Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccc2c(c1)NCC2
Reaction time: 1 h
Yield: 98.6 %

Procedure:
6-Chloroindole (1 g, 6.6 mmol) in glacial acetic acid (10 mL) was treated with sodium cyanoborohydride (829 mg, 13.2 mmol) portionwise at room temperature with stirring. After 1 hour, the reaction was diluted with water (25 mL) and basified with 40% sodium hydroxide with cooling. The mixture was then extracted with dichloromethane (3×50 mL), dried and concentrated to give 1 g of 6-chloroindoline. It was used in the next step without further purification. 1HNMR (300 MHz, dimethylsulfoxide-d6) δ 6.95 (d, 1H), 6.46 (dd, 1H), 6.43 (d, 1H), 5.74 (br s, 1H, NH), 3.42 (t, 2H, CH2), 2.85 (t, 2H, CH2). MS m/z 349 [M+1].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][NH2:12]>C(O)C>[CH3:11][NH:12][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: CN
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCO
Product: CNc1ccncc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
29.9 g of (9) were solubilised in 200 ml of hot ethanol; to the solution, brought to 0° C., were added slowly, dropwise, 103 ml of 35% aqueous methylamine. This was left stirring for 30 minutes and then the ethanol evaporated. The residue was crystallised in water giving 24 g of (10) in the form of clear yellow crystals.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][CH2:11][C:12](Cl)=[O:13].C(=O)(O)[O-].[Na+]>>[Cl:10][CH2:11][C:12]([NH:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:13]
Reactant: NCCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(CCl)NCCc1ccccc1

Procedure:
Eur. J. Org. Chem. 2008, 895-913 describes a process comprising: a) reacting phenylethylamine with chloroacetyl chloride in presence of sodium bicarbonate to obtain 2-chloro-N-phenethylacetamide, b) treating 2-chloro-N-phenethylacetamide with aminoacetaldehyde dimethylacetal to give 2-[2,2-dimethoxyethyl)amino]-N-(2-phenylethyl)acetamide, c) making hydrochloride salt of 2-[(2,2-dimethoxyethyl)amino]-N-(2-phenylethyl)acetamide, and d) cyclising using sulphuric acid to form praziquanamine (i.e.4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:27]=[CH:26][C:8]3[C:9]4[N:10]=[C:11]([C:17]5[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=5)[S:12][C:13]=4[CH2:14][CH2:15][O:16][C:7]=3[CH:6]=2)[CH2:2]1.C(N(CC)C(C)C)(C)C.O1CCCC1.[C:42](O)(=[O:46])[C@H:43]([CH3:45])[OH:44]>>[OH:44][C@@H:43]([CH3:45])[C:42]([N:1]1[CH2:4][CH:3]([C:5]2[CH:27]=[CH:26][C:8]3[C:9]4[N:10]=[C:11]([C:17]5[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=5)[S:12][C:13]=4[CH2:14][CH2:15][O:16][C:7]=3[CH:6]=2)[CH2:2]1)=[O:46]
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CNC4)ccc2-3)n(C(C)C)n1
Reactant: C[C@H](O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CN(C(=O)[C@H](C)O)C4)ccc2-3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
To a solution of 8-Azetidin-3-yl-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.811 g, 0.000786 mol) and N,N-diisopropylethylamine (0.274 mL, 0.00157 mol) in tetrahydrofuran (5.0 mL, 0.062 mol) was added simultaneously L-lactic acid (0.0708 g, 0.000786 mol) and N,N,N′,N′-tetramethyl-β-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.329 g, 0.000865 mol). The reaction was stirred at room temperature overnight. The mixture was partitioned between saturated sodium bicarbonate and methylene chloride and extracted 3 times with methylene chloride. The organic phases were combined, dried with MgSO4, and concentrated. The crude was purified by reverse-phase HPLC to give 490 (191.2 mg) as a colorless solid. MS(ESI+) 454.2. 1H NMR (400 MHz, DMSO) δ 8.34 (d, J=8.2, 1H), 7.22 (m, 1H), 7.06 (s, 1H), 5.84-5.66 (m, 1H), 5.09 (dd, J=11.1, 5.8, 1H), 4.65 (m, 1H), 4.37 (t, J=5.0, 2H), 4.28 (m, 2H), 4.16 (quin, J=6.5, 1H), 3.94-3.78 (m, 2H), 3.43 (t, J=5.0, 2H), 2.32 (s, 3H), 1.52 (d, J=6.6, 6H), 1.21 (d, J=6.7, 3H)
Reaction SMILES: [F-].[K+].[Br:3][C:4]1[C:11]([OH:12])=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.O>CS(C)=O>[Br:3][C:4]1[C:11]([O:12][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COc1ccc(C=O)c(Br)c1O
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(C=O)c(Br)c1Oc1ccc([N+](=O)[O-])cc1
Temperature: 140 °C
Reaction time: 4 h
Yield: 65.4 %

