL of THF was added dropwise to 0.57M 3-(2-tetrahydropyranyloxy)phenylmagnesium bromide in THF (120 mL, 68.4 mmol, prepared from 2-(3-bromophenoxy)tetrahydropyran and Mg in THF and filtered to remove the excess of Mg) and the mixture was stirred at r.t. for 30 min. At 0° C., 25% aq NH4OAc was added. The title product was extracted with EtOAc, dried over Na2SO4 and purified by flash chromatography on silica using acetone:toluene:AcOH 5:95:1 and 15:85:1. Yield: 9.74 g, 97%.
Reaction SMILES: [CH2:1]([CH:3]1[NH:8][C:7]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:6]=2[O:5][CH2:4]1)[CH3:2].[CH:16](=O)[CH3:17].[BH3-]C#N.[Na+]>>[CH2:1]([CH:3]1[N:8]([CH2:16][CH3:17])[C:7]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:6]=2[O:5][CH2:4]1)[CH3:2]
Reactant: CCC1COc2cc([N+](=O)[O-])ccc2N1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCC1COc2cc([N+](=O)[O-])ccc2N1CC
Yield: 75 %

Procedure:
This compound was prepared by General Method 3 (EXAMPLE 1) from 3-ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine (EXAMPLE 42) (200 mg, 0.96 mmol), acetaldehyde (424 mg, 9.6 mmol) and NaBH3CN (293 mg, 4.6 mmol) to afford 170 mg (75%) of (±)-3,4-diethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine, a yellow solid. Data for (±)-3,4-diethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine: Rf 0.80 (3:2 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 7.80 (dd, 1H, J=8.9, 2.6), 7.66 (d, 1H, J=2.6), 6.55 (d, 1H, J=9.2), 4.07 (dd, ABX, 1H, J=10.7, 2.5), 3.96 (dd, ABX, 1H, J=10.7, 2.6), 3.60 (m, 1H), 3.55-3.35 (m, 2H), 1.29 (d, 3H, J=6.6), 1.24 (t, 3H, J=7.0).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Br.[CH3:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.[H-].[Na+].O>CN(C=O)C>[CH2:1]([N:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=[C:7]1[CH3:6])[CH:3]1[O:5][CH2:4]1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2ccccc2n1CC1CO1
Temperature: 60 °C

Procedure:
Epibromohydrin (1.0 g, 7.6 mmole) was added to a stirred solution of 2-methylbenzimidazole (1.0 g, 7.6 mmole) and sodium hydride (0.3 g, 7.6 mmole) in anhydrous DMF (20 ml), and the mixture was heated at 60° C. under nitrogen for 0.5 hours. Water (100 ml) was added and the product extracted into CH2Cl2 (3×25 ml). The combined organics were washed with water (25 ml), brine (25 ml) and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo gave the crude product as a light yellow colored oil (1.4 g). This was purified by flash silica gel chromatography (10% methanol in CH2Cl2) to afford the titled product as a light oil (0.64 g, 45% yield).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=O.F[C:9](F)([N:21]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]3)=[C:28]([O:38][CH3:39])[CH:27]=2)[N:23]=[N:22]1)[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[O:11].[CH2:41](O)C>>[F:20][C:17]1[C:16]2[CH2:15][CH2:41][C@H:9]([N:21]3[CH:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([N:32]5[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]5)=[C:28]([O:38][CH3:39])[CH:27]=4)[N:23]=[N:22]3)[C:10](=[O:11])[N:12]([CH2:3][C:2]([F:7])([F:6])[F:1])[C:13]=2[CH:14]=[CH:19][CH:18]=1
Reactant: COc1cc(-c2cn(C(F)(F)C(=O)NCc3ccc(F)cc3)nn2)ccc1-n1cnc(C)c1
Reactant: CCO
Reactant: O=C(O)C(F)(F)F
Product: COc1cc(-c2cn([C@H]3CCc4c(F)cccc4N(CC(F)(F)F)C3=O)nn2)ccc1-n1cnc(C)c1

