Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]([CH3:5])([O-:4])C.[K+].[CH:7]1([CH2:10][O:11][CH2:12][C:13]2[N:18]=[C:17]3[N:19]([CH2:22][CH3:23])[N:20]=[CH:21][C:16]3=[C:15]([C:24]3[CH:25]=[N:26][CH:27]=[C:28]([CH3:30])[CH:29]=3)[C:14]=2[CH:31]=O)[CH2:9][CH2:8]1.C1C[O:36][CH2:35][CH2:34]1>O>[CH:7]1([CH2:10][O:11][CH2:12][C:13]2[N:18]=[C:17]3[N:19]([CH2:22][CH3:23])[N:20]=[CH:21][C:16]3=[C:15]([C:24]3[CH:25]=[N:26][CH:27]=[C:28]([CH3:30])[CH:29]=3)[C:14]=2/[CH:31]=[CH:34]/[C:35]([O:4][CH2:2][CH3:5])=[O:36])[CH2:8][CH2:9]1
Reactant: C1CCOC1
Reactant: CC(C)(C)[O-]
Reactant: CCn1ncc2c(-c3cncc(C)c3)c(C=O)c(COCC3CC3)nc21
Agent: [K+]
Solvent: O
Product: CCOC(=O)/C=C/c1c(COCC2CC2)nc2c(cnn2CC)c1-c1cncc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of triethyl phosphonoacetate (219 mg) in THF (2 ml) was added potassium tert-butoxide (103 mg) at 0° C. and the mixture was stirred at room temperature for 30 minutes. A solution of 6-[(cyclopropylmethoxy)methyl]-1-ethyl-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (190 mg) in THF (4 ml) was added at 0° C. and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a mixture of EtOAc and n-hexane (1:1) to give ethyl (2E)-3-[6-[(cyclopropylmethoxy)methyl]-1-ethyl-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]acrylate (183 mg) as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([NH:9][NH:10][C:11]([CH:13]2[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:15][CH2:14]2)=O)=O)=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>C1(C)C=CC=CC=1>[CH2:19]([C@H:16]1[CH2:17][CH2:18][C@H:13]([C:11]2[S:33][C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[N:9][N:10]=2)[CH2:14][CH2:15]1)[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCC1CCC(C(=O)NNC(=O)c2ccncc2)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H](c2nnc(-c3ccncc3)s2)CC1

Procedure:
A solution of 4-pentyl-cyclohexanecarboxylic acid N′-(pyridine-4-carbonyl)hydrazide (Preparation 19, 50 mg, 0.158 mmol) and Lawesson's reagent (127 mg, 0.32 mmol) in toluene (2 ml) was heated under reflux for 18 h. The solvent was evaporated and the residue purified by flash chromatography (IH-EtOAc, 4:1 then EtOAc) to afford the title compound: RT=5.02 min; m/z (ES+)=316.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([O:4][C:5](=[O:29])[NH:6][CH:7]([C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][C:24]([O:26]CC)=[O:25])[CH2:19][CH2:18]1)[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:3].[OH-].[Na+]>C1COCC1.CO>[CH3:3][C:2]([CH3:30])([O:4][C:5](=[O:29])[NH:6][CH:7]([C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][C:24]([OH:26])=[O:25])[CH2:19][CH2:18]1)[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[CH3:1]
Reactant: CCOC(=O)C[C@H]1CC[C@H](C(CNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(NC(=O)OC(C)(C)C)[C@H]1CC[C@H](CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 2-(trans-4-(2,2,11,11-tetramethyl-4,9-dioxo-3,10-dioxa-5,8-diazadodecan-6-yl)cyclohexyl)acetate (0.58 g, 1.35 mmol) in THF (5 mL) and MeOH (5 mL) was added 3N NaOH (2.25 mL, 6.75 mmol). The resulting mixture was stirred at RT for 3 h. After removal of volatiles by evaporation, the residue was acidified by 0.5N HCl solution to pH ˜4.5 and extracted with EtOAc, dried over Na2SO4. Filtration and evaporation to dryness gave the acid in a quantitative yield. LC/MS: 423.1 (MNa)+.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[NH2:20][C:21]1[S:22][C:23]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=2)=[C:24]([C:26](O)=[O:27])[N:25]=1>>[NH2:20][C:21]1[S:22][C:23]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=2)=[C:24]([C:26]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:27])[N:25]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Reactant: Nc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 2-Amino-5-(3-fluoro-phenyl)-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.21 min; [M+H]+=497.1.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@H:12]([C@@H:21]([C@@H:30]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[OH:31])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:41]([C:44]1[CH:52]=[CH:51][C:47]([C:48](Cl)=[O:49])=[CH:46][CH:45]=1)([O-:43])=[O:42].O>N1C=CC=CC=1>[CH2:1]([O:8][C@H:9]([C@H:12]([C@@H:21]([C@@H:30]([CH2:32][O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[OH:31])[O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([C:48](=[O:49])[C:47]1[CH:46]=[CH:45][C:44]([N+:41]([O-:43])=[O:42])=[CH:52][CH:51]=1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: O=C[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(C(=O)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.5 %

