Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:24]2[N:28]([CH:29]([CH3:31])[CH3:30])[C:27]([CH3:32])=[N:26][CH:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][CH2:18][C@H:17]([NH:20]C(=O)C)[CH2:16]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1>C(O)(C)C.O.Cl>[NH2:20][C@H:17]1[CH2:18][CH2:19][N:15]([C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:5]3[N:4]=[C:3]([C:24]4[N:28]([CH:29]([CH3:30])[CH3:31])[C:27]([CH3:32])=[N:26][CH:25]=4)[C:2]([F:1])=[CH:7][N:6]=3)=[CH:14][CH:13]=2)[CH2:16]1
Reactant: CC(=O)N[C@H]1CCN(c2ccc(Nc3ncc(F)c(-c4cnc(C)n4C(C)C)n3)cc2)C1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: Cc1ncc(-c2nc(Nc3ccc(N4CC[C@H](N)C4)cc3)ncc2F)n1C(C)C
Yield: 94.8 %

Procedure:
N-[(3S)-1-(4-{[5-Fluoro-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidin-2-yl]amino}phenyl)pyrrolidin-3-yl]acetamide (Example 152; 0.49 g, 1.12 mmol) in isopropanol (20 ml), water (5 ml) and hydrochloric acid (2 ml) was heated at reflux under nitrogen for 18 hours. After evaporation under reduced pressure, the mixture was dissolved in water (15 ml) and adjusted to pH 9 with aqueous ammonium hydroxide solution. The solution was extracted with DCM (3×15 ml), dried and after evaporation under reduced pressure to give the title compound as a solid (0.42 g, 95%). NMR: 1.38 (d, 6H), 1.61-1.73 (m, 1H), 2.00-2.13 (m, 1H), 2.44 (s, 3H), 2.80-2.88 (m, 1H), 3.12-3.20 (m, 1H), 3.20-3.42 (m, 2H), 3.49-3.60 (m, 1H), 5.40-5.51 (m, 1H), 6.46 (d, 2H), 7.30 (d, 2H), 7.33 (s, 1H), 8.40 (s, 1H), 9.00 (s, 1H); m/z 396.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH2:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[C:23]([F:24])=[C:22]([F:25])[CH:21]=[CH:20][C:12]=1[C:13]([NH:15][O:16][CH2:17][CH2:18][OH:19])=[O:14]>O1CCCC1.[Pd].CO>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[C:23]([F:24])=[C:22]([F:25])[CH:21]=[CH:20][C:12]=1[C:13]([NH:15][O:16][CH2:17][CH2:18][OH:19])=[O:14]
Reactant: C=Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(Cl)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(Cl)c1
Reaction time: 6 h
Yield: 75.9 %

Procedure:
A solution of the product of Example 2, Step D, 2-(2-chloro-4-vinyl-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide (0.291 g, 0.789 mmol) in tetrahydrofuran (16 mL) was hydrogenated over 10% palladium on carbon (0.08 g) at 6900 psig at room temperature for 17 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to afford a crystalline solid. The solid was dissolved in methanol and concentrated to near dryness. Ether (10 mL) was added and the mixture was allowed to stand at ambient temperature for 6 hours. during which crystallization ensued. The white crystals were filtered, washed with a small volume of ether, and dried in vacuo at 60° C. overnight yielding 2-(2-chloro-4-ethyl-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide (222 mg): m.p. 142.5-145° C.; 1H NMR (400 MHz, DMSO-d6) δ 11.94 (br s, 1 H), 8.85 (br s, 1 H), 7.44 (br t, J=6.4 Hz, 1 H), 7.30 (d, J=2.0 Hz, 1 H), 7.22-7.15 (m, 1 H), 7.05 (dd, J=8.3, 2.0 Hz, 1 H), 6.75 (dd, J=8.3, 6.3 Hz, 1 H), 4.71 (br s, 1 H), 3.89 (br s, 2 H), 3.59 (br s, 2 H), 2.54 (q, J=7.6 Hz, 2 H), 1.15 (t, J=7.6 Hz, 3H); 19F NMR (376 MHz, DMSO-d6) δ −132.7, −142.0; MS (APCI+)=371.0. Anal. Calcd/found for C17H17ClF2N2O3: C, 55.07/55.14; H, 4.62/4.51; N, 7.56/7.38; F, 10.25/9.98.