Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[CH3:16])=[CH:5][C:3]=1[NH2:4].[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2[CH2:23][CH2:24][CH2:25][CH2:26][C:18]1=2>C(O)(=O)C>[F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[CH3:16])=[CH:5][C:3]=1[N:4]1[C:20](=[O:21])[C:19]2[CH2:23][CH2:24][CH2:25][CH2:26][C:18]=2[C:17]1=[O:22]
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: CC1CCCC1Oc1cc(N)c(F)cc1Cl
Solvent: CC(=O)O
Product: CC1CCCC1Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 97.8 %

Procedure:
2-Fluoro-4-chloro-5-(2-methylcyclopentyl)oxyaniline (660 mg, 2.71 mmol), 3,4,5,6-tetrahydrophthalic anhydride (503 mg, 3.31 mmol) and acetic acid (10 ml) were charged into a 50 cc round-bottom flask, and heated for 5 hours while refluxing. After completion of the reaction, the reaction solution was cooled to room temperature, and poured into ice-water (100 ml). The mixture was extracted with ethyl acetate (30 ml×3), and the organic layers were combined, washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, the solvent was distilled off under reduced pressure, and the resulting pale brown oily substance was purified by silica gel column chromatography (development solvent: hexane/ethyl acetate=9/1) to obtain N-{2-fluoro-4-chloro-5-(2-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.65 mmol, 98% yield).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][C:3](Cl)=[O:4].[C:8]([CH2:11][C:12](=[O:14])[CH3:13])(=[O:10])[CH3:9]>>[C:8]([C:11]1[C:1]([OH:6])=[CH:2][C:3](=[O:4])[O:14][C:12]=1[CH3:13])(=[O:10])[CH3:9]
Reactant: O=C(Cl)CC(=O)Cl
Reactant: CC(=O)CC(C)=O
Product: CC(=O)c1c(O)cc(=O)oc1C
Temperature: 25 °C
Yield: 15.3 %

Procedure:
When 7.0 mL (72.0 mmol) of malonyl chloride was added to 7.0 mL (67.8 mmol) of acetylacetone, a violent exothermic reaction occurred to give a black solid within a few minutes. The solid was cooled to room temperature, washed with ether and then ethyl acetate, and filtered. The thus-obtained brown solid was recrystallized from ethyl acetate/methanol to give 1.75 g (10.4 mmol, 15.3%) of 5-acetyl-4-hydroxy-6-methyl-2-pyrone as brown crystals. The filtrates from washing and the recrystallized mother liquor were combined and concentrated; the residue was purified by silica gel column chromatography to give 2.87 g (17.1 mmol, 25.2%) of 5-acetyl-4-hydroxy-6-methyl-2-pyrone as orange crystals.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH2:13][CH2:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:4][CH:3]=1.[CH2:19]([CH:21]1[O:23][CH2:22]1)Cl.N1CCCCC1.[OH-].[Na+]>ClCCl>[O:23]1[CH2:22][CH:21]1[CH2:19][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH2:13][CH2:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:4][CH:3]=1
Reactant: ClCC1CO1
Reactant: O=C1CCC(c2ccc(O)c3ccccc23)=NN1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCNCC1
Solvent: ClCCl
Product: O=C1CCC(c2ccc(OCC3CO3)c3ccccc23)=NN1
Yield: 71.7 %

