Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1.C([N-]C(C)C)(C)C.[Li+].[CH:23]12[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]3)[C:24]1=[O:33])[CH2:30]2.O>O1CCCC1>[OH:33][CH:24]1[CH:23]2[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][C:25]1([CH:6]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)[C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)[CH2:26]3)[CH2:30]2
Reactant: N#Cc1ccc(Cc2ncc[nH]2)cc1
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(C(c2ncc[nH]2)C23CC4CC(CC(C4)C2O)C3)cc1
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
5.0 g of 4-[1-(imidazolyl)methyl]benzonitrile is dissolved in 100 ml of tetrahydrofuran and combined at -50° with 20 ml of 1.5-molar solution of lithium diisopropylamide in tetrahydrofuran, stirred for 0.5 hour at -60°, combined with 4.3 g of 2-adamantanone, further stirred for 1 hour, and heated to 25°. Then water is added, the mixture is extracted three times with ethyl acetate, washed neutral with water, dried over sodium sulfate, and concentrated to dryness under vacuum, thus obtaining 6.66 g of crude 4-[2-hydroxy-adamant-1-yl-1-(imidazolyl)methyl]benzonitrile.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:4][C:5]2[O:9][C:8]([CH:10]=[N:11][OH:12])=[C:7]([C:13]([NH:15][CH3:16])=[O:14])[C:6]=2[CH:17]=1.C1C(=O)N([Cl:31])C(=O)C1>CN(C=O)C>[Br:1][C:2]1[C:3]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:20])=[O:21])=[CH:4][C:5]2[O:9][C:8]([C:10]([Cl:31])=[N:11][OH:12])=[C:7]([C:13](=[O:14])[NH:15][CH3:16])[C:6]=2[CH:17]=1
Reactant: CNC(=O)c1c(C=NO)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1c(C(Cl)=NO)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 60 °C
Reaction time: 18 h
Yield: 65 %

Procedure:
A mixture of 5-bromo-2-((hydroxyimino)methyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (100 mg, 0.25 mmol) and NCS (40 mg, 0.30 mmol) in DMF (2 mL) was stirred at 60° C. for 18 h. The mixture was used for the next step without purification, 5-bromo-N-hydroxy-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-2-carbimidoyl chloride was obtained (90 mg, yield: 65%). 1H-NMR (DMSO-d6, 400 MHz) δ 13.33 (s, 1H), 8.65 (d, J=4 Hz, 1H), 8.13 (s, 1H), 8.05 (s, 1H), 3.20 (s, 6H), 2.80 (d, J=4.8 Hz, 3H). MS (M+H)+: 438/440.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Br:11])[NH:7][CH2:6][CH2:5]2.[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1>CC(O)C>[ClH:12].[Br:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][N:7]2[C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[CH:3][C:2]=1[F:1]
Reactant: Fc1cc2c(cc1Br)NCC2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4cc(F)c(Br)cc43)c2cc1OC
Product: Cl
Yield: 68 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 68% yield from 5-fluoro-6-bromo-indoline (1.1 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 258° C. (dec); LC-MS: 404, 406 (MH+); anal. RP18-HPLC RT: 5.06 min.).
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13](=[O:45])[CH2:14][CH2:15][CH:16]1[CH2:23][N:22]2[C:24]3[CH:25]=[C:26]([C:37]([O:39][CH3:40])=[O:38])[CH:27]=[CH:28][C:29]=3[C:30]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[C:21]2[C:20]2[CH:41]=[CH:42][CH:43]=[CH:44][C:19]=2[O:18][CH2:17]1)(C)(C)C>O.C(Cl)Cl>[CH:31]1([C:30]2[C:29]3[CH:28]=[CH:27][C:26]([C:37]([O:39][CH3:40])=[O:38])=[CH:25][C:24]=3[N:22]3[C:21]=2[C:20]2[CH:41]=[CH:42][CH:43]=[CH:44][C:19]=2[O:18][CH2:17][CH:16]([CH2:15][CH2:14][C:13]([OH:45])=[O:12])[CH2:23]3)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CCC(=O)OC(C)(C)C)COc1ccccc1-3
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CCC(=O)O)COc1ccccc1-3
Temperature: 60 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
TFA (>150 eq) and a few drops of water were added to a stirred solution of methyl 7-(3-tert-butoxy-3-oxopropyl)-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.03 M) in DCM at RT. The reaction was heated at 60° C. (oil bath temp) for 1 h. Further TFA was introduced (circa 60 eq) and heating continued for 2 h. Volatiles were removed in vacuo. The residue was taken up in EtOAc and washed with 1N HCl (aq), brine before being dried (Na2SO4) filtered and concentrated in vacuo. Residual tert-BuOH was removed by sonication in Et2O/PE to afford the product (45%). (ES+) m/z 462 (M+H)+; 484 (M+Na)+.
Reaction SMILES: C([Li:5])CCC.[CH3:6][Si:7]([CH3:14])([CH3:13])[NH:8][Si:9]([CH3:12])([CH3:11])[CH3:10].C(SC1N(CC(OCOC(=O)C(C)(C)C)=O)C(=O)C1)C=C>CCCCCC.O1CCCC1>[CH3:6][Si:7]([CH3:14])([CH3:13])[N-:8][Si:9]([CH3:12])([CH3:11])[CH3:10].[Li+:5]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: [Li]CCCC
Agent: C=CCSC1CC(=O)N1CC(=O)OCOC(=O)C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Si](C)(C)[N-][Si](C)(C)C
Product: [Li+]

