Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][C@H:16]1[C@@H:20]([CH3:21])[CH2:19][N:18]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:17]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:15][C@H:16]3[C@@H:20]([CH3:21])[CH2:19][N:18]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[CH2:17]3)=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Intermediate 2 (1000 mg, 3.64 mmol), (+/−)-(cis)-benzyl 3-amino-4-methylpyrrolidine-1-carboxylate (Intermediate 5, 1024 mg, 4.37 mmol) and DIPEA (1.27 mL, 7.29 mmol) in DMA (4.0 mL) was heated at 90° C. for 5 h then was allowed to cool to rt and stir overnight. The reaction mixture was added to crushed ice, stirred for 30 min, and the resulting solid that had precipitated was collected by vacuum filtration and was rinsed with water and dried to afford the title compound as a cream colored solid. HPLC (method B) retention time=3.67 min. LCMS (m+1)=472/474 (1:1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH2:9][CH2:8]2)(=[O:4])=[O:3].[Cl:14][C:15]1[N:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:14][C:15]1[N:20]=[CH:19][N:18]=[C:17]([N:10]2[C:11]3[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=3)[CH2:8][CH2:9]2)[N:16]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc2c(c1)CCN2c1ncnc(Cl)n1
Temperature: 100 °C
Yield: 83.7 %

Procedure:
5-Methanesulfonyl-2,3-dihydro-1H-indole (79 mg, 0.4 mmol) was dissolved in dioxane (2 mL). 2,4-Dichloro-[1,3,5]-triazine (60 mg, 1 eq), palladium acetate (11 mg, 5% molar), (+/−)binap (15 mg, 8% molar) and cesium carbonate (131 mg, 1 eq) were added and the reaction mixture was heated at 100° C. for 4 h. The mixture was cooled to room temperature and water was added. The mixture was filtered through celite and washed three times with dioxane. The collected filtrate was evaporated to dryness to give 11a (104 mg) which was used for the next step without further purification.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].O1[CH2:14][CH2:13][O:12][CH2:11]C1.CO[C:17]1[CH:22]=[CH:21][C:20](Cl)=[CH:19][CH:18]=1.O>F[B-](F)(F)F.C1(P(C2CCCCC2)C2C(OC)=CC(OC)=CC=2OC)CCCCC1.C(Cl)Cl>[CH3:11][O:12][C:13]1[CH:14]=[CH:19][C:18]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:17][CH:22]=1
Reactant: COc1ccc(Cl)cc1
Reactant: C1COCCO1
Agent: COc1cc(OC)c(P(C2CCCCC2)C2CCCCC2)c(OC)c1
Agent: F[B-](F)(F)F
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90 %

Procedure:
To a rubber-capped Schlenk vessel was added K3PO4 (298.4 mg, 1.4 mmol). This equipment was dried with flame under vacuum and backfilled with nitrogen for three times. Then Pd(OAc) (2.7 mg, 0.012 mmol), dicyclohexyl(2,4,6-trimethoxyphenyl)phosphine tetrafluoroborate (11.0 mg, 0.024 mmol), phenyl bronic acid (99.8 mg, 98%, 0.80 mmol), and 0.5 mL of dioxane were added sequentially to the Schlenk vessel. After being stirred for about 5 min at room temperature, p-methoxyphenyl chloride (56.5 mg, 0.40 mmol), another 0.5 mL of dioxane, and 21.5 μL of water (21.5 mg, 1.2 mmol) were added sequentially in one portion. The resulting mixture was heated at 110° C. with a preheated oil bath. After 11 h, the reaction was complete as monitored by GC. The reaction mixture was then cooled and diluted by 10 mL of CH2Cl2 and filtered through a short column of silica gel (eluent: 2×10 mL of CH2Cl2). Evaporation and purification by chromatography (petroleum ether/ether=60/1) on silica gel afforded 4-Methoxybiphenyl (65.9 mg, 90%)
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[Na+].[CH3:7][N:8]([C:10]([N:13]([CH3:15])[CH3:14])(Cl)[Cl:11])[CH3:9]>O>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:7][N:8]([C+:10]([N:13]([CH3:15])[CH3:14])[Cl:11])[CH3:9]
Reactant: CN(C)C(Cl)(Cl)N(C)C
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Product: CN(C)[C+](Cl)N(C)C
Reaction time: 1 h