Procedure:
A mixture of 6-(4-hydroxy-1-naphthyl)-4,5-dihydro-3(2H)-pyridazinone (0.5 g, 0.002 mole), epichlorohydrin (2g, 0.02 mole), and piperidine (0.02 g) was heated on a steam bath for 1.5 hours. Evaporation under reduced pressure gave an oil which was dissolved in dichloromethane and shaken with dilute sodium hydroxide (5 ml). The organic phase was washed with water, dried and evaporated to an oil which with ethanol-ether gave crystalline 6-[4-(2,3-epoxypropoxy)-1-naphthyl]-4,5-dihydro-3(2H)-pyridazinone (0.425 g, 69%, m.p. 151°-155°C). Crystallisation from ethanol gave the pure epoxide, m.p. 153.5°-155.5°C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[C:14]([O:18][C:19](=[O:36])[NH:20][CH:21]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=1)[C:22](=[O:27])N(OC)C)([CH3:17])([CH3:16])[CH3:15]>O1CCCC1>[C:14]([O:18][C:19](=[O:36])[NH:20][CH:21]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=1)[C:22]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[O:27])([CH3:17])([CH3:15])[CH3:16]
Reactant: Brc1ccc(I)nc1
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(Br)cn1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 0.705 g (2.41 mmol) 5-bromo-2-iodopyridine in 4.8 ml dry tetrahydrofuran were added at 0° C. drop-wise 1.20 ml (2.41 mmol) of a 2M solution of isopropylmagnesium chloride in tetrahydrofuran. The mixture was stirred at 0° C. for 1.5 h and then 0.250 g (0.688 mmol) rac-[(3,4-Dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) were added. The ice bath was removed and stirring continued at ambient temperature for 2 h. The reaction was quenched by addition of 7 ml saturated aqueous ammonium chloride solution. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and evaporated. The crude product was purified by flash-chromatography over silica gel with a heptane/ethyl acetate gradient beginning with 5% ethyl acetate. The title compound was obtained al light yellow solid: MS (ISP): 459.1 and 461.1 (M+H)+, 403.0 and 405.1 ((M-isobutene)+H)+ (100%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]([CH3:25])[C:10]([C@@H:12]1[CH2:16][C@H:15]([F:17])[CH2:14][N:13]1C(OC(C)(C)C)=O)=[O:11]>C(Cl)(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:17][C@@H:15]1[CH2:14][NH:13][C@H:12]([C:10]([N:9]([CH3:25])[CH3:8])=[O:11])[CH2:16]1
Reactant: CN(C)C(=O)[C@@H]1C[C@H](F)CN1C(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)[C@@H]1C[C@H](F)CN1
Reaction time: 2 h

Procedure:
18 mL of trifluoroacetic acid was added under ice cooling to a 60 mL chloroform solution of 5.98 g of the compound obtained in step 2-3, and the reaction mixture was stirred for 2 hours at the same temperature. After this, the solvent was distilled off under reduced pressure to obtain 12.1 g of residue (colorless oily substance). This compound was used in the following reaction without being purified.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:13][Si](C=[N+]=[N-])(C)C>CO>[CH3:13][O:11][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[N:1]=[CH:2][NH:3][C:4]=2[CH:9]=1)=[O:12]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Solvent: CO
Product: COC(=O)c1ccc2nc[nH]c2c1