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:21]=[C:22]=[S:23])[CH2:9][N:10]([CH3:20])[C:11](=[O:19])[O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:24]#[C:25][NH2:26].[Na]>C(O)C.[NH4+].[Cl-].O>[C:25]([NH:26][C:22]([NH:21][C@@H:8]([CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH2:9][N:10]([CH3:20])[C:11]([O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:16])[CH3:18])=[O:19])=[S:23])#[N:24]
Reactant: N#CN
Reactant: CN(C[C@H](CC1CCCCC1)N=C=S)C(=O)OCC[Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CN(C[C@H](CC1CCCCC1)NC(=S)NC#N)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 108.9 %

Procedure:
To a stirred solution of (2-(trimethylsilyl)ethyl) (S)-3-cyclohexyl-2-isothiocyanatopropyl-methylcarbamate (190 mg, 0.53 mmol) in ethanol (5 mL) was added solid sodium hydrogen cyanamide (38 mg, 0.59 mmol). The mixture was stirred at rt for 2 d, diluted with 1:1 sat'd aq NH4Cl/H2O (40 mL) and extracted with ether (2×60 mL). The combined ether extracts were dried over MgSO4 and rotovaped to leave 1-cyano-3-((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)thiourea (230 mg, quant) as a white solid.
Reaction SMILES: [CH:1]1([S:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[CH:15][C:16]([N:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22](C(O)=O)[CH2:21][CH2:20]4)=[N:17][CH:18]=3)[CH2:9][CH2:8]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.ClCCl>[CH:1]1([S:4]([N:7]2[CH2:8][CH2:9][N:10]([C:13]3[CH:14]=[CH:15][C:16]([N:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[NH:22][CH2:21][CH2:20]4)=[N:17][CH:18]=3)[CH2:11][CH2:12]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(O)N1CCN(c2ccc(N3CCN(S(=O)(=O)C4CC4)CC3)cn2)c2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=S(=O)(C1CC1)N1CCN(c2ccc(N3CCNc4ccccc43)nc2)CC1
Reaction time: 5 h

Procedure:
6.14 g of tert-butyl ester of 4-[5-(4-cyclopropanesulfonyl-piperazin-1-yl)pyridin-2-yl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid is put in a 1-liter three-necked flask under nitrogen atmosphere. 102 ml of dichloromethane is added, it is cooled in an ice bath and 92 ml of a 4M solution of hydrochloric acid in dioxane is added dropwise. The temperature of the reaction mixture is allowed to return slowly to room temperature and then it is stirred for 5 h. The reaction mixture is diluted with dichloromethane, then cooled in an ice bath. Then a saturated solution of NaHCO3 is added to pH=8. It is decanted and the aqueous phase is extracted with dichloromethane. The water-based organic phases are washed, dried over Na2SO4, filtered on a frit and concentrated. 4.92 g of 1-[5-(4-cyclopropanesulfonyl-piperazin-1-yl)pyridin-2-yl]-1,2,3,4-tetrahydroquinoxaline is obtained in the form of a white solid.
