Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[OH:7][C@H:8]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@:10]3([O:28][C@H:11]3[CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]3[CH2:15][CH2:16][C:17]2=[O:27])[CH2:9]1>C1COCC1>[CH3:19][C@:18]12[CH2:20][CH2:21][C@H:22]3[C@@H:13]([CH2:12][CH2:11][C@:10]4([OH:28])[C@:23]3([CH3:26])[CH2:24][CH2:25][C@H:8]([OH:7])[CH2:9]4)[C@@H:14]1[CH2:15][CH2:16][C@@H:17]2[OH:27]
Reactant: C[C@]12CC[C@H]3[C@@H](C[C@@H]4O[C@@]45C[C@@H](O)CC[C@]35C)[C@@H]1CCC2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@]12CC[C@H]3[C@@H](CC[C@@]4(O)C[C@@H](O)CC[C@]34C)[C@@H]1CC[C@@H]2O
Yield: 74 %

Procedure:
To a stirred suspension of LiAlH4 (0.247 mg) in THF under N2 (10.5 mL), a solution of 3β-hydroxy-5α,6α-epoxyandrostan-17-one (0.64 g) in THF (20 mL) was added dropwise and the mixture was stirred at reflux for 8 h. The suspension was cooled with an ice bath and then quenched by careful addition of H2O (1 mL) and 4N NaOH (0.20 mL). The mixture was filtered through a Celite pad and the filter cake was washed with THF (3×10 mL). The filtrate was dried over Na2SO4, evaporated to dryness and the residue was purified by flash chromatography (SiO2, n-hexane/CH2Cl2/acetone 40/30/30) to give androstane-3β,5α,17β-triol (0.48 g, 74%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.37 (d, 1H), 4.19 (d, 1H), 3.78 (m, 1H), 3.62 (s, 1H), 3.39 (m, 1H), 1.87-0.80 (m, 21H), 0.86 (s, 3H), 0.59 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([OH:42])=[C:18]([CH:41]=2)[NH:19][C:20](=[O:40])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29]3[S:30][C:31]4[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:32]=4[N:33]=3)[CH:22]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:50][C:51]([O:53]CC)=[O:52].CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:42][CH2:50][C:51]([OH:53])=[O:52])=[C:18]([NH:19][C:20](=[O:40])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29]4[S:30][C:31]5[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:32]=5[N:33]=4)[CH:22]=3)[CH:41]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COc1ccc2nc(COc3cccc(C(=O)Nc4cc(CCCS(=O)(=O)c5ccc(Cl)cc5)ccc4O)c3)sc2c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2nc(COc3cccc(C(=O)Nc4cc(CCCS(=O)(=O)c5ccc(Cl)cc5)ccc4OCC(=O)O)c3)sc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.8 %