Procedure:
To a suspension of benzimidazole-5-carboxylic acid (100 mg, 0.616 mmol, 1 eq) in MeOH (4 mL) was added a 2N solution of trimethylsilyldiazomethane in hexanes (3×0.3 mL, 1.8 mmol, 3 eq). Nitrogen evolution was evident. Eventually a yellow color persisted. The reaction was quenched by the addition of a small amount of acetic acid. The MeOH was removed under reduced pressure and the mixture was purified by preparative thin layer chromatography (eluted with 7% MeOH in CH2Cl2) giving 66 mg of the desired product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].N1C=CC=CC=1.[C:16](Cl)(=[O:21])[O:17][CH:18]([Cl:20])[CH3:19]>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][O:8][CH3:9])[C:16](=[O:21])[O:17][CH:18]([Cl:20])[CH3:19]
Reactant: COCCNCCOC
Reactant: CC(Cl)OC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCN(CCOC)C(=O)OC(C)Cl
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a cooled solution of bis(2-methoxyethyl)amine (1.94 g, 14.5 mmol, Aldrich) and pyridine (1.26 g, 1.29 mL, 15.9 mmol) in methylene chloride (18 mL) at −78° C., was added slowly 1-chloroethyl carbonochloridate (1.98 g, 1.5 mL, 13.8 mmol, Aldrich) over ˜15 min. The reaction mixture was allowed to stir at −78° C. for 3 h, giving a white precipitate. This cold reaction mixture was filtered to remove the solid and the filtrate was concentrated to dryness, giving the crude 1-chloroethyl bis(2-methoxyethyl)carbamate used for the next step without further purification.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([C:11]([C:15]2[CH:16]=[C:17]([CH:21]([CH3:25])[C:22]([OH:24])=[O:23])[CH:18]=[CH:19][CH:20]=2)=[CH:12][CH2:13]O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(Cl)Cl>[C:5]1([C:11]([C:15]2[CH:16]=[C:17]([CH:21]([CH3:25])[C:22]([OH:24])=[O:23])[CH:18]=[CH:19][CH:20]=2)=[CH:12][CH2:13][Cl:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C(=O)O)c1cccc(C(=CCO)c2ccccc2)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C(=O)O)c1cccc(C(=CCCl)c2ccccc2)c1
Reaction time: 1 h

Procedure:
A solution of 18.5 g of dry thionyl chloride in 30 mL methylene chloride was added, along 1 hour, to a solution of 41.7 g of 2-[3-(1-phenyl-3-hydroxy-1-propenyl)phenyl]propionic acid in 60 mL of the same solvent, kept at 5-10° C. After standing for 1 hour, volatile materials were removed under vacuum. The oily residue, mainly formed by the title compound, was used in subsequent reactions without further purification. IR Spectrum (film), cm-1 : 3400-2600, 1710, 1600, 1490, 1410, 1245, 1230, 1070, 790, 770, 700.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Br[C:13]1[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][N:14]=1>>[Br:19][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)[CH:18]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Brc1ccnc(Br)c1
Product: O=Cc1ccc(-c2cc(Br)ccn2)cc1