Procedure:
3.60 g of sodium perchlorate in 10 ml of water are added with stirring to a solution of 5.00 g (29.2 mmol) of bis(dimethylamino)dichloromethane in 20 ml of water. The reaction mixture is subsequently stirred for 1 hour with ice-cooling. The residue is filtered off and washed with 10 ml of ice-water and subsequently dried at 50° C. under reduced pressure (7.0 Pa), giving 6.64 g of bis(dimethylamino)chlorocarbenium perchlorate, corresponding to a yield of 94.0%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1.[Br:18][CH2:19][CH2:20][CH2:21]Br>>[Br:18][CH2:19][CH2:20][CH2:21][O:17][C:14]1[CH:15]=[CH:16][C:9]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:12][S:11][C:10]=2[CH:13]=1
Reactant: BrCCCBr
Reactant: Oc1ccc2c(-c3ccc(F)cc3)csc2c1
Product: Fc1ccc(-c2csc3cc(OCCCBr)ccc23)cc1

Procedure:
In analogy to example 27.1, 3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-ol and 1,3-dibromopropane were converted to yield 6-(3-Bromo-propoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene, MS: 364 (M, 1Br).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O: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][O:24][CH2:25][C:26]([NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:7]([CH2:6][C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[CH:8]=2)=[O:27])=[C:17]([CH:16]=1)[C:30]([OH:32])=[O:31]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Reactant: Nc1cccc(Cc2ccco2)c1
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(Cc2ccco2)c1

Procedure:
Using the same method as in Example 15-(i), 3-(furan-2-ylmethyl)aniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-([3-(furan-2-ylmethyl)phenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 54%).
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]([C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])[C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[NH:23]1[C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2B(O)O)=[N:26][N:25]=[N:24]1.C[O-].[Na+]>CO.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:19][CH2:18][CH2:17][CH2:16][C:15]([N:7]([C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[NH:23][N:24]=[N:25][N:26]=2)=[CH:22][CH:21]=1)=[O:20]
Reactant: OB(O)c1ccccc1-c1nnn[nH]1
Reactant: CCCCC(=O)N(Cc1ccc(Br)cc1)[C@H](C(=O)O)C(C)C
Agent: Cl[Pd]Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)O)C(C)C
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 55.6 %