Procedure:
Resolution (of the free base):75% ethanol/25% heptane Column: Chiralcel OJ-H; 254 nm detection; enantiomer 1 (465 mg), enantiomer 2 (489 mg).
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C([Li])CCC.C1(O[C:34]#[N:35])C=CC=CC=1.O>O1CCCC1.CCCCCC>[CH2:16]([C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]#[C:2][C:34]#[N:35])=[CH:5][CH:6]=2)=[CH:11][CH:12]=1)[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: N#COc1ccccc1
Reactant: CCCCCc1ccc(-c2ccc(C=C(Br)Br)cc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCc1ccc(-c2ccc(C#CC#N)cc2)cc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
A solution of 2.60 g of 4-(2,2-dibromovinyl)-4'-pentylbiphenyl in 50 ml of absolute tetrahydrofuran was placed at -78° C. in a sulphonation flask under argon gasification and treated within 5 minutes with 14.5 ml of a 1.2N solution of butyl lithium in hexane. After completion of the addition, the mixture was warmed to -10° C. within 10 minutes and then, after renewed cooling to -78° C., treated with a solution of 1.5 ml of phenyl cyanate in 10 ml of absolute tetrahydrofuran. The mixture was subsequently stirred at -78° C. for a further 30 minutes, then poured into 100 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed twice with 50 ml of water each time, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the residue (2.51 g) on silica gel with hexane followed by 2% ethyl acetate/petroleum ether and subsequent recrystallization from methanol gave 1.02 g (58%) of (4'-pentyl-4-biphenylyl)propiolonitrile as colourless crystals (purity 99.6%); m.p. (C-N) 51.0° C., cl.p. (N-I) 120.2° C.
Reaction SMILES: [CH3:1][NH2:2].[CH:3]1[C:8](=[O:9])[C:7]([OH:10])=[CH:6]O[C:4]=1[CH2:11][OH:12]>O>[OH:12][CH2:11][C:4]1[N:2]([CH3:1])[CH:6]=[C:7]([OH:10])[C:8](=[O:9])[CH:3]=1
Reactant: O=c1cc(CO)occ1O
Reactant: CN
Solvent: O
Product: Cn1cc(O)c(=O)cc1CO

Procedure:
A solution of 40% methylamine in water is added to a solution of kojic acid dissolved in hot distilled water. The pH of this solution is adjusted to 9.8 by the addition of HCl solution. The mixture is kept under reflux overnight and then decolorized with activated charcoal. The solvent is removed under reduced pressure. The white product is obtained upon recrystallization from hot water.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]2[S:15][C:16]([C:20]3[CH:25]=[C:24]([CH3:26])[N:23]=[C:22](S(C)=O)[N:21]=3)=[C:17]([CH3:19])[N:18]=2)=[O:12])[N:5]=[CH:4]1)[CH3:2].[CH3:30][N:31]([CH3:36])[CH2:32][CH2:33][NH:34][CH3:35]>O1CCOCC1>[CH3:30][N:31]([CH3:36])[CH2:32][CH2:33][N:34]([CH3:35])[C:22]1[N:21]=[C:20]([C:16]2[S:15][C:14]([NH:13][C:11]([NH:10][CH2:9][CH2:8][C:6]3[N:5]=[CH:4][N:3]([CH2:1][CH3:2])[CH:7]=3)=[O:12])=[N:18][C:17]=2[CH3:19])[CH:25]=[C:24]([CH3:26])[N:23]=1
Reactant: CNCCN(C)C
Reactant: CCn1cnc(CCNC(=O)Nc2nc(C)c(-c3cc(C)nc(S(C)=O)n3)s2)c1
Solvent: C1COCCO1
Product: CCn1cnc(CCNC(=O)Nc2nc(C)c(-c3cc(C)nc(N(C)CCN(C)C)n3)s2)c1