Procedure:
Alternatively, as illustrated in Scheme 40, Example 2, the phenylboronic acid 40.1 is coupled, as described above, with 2,4-dibromopyridine 40.14 to afford 4-(4-bromo-2-pyridyl)benzaldehyde 40.15. The product is then reacted with a dialkyl mercaptoethyl phosphonate 40.16, the preparation of which is described in Zh. Obschei. Khim., 1973, 43, 2364, to yield the thioether 40.17. Equimolar amounts of the reactants are combined in dimethylformamide at 80° in the presence of potassium carbonate, to effect the displacement reaction.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]#[N:18])=[C:12]([Cl:19])[CH:11]=1.C([Li])(C)(C)C.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:35])(=O)=O)=CC=1>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH:16]([F:35])[C:17]#[N:18])=[C:12]([Cl:19])[CH:11]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: N#CCc1ccc(-c2nc3ccccc3o2)cc1Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: N#CC(F)c1ccc(-c2nc3ccccc3o2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of [4-(1,3-benzoxazol-2-yl)-2-chlorophenyl]acetonitrile (98 mg, 0.36 mmol) and dry THF (5 mL) was cooled to −78° C. A solution of tert-butyllithium (500 μL, 0.80 mmol, 1.7M solution in pentane) was added dropwise via syringe at −78° C. After 1 h, a solution of N-fluorobenzenesulfonimide (113 mg, 0.36 mmol) and dry THF (1.5 mL) was added dropwise via syringe at −78° C. The cooling bath was removed, and the reaction mixture was gradually allowed to warm to rt, and was maintained at rt for 8 h. The reaction was quenched with silica gel (300 mg) and concentrated to dryness. The residue was purified by flash chromatography on silica gel (EtOAc:hexanes, 1:3) to afford the desired [4-(1,3-benzoxazol-2-yl)-2-chlorophenyl](fluoro)acetonitrile as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 8.32 (s, 1H), 8.24 (2, 1H), 7.74–7.84 (m, 2H), 7.56–7.60 (m 1H), 7.35–7.43 (m, 2H), 6.45 (d, 1H). MS (ESI) 287 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:16][N:17]=2)[CH:5]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:7]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:3]3[N:4]([C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[N:16][N:17]=3)[CH:5]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:7]=2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c2nnc(-c3ccccn3)n2c1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1cc(-c2ccc(F)cc2)c2nnc(-c3ccccn3)n2c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
To a solution of tert-butyl 8-chloro-3-pyridin-2-yl[1,2,4]triazolo[4,3-a]pyridine-6-carboxylate (0.5 g, 1.51 mmol) in toluene (12 mL) were added (4-fluorophenyl)boronic acid (0.32 g, 2.27 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (72.1 mg, 0.15 mmol), palladium(II) acetate (33.9 mg, 0.15 mmol) and potassium phosphate tribasic (0.96 g, 4.53 mmol). The mixture was heated to 110° C. After 2 h, the mixture was cooled to ambient temperature, filtered with Celite and the filtrate was concentrated. Purification by silica gel chromatography (100% dichloromethane→60% dichloromethane/ethyl acetate) gave of the title compound (0.53 g): LC-MS [M+1]=391.2.
Reaction SMILES: O=C1N2C=CC3C(=O)C([C:21]4[CH:22]=[CH:23][C:24]([C:27]5([NH:31][S:32]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:33])[CH2:30][CH2:29][CH2:28]5)=[N:25][CH:26]=4)=C(C4C=CC=CC=4)OC=3C2=NN1COCC[Si](C)(C)C.I[C:48]1[C:49](=[O:68])[C:50]2[C:55]([O:56][C:57]=1[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[C:54]1[N:64]([CH3:67])[N:65]=[CH:66][C:53]1=[CH:52][CH:51]=2>>[CH3:67][N:64]1[C:54]2=[C:55]3[C:50](=[CH:51][CH:52]=[C:53]2[CH:66]=[N:65]1)[C:49](=[O:68])[C:48]([C:21]1[CH:22]=[CH:23][C:24]([C:27]2([NH:31][S:32]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:33])[CH2:30][CH2:29][CH2:28]2)=[N:25][CH:26]=1)=[C:57]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[O:56]3
Reactant: Cn1ncc2ccc3c(=O)c(I)c(-c4ccccc4)oc3c21
Reactant: CC(C)(C)S(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccn5c(=O)n(COCC[Si](C)(C)C)nc45)c3=O)cn2)CCC1
Product: Cn1ncc2ccc3c(=O)c(-c4ccc(C5(NS(=O)C(C)(C)C)CCC5)nc4)c(-c4ccccc4)oc3c21
Yield: 81 %

Procedure:
Following the procedure used to prepare 2-methyl-propane-2-sulfinic acid (1-{5-[3,6-dioxo-8-phenyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,6-dihydro-3H-9-oxa-1,2,3a-triaza-cyclopenta[a]naphthalen-7-yl]-pyridin-2-yl}-cyclobutyl)-amide, 7-iodo-1-methyl-8-phenyl-1H-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-6-one was reacted to give the title compound (34 mg, 81%) as a pale orange gum. LCMS (Method H): RT=3.41 min, [M+H]+=527.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.[F:16][C:17]1([F:33])[C@H:21]([CH3:22])[N:20](C(=O)[C@H](CC(C)C)N)[C@H:19]([C:31]#[N:32])[CH2:18]1>>[F:16][C:17]1([F:33])[C@H:21]([CH3:22])[N:20]([C:13](=[O:15])[C@H:9]([CH:10]([CH3:11])[CH3:12])[NH2:8])[C@H:19]([C:31]#[N:32])[CH2:18]1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)N1[C@H](C#N)CC(F)(F)[C@@H]1C
Product: CC(C)[C@H](N)C(=O)N1[C@H](C#N)CC(F)(F)[C@@H]1C