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Cl[C:36]1[C:45]2[C:40](=[CH:41][C:42]([F:46])=[CH:43][CH:44]=2)[N:39]=[C:38]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=2)[C:37]=1[CH3:53].[NH2:54][C:55]1[CH:56]=[C:57]([NH:67][C:68](=[O:70])[CH3:69])[CH:58]=[C:59]([N:61]2[CH2:66][CH2:65][O:64][CH2:63][CH2:62]2)[CH:60]=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(C)(C)C>[F:46][C:42]1[CH:41]=[C:40]2[C:45]([C:36]([NH:54][C:55]3[CH:56]=[C:57]([NH:67][C:68](=[O:70])[CH3:69])[CH:58]=[C:59]([N:61]4[CH2:66][CH2:65][O:64][CH2:63][CH2:62]4)[CH:60]=3)=[C:37]([CH3:53])[C:38]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=3)=[N:39]2)=[CH:44][CH:43]=1
Reactant: CC(=O)Nc1cc(N)cc(N2CCOCC2)c1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CC(C)(C)O
Product: CC(=O)Nc1cc(Nc2c(C)c(-c3ccccn3)nc3cc(F)ccc23)cc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure X using palladium (II) acetate (2.1 mg, 9.17 μmol), XPhos (0.013 g, 0.028 mmol), 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (0.050 g, 0.183 mmol), N-(3-amino-5-morpholinophenyl)acetamide (0.043 g, 0.183 mmol), potassium carbonate (0.063 g, 0.458 mmol), and tert-butanol (0.5 mL). Purification by column chromatography (silica; 0-5% methanol in DCM) afforded N-(3-((7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)amino)-5-(4-morpholinyl)phenyl)acetamide as a yellow amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.59 (1H, s), 8.68-8.71 (1H, m), 8.43 (1H, s), 8.08 (1H, dd, J=9.3, 6.2 Hz), 7.98 (1H, dd, J=7.7, 1.9 Hz), 7.83-7.87 (1H, m), 7.68-7.76 (1H, m), 7.44-7.51 (2H, m), 6.80-6.83 (1H, m), 6.34-6.36 (1H, m), 6.11 (1H, t, J=2.1 Hz), 5.76 (1H, s), 3.67-3.73 (4H, m), 2.96-3.01 (4H, m), 2.20 (3H, s), 1.93 (3H, s). Mass Spectrum (ESI) m/e=472.1 (M+1).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8](O)=[O:9])[CH:2]=1.Cl.[CH3:13][NH:14][O:15][CH3:16].Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C>ClCCl>[CH3:16][O:15][N:14]([CH3:13])[C:8](=[O:9])[CH2:7][C:3]1[CH:2]=[C:1]([CH3:11])[CH:6]=[CH:5][CH:4]=1
Reactant: CNOC
Reactant: Cc1cccc(CC(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)Cc1cccc(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
A mixture of 2-m-tolylacetic acid (1 g, 6.7 mmol), N,O-dimethylhydroxylamine hydrochloride (654 mg, 6.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.28 g, 6.7 mmol), hydroxybenzotriazole (910 mg, 6.7 mmol) and triethylamine (3.38 g, 33.5 mmol) in dichloromethane (30 mL) was stirred at room temperature overnight. When TLC indicated that 2-m-tolylacetic acid was consumed, the reaction mixture was diluted with water (30 mL), and extracted with EtOAc (30 mL×3). The combined organic layer was dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (PE: EtOAc=10:1) to afford N-methoxy-N-methyl-2-m-tolylacetamide (900 mg, yield 70%).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([CH3:19])[CH2:5][NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:8].[OH-].[Li+]>CO>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][O:9][C:7]([NH:6][CH2:5][CH:4]([CH3:19])[C:3]([OH:20])=[O:2])=[O:8])=[CH:16][CH:15]=1
Reactant: COC(=O)C(C)CNC(=O)OCc1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(COC(=O)NCC(C)C(=O)O)cc1
Yield: 97.3 %

Procedure:
A solution of N-4-methoxybenzyloxycarbonyl α-methyl β-alanine methyl ester (2.61 g, 10.0 mmol) in 30 mL of 25% aqueous methanol was treated with lithium hydroxide (1.3 equivalents) at room temperature for a period of 2 h. The solution was concentrated in vacuo and the residue taken up in a mixture of water and ether and the phases separated and the organic phase discarded. The aqueous phase was acidified with aqueous potassium hydrogen sulfate to pH=1.5 and then extracted three times with ether. The combined ethereal phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 2.60 g, 97% of N-4-Methoxybenzyloxycarbonyl α-methyl β-alanine (N-Moz-AMBA) which was purified by recrystallization from a mixture of ethyl acetate and hexane to give 2.44 g, 91% of pure product, mp 96°-97° C., MH+=268. 1H NMR (D6-acetone/300 MHz) 1.16 (3H, d, J=7.2Hz), 2.70 (1H, m), 3.31 (2H, m), 3.31 (3H, s), 4.99 (2H, s), 6.92 (2H, 4, J=8.7 Hz), 7.13 (2H, d, J=8.7 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([NH:10][C:11]([C:13]2([NH:19][C:20]([C:22]3[N:26]4[C@@:27]([CH2:40][C:41]5[CH:46]=[CH:45][C:44]([C:47]#[N:48])=[CH:43][CH:42]=5)([CH3:39])[C:28](=[O:38])[N:29]([C:30]5[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[CH:31]=5)[C:25]4=[N:24][CH:23]=3)=[O:21])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])[CH2:9][CH2:8]1.[C:49](OC(=O)C)(=[O:51])[CH3:50]>N1C=CC=CC=1>[C:49]([N:16]1[CH2:17][CH2:18][C:13]([NH:19][C:20]([C:22]2[N:26]3[C@@:27]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([C:47]#[N:48])=[CH:43][CH:42]=4)([CH3:39])[C:28](=[O:38])[N:29]([C:30]4[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[CH:31]=4)[C:25]3=[N:24][CH:23]=2)=[O:21])([C:11](=[O:12])[NH:10][C:7]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:9][CH2:8]2)[CH2:14][CH2:15]1)(=[O:51])[CH3:50]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(c5ccccn5)CC4)CCNCC3)n21
Solvent: c1ccncc1
Product: CC(=O)N1CCC(NC(=O)c2cnc3n2[C@](C)(Cc2ccc(C#N)cc2)C(=O)N3c2cc(Cl)cc(Cl)c2)(C(=O)NC2(c3ccccn3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-5-(4-cyanobenzyl)-7-(3,5-dichlorophenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid [4-(1-pyridin-2-yl-cyclopropylcarbamoyl)-piperidin-4-yl]-amide (20 mg, 0.03 mmol) in pyridine (0.5 mL) was added acetic anhydride (0.5 mL). The reaction mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo and the remaining residue was dissolved in water and extracted with CH2Cl2 (3×10 mL). The organic layer was washed with brine and dried over Na2SO4. After removal of the solvent in vacuo, the title compound was obtained as a white solid (21 mg), m/z 725.5 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][S:32]([CH2:35][CH:36]([CH3:38])[CH3:37])(=[O:34])=[O:33]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[NH:31][S:32]([CH2:35][CH:36]([CH3:38])[CH3:37])(=[O:34])=[O:33])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: CC(C)CS(=O)(=O)Nc1ccccc1Br
Product: CC(C)CS(=O)(=O)Nc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 34 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and N-(2-bromophenyl)isobutylsulfonamide. MS (ESI): mass calcd. for C20H21FN4O2S, 400.14; m/z found, 401.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.38 (s, 1H), 8.14 (s, 1H), 7.96 (m, 1H), 7.49 (d, J=7.0, 1H), 7.45-7.30 (m, 5H), 2.77 (d, J=6.5, 2H), 2.15-2.02 (m, 1H), 0.97 (d, J=6.7, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=2)[NH2:10])=[CH:3][CH:2]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][S:24][CH2:25][C:26](O)=[O:27])=[C:17]([C:30]([O:32]C)=[O:31])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][S:24][CH2:25][C:26](=[O:27])[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH:8]=2)=[C:17]([CH:16]=1)[C:30]([OH:32])=[O:31]