Procedure:
This material is prepared from 1-[2-(1-ethyl-1H-imidazol-4-yl)-ethyl]-3-[5-(2-methanesulfinyl-6-methyl-pyrimidin-4-yl)-4-methyl-thiazol-2-yl]-urea and N,N,N′-trimethyl-ethane-1,2-diamine using the protocol described for Example 42 but replacing DMF by dioxane.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)c2ccc(I)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(c1ccc(O)cc1)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
To a solution of (4-iodo-phenyl)-(4-methoxy-phenyl)-methanone (1.7 g, 5 mmol in CH2Cl2 (20 mL) was added BBr3 (15 mL, 15 mmol; 1 M in CH2Cl2) at −78° C. The resulting mixture was allowed to warm to rt and stir at rt for 6 h. The mixture was poured onto 50 mL ice-water solution and extracted with CH2Cl2 (3×30 mL). The combined organic layers were washed with water (2×30 mL) and brine (20 mL) and dried over anhy. Na2SO4. The solvent was removed in vacuo to obtain the crude product which was purified by recrystallization from acetone-EtOAc-hexane to provide the title product (1.4 g, 85%) which was directly used for the next step.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][C:10]1([OH:24])[CH2:13][N:12]([C:14]([O:16]CC2C=CC=CC=2)=O)[CH2:11]1)=[O:7])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[F:34][C:35]1[C:36]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([I:52])=[CH:48][C:47]=2[F:53])=[C:37]([CH:41]=[CH:42][C:43]=1[F:44])C(F)=O>[Pd].CO>[F:34][C:35]1[C:36]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([I:52])=[CH:48][C:47]=2[F:53])=[C:37]([C:14]([N:12]2[CH2:11][C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])([OH:24])[CH2:13]2)=[O:16])[CH:41]=[CH:42][C:43]=1[F:44]
Reactant: CC(C)(C)OC(=O)NCC1(O)CN(C(=O)OCc2ccccc2)C1
Reactant: O=C(F)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
Phenylmethyl 3-[({[(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]-3-hydroxyazetidine-1-carboxylate (16.5 mg, 0.05 mmol) and 10% Pd/C (8 mg) were taken into methanol (2 mL) and hydrogenated at ambient pressure over 12 hours. The catalyst was removed by filtration and the filtrate concentrated and dried in vacuo. The residue was taken into THF (1 mL) followed by addition of DIPEA (10 μL, 0.06 mmol) and 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl fluoride (19.8 mg, 0.05 mmol), prepared using procedures similar to those described in Reference 1, and the solution was stirred at room temperature for 30 minutes. Concentration and purification of the residue by silica gel flash chromatography using hexanes:ethyl acetate (1:1.5) afforded 1,1-dimethylethyl {[1-({3,4-difluoro-2 [(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidine-3-yl]methyl}carbamate (19 mg, 66% yield).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]1=O.B#B.Cl>O1CCCC1.O>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]([CH3:12])[CH2:3]1
Reactant: Cc1nc2ccccc2n(C)c1=O
Agent: B#B
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC1CN(C)c2ccccc2N1

Procedure:
To a stirred solution of 0.2 mole (34.8 g) of 1,3-dimethyl-2-oxoquinoxaline in 300 ml of dry tetrahydrofuran was added dropwise 0.24 mole (240 ml of 1 M) diborane in tetrahydrofuran. The solution was stirred one additional hour, then heated at its reflux temperature for one day. After cooling, about 40 ml of water was added, followed by 2 equivalents of 4 N hydrochloric acid. The solution was heated at reflux for one hour, then evaporated to provide a solid residue. The residue was dissolved in water. The solution was basified and then extracted with diethyl ether. The ether was dried, then evaporated to provide an oil. Distillation provides 1,3-dimethyl-1,2,3,4-tetrahydroquinoxaline, b.p. 85° C./0.1 mm of Hg. Analysis: Calculated for C10H14N2 :%C, 74.0; %H, 8.7; %N, 17.4; Found : %C, 74.2; %H, 8.9; %N, 17.3.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([O:15][CH2:16][CH:17]([CH2:19][OH:20])[OH:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]([NH:28][C@H:29]([C:33](O)=[O:34])[CH:30]([CH3:32])[CH3:31])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([O:15][CH2:16][CH:17]([CH2:19][O:20][C:33](=[O:34])[C@H:29]([CH:30]([CH3:31])[CH3:32])[NH:28][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[OH:18])=[O:14])[CH:10]([CH3:11])[CH3:12])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(O)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(O)COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Yield: 49 %

Procedure:
1-O-(N-tert-butoxycarbonyl-L-valyl)glycerol (17.95 g. 61.6 mmol), Boc-L-valine (6.69 g, 30.8 mmol), DMAP (0.38 g, 3.1 mmol), and DCC (7.10 g, 34.4 mmol) in 240 mL CH2Cl2 and 60 mL DMF were stirred at rt under N2 for 18 h. The reaction mixture was filtered, concentrated under vacuum, and redissolved in 200 mL EtOAc. The organic solution was washed with 50 mL saturated NH4Cl. The aqueous phase was reextracted with 50 mL EtOAc. The organic phases were combined, washed successively with 50 mL saturated NaHCO3 and 50 mL brine, dried over Na2SO4, and concentrated under vacuum. Flash column chromatography of the crude material on silica gel (eluent 2/1 petroleum ether-EtOAc, and then EtOAc) gave 7.41 g (49%) of the title compound (alternative nomenclature: 1,3-bis(N-tertbutoxycarbonyl-L-valyloxy)-2-propanol).
Reaction SMILES: [Br:1]C[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[N:13]12[CH2:20][CH2:19][N:16]([CH2:17][CH2:18]1)[CH2:15][CH2:14]2.O.[CH3:22]S(C)=O>>[Br-:1].[C:10]([CH2:9][C:5]1[CH:4]=[CH:3][C:8]([CH2:22][N+:13]23[CH2:20][CH2:19][N:16]([CH2:17][CH2:18]2)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)([OH:12])=[O:11]
Reactant: O=C(O)Cc1cccc(CBr)c1
Reactant: C1CN2CCN1CC2
Reactant: CS(C)=O
Solvent: O
Product: O=C(O)Cc1ccc(C[N+]23CCN(CC2)CC3)cc1
Product: [Br-]
Reaction time: 1 h