Procedure:
Nitrogen is bubbled for 5 min. To a mixture made up of 0.50 g (1.35 mmol) of N-(4-bromobenzyl)-N-valeryl-L-valine, 0.308 g (1.52 mmol) of 2-(1H-tetrazol-5-yl)phenylboronic acid, 0.0028 g (0.016 mmol) of palladium chloride and 0.0084 g (0.032 mmol) of triphenylphosphine in a solution of 2.06 mL (13.0 mmol) of sodium methoxide in methanol al 30% and 5 mL of methanol are added. It is heated at 70° C. under nitrogen atmosphere for 5 h, 0.050 g of activated carbon is added and it is stirred at the same temperature for a further 15 min. After cooling to 20-25° C. it is filtered, the methanol is evaporated and it is treated with 25 mL of HCl 1N and 25 mL of AcOEt. The AcOEt phase is dried with anhydrous sodium sulphate and after distilling the solvent the crude product obtained is purified by silica gel chromatography (eluent AcOEt/heptane/AcOH 15:5:0.2) to provide 0.327 g (55.6%) of Valsartan.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH:52]([C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)[CH3:53])[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[N:68]1([C:74]2[CH:81]=[CH:80][C:77]([CH:78]=O)=[CH:76][CH:75]=2)[CH2:73][CH2:72][O:71][CH2:70][CH2:69]1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH:52]([C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)[CH3:53])[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:78]([C:77]3[CH:76]=[CH:75][C:74]([N:68]4[CH2:73][CH2:72][O:71][CH2:70][CH2:69]4)=[CH:81][CH:80]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: CC(c1ccncc1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(c1ccncc1)N1CCN(c2c(Br)cnc3[nH]c(-c4ccc(N5CCOCC5)cc4)nc23)CC1
Reaction time: 6 h
Yield: 26 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(1-(pyridin-4-yl)ethyl)piperazin-1-yl)pyridin-2-amine (20 mg, 0.049 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.15 mmol, 0.15 mL) and 4-morpholin-4-yl-benzaldehyde (1.1 eq, 0.054 mmol, 10 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (7 mg, 27%) as an off-white solid; δH (500 MHz, DMSO-d6) 1.36 (d, J=6.4 Hz, 3H, CH3), 2.36 (s, br, 2H, piperazine NCH2), 2.63 (s, br, 2H, piperazine NCH2), 3.30 (hidden by DMSO peak, 4H, morpholine N(CH2)2), 3.58-3.60 (m, 1H, CHCH3), 3.64 (s, br, 4H, piperazine N(CH2)2), 3.76 (t, J=4.6 Hz, 4H, morpholine O(CH2)2), 7.07 (d, J=8.9 Hz, 2H, phenyl H-3 & H-5), 7.39 (d, br, J=6.2 Hz, 2H, pyridine H-3 & H-5), 8.04 (d, J=8.9 Hz, 2H, phenyl H-2 & H-6), 8.16 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.55 (d, br, J=6.0 Hz, 2H, pyridine H-2 & H-6), 13.22 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](Br)[N:16]=2)[N:11]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:10]=1)=[O:8])[CH3:5].I[C:28]1[N:32]2[CH:33]=[CH:34][C:35]([C:37]#[N:38])=[CH:36][C:31]2=[N:30][CH:29]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:28]3[N:32]4[CH:33]=[CH:34][C:35]([C:37]#[N:38])=[CH:36][C:31]4=[N:30][CH:29]=3)[N:16]=2)[N:11]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:10]=1)=[O:8])[CH3:5]
Reactant: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: N#Cc1ccn2c(I)cnc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cnc4cc(C#N)ccn34)nc12
Temperature: 95 °C