Procedure:
To a stirred suspension of potassium fluoride (1.89 gm, 0.0326 mol) in dry DMSO (10 ml) was added a solution of 2-bromoisovanillin (5.0 gm, 0.0217 mol) in DMSO (10 ml). A solution of 4-fluoronitrobenzene (5.0 gm, 0.0260 mol) in DMSO (5 ml) was added to the above suspension and the reaction mixture was stirred at 140° C. for 4 h. The reaction mixture was cooled to room temperature and the contents were poured into water (150 ml) and extracted with ethyl acetate (50 ml×3). The organic extracts were combined and washed with 1N sodium hydroxide (25 ml×2), water and brine and dried over anhydrous sodium sulfate. The dried organic layer was concentrated in vacuo and the residue was purified by silica-gel column chromatography using 20% ethyl acetate-petroleum ether as the eluent to give 2-bromo-3-(p-nitrophenoxy)-4-methoxy benzaldehyde as a pale yellow solid (5.0 gm) mp:132-140° C.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(O)C>ClCCl>[CH2:16]([O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Oc1ccccc1O
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: CCCCCCOc1ccccc1O
Yield: 28.8 %

Procedure:
Catechol (35.0 g, 0.32 mol), potassium carbonate (109.0 g, 0.79 mol) and 1-bromohexane (52.5 g, 0.32 mol) were added to ethanol (300 ml) and heated under reflux for 48 h. After cooling, dichloromethane (300 ml) was added and the solid residues removed by filtration. The solvents were then removed in vacuo and the crude product was purified by column chromatography on silica gel to give title compound (17.9 g, 29%) as a colourless liquid. Found: C, 73.90; H, 9.20. C12H18O2 requires C, 74.19; H, 9.34. δH (CHCl3) 6.95-6.83 (m, 4H, ArH), 5.66 (s, 1H, OH), 4.04 (t, J 7, 2H, ArOCH2), 1.89-1.79 (m, 2H, ArOCH2CH), 1.55-1.35 (m, 6H, CH2), 0.95 (t, J 7, 3H, CH2CH3). MS (FAB), 194 (M+, 100%), 110 (45%), 95 (7%), 83 (12%), 69 (9%), 55 (18%).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=O)[CH2:3][CH2:4][S:5][CH3:6].Cl.CN(C)CCCN=C=NCC.[CH:22]1[CH:23]=[CH:24][C:25]2N(O)N=N[C:26]=2[CH:27]=1.[C:32]([O:36][C:37](=[O:41])[C@H:38]([CH3:40])[NH2:39])([CH3:35])([CH3:34])[CH3:33]>CN(C=O)C.C(N(CC)CC)C>[CH2:32]([O:36][C:37]([NH:1][C@H:2]([C:7]([NH:39][C@H:38]([C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:41])[CH3:40])=[O:9])[CH2:3][CH2:4][S:5][CH3:6])=[O:41])[C:26]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:27]=1
Reactant: CSCC[C@H](N)C(=O)O
Reactant: On1nnc2ccccc21
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 109.3 %

Procedure:
Z-Protected L-methionine (10 g) was dissolved in DMF (200 ml) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (8.13 g) was added followed by HOBT (5.72 g) and triethylamine (19.7 ml). The mixture was stirred for 1 h then L-alanine tert-butyl ester (7.7 g) was added and stirring continued for 18 h. The mixture was concentrated under reduced pressure and partitioned between diethyl ether and water. The separated organic phase was washed with hydrochloric acid (1M), saturated sodium bicarbonate solution and brine, dried (over magnesium sulphate) and concentrated under reduced pressure to give the title compound (11.9 g) as an orange oil which crystallised on standing.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@H:11]1[C:39](=[O:40])[N:13]2[C:14]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:15](S(C3C=CC=CC=3)=O)[C@H:16]([CH3:17])[C@H:12]12)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N+:41]([C:44]1[CH:57]=[CH:56][C:47]([CH2:48][O:49][C:50]([NH:52][CH2:53][CH2:54][SH:55])=[O:51])=[CH:46][CH:45]=1)([O-:43])=[O:42]>>[Si:1]([O:8][C@@H:9]([C@H:11]1[C:39](=[O:40])[N:13]2[C:14]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:15]([S:55][CH2:54][CH2:53][NH:52][C:50]([O:49][CH2:48][C:47]3[CH:56]=[CH:57][C:44]([N+:41]([O-:43])=[O:42])=[CH:45][CH:46]=3)=[O:51])[C@H:16]([CH3:17])[C@H:12]12)[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: O=C(NCCS)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S(=O)c3ccccc3)[C@H](C)[C@H]12
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)[C@H](C)[C@H]12
Yield: 81 %