Procedure:
First, 59 g (109 mmol) of 2,3,4,6-tetra-O-benzyl glucose, from Sigma Chemical Company, was dissolved in 200 ml of pyridine and 22.3 g (120 mmol) of p-nitrobenzoyl chloride was added. The mixture was stirred at room temperature for 72 hours, poured into 750 ml of water, and the solid was isolated by filtration and recrystallized from 95% ethanol to produce 68.8 g (91%) of 2,3,4,6-tetra-O-benzyl-1-p-nitrobenzoyl glucose.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:27][CH:28]3[CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29]3)[C:12]3[N:13]([C:15]([C:18](=[O:26])[NH:19][C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:27][CH:28]3[CH2:31][NH:30][CH2:29]3)[C:12]3[N:13]([C:15]([C:18]([NH:19][C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)=[O:26])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC(Nc2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4)cnc23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@H](Nc2cc(NC3CNC3)c3ncc(C(=O)Nc4ccncc4)n3n2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 2A (4.0 mg, 0.008 mmol) in CH2Cl2 (1 mL) was treated with TFA (0.1 mL) and stirred at room temperature for five hours. The resulting solution was concentrated and the crude product was purified by reversed-phase preparative HPLC ((YMC ODS-A 5 um 20×100 mm, 10% to 90% MeOH/H2) containing 0.1% TFA, 30 minute gradient, 20 mL/min) to afford the title compound (2.0 mg, 61%). LC/MS, m/z 422.27 (M+1). HPLC Rt=1.405 min. YMC S5 ODS-A column (4.6×50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.2% H3PO4). Solvent A: (10% MeOH, 90% H2O, 0.2% H3PO4). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% 1 min, flow rate 4 mL/min.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[F:12][C:13]1([F:27])[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:15]([CH2:25]O)[CH2:14]1.C1COCC1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:25][C@@H:15]3[CH2:14][C:13]([F:27])([F:12])[CH2:17][N:16]3[C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[N:3]=[C:2]([I:1])[C:10]=12
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1Cn1nc(I)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.8 %

Procedure:
Under nitrogen, to a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.61 g, 10.00 mmol, 1.00 equiv), tert-butyl (2S)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (2.37 g, 9.99 mmol, 1.00 equiv) and TPP (4 g, 15.2 mmol, 1.50 equiv) THF was DIAD (3.00 g, 15.0 mmol, 1.50 equiv) at 0° C. in 30 min. The resulting solution was stirred overnight at room temperature. The mixture was then concentrated under vacuum and the residue was applied onto a silica gel column with dichloromethane/ethyl acetate (3/1) to give 1 g of tert-butyl (2S)-2-([4-amino-3-iodo-1H-pyrazolo[3,4-d]-pyrimidin-1-yl]methyl)-4,4-difluoropyrrolidine-1-carboxylate as reddish oil.
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:35]=[C:34]([CH3:36])[C:29]3[NH:30][C:31](=[O:33])[S:32][C:28]=3[CH:27]=2)[CH:20]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[CH3:36][C:34]1[C:29]2[NH:30][C:31](=[O:33])[S:32][C:28]=2[CH:27]=[C:26]([O:25][C:21]2[N:22]=[CH:23][N:24]=[C:19]([N:14]3[CH2:13][CH2:12][C:5]4([O:4][C:3](=[O:17])[NH:2][C:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]4=5)[CH2:16][CH2:15]3)[CH:20]=2)[CH:35]=1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2sc(=O)[nH]c12
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cc(Oc2cc(N3CCC4(CC3)OC(=O)Nc3ncccc34)ncn2)cc2sc(=O)[nH]c12
Reaction time: 0.5 h