Procedure:
At 70° C., 1.0 g of (3-bromomethylphenyl) acetic acid in 5 ml of dimethyl sulfoxide were added to a solution of 1.5 g of 1,4-diazabicyclo[2.2.2]octane in 10 ml of dimethyl sulfoxide. After 1 h, 100 ml of water were added and the mixture was freeze-dried. The residue was digested with acetone. The residue contained the product of molecular weight 261.35 (cation: C15H21N2O2+); MS (ESI) 261.1 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.CCN(C(C)C)C(C)C.[C:52]1([NH2:58])[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>ClCCCl.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])([C:13](=[O:15])[NH:58][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)OCc2ccccc2)(C(=O)O)C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)OCc2ccccc2)(C(=O)Nc2ccccc2)C1
Reaction time: 0.25 h
Yield: 68.3 %

Procedure:
To a solution of 3-(benzyloxycarbonylamino-methyl)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (2200.00 mg; 5.81 mmol; 1.00 eq.) in DCE (40.0 ml), bis(2-oxo-1,3-oxazolidin-3-yl)phosphinic chloride (1627.95 mg; 6.40 mmol; 1.10 eq.) was added. After stirring for 15 mins. DIEA (1.25 ml; 6.98 mmol; 1.20 eq.) and phenylamine (595.55 mg; 6.40 mmol; 1.10 eq) were added. The reaction mixture was stirred overnight at RT. DCM (100 ml) was added. The solution was washed with brine, dried and concentrated to give the crude product, which was subjected for biotage for purification (20-50% EtOAc in hexane) to afford the title compound (1800 mg, 68.3%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([NH2:19])=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2].N1(C2CCCCCCCCCC2)CCCCCC[CH2:24][CH2:23][CH2:22]N1.[CH2:42](Br)[CH:43]=[CH2:44]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([N:19]([CH2:44][CH:43]=[CH2:42])[CH2:24][CH:23]=[CH2:22])=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(N)cc3c2n1
Reactant: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Reactant: C=CCBr
Solvent: CCO
Product: C=CCN(CC=C)c1ccc2[nH]c3cnc(C(=O)OCC)nc3c2c1

Procedure:
Under argon, 0.4 g of 8-amino-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester (Example 11) is agitated in 8 ml of ethanol with 0.16 ml of diazabicycloundecane and 0.25 ml of allyl bromide for 5 hours at 50°-60° C. The reaction solution is subsequently evaporated, and the residue is taken up in ethyl acetate. This solution is washed first with water, then with sodium bicarbonate solution, and finally again with water, dried with sodium sulfate, and concentrated, thus obtaining 0.18 g of 8-diallylamino-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester, mp 188°-190° C.
Reaction SMILES: C[O:2][CH:3]([O:10][CH3:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:12](N(CC)CC)C>CC(C)=O.O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:2][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:12][CH2:11][O:10]1
Reactant: CCN(CC)CC
Reactant: COC(OC)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: OC1OCCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 605.4 %