Procedure:
A mixture of 5'-[3-(4-chlorophenylsulfonyl)propyl]-2'-hydroxy-3-(6-methoxy-2-benzothiazolylmethoxy)benzanilide (301 mg, 0.48 mmol), potassium carbonate (135 mg, 0.98 mmol), ethyl bromoacetate (81 mg, 0.49 mmol) and dimethylformamide (5 ml) was stirred at room temperature for 12 hours. Water was added to the reaction solution and the product formed was extracted with ethyl acetate. The extract was washed with water and brine in that order, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Tetrahydrofuran (2 ml), methanol (1 ml) and 1 N sodium hydroxide were added to the resulting residue and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated, and water was added to the resulting residue, and the mixture was adjusted to pH 3 with 10% citric acid aqueous solution. Thereafter, the solid material formed was collected by filtration and washed with acetonitrile to give 4-[3-(4-chlorophenylsulfonyl)propyl]-2-[3-[(6-methoxy-2-benzothiazolyl)methoxy]benzoylamino]phenoxyacetic acid (145 mg, 0.21 mmol, 44%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[S:5][C:6]=1[CH:7]=[O:8].[CH2:19]([Mg]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=2)[S:5][C:6]=1[CH:7]([OH:8])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbaldehyde (0.5 g, 1.84 mmole) in THF (20 mL) at 0° C., is added a solution of benzyl magnesium chloride in tetrahedronfuran (2.0M, 1.0 mL, 2 mmole) dropwise. The reaction is stirred for 5 minutes and then warmed up to room temperature for 2 hrs. The reaction is quenched with NH4Cl(aq), partitioned between ethyl ether and water. Extracted the aqueous layer with ethyl ether. The combined organic is washed with brine, dried over Na2SO4, filtered and concentrated. Column chromatography on silica gel yields the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[CH2:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[CH:25]=[CH:24][C:23]=1[S:32]([NH:20][C:4]1[CH:5]=[C:6]([Cl:19])[C:7]([CH2:8][C:9]2[N:10]=[CH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:2]([Cl:1])[CH:3]=1)(=[O:34])=[O:33]
Reactant: Nc1cc(Cl)c(Cc2cc3ccccc3cn2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)c(Cc2cc3ccccc3cn2)c(Cl)c1)c1ccc(C(F)(F)F)cc1Cl

Procedure:
2-Chloro-N-(3,5-dichloro-4-isoquinolin-3-ylmethyl-phenyl)4-trifluoromethyl-benzenesulfonamide was synthesized (65%) from 3,5-dichloro-4-isoquinolin-3-ylmethyl-phenylamine (236), 2-chloro-4-trifluromethyl-benzenesulfonyl chloride (Maybridge) and pyridine (EM) in a similar manner as described in Examples 70-91. 1H NMR (400 MHz, DMSO-d6) δ 11.46 (br s, 1H), 9.19 (s, 1H), 8.35 (d, J=8.2 Hz, 1H), 8.19 (d, J=1.1 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.99 (dd, J=8.3, 1.2 Hz, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.71 (td, J=7.5, 1.0 Hz, 1H), 7.60 (td, J=7.5, 0.8 Hz, 1H), 7.22 (s, 2H), 4.42 (s, 2H). MS (EI): m/z 543 (M−H).
Reaction SMILES: [OH-].[K+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2([CH2:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])[C:4]1=[O:18].[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.Cl>CS(C)=O.O>[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]3([CH2:15][C:14](=[O:16])[NH:13][C:12]3=[O:17])[C:4]2=[O:18])=[CH:22][CH:21]=1
Reactant: O=C1CC2(C(=O)N1)C(=O)Nc1ccccc12
Reactant: BrCc1ccc(Br)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C1CC2(C(=O)N1)C(=O)N(Cc1ccc(Br)cc1)c1ccccc12
Reaction time: 4 h
Yield: 8.4 %

Procedure:
Ethanolic potassium hydroxide (12 ml., 1M) was added to a stirred solution of spiro[pyrrolidine-3,3'-indoline]-2,2',5-trione (1.0 g.) in dimethyl sulphoxide (10 ml.). 4-Bromobenzyl bromide (1.4 g.) was then added to the clear solution which was stirred for 4 hours. This solution was then added to water (100 ml.). The mixture was acidified (concentrated hydrochloric acid). The precipitate was collected, washed with water, air-dried and recrystallised from ethyl acetate/petrol 60-80 to give 1'-(4-bromobenzyl)-spiro[pyrrolidine-3,3'-indoline]-2,2',5-trione (0.15 g.) m.p. 218°-220° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:33])[C:19]([C:27]3[N:28]=[C:29]([NH2:32])[S:30][CH:31]=3)=[N:20][O:21][CH2:22][CH2:23][N:24]=[N+:25]=[N-:26])[C:15](=[O:34])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].C([O-])(=O)C.[Na+:39].C(O)C>CO>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:33])[C:19]([C:27]3[N:28]=[C:29]([NH2:32])[S:30][CH:31]=3)=[N:20][O:21][CH2:22][CH2:23][N:24]=[N+:25]=[N-:26])[C:15](=[O:34])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=[O:3])[CH3:2].[Na+:39]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCN=[N+]=[N-])c3csc(N)n3)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NOCCN=[N+]=[N-])c3csc(N)n3)[C@H]2SC1