Procedure:
A solution of lithium hexamethyldisilazide was prepared by the addition of 3.53 ml of a 1.6M solution of n-butyllithium in hexane to 1.19 ml of hexamethyldisilazane in 25 ml of dry tetrahydrofuran at -10° with stirring under argon. The solution was cooled to -78° and added by cannula to 1.02 g of pivaloyloxymethyl 2-(4-allylthioazetidin-2-on-1-yl)acetate in 10 ml of dry tetrahydrofuran at -78° with stirring under argon.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.[C:22](OC)(=[O:27])[CH2:23][C:24]([CH3:26])=[O:25].[H-].[Na+].C([Li])CCC>C1COCC1>[OH:25][C:24]1[CH2:26][C:17]([CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)([CH:18]([CH3:19])[CH3:20])[O:21][C:22](=[O:27])[CH:23]=1
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)C(=O)CCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C1(CCc2ccc(O)cc2)CC(O)=CC(=O)O1

Procedure:
The title compound was prepared as described in General Method 6 using 40 g (142 mmol) of 1-(4-benzyloxyphenyl)-4-methyl-pentan-3-one (prepared in Example F ), 41.2 g (355 mmol) of methyl acetoacetate, 14.2 g (355 mmol) of 60% NaH dispersion in mineral oil, 216 mL (1.64 M, 355 mmol) of n-butyllithium and 700 mL of THF. The reaction mixture was quenched with 0.1N HCl and the product was extracted into EtOAc. The organic layer was dried (MgSO4), and the solvents were evaporated.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2.O.C(=O)([O-])[O-:18].[K+].[K+]>COCCOC>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]([OH:18])[CH2:10][CH:9]=[CH:8]2
Reactant: COC(=O)Cc1ccc2ncccc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1ccc2c(c1)C=CCN2O
Reaction time: 2 h