Procedure:
Following a procedure similar to that described in Example 21(b), but using the S-oxide isomer of lower polarity of the 4-nitrobenzyl (1R, 5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-methyl-2-phenylsulfinyl-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 2) and 2-(4-nitrobenzyloxycarbonyl)aminoethylmercaptan as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 81%.
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:7][CH2:6]1.[NH3:18].O>ClCCl>[CH:5]1([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:18])=[O:14])=[CH:11][CH:10]=2)[CH2:7][CH2:6]1
Reactant: O=C(O)c1ccc(SC2CC2)cc1
Reactant: N
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1ccc(SC2CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (340 μL, 4.7 mmol) is added to a solution of 4-cyclopropylsulfanyl-benzoic acid (prepared as described in WO07003960, 190 mg, 0.98 mmol) in dichloromethane (1.9 mL), and the mixture is heated at reflux for 30 min. All volatiles are removed under reduced pressure, and the residue is dissolved in chloroform (1.9 mL). Concentrated aqueous ammonia (28%, 770 μL, 9.8 mmol) is added and the mixture is stirred at room temperature for 1 h. Water is added and the phases are separated. The organic layer is concentrated under reduced pressure. Yield: 137 mg (72% of theory); ESI mass spectrum: [M+H]+=194; r.t. HPLC: 0.45 min (X011_S03).
Reaction SMILES: C([Li:5])CCC.[CH3:6][Si:7]([CH3:14])([CH3:13])[NH:8][Si:9]([CH3:12])([CH3:11])[CH3:10].CN(C)P(N(C)C)(N(C)C)=O.C(OC1C=CC(CBr)=CC=1)C1C=CC=CC=1>O1CCCC1.[Cl-].[NH4+]>[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: BrCc1ccc(OCc2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)[N-][Si](C)(C)C
Product: [Li+]
Reaction time: 0.75 h

Procedure:
A solution of lithium hexamethyldisilazide was prepared by adding 5.5 mmol of butyllithium (2.2 M solution in hexane) to a cooled (-70° C.) solution of 1.15 ml of hexamethyldisilazane in 12.5 ml of tetrahydrofuran. To this solution was added first 3.5 ml of hexamethylphosphoramide and then a solution of 1.15 g of N-benzylidine-2-aminocrotonic acid methyl ester in 12.5 ml of tetrahydrofuran. After 45 minutes, a solution of 1.385 g of p-benzyloxybenzyl bromide in 7.5 ml of tetrahydrofuran was added. Stirring was continued for one hour at -70° C. and then for two hours at room temperature. The reaction mixture was diluted with saturated ammonium chloride solution and extracted three times with 50 ml of ether. The combined organic portions were washed twice with water and once with brine and dried with anhydrous magnesium sulfate. The residue upon removal of solvent was dissolved in 5 ml of methylene chloride and placed onto a column of acid-washed silica gel (25 g of silica gel 60, E. Merck cat. no. 7736, previously washed with 6 N hydrochloric acid, water to neutrality, saturated disodium EDTA solution, water, and then 0.3 N hydrochloric acid and dried in air for 72 hours, was slurrypacked in hexane). Elution was carried out under a positive pressure of nitrogen with hexane (100 ml), ether (100 ml), 10:1 ether: acetonitrile (150 ml), and 100:10:2 ether: acetonitrile:triethylamine. The last solvent mixture brought about elution of 1.206 g of benzyloxy-α-vinyltyrosine methyl ester. NMR (CDCl3) showed: 1.57 (2H, broad s), 3.13 (2H,AB, JAB =14, δAB =30), 3.62 (3H,s), 4.92 (2H,s), 5.07 (1H,d of d, J=10,1), 5.22 (1H, d of d, J=17,1), 6.08 (1H, d of d, J=17,10), 7.20 (4H,AB,JAB =9, δAB =14), 7.3-7.5 (5H,m). IR (CHCl3) 3400, 1730 cm-1.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[S:8])[N:5]([CH2:9][C:10]([OH:12])=[O:11])[C:4]2[CH2:13][CH2:14][CH2:15][C:3]1=2.[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+].[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1.C(O)=O>O.C(O)(C)C>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][S:8][C:6]2[N:5]([CH2:9][C:10]([OH:12])=[O:11])[C:4]3[CH2:13][CH2:14][CH2:15][C:3]=3[C:2](=[O:1])[N:7]=2)=[CH:27][CH:26]=1
Reactant: O=C(O)Cn1c2c(c(=O)[nH]c1=S)CCC2
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: O=CO
Product: O=C(O)Cn1c(SCc2ccc(F)cc2)nc(=O)c2c1CCC2
Temperature: 40 °C
Yield: 96.8 %