Procedure:
0.385 g of the acid of Example 32 was added to 1 ml of a molar solution of sodium acetate in methanol to obtain a lipid solution to which 5 ml of ethanol were slowly added. The mixture was vacuum filtered and the recovered product was rinsed with ethanol and then ether to obtain 0.215 g of the syn isomer of sodium 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-(2-azidoethoxyimino)-acetamido]-ceph-3-eme-4-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([O:13][CH:10]2[CH2:9][CH2:8][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[O:31])=[CH:28][CH:27]=1
Reactant: OC1CCN(Cc2ccc(Br)cc2)CC1
Reactant: O=C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(OC1CCN(Cc2ccc(Br)cc2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.8 %

Procedure:
0.428 g (0.00184 mol) of 1-(4-bromo-benzyl)-piperidin-4-ol was dissolved in 8 ml of dimethylformamide and treated with 0.097 g (0.00079 mol) of dimethylaminopyridine and 0.222 g (0.00158 mol) of 4-fluoro-benzoic acid. The mixture was cooled to 0° and 0.334 g (0.00174 mol) of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride was added. The mixture was warmed to room temperature and stirred for 18 hrs. The solvent was distilled off and the residue was taken up in ethyl acetate and treated with silica gel. After removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane (1:2) as the eluent. 0.47 g (76%) of 1-(4-bromo-benzyl)-piperidin-4-yl 4-fluoro-benzoate was obtained as a colorless oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(-c2cccc(-c3cccc(Br)n3)n2)c1O
Reactant: OB(O)c1ccccc1O
Product: COc1cccc(-c2cccc(-c3cccc(-c4ccccc4O)n3)n2)c1O
Yield: 39 %

Procedure:
6-(2-Hydroxyphenyl)-6′-(2-hydroxy-3-methoxyphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-3-methoxyphenyl)-2,2′-bipyridine and 2-hydroxyphenyl boronic acid in 39% yield using method F; δH [2H6]-DMSO 13.48,(1H, b), 13.38,(1H, b), 8.33,(2H, m), 8.23,(2H, t), 8.17,(2H, d), 8.13,(1H, d), 7.70,(2H, d), 7.37,(1H, t), 7.09,(1H, d), 7.02,(1H, d), 6.94,(1H, t), 3.84,(3H, s); MS 371 (MH)+; HPLC retention time (system 1) 4.03 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[C@@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[CH2:7][N:8]=1.C([Li])(C)(C)C.I[CH2:20][CH2:21][CH:22]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23]([F:26])([F:25])[F:24].[Cl-].[NH4+]>O1CCCC1>[CH:11]([C@@H:4]1[C:3]([O:2][CH3:1])=[N:8][C@@H:7]([CH2:20][CH2:21][CH:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23]([F:25])([F:26])[F:24])[C:6]([O:9][CH3:10])=[N:5]1)([CH3:13])[CH3:12]
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Reactant: FC(F)(F)C(CCI)c1ccccc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1CCC(c1ccccc1)C(F)(F)F
Reaction time: 1 h