Procedure:
2-Bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide (100 mg, 0.196 mmol) and hexamethyltin (72 mg, 0.22 mmol) were combined in a nitrogen sparged toluene (5 ml) solution. Tetrakis(triphenylphosphine)palladium(0) (19.5 mg, 0.17 mmol) was added and the solution heated to 95° C. for 2 h. The reaction was cooled and 3-iodo-imidazo[1,2-a]pyridine-7-carbonitrile (54 mg, 0.2 mmol) was added with additional tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.02 mmol). The mixture was heated at 100° C. for 14 h, cooled and directly purified by silica gel chromatography to afford 2-(7-cyano-imidazo[1,2-a]pyridin-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide.
Reaction SMILES: C(O[C:6](=[O:25])[NH:7][C@@H:8]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH3:24])[CH:15]=1)[CH2:9][C:10]([OH:13])([CH3:12])[CH3:11])(C)(C)C.Cl.O1CCOCC1.COC(=O)[C:36]1[C:41]([NH:42][C:43]([CH:45]2[CH2:47][CH2:46]2)=[O:44])=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:48]Br.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH2:23]([O:22][C:16]1[CH:15]=[C:14]([C@H:8]([N:7]2[C:6](=[O:25])[C:36]3[C:37](=[CH:38][CH:39]=[CH:40][C:41]=3[NH:42][C:43]([CH:45]3[CH2:47][CH2:46]3)=[O:44])[CH2:48]2)[CH2:9][C:10]([OH:13])([CH3:11])[CH3:12])[CH:19]=[CH:18][C:17]=1[O:20][CH3:21])[CH3:24]
Reactant: COC(=O)c1c(CBr)cccc1NC(=O)C1CC1
Reactant: CCOc1cc([C@@H](CC(C)(C)O)NC(=O)OC(C)(C)C)ccc1OC
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCOc1cc([C@@H](CC(C)(C)O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Temperature: 80 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
To a solution of (1R)-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-3-methyl-butyl]-carbamic acid tert-butyl ester (150 mg, 0.42 mmol) in methylene chloride (5 mL) was added a solution of HCl in dioxane (0.5 mL, 4N, 2 mmol). After 2 hrs, the solvent was removed and the crude oil was used in the next step without further purification. A mixture of the resulted oil, 2-bromomethyl-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester (130 mg, 0.42 mmol) and triethyl amine (0.12 mL, 0.86 mmol) in DMF (3 mL) was heated at 80° C. for 27 hrs. The solvent was removed in vacuo. The residue was extracted with ethyl acetate (50 mL) and 1N HCl (50 mL). The organic layer was washed with 1N HCl (50 mL), brine (50 mL), and dried over MgSO4. The solvent was removed in vacuo. The residue was purified with Preparative HPLC to give (1R)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-3-methyl-butyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (100 mg, 51% yield): mp, 90-92° C.; 1H NMR (CDCl3) δ 0.85-0.93 (m, 2H, CH2), 1.08-1.13 (m, 2H, CH2), 1.25 (s, 3H, CH3), 1,34 (s, 3H,CH3), 1.45 (t, J=7 Hz, 3H, CH3), 1.67-1.74 (m, 1H, CH), 2.18 (dd, J=4, 14 Hz 1H, CHH), 2.32 (dd, J=9, 14 Hz, 1H, CHH), 2.38 (s, 1H, OH), 3.86 (s, 3H, CH3), 3.94 (d, J=17 Hz, 1H, NCHH), 4.07 (q, J=7 Hz, 2H, CH2), 4.36 (d, J=17 Hz, 1H, NCHH), 5.70 (dd, J=4, 9 Hz, 1H, NCH), 6.82-6.99 (m, 4H, Ar), 7.41 (t, J=8 Hz, 1H, Ar), 8.42 (d, J=8 Hz, 1H, Ar), 10.58 (s, 1H, NH); 13C NMR (CDCl3) δ 8.27, 14.78, 16.19, 29.98, 30.22, 43.95, 46.13, 50.96, 55.98, 64.60, 70.02, 111.43, 112.90, 116.71, 117.51, 117.69, 119.72, 132.48, 133.16, 137.99, 141.50, 148.50, 149.12, 169.63, 172.72; Anal Calcd for C26H32N2O5+1.1H2O: C, 66.11; H, 7.30; N, 5.93. Found: C, 65.73; H, 6.90; N, 5.82.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][N:6]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH2:8][C:7]1=[O:16])C.Cl>C1COCC1>[O:16]=[C:7]1[N:6]([CH2:5][CH:4]=[O:3])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: CCOC(CN1C(=O)COc2ccccc21)OCC
Agent: Cl
Solvent: C1CCOC1
Product: O=CCN1C(=O)COc2ccccc21
Temperature: 25 °C
Reaction time: 7 h
Yield: 95.6 %

Procedure:
Dissolve 4-(2,2-diethoxyethyl)-1,4-benzoxazin-3-one (710 mg, 2.68 mmol) in THF (5.35 mL) and add aqueous HCl (3 M, 3.57 mL, 10.7 mmol). Stir at ambient temperature for 7 hours. Remove the organic solvent using a stream of nitrogen gas, and extract the aqueous residue with EtOAc. Combine the organic extracts; wash with water and saturated aqueous NaHCO3; and dry over Na2SO4. Filter and remove the solvents from the filtrate under reduced pressure to provide the title compound as a white solid (490 mg, 89.07%). MS (m/z): 192 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:22]([N:25](CC2C=CC(OC)=CC=2OC)[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][N:27]=2)(=[O:24])=[O:23])[CH:6]=[CH:7][C:8]=1[O:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[C:16]1[N:20]([CH3:21])[N:19]=[CH:18][CH:17]=1)#[N:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([S:22]([NH:25][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][N:27]=2)(=[O:23])=[O:24])[CH:6]=[CH:7][C:8]=1[O:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[C:16]1[N:20]([CH3:21])[N:19]=[CH:18][CH:17]=1)#[N:2]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCCC[C@@H]3c3ccnn3C)c(C#N)c2)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)cc1C#N
Yield: 65.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using 3-cyano-N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (0.090 g, 0.15 mmol) prepared in Example 56a, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (43 mg, 64%) as a colorless solid.
Reaction SMILES: CO[C:3](=[O:21])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]1=[O:20].C(O)(=O)C.C(OCC)(=O)C.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[O:20]=[C:6]1[CH:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]1[CH2:4][C:3]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:21]
Reactant: C1COCCN1
Reactant: COC(=O)CN1C(=O)C(c2ccccc2)c2ccccc21
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(CN1C(=O)C(c2ccccc2)c2ccccc21)N1CCOCC1

