Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[F:17][C:18]1[C:23]([CH2:24]O)=[CH:22][CH:21]=[CH:20][N:19]=1.[F:26][C:27]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])=[CH:32][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[F:26][C:27]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:28]=1[O:29][C:30]1[CH:31]=[CH:32][C:33]([N:36]([CH2:24][C:23]2[C:18]([F:17])=[N:19][CH:20]=[CH:21][CH:22]=2)[S:37]([CH2:40][CH3:41])(=[O:38])=[O:39])=[CH:34][CH:35]=1
Reactant: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)cc1
Reactant: OCc1cccnc1F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCS(=O)(=O)N(Cc1cccnc1F)c1ccc(Oc2ccc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 42.5 %

Procedure:
Di-tert-butyl azodicarboxylate (0.36 g, 1.57 mmol) was added to a suspension of (2-fluoropyridin-3-yl)methanol (10, 0.20 g, 1.57 mmol), N-(4-(2,4-difluorophenoxy)phenyl)-N-ethylsulfonylamine (0.49 g, 1.56 mmol) and polystyrene resin-bound triphenylphosphine (0.52 g, 1.57 mmol, ˜3 mmol/g) in anhydrous tetrahydrofuran (5 mL) at 0° C. under nitrogen. The resulting yellow suspension was warmed to room temperature and stirred for 19 h, after which additional polystyrene resin bound triphenylphosphine (0.52 g, 1.57 mmol, ˜3 mmol/g) and di-tert-butyl azodicarboxylate (0.36 g, 1.57 mmol) were added. This solution was stirred for 24 h after which the suspension was diluted with anhydrous tetrahydrofuran (100 mL) and the solids were removed by vacuum filtration. The filtrate solvent was removed under reduced pressure to provide the crude product as a yellow oil. This oil was purified by medium pressure liquid chromatography on silica gel, eluting with hexanes/ethyl acetate (7:3), to provide a colorless oil. This oil was triturated with hexanes/ethyl acetate (4-5 mL) to give the title compound as a white powder (0.28 g, 53%): mp 110-112° C.; TLC Rf (3:2 hexanes/ethyl acetate)=0.44; 1H NMR (300 MHz) 8.11 (m, 1H), 7.90 (m, 1H), 7.24-7.15 (m, 3H), 7.11-7.03 (m, 1H), 6.98-6.86 (m, 2H), 6.84 (d, J=6.8 Hz, 2H), 4.91 (s, 2H), 3.15-3.07 (q, J=7.4 Hz, 2H), 1.43 (t, J=7.4 Hz, 1H) ppm; 13C NMR (75 MHz) 163.3, 161.3, 160.1, 157.8, 156.5, 153.1, 147.5 (d, J=14.9 Hz), 141.7, 139.1, 133.6, 130.5, 123.8 (d, J=9.7 Hz), 122.1, 119.1 (d, J=29.2 Hz), 117.5, 112.0 (d, J=22.9 Hz), 106.0 (t, J=24.3 Hz), 49.1, 46.0, 8.44 ppm; APCI MS m/z 423 [C20H17F3N2O3S+H]+. Anal. Calcd. for C20H17F3N2O3S: C, 56.87; H, 4.06; N, 6.63. Found: C, 56.90; H, 4.10; N, 6.45.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH2:13][CH2:14][CH3:15])(=[O:12])=[O:11].C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.CN(C)[CH:38]=[O:39]>O1CCCC1.O>[F:1][C:2]1[C:7]([CH:38]=[O:39])=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH2:13][CH2:14][CH3:15])(=[O:12])=[O:11]
Reactant: CN(C)C=O
Reactant: CCCS(=O)(=O)Nc1ccc(F)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C=O)c1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To propane-1-sulfonic acid (2,4-difluoro-phenyl)-amide (72, 1.5 g, 6.38 mmol) in tetrahydrofuran (10 mL) under an atmosphere of nitrogen, cooled in a −78° C. acetone/dry ice bath was added lithium diisopropylamide (0.80 M in tetrahydrofuran, 24 mL, freshly prepared from n-butyllithium and diisopropylamine). After 30 minutes, N,N-dimethyl-formamide (542 μL, 7.018 mmol) was added dropwise to the reaction. The reaction was stirred for 30 minutes at −78° C. and then allowed to warm to room temperature for 40 minutes. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 5% ethyl acetate in hexane to give a light yellow solid (73, 300 mg, 18%). MS (ESI) [M−H+]−=262.3.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:15]#[N:16])=[CH:10][N:9]=1)=[O:7])(C)(C)C.COC1C=CC=C(OC)C=1.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[NH2:14][C:13]1[C:8]([C:6]([OH:7])=[O:5])=[N:9][CH:10]=[C:11]([C:15]#[N:16])[CH:12]=1
Reactant: CC(C)(C)OC(=O)c1ncc(C#N)cc1N
Agent: COc1cccc(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: N#Cc1cnc(C(=O)O)c(N)c1
Reaction time: 6 h