Procedure:
m-Perchlorobenzoic acid (6.85 g, 39.8 mmol) was added to a solution of commercially available quinolin-6-yl-acetic acid methyl ester (5.00 g, 24.8 mmol) in 1,2-dimethoxyethane at room temperature and stirred for 2 hours. Water was added and the solution was basified to pH 9-10 with saturated potassium carbonate and the product was extracted with ethyl acetate to give quantitative yield of (1-hydroxy-quinolin-6-yl)-acetic acid methyl ester. 1H NMR (400 MHz, CDCl3) δ 7.99 (d, 1H, J=8.4 Hz), 7.93 (d, 1H, J=8.4 Hz), 7.65 (m, 1H), 7.60 (m, 1H), 7.32 (d, 1H, J=8.8 Hz), 7.19 (s, 1H), 3.74 (s, 2H), 3.65 (s, 3H).
Reaction SMILES: [CH2:1]1[O:12][CH:4]([C:5]2[S:9][C:8](Cl)=[N:7][C:6]=2[Cl:11])[O:3][CH2:2]1.C([Li:17])CCC.[C:18](=[O:20])=[O:19].CC(C)=O.C(=O)=O>O1CCCC1>[Cl:11][C:6]1[N:7]=[C:8]([C:18]([O-:20])=[O:19])[S:9][C:5]=1[CH:4]1[O:12][CH2:1][CH2:2][O:3]1.[Li+:17]
Reactant: Clc1nc(Cl)c(C2OCCO2)s1
Reactant: [Li]CCCC
Reactant: O=C=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=C([O-])c1nc(Cl)c(C2OCCO2)s1
Product: [Li+]
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2,4-Dichlorothiazole-5-carbaldehyde ethyleneacetal (J. Chem. Soc. Perkin Trans. 1, 1992, p. 973) (2.26 g) was dissolved in tetrahydrofuran (15 ml), and n-butyllithium (1.5N hexane solution, 6.8 ml) was added under cooling with dry ice-acetone to stir the mixture for 20 minutes. At the same temperature, carbon dioxide was then introduced. The reaction mixture was gradually heated to room temperature over 1.5 hours and then concentrated. Hexane was added to the reaction mixture to powder the product. The product was collected by filtration and suspended in ethyl acetate, and formed powder was collected again by filtration to obtain the title compound (1.65 g).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:21])[N:4]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:13]([NH:15][CH3:16])=[O:14])[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O.[F:35][C:36]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:37]=1[CH2:38]Br>O>[F:35][C:36]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:37]=1[CH2:38][O:8][C:7]1[CH:6]=[C:5]([CH3:9])[N:4]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:13]([NH:15][CH3:16])=[O:14])[C:3](=[O:21])[C:2]=1[Br:1]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: CNC(=O)c1ccc(C)c(-n2c(C)cc(O)c(Br)c2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CNC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 30 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
3-(3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-N,4-dimethylbenzamide (9) (1 kg, 2.85 moles), potassium carbonate (0.43 kg, 3.11 moles), 1-methyl-2-pyrrolidinone (4.0 L) and 2,4-difluorobenzyl bromide (0.71 kg, 3.42 moles) were mixed together and heated at 30° C. for 2 hours. The reaction mixture was diluted with water (12.5 L) over a period of 30 to 60 minutes and then stirred for 30 to 60 minutes. The product was filtered and washed with water. (−)-3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)-N,4-dimethylbenzamide (1) (1.36 kg, 95% purity, greater than 99% ee) was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:15])[S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1.Cl.[F:24][C:25]1[CH:26]=[N:27][C:28]([C@@H:31]([NH2:33])[CH3:32])=[N:29][CH:30]=1.CCN(C(C)C)C(C)C>CCCCO>[F:24][C:25]1[CH:26]=[N:27][C:28]([C@@H:31]([NH:33][C:2]2[N:7]=[C:6]([N:8]([CH3:15])[S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:5]=[C:4]([NH:16][C:17]3[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=3)[N:3]=2)[CH3:32])=[N:29][CH:30]=1
Reactant: C[C@H](N)c1ncc(F)cn1
Reactant: Cc1cc(Nc2cc(N(C)S(=O)(=O)N(C)C)nc(Cl)n2)n[nH]1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cc(Nc2cc(N(C)S(=O)(=O)N(C)C)nc(N[C@@H](C)c3ncc(F)cn3)n2)n[nH]1
Temperature: 180 °C
Yield: 70.1 %