Procedure:
This compound was prepared from 51 mg (0.23 mmol) of (S)—N-tert-butoxycarbonylvaline and 50 mg (0.23 mmol) of (2,5-cis) 4,4-difluoro-5-methyl-pyrrolidine-2-carboxylic acid methyl ester hydrochloride (Example 95G) according to the same five step sequence as for (2S,5S)-4,4-difluoro-1-L-leucyl-5-methylpyrrolidine-2-carbonitrile (example 95H through example 95L) to give the titled compound as a colorless foam. 1H NMR (500 MHz, DMSO-d6) (mixture of rotamers, major rotamer only) δ ppm 0.99 (m, 6H) 1.37 (m, 3H) 2.11 (m, 1H) 2.96 (m, 1H) 3.09 (m, 1H) 4.09 (bs, 1H) 4.65 (m, 1H) 5.06 (t, J=8.6 Hz, 1H) 8.31 (bs, 3H) MS (ESI) m/z=246 (M+H)+.
Reaction SMILES: [Li][CH3:2].[CH3:3][C:4](=[O:25])[C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C@H:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C@H:12]([CH2:13][C:14](=[O:24])[CH2:15][CH2:16]2)[CH2:11][CH2:10]3)[CH2:7][CH2:6]1>C1(C)C=CC=CC=1>[CH3:3][C:4]([C@@H:5]1[C@@:22]2([CH3:23])[CH2:21][CH2:20][C@@H:19]3[C@@:17]4([CH3:18])[CH2:16][CH2:15][C@:14]([OH:24])([CH3:2])[CH2:13][C@@H:12]4[CH2:11][CH2:10][C@H:9]3[C@@H:8]2[CH2:7][CH2:6]1)=[O:25]
Reactant: [Li]C
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: Cc1ccccc1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@](C)(O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -25 °C
Reaction time: 5 h