Reactant: Nc1cccc(-c2ccncc2)c1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)CSCC(=O)O
Product: O=C(CSCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-c2ccncc2)c1

Procedure:
Using the same method as in Example 1-(ii), 3-(pyridin-4-yl)aniline was reacted with the [(2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethyl)sulfanyl]acetic acid obtained in Example 12-(i) to give 5-chloro-2-(([(2-oxo-2-([3-(pyridin-4-yl)phenyl]amino)ethyl)sulfanyl]acetyl)amino)benzoic acid.methyl ester (yield: 74%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[CH3:11])[NH2:7])([O-:3])=[O:2].C([Al](CC(C)C)CC(C)C)C(C)C.C[O:26][C:27](=O)[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[CH3:11][C:10]1[CH:9]=[CH:8][C:6]([NH:7][C:27](=[O:26])[C:28]2[CH:29]=[CH:30][C:31]([CH2:34][N:35]3[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]3)=[CH:32][CH:33]=2)=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: COC(=O)c1ccc(CN2CCN(C)CC2)cc1
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Agent: CC(C)C[Al](CC(C)C)CC(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1[N+](=O)[O-]
Reaction time: 6 h

Procedure:
To a solution of 10.95 g (72 mmol) of 3-nitro-4-methyl-aniline in 80 ml of toluene is added a solution of triisobutylaluminium (28% in hexane), 66.5 ml (61 mmol) over a period of 30 min at 0° C. followed by the addition of a solution of, 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid methyl ester (14.9 g, 60 mmol) in toluene (30 ml) during 1 hour at 0° C. under an atmosphere of argon. After stirring for 12 h at room temperature an other portion of triisobutylaluminium (66.5 ml (61 mmol) is added to the dark brown reaction mixture. The mixture is stirred for additional 6 h, then 2 additional small portions of triisobutylaluminium (each 18 ml, 18 mmol) are added and stirring is continued for several hours at room temperature. After acidic and basic workup with sulfuric acid and NaOH the combined organic toluene phases are evaporated in vacuo to give a brown crude product which was crystallized from t-butyl methyl ether to give the title compound as brownish yellow crystals: first crop (11.65 g), sec. crop (3.8 g) and a third crop (1.2 g). in summary 16.65 g (75.3%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]([CH:10]=[O:11])=[C:8]([CH2:12][CH3:13])[N:7]=[C:6]1[CH2:14][CH2:15][CH3:16].[CH3:22][Mg]Br>C1COCC1.[O-2].[Mn+4].[O-2]>[F:1][C:2]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]([C:10](=[O:11])[CH3:22])=[C:8]([CH2:12][CH3:13])[N:7]=[C:6]1[CH2:14][CH2:15][CH3:16]
Reactant: C[Mg]Br
Reactant: CCCc1nc(CC)c(C=O)n1Cc1ccc(I)cc1F
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: CCCc1nc(CC)c(C(C)=O)n1Cc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 27.5 %

Procedure:
To a solution of 1-(2-fluoro-4-iodobenzyl)-4-ethyl-2-propyl-1H-imidazole-5-carboxaldehyde (16.52 g, 41.3 mmol) in THF (100 mL) was added methylmagnesium bromide (44.0 mL of 1.4/M in toluene/THF, 61.6 mmol) over 30 minutes. The reaction mixture was stirred at room temperature for 1.5 h. It was then quenched with 100 mL of 1N aqueous HCl. The mixture was extracted with CH2Cl2, the organic solution was washed with H2O and brine, dried over MgSO4, and concentrated to a yellow oil (16.87 g). The yellow oil was dissolved in 400 mL of CH2Cl2, and Manganese(IV) oxide (70.50 g, 811 mmol) was added. The mixture was refluxed under N2 overnight. The mixture was cooled. It was then filtered through celite and washed with CH2Cl2. The CH2Cl2 solution was concentrated and chromatographed on silica gel with 50% EtOAc/hexane and 10% MeOH/CH2Cl2 to give 4.70 g of the desired product and 6.87 g of the alcohol. MS m/e 415.0, [M+H]+ ; 1H NMR (300 MHz, CDCl3): δ 0.98 (t, 3H, CH3), 1.35 (t, 3H, CH3), 1.68 (m, 2H, CH2), 2.42 (s, 3H, CH3) 2.58 (m, 2H, CH2), 2.92 (q, 2H, CH2), 5.45 (s, 2H, CH2Ar), 6.28 (t, 1H, ArH), 7.35 (d, 1H, ArH), 7.42 (d, 1H, ArH). ##STR63##
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Br.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1([CH:25]2[C:34]3[C:29](=[CH:30][C:31]([F:36])=[C:32]([OH:35])[CH:33]=3)[CH2:28][CH2:27][N:26]2[CH3:37])[CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C.O>ClCCl>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1([CH:25]2[C:34]3[C:29](=[CH:30][C:31]([F:36])=[C:32]([O:35][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:33]=3)[CH2:28][CH2:27][N:26]2[CH3:37])[CH2:24][CH2:23][CH2:22]1
Reactant: CN1CCc2cc(F)c(O)cc2C1C1(c2ccccc2Cl)CCC1
Reactant: CCCCCCCCCC(=O)Cl
Agent: Br
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCC(=O)Oc1cc2c(cc1F)CCN(C)C2C1(c2ccccc2Cl)CCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Decanoyl chloride (0.66 g) in dichloromethane (5 ml) was added to a stirring mixture of (+)-1-[1-(2-chlorophenyl)cyclobutyl]-6-fluoro-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrobromide (1.5 g, prepared in a similar manner to that described in Example 64), triethylamine (1.06 g) and dichloromethane (25 ml). The mixture was stirred at ambient temperature for 20 minutes, then water (20 ml) was added and stirring continued for 1 hour. The organic layer was washed with saturated aqueous sodium bicarbonate solution, water and brine, then dried over magnesium sulphate, filtered and concentrated in vacuo to yield (-)-1-[1-(2-chlorophenyl)cyclobutyl]-7-decanoyloxy-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinoline (1.31 g). This had a specific optical rotation αD of -5.59°.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:9])[C:6]=1[CH:7]=[O:8].[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:3]=[N:4][N:5]([CH3:9])[C:6]=2[CH:7]=[O:8])=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cn1ncc(Br)c1C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1ncc(-c2ccc(Cl)cc2)c1C=O
Temperature: 45 °C
Reaction time: 2.5 h

Procedure:
4-Bromo-1-methyl-1H-pyrazole-5-carbaldehyde (0.500 g), 4-chlorophenylboronic acid (0.455 g), tetrabutylammonium bromide (0.853 g), potassium carbonate (0.914 g) and palladium acetate (0.030 g) were stirred together in 5 mL of water and heated to 45° C. After stirring for 2.5 hours, the reaction was diluted with ethyl acetate (75 mL) and washed with water (25 mL), brine (50 mL), dried over magnesium sulfate, filtered and concentrated to give the crude material. The solid was chromatographed over silica gel (SF40-80) eluted using a gradient of 5% to 25% ethyl acetate/hexanes over 30 minutes.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15][C@H:16]2[O:33][C@H:32]([CH2:34][O:35]C(=O)C)[C@@H:27]([O:28]C(=O)C)[C@H:22]([O:23]C(=O)C)[C@H:17]2[O:18]C(=O)C)[C@@H:8]([CH2:39][O:40]C(=O)C)[O:7][C@H:6]1[S:44][C:45]1[CH:50]=[CH:49][C:48]([NH:51][C:52]([C:54]2[CH:59]=[C:58]([C:60]([NH:62][C:63]3[CH:68]=[CH:67][C:66]([S:69][C@@H:70]4[O:107][C@H:106]([CH2:108][O:109]C(=O)C)[C@@H:81]([O:82][C@H:83]5[O:100][C@H:99]([CH2:101][O:102]C(=O)C)[C@@H:94]([O:95]C(=O)C)[C@H:89]([O:90]C(=O)C)[C@H:84]5[O:85]C(=O)C)[C@H:76]([O:77]C(=O)C)[C@H:71]4[O:72]C(=O)C)=[CH:65][CH:64]=3)=[O:61])[CH:57]=[C:56]([C:113]([NH:115][C:116]3[CH:121]=[CH:120][C:119]([S:122][C@@H:123]4[O:160][C@H:159]([CH2:161][O:162]C(=O)C)[C@@H:134]([O:135][C@H:136]5[O:153][C@H:152]([CH2:154][O:155]C(=O)C)[C@@H:147]([O:148]C(=O)C)[C@H:142]([O:143]C(=O)C)[C@H:137]5[O:138]C(=O)C)[C@H:129]([O:130]C(=O)C)[C@H:124]4[O:125]C(=O)C)=[CH:118][CH:117]=3)=[O:114])[CH:55]=2)=[O:53])=[CH:47][CH:46]=1)(=O)C.N>CO>[C@H:16]1([O:15][C@@H:9]2[C@@H:8]([CH2:39][OH:40])[O:7][C@@H:6]([S:44][C:45]3[CH:50]=[CH:49][C:48]([NH:51][C:52]([C:54]4[CH:59]=[C:58]([C:60]([NH:62][C:63]5[CH:68]=[CH:67][C:66]([S:69][C@@H:70]6[O:107][C@H:106]([CH2:108][OH:109])[C@@H:81]([O:82][C@H:83]7[O:100][C@H:99]([CH2:101][OH:102])[C@@H:94]([OH:95])[C@H:89]([OH:90])[C@H:84]7[OH:85])[C@H:76]([OH:77])[C@H:71]6[OH:72])=[CH:65][CH:64]=5)=[O:61])[CH:57]=[C:56]([C:113]([NH:115][C:116]5[CH:117]=[CH:118][C:119]([S:122][C@@H:123]6[O:160][C@H:159]([CH2:161][OH:162])[C@@H:134]([O:135][C@H:136]7[O:153][C@H:152]([CH2:154][OH:155])[C@@H:147]([OH:148])[C@H:142]([OH:143])[C@H:137]7[OH:138])[C@H:129]([OH:130])[C@H:124]6[OH:125])=[CH:120][CH:121]=5)=[O:114])[CH:55]=4)=[O:53])=[CH:47][CH:46]=3)[C@H:5]([OH:4])[C@H:10]2[OH:11])[O:33][C@H:32]([CH2:34][OH:35])[C@@H:27]([OH:28])[C@H:22]([OH:23])[C@H:17]1[OH:18]
Reactant: CC(=O)OC[C@H]1O[C@@H](Sc2ccc(NC(=O)c3cc(C(=O)Nc4ccc(S[C@@H]5O[C@H](COC(C)=O)[C@@H](O[C@H]6O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]6OC(C)=O)[C@H](OC(C)=O)[C@H]5OC(C)=O)cc4)cc(C(=O)Nc4ccc(S[C@@H]5O[C@H](COC(C)=O)[C@@H](O[C@H]6O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]6OC(C)=O)[C@H](OC(C)=O)[C@H]5OC(C)=O)cc4)c3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1O[C@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: N
Solvent: CO
Product: O=C(Nc1ccc(S[C@@H]2O[C@H](CO)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)cc1)c1cc(C(=O)Nc2ccc(S[C@@H]3O[C@H](CO)[C@@H](O[C@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)[C@H](O)[C@H]3O)cc2)cc(C(=O)Nc2ccc(S[C@@H]3O[C@H](CO)[C@@H](O[C@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)[C@H](O)[C@H]3O)cc2)c1
Reaction time: 6 h
Yield: 86.8 %

Procedure:
A solution of 2.56 g of N,N',N"-tris-[4-[[2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)-β-D-glucopyranosyl]thio]phenyl]-1,3,5-benzenetricarboxamide in 35 ml of methanol saturated with ammonia at 0° C. was allowed to stand at ambient temperature for 6 hours. The solution was clarified by filtration and taken to dryness. The residual material was triturated with absolute ethanol and filtered giving 1.4 g of the desired intermediate as a cream-colored powder.