Procedure:
11 g of methyl(2,3-dihydro-2-oxo-3-phenyl-1-indolyl)-acetate were dissolved in 50 ml of morpholine and the mixture was heated under nitrogen on a steam bath for 9 hours and then poured into a mixture of glacial acetic acid and ethyl acetate; the aqueous phase was extracted with methylene chloride and the organic phase was dried and concentrated. The crude product was recrystallized from isopropanol. Melting point 153°-154° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=2[CH3:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>C(OCC)(=O)C>[ClH:23].[ClH:23].[CH3:22][C:16]1[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=1[NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: Cc1ccc(C)c(NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(C)c(NC2CCNCC2)c1
Yield: 80 %

Procedure:
A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1 g, 0.00502 mole) in dry 1,2-dichloroethane (10 mL) was stirred under an atmosphere of nitrogen for 10 minutes. 2,5-dimethylaniline (0.73 g, 0.00602 mole), acetic acid (0.301 g, 0.005 mole) and sodium triacetoxyborohydride (1.596 g, 0.00753 mole) were then added portionwise and stirring was continued at ambient temperature for 16 hours. The reaction mixture was basified with sodium bicarbonate solution and the product was extracted with dichloromethane. The dichloromethane layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting transparent viscous liquid was purified by column chromatography using neutral aluminium oxide (1% ethyl acetate in hexane) to afford 1.5 g (82%) of 4-(2,5-dimethyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (CDCl3): δ 7.0 (t, 1H), 6.6 (d, 2H), 4.2 (dd, 2H), 3.5 (m, 1H), 2.9 (t, 2H), 2.3 (t, 3H), 2.15 (s, 3H), 2.05 (s, 3H), 1.5 (s, 9H), 1.3 (t, 2H). A solution of 4-(2,5-dimethyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.5 g, 0.00492 mole) in ethyl acetate.HCl (7 mL) was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was washed with ether and dried to afford 1.1 g (80%) of (2,5-dimethyl-phenyl)-piperidin-4-yl-amine dihydrochloride. LCMS: 205.16 (M+1)+, 92.74%, 1H NMR (DMSO-d6): δ 9.4 (d, 1H), 9.0 (d, 1H), 7.2 (d, 2H), 7.1 (s, 1H), 3.7 (m, 1H), 3.6 (s, 1H), 3.4 (d, 2H), 3.2 (bs, 1H), 2.9 (m, 2H), 2.4 (s, 3H), 2.3 (s, 3H), 2.1 (m, 4H).
Reaction SMILES: [C@@H:1]1([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[O:7][C@H:4]([CH2:5][OH:6])[CH:3]=[CH:2]1.[CH:17](O)([CH3:19])[CH3:18]>>[CH3:15][C:14]1[C:12](=[O:13])[NH:11][C:9](=[O:10])[N:8]([C@@H:1]2[O:7][C@H:4]([CH2:5][OH:6])[CH:3]=[CH:2]2)[CH:16]=1.[CH3:1][N:8]1[C:9](=[O:10])[N:11]([CH3:12])[CH2:19][CH2:17][CH2:18]1
Reactant: CC(C)O
Agent: Cc1cn([C@H]2C=C[C@@H](CO)O2)c(=O)[nH]c1=O
Product: CN1CCCN(C)C1=O
Temperature: 72.5 °C
Reaction time: 0.25 h