Procedure:
(4-oxo-2-thioxo-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetic acid (20.0 g, 1.0 eq) was slurried in a mixture of water (112 mL) and isopropyl alcohol (20 mL). NaOH solution (50.9% aqueous, 13.82 g, 1.99 eq) was added followed by a water line wash (10 mL) resulting in a solution. Then Na2CO3 (1.50 g, 0.16 eq) was charged and the solution was heated to 40±3° C. Thereafter 4-fluorobenzyl chloride (13.4 g, 1.05 eq) was added, followed by a line wash of isopropyl alcohol (12 mL) and the reaction mixture was stirred at 40±3° C. until the reaction was deemed complete (˜2.5 hours). The reaction mixture was cooled to 20±3° C. and formic acid (2.4 g, 0.6 eq) was added resulting in crystallisation of the product within 30 minutes. A second charge of formic acid (6.9 g, 1.7 eq) was added over 1 hour and the slurry was stirred at 20±3° C. for at least one hour. The slurry was filtered to isolate the product, which was washed twice with a mixture of water (32 mL) and isopropyl alcohol (8 mL), then with isopropyl alcohol (40 mL) and dried in vacuo at 50° C. to yield the title compound as an off-white solid (28.6 g, 97% th). 1H NMR (d6 DMSO) δ 1.95 (2H, m), 2.57 (2H, t), 2.85 (2H, t), 4.4 (2H, s), 4.7 (2H, s), 7.15 (2H, dd), 7.45 (2H, dd), ˜13.6 (1H, vbrs).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([CH2:27][N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(C=O)cc4)cc23)CC1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CN5CCOCC5)cc4)cc23)CC1
Reaction time: 2 h
Yield: 69.2 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.114 mmol) in DMSO (3 mL) and acetic acid was added morpholine (30 μL, 0.342 mmol). After 2 h, sodium triacetoxyborohydride (290 mg, 1.36 mmol) was added. Reaction mixture was stirred overnight. Compound was purified by Gilson Preparatory HPLC to afford 40.3 mg of the title compound (70%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.B([C:20]1[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:22]=[CH:23][CH:24]=1)(O)O.C([O-])([O-])=O.[K+].[K+]>O>[O:11]=[C:6]1[C:5]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:20]3[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:22]=[CH:23][CH:24]=3)[CH:3]=2)[NH:7]1
Reactant: O=C1Nc2ccc(Br)cc2C12CCCCC2
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(c1)C1(CCCCC1)C(=O)N2
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 77.3 %

Procedure:
To a solution of 5′-bromo-spiro[cyclohexane-1,3′-indolin]-2′-one (3.4 g, 12 mmol) in 1,2-DME (100 mL) under a nitrogen atmosphere was added tetrakis(triphenylphospine)palladium(0) (70 mg, 5 mol %). After 15 min, 2-borono-1H-pyrrole-1-carboxylic acid, 1-tert butyl ester (1.3 eq, 3.31 g, 15.6 mmol) and a solution of K2CO3 (2.3 eq, 3.83 g, 27.6 mmol) in water (5 mL) were added sequentially. The solution was heated to 80° C. for 3 h and allowed to cool. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (2×100 mL). The organic layers were combined, washed with brine (150 mL) and dried over MgSO4. The solution was filtered, concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with 30% EtOAc/hexane) to give 2-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-1H-pyrrole-1-carboxylic acid, tert-butyl ester (3.4 g, 76%) as a white powder, mp 177° C. 1H NMR (CDCl3; 300 MHz) δ 1.38 (s, 9 H), 1.59–1.93 (m, 10 H), 6.18 (m, 1 H), 6.23 (‘t’, 1H, 3 Hz), 6.91 (d, 1H, J=8 Hz), 7.21 (d, 1 H, J=8 Hz), 7.34 (m, 1 H), 7.44 (s, 1 H), 8.33 (br s, 1 H, D2Oex). MS ((+)-APCI) m/z 367 [(M+H)+]. Anal. Calcd for C22H26N2O3: C, 72.11; H, 7.15; N, 7.64. Found: C, 71.7; H, 7.16; N, 7.5.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH3:9][C:10](=[CH2:12])[CH3:11]>C(Cl)Cl>[C:10]([O:4][C:3](=[O:5])[C@@H:2]1[CH2:6][CH2:7][CH2:8][NH:1]1)([CH3:12])([CH3:11])[CH3:9]
Reactant: C=C(C)C
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1