Procedure:
To a stirred solution of crude product from step 5 (1.89 g; 5.49 mmol) in a mixture of acetone (80 ml) and water (25 ml) was added p-toluene sulfonic acid monohydrate (70 mg; 0.37 mmol). After stirring at room temperature for 3 hours, triethylamine (2 ml; 1.43 mmol) was added and stirred for 5 minutes. The mixture was evaporated until volume went down to 10 ml. A mixture of acetone (80 ml) and water (15 ml) was added followed by addition of p-toluene sulfonic acid monohydrate (70 mg; 0.37 mmol). After 3.5 hours, triethylamine (3 ml; 2.15 mmol) was added, evaporated to a small volume, extracted with ether (3×100 ml). The extract was washed with brine (50 ml), dried over MgSO4 and evaporated yielding quite pure 1-hydroxyisochroman (1.3 g; 94%), (MP. 136°-138° C.). NMR (CDCl3 ; 300 MHz) δ:2.32 (3H, s, CH3O), 2.51 (1H, dd, J=12.4, 17.5 Hz, H-4), 2.97 (1H, d, J=3.5 Hz; --OH), 3.06 (1H, dd, J=4.1, 17.5 Hz, H-4), 3.77, 3.82 (3H, s each, ArOCH3), 4.70 (1H, dd, J=4.1, 12.4 Hz, H-3), 6.22 (1H, d, J=3.4 Hz, 1H), 6.71, 6.76, (1H, d each, J=9.0 Hz, ArH).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[C:11]([C:12]([F:15])([F:14])[F:13])=CC=C2[C:4]=1[C:5](=O)[C:6](=O)[NH:7]2.ClC1C=CC=C(C(OO)=[O:28])C=1.[C:31]([O:34][CH2:35][CH3:36])(=[O:33])C>>[F:1][C:2]([F:18])([F:19])[C:3]1[C:11]([C:12]([F:13])([F:14])[F:15])=[C:36]2[C:35]([O:34][C:31](=[O:33])[NH:7][C:6]2=[CH:5][CH:4]=1)=[O:28]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1Nc2ccc(C(F)(F)F)c(C(F)(F)F)c2C1=O
Reactant: CCOC(C)=O
Product: O=c1[nH]c2ccc(C(F)(F)F)c(C(F)(F)F)c2c(=O)o1

Procedure:
4,5-Bis(trifluoromethyl)isatin (283 g., 1 mol.) is suspended in 1 L. of ethyl acetate and treated with m-chloroperbenzoic acid (172 g., 1 mol.), stirred until the oxidation is complete to yield 5,6-bis(trifluoromethyl)-isatoic anhydride.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11]([O:15][C:16]([NH:18][CH:19]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[F:37])[C:20]([O:22][C@@H:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1)=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12]>CCOC(C)=O.C(#N)C>[Br-:1].[C:11]([O:15][C:16]([NH:18][CH:19]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[F:37])[C:20]([O:22][C@@H:23]1[CH:28]2[CH2:29][CH2:30][N+:25]([CH2:2][C:3](=[O:4])[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)([CH2:26][CH2:27]2)[CH2:24]1)=[O:21])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(C(=O)O[C@H]1C[N+]2(CC(=O)c3ccccc3)CCC1CC2)c1ccccc1F
Product: [Br-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 63.3 %

Procedure:
2-Bromo-1-phenylethanone (57.9 mg, 0.29 mmol) was added to a solution of (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)acetate (C56) (100 mg, 0.26 mmol) in EtOAc (3 ml) and acetonitrile (3 ml). The reaction was stirred at RT for 15 hours, and then the solvent was evaporated. The crude was purified by flash chromatography (DCM/MeOH=94/6) to obtain (3R)-3-(2-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)acetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane bromide (95.1 mg; 62% yield).
Reaction SMILES: [C:1]([O:4][C@@H:5]([C:7]1[N:12]=[C:11](Cl)[CH:10]=[CH:9][N:8]=1)[CH3:6])(=[O:3])[CH3:2].C(N(CC)CC)C.[N:21]1([C:27]2[CH:36]=[N:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(O)(C)C>[C:1]([O:4][C@@H:5]([C:7]1[N:12]=[C:11]([N:24]2[CH2:25][CH2:26][N:21]([C:27]3[CH:36]=[N:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)[CH2:22][CH2:23]2)[CH:10]=[CH:9][N:8]=1)[CH3:6])(=[O:3])[CH3:2]
Reactant: c1ccc2nc(N3CCNCC3)cnc2c1
Reactant: CC(=O)O[C@H](C)c1nccc(Cl)n1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H](C)c1nccc(N2CCN(c3cnc4ccccc4n3)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl acetate (prepared according to the method of Preparation Five, 7.3 g, 36.2 mmol) in isopropanol (240 mL) was added triethylamine (10.1 mL, 72.4 mmol) followed by 2-(1-piperazinyl)quinoxaline (10.1 g, 47.1 mmol; J. Med. Chem. 1981, 24, 93). This mixture was stirred at room temperature overnight then concentrated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform (5×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (2% methanol/chloroform) to give 12.4 g (91%) of the title compound of Example 1, Step A as a yellow foam. 1H NMR (CDCl3, 250 MHz) δ 8.61 (s, 1H), 8.27 (d, 1H), 7.91 (dd, 1H), 7.72 (dd, 1H), 7.61 (td, 1H), 7.44 (td, 1H), 6.43 (d, 1H), 5.70 (q, 1H), 3.96-3.84 (c, 8H), 2.18 (s, 3H), 1.61 (d, 3H); MS (Cl/NH3) 379 (MH+).