Procedure:
90 mg (0.35 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 105 mg (0.36 mmol) 6-(6-chloropyrimidin-4-yloxy)-4-methylbenzo[d]thiazol-2(3H)-one and 200 μL (1.16 mmol) DIPEA in 2.0 mL DMF were stirred for 14 h at 60° C. The reaction mixture was cooled, mixed with water and stirred for 30 min. The precipitate formed was suction filtered, stirred with methanol, suction filtered again and dried.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:7]1)=O)C.C(O)C.[OH-].[Na+].[ClH:31]>CCOCC.C(OCC)(=O)C>[ClH:31].[F:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][C@H:9]2[CH2:10][CH2:11][NH:6][CH2:7][C@H:8]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)N1CC[C@H](Oc2ccc(F)cc2)[C@H](c2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Fc1ccc(O[C@H]2CCNC[C@H]2c2ccccc2)cc1
Reaction time: 8 h

Procedure:
A mixture of 3.62 g of cis-1-ethoxycarbonyl-4-(4-fluorophenoxy)-3-phenylpiperidine, 52 ml of absolute ethanol and 28 ml of 20% sodium hydroxide solution is refluxed overnight under nitrogen. The ethanol is then removed in vacuo and the aqueous residue partitioned between water (50 ml) and ether (100 ml). The phases are separated and the aqueous phase extracted with 2×100 ml of ether. The combined ether extracts are washed with 100 ml of saturated sodium chloride solution and dried overnight over anhydrous sodium sulfate. Filtration and concentration in vacuo affords a cloudy yellow oil. The oil is dissolved in ether and treated dropwise with saturated etheral hydrogen chloride. The solvent is removed in vacuo and the resulting foam triturated with ether to afford a nearly colorless solid. The solid is dissolved in 70 ml of boiling ethyl acetate, filtered hot, and the filtrate concentrated to a volume of 30 ml. The solution is scratched, seeded and allowed to stand overnight at room temperature. Filtration followed by washing with ethyl acetate and ether and drying in vacuo affords the product as a colorless crystalline solid, mp 150°-152° C.
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([CH3:24])=[C:16]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:17]=3)[CH:14]=2)=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>FC(C1C=CC=CC=1)(F)F>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([CH3:24])=[C:16]([NH:18][C:19]([CH:21]3[CH2:22][CH2:23]3)=[O:20])[N:17]=2)[CH:14]=1
Reactant: COc1ccc(COc2ccc3nc(NC(=O)C4CC4)c(C)n3c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: FC(F)(F)c1ccccc1
Product: Cc1c(NC(=O)C2CC2)nc2ccc(O)cn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.1 %

Procedure:
To a solution of N-{6-[(4-methoxybenzyl)oxy]-3-methylimidazo[1,2-a]pyridin-2-yl}cyclopropanecarboxamide (700 mg, 1.99 mmol) and anisole (1.73 mL, 15.9 mmol) in trifluoromethylbenzene (7 mL) was added trifluoroacetic acid (1.4 mL), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 4 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound (65 mg, 14%) as a slightly-yellow solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[C:10]1([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Brc1ccccc1
Reactant: OB(O)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: c1ccc(-c2ccco2)cc1
Temperature: 95 °C
Reaction time: 3 h
Yield: 62.2 %