Procedure:
A microwave reaction vessel was charged with N-{2-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N,N′,N′-trimethylsulfamide (Method 30, 51.9 mg, 0.150 mmol), (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 53.3 mg, 0.301 mmol), and DIPEA (0.079 ml, 0.449 mmol). Anhydrous n-BuOH (1 ml) was added, and the tube was sealed and heated in a microwave reactor at 180° C. for 4 hours. The reaction mixture was purified by silica gel chromatography (by ISCO Combiflash with gradient EtOAc and hexanes) to afford the title compound as a white solid (47.4 mg, 70%). LC-MS, 451 (M+1). 1H NMR (DMSO-d6, 400 MHz, 80° C.) δ 11.61 (s, 1H), 8.95 (s, 1H), 8.77 (s, 2H), 5.84-6.89 (m, 3H), 5.17-5.23 (m, 1H), 3.17 (s, 3H), 2.74 (s, 6H), 2.18 (s, 3H), 1.54 (d, 3H).
Reaction SMILES: C[Mg]Br.[NH2:4][C:5]1[C:10]2=[CH:11][C:12]([CH:14]=[O:15])=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1.[CH3:16]O.[NH4+].[Cl-]>C(OCC)C.C1COCC1.CCOC(C)=O>[NH2:4][C:5]1[C:10]2=[CH:11][C:12]([CH:14]([OH:15])[CH3:16])=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1
Reactant: CO
Reactant: Nc1ncnn2cc(C=O)cc12
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1cc2c(N)ncnn2c1
Temperature: 25 °C
Yield: 56 %

Procedure:
To a solution of THF (100 mL) was added 3.0 M methylmagnesium bromide in diethyl ether (14.0 mL, 41.9, mmol) cooled in an ice bath. Then 4-aminopyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde (0.68 g, 4.19 mmol) was added as a solution in THF (200 mL) via an addition funnel. The reaction was allowed to slowly warm to rt over the following 17 h. The reaction was carefully treated with MeOH (10 mL) followed by aq saturated NH4Cl (50 mL) and EtOAc (50 mL). The solution was transferred to a separatory funnel and the organic layer was isolated while the aqueous layer was back extracted with EtOAc (4×20 mL). The combined organic layers were collected, dried (MgSO4), filtered, and concentrated to dryness. The crude material was then purified by flash chromatography (85:15 v/v CH2Cl2-MeOH). The purified fractions were concentrated in vacuo and then dried under vacuum to afford 422 mg of the above compound (2.37 mmol, yield 56%). 1H-NMR (DMSO-d6) δ 7.72 (s, 1H), 7.59 (br s, 2H), 7.45 (dd, J=0.5 Hz, 1.7 Hz, 1H), 6.76 (dd, J=0.5 Hz, 1.7 Hz, 1H), 5.03 (d, J=4.7 Hz, 1H), 4.79 (m, 1H), 1.38 (d, J=6.5 Hz, 3H); MS [M+H]+=179.3; LCMS RT=1.04 min.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([O:18][C:19]3[C:20]([CH3:29])=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[OH:30].C(=O)([O-])[O-].[K+].[K+].[CH2:37]([CH:39]1[O:41][CH2:40]1)Br>O>[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([O:18][C:19]3[C:20]([CH3:29])=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:30][CH2:37][CH:39]1[CH2:40][O:41]1
Reactant: COc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1OCC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.7 %

Procedure:
N,N-Dimethylformamide (6 ml) was added to 7-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-6-ol (189 mg), potassium carbonate (236 mg), and epibromohydrin (234 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give 7-methoxy-4-(2-methyl-quinolin-3-yloxy)-6-oxiranylmethoxy-quinoline (59 mg, yield 27%).
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)([OH:17])[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[C:28](OC(=O)C)(=[O:30])[CH3:29]>CN(C=O)C>[CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]([O:17][C:28](=[O:30])[CH3:29])([CH3:16])[C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cccnc2)CCN(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OC(C)(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1cccnc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 4.9 %