Procedure:
Crude Stavudine (25 g, 96.7% pure, 0.1116 mole), N,N-dimethyl propylene urea (37.5 g, 1.5 parts) are added to isopropanol (50 ml, 2 volumes) and heated to 70-75° C. for dissolution. The obtained solution is stirred for 15 min. at 75° C. and cooled to 6-8° C. The precipitated product is filtered, washed with IPA and dried to give 34.1 g of Stavudine DMPU solvate (86.7%) with a chromatographic purity of 99.91%
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:14][CH:15]([C:24]#[N:25])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[F:23])[C:10](OC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:14][C@@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[CH2:24][NH:25][C:10]1=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(CC(C#N)c1cccc(F)c1F)NC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2cccc(F)c2F)CNC1=O
Reaction time: 1.5 h

Procedure:
To a solution of methyl 2-[(tert-butoxycarbonyl)amino]-4-cyano-4-(2,3-difluorophenyl)butanoate (11.0 g, 31.0 mmol) in methanol (621 mL) was added palladium hydroxide on carbon powder (20% palladium, with moisture ca 60%) (5.45 g, 3.10 mmol). The mixture was pressurized to 50 psi under an atmosphere of hydrogen. After 90 min, the mixture was filtered and concentrated. Purification by chromatography (Chiral Pak® AD® column, 60% ethanol/hexanes with 0.1% diethylamine) gave the title compound. MS: m/z=349.3 (M+Na). 1H NMR (500 MHz, CDCl3): δ 7.11-6.96 (m, 3H); 5.87 (s, 1H); 5.47 (s, 1H); 4.22-4.16 (m, 1H); 3.63-3.52 (m, 2H); 3.38 (t, J=11.2 Hz, 1H); 2.70 (s, 1H); 2.09 (q, J=12.3 Hz, 1H); 1.45 (s, 9H).
Reaction SMILES: [Si:1]([O:8][C:9]1[C:17]([CH2:18][CH:19](O)/[C:20](/[CH3:33])=[CH:21]/[CH2:22]C(C)C(C)(O[SiH3])C(C)(C)C)=[C:16]([O:35][CH3:36])[C:15]([CH3:37])=[C:14]2[C:10]=1[C:11](=[O:38])[O:12][CH2:13]2)(C(C)(C)C)([CH3:3])[CH3:2].C(O)(=O)[C:40]([CH3:43])([CH3:42])[CH3:41]>C(OCC)(OCC)(OCC)C.CCOCC>[Si:1]([O:8][C:9]1[C:17]([CH2:18]/[CH:19]=[C:20](\[CH3:33])/[CH:21]([CH2:22][CH2:17][CH2:9][O:8][Si:1]([C:40]([CH3:41])([CH3:42])[CH3:43])([CH3:3])[CH3:2])[CH2:10][C:11]([O:12][CH2:13][CH3:14])=[O:38])=[C:16]([O:35][CH3:36])[C:15]([CH3:37])=[C:14]2[C:10]=1[C:11](=[O:38])[O:12][CH2:13]2)([C:20]([CH3:21])([CH3:33])[CH3:19])([CH3:3])[CH3:2]
Reactant: COc1c(C)c2c(c(O[Si](C)(C)C(C)(C)C)c1CC(O)/C(C)=C/CC(C)C(C)(O[SiH3])C(C)(C)C)C(=O)OC2
Reactant: CC(C)(C)C(=O)O
Agent: CCOC(C)(OCC)OCC
Solvent: CCOCC
Product: CCOC(=O)CC(CCCO[Si](C)(C)C(C)(C)C)/C(C)=C/Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Reaction time: 0.5 h
Yield: 276.5 %

Procedure:
(E)-7-(4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl -3-oxoisobenzofuran-5-yl)-1-tert-butyldimethyl-silyloxy-6-hydroxy -5-methylhept-4-ene (4.74 g) was dissolved in triethyl orthoacetate (76 ml) and pivalic acid (171 mg) was added. The solution was placed in an oil bath preheated to 130° C., and stirred for 2 1/2 hrs. After cooling, the reaction was diluted with ether, washed with 1N NaHSO4 (3×), saturated sodium bicarbonate, brine, and dried. The solvent was evaporated and the resulting oil chromatographed on silica gel (20% ethyl acetate in hexanes) to give ethyl (E) 6-(4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy -7-methyl-3-oxoisobenzofuran -5-yl)-3-(3-tert -butyldimethylsilyloxypropyl) -4-methylhex-4-enoate (2.94 g), a compound of Formula 802.