Procedure:
To a solution of (furan-2-yl)boronic acid (3.0 g, 26.81 mmol) in dioxane (50.0 mL) and water (1.0 mL) was added bromobenzene (2.10 g, 13.38 mmol), K3PO4 (9.3 g, 43.81 mmol) and Pd(PPh3)4 (767 mg, 0.66 mmol) with stirring for 3 h at 95° C. in an oil bath under an inert atmosphere of nitrogen. The reaction mixture was concentrated under reduced pressure to give the residue, which was purified by silica gel column chromatography (1% ethyl acetate in petroleum ether) to afford 2-phenylfuran as colorless oil (1.20 g, 62%).
Reaction SMILES: C[Li].[CH3:3]N(C)CCN(C)C.[CH3:11][C:12](=[CH2:21])[CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]([OH:20])=[O:19].CO>C(OCC)C.CCCCCC>[CH3:3][C:16]([CH2:15][CH2:14][CH2:13][C:12]([CH3:11])=[CH2:21])=[CH:17][C:18]([OH:20])=[O:19]
Reactant: C=C(C)CCCC#CC(=O)O
Reactant: CN(C)CCN(C)C
Agent: [Li]C
Solvent: CCCCCC
Solvent: CO
Solvent: CCOCC
Product: C=C(C)CCCC(C)=CC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 11.0 mmol of cuprous iodide in 30 ml of dry diethyl ether at -40° under nitrogen is added 10.6 mmol of methyllithium in hexane, followed immediately by 13.0 mmol of tetramethylethylenediamine (TMEDA). After stirring for 30 min, the suspension is cooled to about -50°, and 10 mmol of the methyl ester of 7-methyl-7-octen-2-ynoic acid in 1 ml ether is added dropwise. The temperature is maintained at -45° to -50° for 20 min and then 2 ml of methanol is added dropwise to quench the reaction, followed by 1 ml sat. (NH4)2SO4. The suspension is allowed to warm to RT, after which the solid is filtered off and washed with ether. The combined organic layers are washed with sat. (NH4)2SO4, 5% HCl, sat. NaHCO3 and brine, then dried over CaSO4. The solvent is removed by distillation, yielding the Z methyl ester of 3,7-dimethyl-2,7-octadienoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([O:27]C)=[O:26])[CH:11]3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[C:5]2=[CH:4][CH:3]=1.CO.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([OH:27])=[O:26])[CH:11]3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)CN1C(=O)CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C1c1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccccc1C1N(CC(=O)O)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(methoxycarbonyl)-methyl]-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.21 g, 0.4 mmol) prepared in 29b in the mixture of methanol (10 mL) and tetrahydrofuran (20 mL) was added aqueous NaOH solution (1N, 10 mL, 10 mmol). The reaction mixture was stirred at room temperature for overnight and then concentrated. The residue was neutralized to “pH” ˜7, then extracted with ethyl acetate. The organic layer was separated, washed with H2O, brine, dried over MgSO4 and concentrated to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(hydroxycarbonyl)-methyl]-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white foam.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[S:13][C:14]([S:17]([N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)(=[O:19])=[O:18])=[CH:15][CH:16]=2)=[O:9])=[CH:6][CH:5]=[CH:4][NH:3]1.[F:27][C:28]([F:38])([F:37])[C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:53]CCCl>C(Cl)Cl>[O:1]=[C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[S:13][C:14]([S:17]([N:20]3[CH2:25][CH2:24][CH:23]([NH:34][CH2:33][C:32]4[CH:31]=[CH:30][C:29]([C:28]([F:27])([F:37])[F:38])=[CH:36][CH:35]=4)[CH2:22][CH2:21]3)(=[O:19])=[O:18])=[CH:15][CH:16]=2)=[O:9])=[CH:6][CH:5]=[CH:4][NH:3]1.[ClH:53]
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: O=C1CCN(S(=O)(=O)c2ccc(CNC(=O)c3ccc[nH]c3=O)s2)CC1
Reactant: ClCCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cl
Product: O=C(NCc1ccc(S(=O)(=O)N2CCC(NCc3ccc(C(F)(F)F)cc3)CC2)s1)c1ccc[nH]c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of the ketone 198b (2.33 g, 5.89 mmol, 1.0 eq), 4-(trifluoromethyl)benzylamine (0.98 g, 5.59 mmol, 0.95 eq) and NaBH(OAc)3 (1.62 g, 7.66 mmol, 1.3 eq) in 1,2-dichloroethane (70 ml) was stirred for at r.t. After 3 days, it was poured in CH2Cl2 (600 ml), rinsed with sat. aq. NaHCO3 (100 ml), dried (MgSO4), and concentrated. The colourless oily crude was dissolved in MeOH (100 ml) and treated with 2 ml fuming HCl (pre-diluted with 20 ml MeOH). After 30 seconds, a white precipitate started appearing. This was collected after 10 minutes by filtration to give the desired product as its HCl salt, and in excellent purity (1.6 g, 47% yield). Concentration of the filtrate to 10 ml afforded more precipitate (0.6 g, 17% yield). Mp=288-289° C., 1H NMR (DMSO-d6) δ 12.5 (s, 1H), 10.38 (t, J=6.0 Hz, 1H), 9.90-9.70 (br.s, 1.5H), 8.37 (dd, J=7.2 & 2.1 Hz, 1H), 7.85-7.70 (m, 5H), 7.48 (d, J=3.7 Hz, 1H), 7.16 (d, J=3.8 Hz, 1H), 6.49 (t, J=6.8 Hz, 1H), 4.73 (d, J=5.8 Hz, 2H), 4.24-4.16 (br s, 2H), 3.66 (d, J=11.7 Hz, 2H), 3.20-3.05 (br. m, 1H), 2.39 (t, J=11.3 Hz, 2H), 2.19 (d, J=10.7 Hz, 2H), 1.76 (qd, J=11.5, 3.2 Hz, 2H). 19F NMR (DMSO-d6)−61.64.
Reaction SMILES: Br([O-])(=O)=O.[Na+].[OH:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH:9]([C:13]([O:15][CH3:16])=[O:14])[CH2:8]1.C(O)(C)C>C(OCC)C.O.O.[Ru](=O)=O>[O:6]=[C:7]1[CH2:12][CH2:11][CH2:10][CH:9]([C:13]([O:15][CH3:16])=[O:14])[CH2:8]1
Reactant: COC(=O)C1CCCC(O)C1
Agent: O=[Ru]=O
Agent: [Na+]
Agent: [O-][Br+2]([O-])[O-]
Solvent: CC(C)O
Solvent: O
Solvent: CCOCC
Product: COC(=O)C1CCCC(=O)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
Ruthenium (IV) oxide hydrate (1.47 g, 11.1 mmol) and sodium bromate (100 g, 664 mmol) were combined in diethyl ether (600 mL) and water (300 mL). The resulting black mixture was stirred for 10 min and then cooled in an ice bath. Methyl 3-hydroxycyclohexanecarboxylate (35 g, 221 mmol) was dissolved in ether (to bring total volume to 100 mL) and was added dropwise to the ice cold reaction mixture. The temperature was not allowed to go above 30° C. The reaction mixture was stirred for 1 h with the reaction temperature at ˜15° C. Isopropanol was carefully added to the reaction mixture at a rate necessary to keep the reaction temperature at ˜27° C. The layers were separated and the organic layers were washed with ether. The combined organics were washed with saturated aqueous NaHCO3 solution and brine. The organics were then dried over MgSO4, filtered, and concentrated to provide methyl 3-oxocyclohexanecarboxylate (34.5 g, 100% yield) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 3.68 (s, 3H), 2.79 (m, 1H), 2.52 (d, J=7.78 Hz, 2H), 2.23-2.42 (m, 2H), 1.98-2.15 (m, 2H), 1.82 (d, J=10.29 Hz, 1H), 1.61-1.77 (m, 1H).
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([NH2:25])(=[O:24])[CH2:22][CH3:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][C:9]=1[NH:25][C:21](=[O:24])[CH2:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(N)=O
Reactant: COc1ccc2c(c1)C(Cc1ccccc1)C(=O)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(=O)NC1=C(Cc2ccccc2)c2cc(OC)ccc2CC1
Temperature: 25 °C
Yield: 64.5 %