Procedure:
1-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyridin-3-yl-propan-2-ol (2.0 g, 5.97 mmol) was dissolved in DMF (20 ml), sodium hydride (716 mg, 17.9 mmol) was added and the mixture stirred at RT for 20 min. Acetic anhydride (913 mg, 8.95 mmol) was added dropwise at the same temperature and stirring continued for 1.5 h. The reaction was monitored by TLC and LCMS. The reaction mixture was poured into 250 mL ice water and extracted with EtOAc (3×200 mL), washed with water (3×300 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product that was purified by column chromatography (silica gel: 100-200 mesh, eluent:−6-8% MeOH in DCM) to obtain 110 mg of acetic acid 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-methyl-1-pyridin-3-yl-ethyl ester, which was followed by chiral separation. 1H NMR (CD3OD, Free base) δ (ppm): 8.38 (d, 1H), 8.15 (s, 1H), 7.45 (d, 1H), 7.22 (t, 1H), 7.1 (s, 1H), 7.0 (s, 1H), 6.8 (d, 1H), 4.43 (d, 1H), 4.2 (d, 1H), 3.7 (d, 1H), 3.5 (d, 1H), 2.8 (m, 2H), 2.53 (m, 1H), 2.5 (s, 3H), 2.4 (s, 3H), 2.2 (m, 1H), 2.07 (d, 6H). Separation by chiral HPLC provided enantiomers II-15a-b.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([CH:14]=1)[CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C(O)C.O.NN>C1COCC1.[Ni]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:15])=[C:6]([CH2:7][N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:14]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1CN1CCOCC1
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Nc1ccc(F)cc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
To a solution of 4-(5-fluoro-2-nitrobenzyl)morpholine (240 mg; 1.0 mmol) in THF:ethanol mixture (1:1) (40 mL) was added a catalytical amount of Raney-Nickel and hydrazine hydrate (6.0 mmol). The mixture was stirred for 30 minutes at ambient temperature, then filtered through a Celite pad and the filtrate was evaporated to provide the title compound (208 mg, 99%), which was used in further reactions without purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[C:23]([CH2:27][C:28](Cl)=[O:29])([CH3:26])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:28](=[O:29])[CH2:27][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC(=O)NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 18 h
Yield: 33.7 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and t-butylacetyl chloride (0.40 g, 3.00 mmol) in CH2Cl2 (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. After 18 h, solution was washed with dil. aq. HCl (2×50 mL), water (2×50 mL), dried (MgSO4) and then concentrated. The crude product was purified by column chromatography (0-5% MeOH CH2Cl2). The product fractions were combined, concentrated and triturated in EtOAc for 18 h. The product was dried in vacuo to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3,3-dimethyl-butyramide as a white solid (0.39 g, 34% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.13 min (95.97%); mp: 232-234° C.; 1H NMR (DMSO-d6) δ 0.97 (s, 9H, CH3, CH3, CH3), 1.97-2.17 (m, 3H, CHH, CH2), 2.53-2.69 (m, 2H, CHH, CHH), 2.77-3.01 (m, 1H, CHH), 4.43 (d, J=5.9 Hz, 2H, CH2), 5.14 (dd, J=5.4, 12.7 Hz, 1H, CH), 7.71-7.83 (m, 2H, Ar), 7.89 (d, J=7.6 Hz, 1H, Ar), 8.46 (t, J=5.9 Hz, 1H, NH), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 29.68, 30.52, 30.93, 41.87, 48.66, 48.99, 121.91, 123.45, 129.69, 131.57, 133.41, 147.87, 166.97, 167.10, 169.83, 171.11, 172.73; LCMS: MH=386; Anal Calcd for C20H23N3O5: C, 62.33; H, 6.02; N, 10.90. Found: C, 61.96; H, 5.95; N, 10.75.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[CH3:12]/[C:13](/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:14]\[C:15](O)=[O:16]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:15](=[O:16])/[CH:14]=[C:13](\[CH3:12])/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:4]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: C/C(=C\C(=O)O)c1ccccc1
Agent: Cl
Product: C/C(=C\C(=O)N[C@H]1CN2CCC1CC2)c1ccccc1