Procedure:
It was found that reaction of proline and excess isobutylene in methylene chloride using anhydrous benzenesulfonic acid in situ to effect phase transfer and N-protection of free proline (solubilization via protonation) afforded an 80% assay yield of proline t-butyl ester. This equilibrium reaction required three days to complete at 0°-5° C. at an optimized charge ratio of proline:benzenesulfonic acid:isobutylene of 1:1.5:12. A strongly basic workup neutralized the benzenesulfonate salts and freed the t-butyl ester for extraction into a neutral organic solvent. The product was typically used as a solution in methylene chloride or alternatively isolated in pure form by concentration and vacuum distillation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][C:4]=1[CH3:12].C([O:15][C:16](=O)[C:17]([F:20])([F:19])[F:18])C.[O-]CC.[Na+].Cl>C(O)C.O.O1CCCC1>[F:18][C:17]([F:20])([F:19])[C:16](=[O:15])[CH2:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:12])[CH:5]=1)=[O:11]
Reactant: CCOC(=O)C(F)(F)F
Reactant: COc1ccc(C(C)=O)cc1C
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(C(=O)CC(=O)C(F)(F)F)cc1C
Yield: 91.5 %

Procedure:
At room temperature, to a mixture of 1 (4 methoxy-3-methylphenyl)-ethanone (described in Reference Preparation example 48) 6.9 g and tetrahydrofuran 200 ml was added trifluoroacetic acid ethyl ester 11.9 g and 20% solution of sodium ethoxide in ethanol 28.5 g. The resulting mixture was stirred with heating under reflux for six hours. To the reaction mixture was added water, and the resulting mixture was acidified with 6N aqueous hydrochloric acid solution. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 4,4,4-trifluoro-1-(4-methoxy-3-methyl-phenyl)-butane-1,3-dione 10 g.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].[F:11][C:12]([F:24])([F:23])[C:13](=O)[CH2:14][C:15]([C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)=O>C(O)(=O)C>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:15]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[CH:14][C:13]([C:12]([F:24])([F:11])[F:23])=[N:10]1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccco1
Reactant: NNc1ccccc1Cl
Agent: Cl
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(-c2ccco2)n(-c2ccccc2Cl)n1
Temperature: 80 °C

Procedure:
Into a 500 mL flask was weighed 25.0 g (139.6 mmol) of 2-chlorophenylhydrazine hydrochloride, 27.4 g (153 mmol) of 4,4,4-trifluoro-1-furan-2-yl-butane-1,3-dione, and 200 mL of acetic acid. The resulting solution was heated at 80° C. for 18 h then was cooled and was washed into a separatory funnel with 1.0 M NaOH and ethyl acetate. The ethyl acetate was separated, washed with 1.0 M NaOH, brine, dried (Na2SO4), and was concentrated in vacuo. The residue was filtered through a short column of silica gel affording 1-(2-chlorophenyl)-5-furan-2-yl-3-trifluoromethyl-1H-pyrazole as a brown oil, yield: 37.31 g (85%); MS (ES): 313 [M+H]+.
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][O:3]1)=[O:2].[Br:11]N1C(=O)CCC1=O.C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl>[Br:11][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1](=[O:2])[O:3]1
Reactant: O=C1OCc2ccccc21
Reactant: O=C1CCC(=O)N1Br
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1OC(Br)c2ccccc21
Yield: 81 %

Procedure:
Phthalide (10.0 g; 0.075 moles) and N-bromosuccinimide were refluxed in dry carbon tetrachloride (200 ml.) in the presence of a catalytic amount of α-azo-iso-butyronitrile for 3-4 hours. The end of the reaction was indicated by the disappearance of N-bromosuccinimide from the bottom of the reaction vessel and the accumulation of succinimide at the top. The succinimide was removed by filtration and the filtrate concentrated in vacuo to 15-20 ml. Cooling of this concentrate followed by filtration gave 13.0 g. (81% yield) of crude 3-bromophthalide, m.p. 75°-80°, as a white crystalline solid. The product was recrystallised from cyclohexane as colourless plates, m.p. 78°-80° with a 95% recovery.