Procedure:
In a three-necked flask equipped with a Dean-Stark apparatus, heating mantle and magnetic stirrer were charged 1-benzyl-7-methoxy-3,4-dihydronaphthalen-2(1H)-one (120 g, 451 mmol), propionamide (82 g, 1126 mmol) and p-toluenesulfonic acid monohydrate (17.14 g, 90 mmol) followed by toluene (1.8 I). The resulting solution was heated to reflux for 5 days and monitored by HPLC (about 16% of starting material remained). The reaction mixture was cooled to r.t. and washed with 8% aqueous sodium bicarbonate solution (250 ml) and water (250 ml). The layers were separated. The organic layer was concentrated to near dryness and chase distilled with IPA (100 ml). The crude product was transferred to a flask equipped with a mechanical stirrer, heating mantle and nitrogen inlet. IPA (500 ml) was added to the flask and suspension was heated to 62° C. and all the solids were dissolved. The suspension was allowed to cool over 2 hrs to 30° C. then cooled to 5° C. Solids were filtered and washed with mixture of heptane/IPA (4:1, 100 ml). Solids were dried under vacuum to give 93.5 g (yield: 65%) product as a white solid.
Reaction SMILES: C1(C[O:8][C:9](=[O:51])[CH2:10][N:11]([C:23]2[CH:28]=[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:26]=[C:25]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:24]=2)[CH2:12][C:13](=[O:22])[O:14]CC2C=CC=CC=2)C=CC=CC=1.[H][H]>[Pd]>[C:9]([CH2:10][N:11]([C:23]1[CH:28]=[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:26]=[C:25]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:24]=1)[CH2:12][C:13]([OH:22])=[O:14])([OH:51])=[O:8]
Reactant: [H][H]
Reactant: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)c1
Agent: [Pd]
Product: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(N(CC(=O)O)CC(=O)O)c1
Yield: 74.8 %

Procedure:
A mixture of 10.2 g (0.0145 mol) of N-[3,5-bis(decyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycine phenylmethyl ester and 1.5 g of 10% palladium on charcoal in 500 ml of THFwas shaken in a hydrogen atmosphere at room temperature for 7 hours. The catalyst was removed by filtration and the filtrate was concentrated underreduced pressure to a solid which was recrystallized from acetonitrile to give 5.66 g (75% yield, mp 110°-114°) of N-(carboxymethyl)-N-[3,5-bis(decyloxy)phenyl]glycine.