Procedure:
A solution of (R)-(−)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (1.1 g) in tetrahydrofuran (25 ml) was cooled to −70° C., then tert.butyllithium (1.7 M in pentane, 3.88 ml) was added and the mixture was stirred for 1 hour. A solution of (3-iodo-1-trifluoromethylpropyl)-benzene (1.98 g) in tetrahydrofuran (7 ml) was added slowly and the mixture was stirred overnight at −70° C. At room temperature saturated ammonium chloride solution was added and the mixture was extracted three times with ether. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (SiO2, heptane/EtOAc=9:1 to yield a yellow liquid, (1.86 g, 83%).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([CH2:9]Cl)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.[CH3:14][O:15][CH2:16][CH2:17][CH2:18][NH2:19].CS(C)=O>C(OCC)(=O)C>[CH3:14][O:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:2][CH2:3][N:4]2[N:5]=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[C:8]2[CH2:9]1
Reactant: COCCCN
Reactant: O=[N+]([O-])c1cc(CCl)n(CCBr)n1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COCCCN1CCn2nc([N+](=O)[O-])cc2C1
Temperature: 120 °C
Yield: 66.2 %

Procedure:
A microwave vial equipped with a magnetic stirrer was charged with 1-(2-bromoethyl)-5-(chloromethyl)-3-nitro-1H-pyrazole 296c (600 mg, 2.2 mmol), 3-methoxypropan-1-amine (595 mg, 6.6 mmol), and DMSO (6 mL). It was heated at 120° C. under microwave irradiation for 0.5 h. The mixture was then cooled to room temperature and diluted with ethyl acetate (30 mL). The resulting mixture was washed with water (3×10 ml). The organic layer was dried and filtered. The filtrate was concentrated under pressure and the residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 309a (350 mg, 66%) as a yellow solid. MS-ESI: [M+H]+ 241.1
Reaction SMILES: [OH:1][C@@H:2]([C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[OH:33])[N:17]=2)[CH2:12][CH2:11]1)=[O:9])[CH2:3][C:4]([O:6]C)=[O:5].O[Li].O>C1COCC1.O>[OH:1][C@@H:2]([C:8]([N:10]1[CH2:11][CH2:12][N:13]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[OH:33])[N:17]=2)[CH2:14][CH2:15]1)=[O:9])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: COC(=O)C[C@@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)CC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(N3CCN(C(=O)[C@H](O)CC(=O)O)CC3)nc(-c3ccccc3O)nc2c1
Yield: 85.9 %