Procedure:
Ferrous chloride (4 g) is reacted with MeLi (3 equiv. based on FeCl2) in toluene (anhydrous, 200 mL) at −25° C. under nitrogen. 5α-pregnane 3,20-dione (10 g) is then added to this mixture. The mixture is stirred at −25° C. for 5 h. It is quenched by adding acetic acid (32 mL). The mixture is concentrated in vacuo and the residue is stirred in 3N HCl (200 mL) for 6 h. The solid is collected by filtration, washed with water and dried. The crude product is dissolved in THF (33 mL) at reflux and filtered hot. The filtrate is mixed with water (45 mL) and the solid is collected by filtration, washed with water and dried. The solid is further slurried in ethyl acetate (50 mL) at 70° C. for 8 h. It is cooled to 5° C. and filtered, washed with cold ethyl acetate and dried to obtain ganaxolone.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:24][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[C:18]([CH:22]=[O:23])[CH:17]=[CH:16]3.[BH4-].[Na+]>CO.CS(C)=O>[OH:23][CH2:22][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][C:12]3[CH2:11][C@:3]4([C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:10][C:2]4=[O:1])[CH2:24][C:13]=3[CH:14]=2)[N:19]=1
Reactant: O=Cc1ccc2cc3c(cc2n1)C[C@]1(C3)C(=O)Nc2ncccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: O=C1Nc2ncccc2[C@@]12Cc1cc3ccc(CO)nc3cc1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of (S)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-2-carbaldehyde (80 mg, 025 mmol, described in Intermediate 6) in a mixture of MeOH (5 mL) and DMSO (1 mL) was added sodium borohydride (19 mg, 0.51 mmol). The resulting mixture was stirred at ambient temperature for 1 h, then the MeOH was removed in vacuo. The residue was partitioned between saturated aqueous NaHCO3 (20 mL) and CH2Cl2 (20 mL). The aqueous layer was extracted further with CH2Cl2 (2×20 mL). The combined organic extracts were dried over Na2—SO4, filtered, and concentrated in vacuo to give the title compound in sufficient purity for use in the next step. MS: m/z=318 (M+1).
Reaction SMILES: [CH3:1][Mg]Br.[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([C:24](=[O:26])[CH3:25])([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>C1(C)C=CC=CC=1.O1CCCC1.O1CCCC1>[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)([C:24]([OH:26])([CH3:1])[CH3:25])[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(=O)C1(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Reactant: C[Mg]Br
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Cl)cc2)(C(C)(C)O)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a dry round bottom flask was added via syringe 16 ml methyl magnesium bromide in toluene/tetrahydrofuran (75:25, 1.4 M). The flask was cooled in an ice bath under a stream of nitrogen. A solution 4-acetyl-4-(4-chloro-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (337 mg, 1.02 mmol) in 5 ml tetrahydrofuran was added dropwise to the flask over 20 minutes and the resulting mixture was stirred at 0° C. for 8 hours. The reaction mixture was warmed to room temperature and stirred for 5 days. The reaction was quenched by slow addition of 150 ml saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated under vacuum. The yellow residue was purified by silica gel chromatography, eluting with hexane-ethyl acetate (7.5:2.5) to give the title compound (242 mg, 67%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH:10]2[CH2:13][N:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[CH2:11]2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]1.C(N(CC)CC)C>CS(C)=O>[Br:1][C:2]1[C:3]([O:9][CH:10]2[CH2:13][N:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[CH2:11]2)=[N:4][C:5]([N:24]2[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]2)=[N:6][CH:7]=1
Reactant: OCC1CCNCC1
Reactant: Clc1ncc(Br)c(OC2CN(c3ccc4ccccc4n3)C2)n1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: OCC1CCN(c2ncc(Br)c(OC3CN(c4ccc5ccccc5n4)C3)n2)CC1
Temperature: 150 °C
Yield: 16 %

Procedure:
To a mixture of 2-(3-((5-bromo-2-chloropyrimidin-4-yl)oxy)azetidin-1-yl)quinoline (see PREPARATION P2.11; 0.1 g, 0.25 mmol) and piperidin-4-yl-methanol (0.028 g, 0.25 mmol) was added DMSO (2 mL) and triethylamine (0.05 g, 0.50 mmol). The solution was heated to 150° C. under microwave for 3 hours. The mixture was then extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 60% EtOAc in hexanes) to give the title product (0.02 g, 0.04 mmol, 17% yield) as white solid. ESI-MS (M+1): 471 calc. for C22H24BrN5O2 470.
Reaction SMILES: Br[C:2]1[C:3]([O:23][CH3:24])=[C:4]([CH:10]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].CC1(C)C(C)(C)OB([C:33]2[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH:38]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl.N#N>C(#N)C.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH2:15]([O:14][C:13]([NH:12][CH:10]([C:4]1[C:3]([O:23][CH3:24])=[C:2]([C:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH:34]=2)[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=1)[CH3:11])=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1c(C(C)NC(=O)OCc2ccccc2)cc(Cl)c(C)c1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: COc1c(C(C)NC(=O)OCc2ccccc2)cc(Cl)c(C)c1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 95 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
A mixture of benzyl [1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]carbamate (0.48 g, 1.2 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.40 g, 1.3 mmol, from Aldrich), sodium carbonate (250 mg, 2.3 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (110 mg, 0.14 mmol) in acetonitrile (4.0 mL)/water (1 mL) was placed under vacuum and then refilled with N2. The reaction was stirred at 95° C. for 3 hours. The mixture was diluted with EtOAc, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The resultant residue was purified by chromatography eluting with 0 to 20% EtOAc in hexanes to provide the desired product (0.55 g, 90%). LCMS calculated for C28H35ClN2O5Na (M+Na)+: m/z=537.2. found: 537.3.