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-methyl-3-phenylpropenoic acid, giving a light tan solid; MS (ES+) 271 (MH+).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[NH2:15])[CH2:5][C@H:6]1[CH2:10][O:9][C:8](=[O:11])[NH:7]1.C([Si](CC)(CC)[CH:19]([OH:30])[CH2:20][C:21]#[C:22][Si](CC)(CC)CC)C.C(NC[C@@H]1CCN(CCC2C3C(=CC=C(CS(N)(=O)=O)C=3)NC=2)C1)C1C=CC=CC=1>CS(C)=O>[O:11]=[C:8]1[NH:7][C@@H:6]([CH2:5][C:4]2[CH:3]=[C:2]3[C:14](=[CH:13][CH:12]=2)[NH:15][CH:22]=[C:21]3[CH2:20][CH2:19][OH:30])[CH2:10][O:9]1
Reactant: CC[Si](C#CCC(O)[Si](CC)(CC)CC)(CC)CC
Reactant: Nc1ccc(C[C@H]2COC(=O)N2)cc1I
Agent: NS(=O)(=O)Cc1ccc2[nH]cc(CCN3CC[C@@H](CNCc4ccccc4)C3)c2c1
Solvent: CS(C)=O
Product: O=C1N[C@@H](Cc2ccc3[nH]cc(CCO)c3c2)CO1

Procedure:
Prepared from (S)-4-(3-iodo-4-aminobenzyl)-1,3-oxazolidin-2-one and 1,4-bis-triethylsilyl-3-butyn-1-ol as described for Intermediate 2, δ (360 MHz, D6 -DMSO) 2.74-2.91 (4H, m, 2 of CH2), 3.64 (2H, t, J=7.3Hz, CH2), 4.00-4.08 (2H, m, CH2), 4.20-4.26 (1H, m, CH), 6.92 (1H, dd, J=1.4 and 8.2Hz. Ar--H), 7.10 (1H, s, Ar--H), 7.25 (1H, d, J=8.2Hz, Ar--H), 7.36(1H, s, Ar--H), 7.75 (1H, s, NH), 10.69 (1H, s. NH).
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][CH2:18]/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][C:24]([O:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:23][CH:22]=2)=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Li+]>CO.C1COCC1.O>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][CH2:18]/[CH:19]=[CH:20]/[C:21]2[CH:22]=[CH:23][C:24]([O:27][S:28]([CH3:31])(=[O:29])=[O:30])=[CH:25][CH:26]=2)=[CH:15][CH:16]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(NC/C=C/c2ccc(OS(C)(=O)=O)cc2)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCO[C@@H](Cc1ccc(NC/C=C/c2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)O

Procedure:
The title compound was synthesized by hydrolyzing ethyl 2-ethoxy-3-{4-[(E)-3-(4-methylsulfonyloxyphenyl)-2-propenylamino]-phenyl}propionate obtained in Example 12 (4 g, 8.95 mmol) in methanol-THF-water (45:4:9, 58 mL) using lithium hydroxide (563 mg, 13.42 mmol) following the same procedure as described in the Example 14 (1.2 g, 32%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[NH:16][CH2:15][C:14]([CH3:18])([CH3:17])[S:13]1.[CH3:19][C:20](=[CH2:23])[CH2:21][Br:22]>>[BrH:22].[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:16]([CH2:21][C:20]([CH3:23])=[CH2:19])[CH2:15][C:14]([CH3:18])([CH3:17])[S:13]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NCC(C)(C)S1
Reactant: C=C(C)CBr
Product: Br
Product: C=C(C)CN1CC(C)(C)SC1=Nc1ccc([N+](=O)[O-])cc1C

Procedure:
2-Methyl-2-hydroxypropylamine was reacted with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to afford 2-(2-methyl-4-nitrophenylimino)-5,5-dimethyl-1,3-thiazolidine. The thiazolidine was reacted with 2-methylprop-2-en-1-yl bromide according to Method D2g to afford 2-(2-methyl-4-nitrophenylimino)-3-(2-methylprop-2-en-1-yl)-5,5-dimethyl-1,3-thiazolidine HBr salt.