Procedure:
(R)-Methyl 3-hydroxy-4-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-oxobutanoate (88 mg, 0.20 mmol) and LiOH.H2O (33 mg, 0.78 mmol) were stirred in THF:H2O 1:1 at room temperature for 3 h. After acidification with 1 M HCl and extraction with EtOAc, the organic extracts were washed with water, dried over Na2SO4, and concentrated. The crude material was then purified via silica gel chromatography using 0-10% MeOH/CH2Cl2 to obtain (R)-3-hydroxy-4-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-oxobutanoic acid (75 mg, 88%). LC/MS: m/z 437.3 (M+H)+ at 2.04 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.OC[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:17][CH3:18])([CH3:16])[CH3:15])[N:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:5][CH2:1][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:17][CH3:18])([CH3:15])[CH3:16])[N:9]=1
Reactant: BrC(Br)(Br)Br
Reactant: COC(C)(C)c1cccc(CO)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(C)(C)c1cccc(CBr)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
Carbon tetrabromide (1.59 g, 4.80 mmol) was added portionwise to a stirred solution of 2-hydroxymethyl-6-(1-methoxy-1-methylethyl)pyridine (724 mg, 4.00 mmol) and triphenylphosphine (1.15 g, 4.40 mmol) in DCM (50 mL) at 0° C. The mixture was stirred at 0° C. for 1 h then concentrated in vacuo. The residue was purified by column chromatography (20:1 to 5:1 isohexane:EtOAc) to give the title compound (732 mg, 75%) as a colourless oil; NMR δH (400 MHz, CDCl3) 7.69-7.65 (1H, m), 7.46-7.43 (1H, m), 7.32-7.30 (1H, m), 4.55 (2H, s), 3.17 (3H, s), 1.55 (6H, s).
Reaction SMILES: [CH2:1]1[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[S:4][S:3][CH2:2]1.[NH2:13][C:14]1[N:19]=[N:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])=[O:27])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1>>[F:37][C:34]([F:35])([F:36])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:26]([N:23]1[CH2:22][CH2:21][N:20]([C:17]2[N:18]=[N:19][C:14]([NH:13][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]3[CH2:1][CH2:2][S:3][S:4]3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1)=[O:27]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Product: O=C(CCCCC1CCSS1)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 2, making variations only as required to use lipoic acid in place of benzyloxyacetic acid to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (yield 8%). 1H NMR (300 MHz, CDCl3) δ 10.11, 8.37, 7.72, 7.61, 7.53, 7.35, 7.04, 4.08-3.84, 3.70-3.57, 3.56-3.46, 3.33-3.30, 3.17-3.02, 2.59, 2.39, 1.84, 1.78-1.56, 1.51-1.37. 13C NMR (300 MHz, CDCl3): 172.52, 167.57, 157.94, 150.00, 134.42, 132.38, 129.45, 127.79, 127.29, 127.14, 126.93, 126.88, 126.82, 121.92, 116.27, 56.34, 46.47, 45.65, 45.33, 41.25, 40.26, 38.49, 37.05, 34.74, 28.85, 25.14. MS (ES+) m/e 540.1 (M+1).
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31]CC)=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1.[CH3:35][O:36][C:37]1[S:38][CH:39]=[C:40]([Sn](CCCC)(CCCC)CCCC)[N:41]=1>CN(C=O)C.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>[CH2:15]([NH:14][C:12]([NH:11][C:8]1[S:9][C:10]2[C:2]([C:40]3[N:41]=[C:37]([O:36][CH3:35])[S:38][CH:39]=3)=[CH:3][C:4]([C:17]3[CH:22]=[N:21][C:20]([N:23]4[CH2:24][CH2:25][C:26]([CH3:34])([C:29]([OH:31])=[O:30])[CH2:27][CH2:28]4)=[N:19][CH:18]=3)=[CH:5][C:6]=2[N:7]=1)=[O:13])[CH3:16]
Reactant: CCCC[Sn](CCCC)(CCCC)c1csc(OC)n1
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(Br)c2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)cc(-c3csc(OC)n3)c2s1
Temperature: 110 °C
Yield: 65.3 %

Procedure:
A stirred mixture of ethyl 1-(5-(7-bromo-2-(3-ethylureido)benzo[d]thiazol-5-yl)pyrimidin-2-yl)-4-methylpiperidine-4-carboxylate (150 mg, 0.274 mmol), tetrakis(triphenylphosphine)palladium (16 mg, 0.0138 mmol) and 2-methoxy-4-(tributylstannyl)thiazole (0.33 mL, 0.822 mmol) in anhydrous DMF (3.0 mL) was purged with N2 for 20 min. The reaction vessel was sealed and heated at 110° C. for 10 h. After cooling to rt, the mixture was diluted with water (50 mL) and extracted with EtOAc (3×20 mL) which was washed with brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash silica chromatography eluting with 0 to 100% EtOAc in iso-hexane to give 99 mg of the desired product as an off white gummy solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[CH3:17][C:18]1[S:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[CH3:23][C:21]1[S:22][C:18]([CH:17]2[C:8]3[NH:9][C:10]4[C:15]([C:7]=3[CH2:6][CH:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]2)=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:19][CH:20]=1
Reactant: Cc1ccc(C=O)s1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Product: COC(=O)C1Cc2c([nH]c3ccccc23)C(c2ccc(C)s2)N1

Procedure:
The same method but starting from racemic tryptophan methyl ester and 5-methyl-2-thiophenecarboxaldehyde gave the cis and trans isomers of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[C:15]1([C:23](Cl)=[O:24])([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[O:21]=[C:20]1[C:11]2[C:12](=[C:13]([Cl:14])[C:2]([CH3:1])=[C:3]([O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH:10]=2)[C:23](=[O:24])[C:15]21[CH2:19][CH2:18][CH2:17][CH2:16]2
Reactant: O=C(Cl)C1(C(=O)Cl)CCCC1
Reactant: COC(=O)COc1cccc(Cl)c1C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)COc1cc2c(c(Cl)c1C)C(=O)C1(CCCC1)C2=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of methyl (2-methyl-3-chlorophenoxy)acetate (3.7 g., 0.0172 mole) and cyclopentane-1,1-dicarbonyl chloride (3.5 g., 0.018 mole) in methylene chloride (200 ml.) is cooled to 0°C. and treated with aluminum chloride (7.2 g., 0.054 mole) in several portions during a 15 minute period. The reaction is stirred at 25°C. for 18 hours than at reflux for 5 hours, cooled and poured into 1N-hydrochloric acid. Evaporation of the methylene chloride at reduced pressure affords methyl [1',3'-dioxo-4'-chloro-5'-methyl-spiro(cyclopentane-1,2'-indan)-6'-yloxy]acetate which melts at 152°-153.5°C. after recrystallization from ethanol-water.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:20]=[CH:19][C:18]2[N:14]([C:15]([C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])=[C:16]([CH2:30][C:31]([CH3:38])([CH3:37])[C:32]([O:34]CC)=[O:33])[C:17]=2[C:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[O:22])[CH:13]=1.[OH-].[Na+].Cl>C1COCC1.CO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:20]=[CH:19][C:18]2[N:14]([C:15]([C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])=[C:16]([CH2:30][C:31]([CH3:38])([CH3:37])[C:32]([OH:34])=[O:33])[C:17]=2[C:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[O:22])[CH:13]=1
Reactant: CCOC(=O)C(C)(C)Cc1c(C(=O)c2ccc(Cl)cc2)c2ccc(OCc3nc4ccccc4s3)cn2c1C(=O)C(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C(=O)c1c(CC(C)(C)C(=O)O)c(C(=O)c2ccc(Cl)cc2)c2ccc(OCc3nc4ccccc4s3)cn12
Temperature: 23 °C
Yield: 81.5 %

Procedure:
A solution of ethyl 3-[6-(1,3-benzothiazol-2-ylmethoxy)-1-[(4-chlorophenyl)carbonyl]-3-(2,2-dimethylpropanoyl)indolizin-2-yl]-2,2-dimethylpropanoate (74 mg, 0.12 mmol) in THF (0.5 mL), MeOH (1.0 mL), and 6M aqueous NaOH (1.0 mL) is heated at 70° C. for 1 h then cooled to 23° C. and acidified to pH=1 with concentrated aqueous HCl. The mixture is partitioned between CH2Cl2 and brine and organics are collected, dried with MgSO4, filtered, and concentrated in vacuo. Purification of the crude by flash chromatography (SiO2, CH2Cl2 to 10% MeOH in CH2Cl2) gives the title compound (59 mg, 83%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][N:3]=1.[H-].[Na+].C1(=O)O[CH2:18][CH2:17][O:16]1>CN(C=O)C.O>[CH3:1][C:2]1[N:3]([CH2:18][CH2:17][OH:16])[N:4]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=1
Reactant: Cc1cc(-c2ccccc2)[nH]n1
Reactant: O=C1OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccccc2)nn1CCO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48 %

Procedure:
A solution of 497 mg (3.14 mmol) of 3-methyl-5-phenylpyrazole in 12.6 mL of DMF at 0° C. was treated with 138 mg (3.45 mmol, 60% in oil) of NaH. After stirring for 15 min, 1.38 g (15.7 mmol) of ethylene carbonate was added, and the reaction was warmed to 25° C. and stirred overnight. The reaction was diluted with H2O and the product was extracted with hexanes/EtOAc (1:1). The combined organics were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography using hexanes/EtOAc (1:3) as eluent to give 305 mg (48%) of title compound: low resolution MS (ES) m/e 225 (MNa+), 203 (MH+).