Procedure:
To a mixture of 3-amino-5-cyano-pyridine-2-carboxylic acid tert-butyl ester (60 mg, 0.274 mmol) and 1,3-dimethoxybenzene (0.358 ml, 2.74 mmol) was added dropwise within 10 min TFA (0.59 ml, 7.66 mmol) and the reaction mixture was stirred for 6 h. Toluene was added and the solvents were evaporated to provide the title compound as yellow solid. The product was used for the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1>O1CCCC1>[CH3:10][O:9][C:4]1[N:3]=[C:2]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:7]=[C:6]([CH3:8])[N:5]=1
Reactant: COc1nc(C)cc(Cl)n1
Reactant: c1nc[nH]n1
Solvent: C1CCOC1
Product: COc1nc(C)cc(-n2cncn2)n1
Yield: 22.5 %

Procedure:
In anhydrous tetrahydrofuran, 159 mg of 4-chloro-2-methoxy-6-methylpyrimidine was substituted with 69 mg of 1,2,4-triazole. The reaction mixture was treated according to the procedure of Example 5 to yield 43 mg of 2-methoxy-6-methyl-4-(1,2,4-triazol-1-yl)pyrimidine, recrystallized from n-hexane, having a melting point of 98°-98.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH:23]=[CH2:24])=[C:13]([C:17]3[CH2:18][CH2:19][O:20][CH2:21][CH:22]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]2[C:15](=[CH:14][C:13]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:12]([CH2:23][CH3:24])[CH:11]=2)[CH2:16]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1cc2c(cc1C1=CCOCC1)CN(C(=O)OC(C)(C)C)C2
Agent: O=C[O-]
Agent: [NH4+]
Product: CCc1cc2c(cc1C1CCOCC1)CN(C(=O)OC(C)(C)C)C2

Procedure:
Prepared in analogy to Example A49(b) from 5-(3,6-dihydro-2H-pyran-4-yl)-6-vinyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and ammonium formate. Yellow oil. MS (m/e): 276.3 ([M+H-Me2C═CH2]+, 100%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:3]=12.[H-].[Na+].[C:17](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.[CH3:38]N(C=O)C>>[CH3:38][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:3]=12
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1n[nH]c2nccc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1ccnc2c1c(C(F)(F)F)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
4-iodo-3-(trifluoromethyl)-1H-pyrazolo[5,4-b]pyridine (28.7 g, 91.69 mmol) was dissolved in dry DMF (300 mL). The mixture was cooled in an ice bath and sodium hydride (4.036 g, 100.9 mmol) was added portionwise over 10 minutes. The mixture was stirred at 0° C. for 30 minutes and then treated with trityl chloride (26.84 g, 96.27 mmol) in one portion. The reaction was allowed to warm to ambient and stirred for 16 hours. The reaction mixture was cooled in an ice bath and water (500 ml) was added slowly. The resultant solid was allowed to stir for 30 minutes and then filtered, washed with water and dried at 50° C. under high vacuum (50.5 g, 99% Yield).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[CH:9]2)=[O:5].[CH2:16]([Mg]Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[NH4+]>O1CCCC1>[NH:11]1[C:12]2[C:8](=[CH:7][C:6]([C:4](=[O:5])[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][CH:13]=2)[CH:9]=[N:10]1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CON(C)C(=O)c1ccc2[nH]ncc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of Example 75B (900 mg, 4.39 mmol) in tetrahydrofuran (10 mL) was cooled under argon with an ice bath and treated with a 2M solution of benzyl magnesium chloride in tetrahydrofuran (6.6 mL, 13.16 mmol). The reaction was stirred overnight at room temperature followed by the addition of one more equivalent of benzyl magnesium chloride. The mixture was heated at 70° C. for 9 hours. One more equivalent of benzylmagnesium chloride was added, and the reaction was heated at 70° C. for another 90 minutes and was allowed to cool to room temperature. Aqueous saturated ammonium chloride was added, and the product was extracted with ethyl acetate and purified by silica gel column chromatography using 30% ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z 237.1 (M+H)+.
Reaction SMILES: BrC1C=CC2C3N(CC(C)C)C(CCCC)=NC=3C=[N:9]C=2C=1.COC1C=C(OC)C=CC=1B(O)O.[CH2:36]([C:40]1[N:41]([CH2:63][CH:64]([CH3:66])[CH3:65])[C:42]2[C:51]3[CH:50]=[CH:49][C:48]([C:52]4[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][C:53]=4[O:60][CH3:61])=[CH:47][C:46]=3[N:45]=[CH:44][C:43]=2[N:62]=1)[CH2:37][CH2:38][CH3:39]>>[CH2:36]([C:40]1[N:41]([CH2:63][CH:64]([CH3:65])[CH3:66])[C:42]2[C:51]3[CH:50]=[CH:49][C:48]([C:52]4[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][C:53]=4[O:60][CH3:61])=[CH:47][C:46]=3[N:45]=[C:44]([NH2:9])[C:43]=2[N:62]=1)[CH2:37][CH2:38][CH3:39]
Reactant: CCCCc1nc2cnc3cc(-c4ccc(OC)cc4OC)ccc3c2n1CC(C)C
Reactant: CCCCc1nc2cnc3cc(Br)ccc3c2n1CC(C)C
Agent: COc1ccc(B(O)O)c(OC)c1
Product: CCCCc1nc2c(N)nc3cc(-c4ccc(OC)cc4OC)ccc3c2n1CC(C)C

Procedure:
7-Bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinoline and 2,4-dimethoxybenzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. The resulting 2-butyl-7-(2,4-dimethoxyphenyl)-1-isobutyl-1H-imidazo[4,5-c]quinoline was oxidized and then aminated according to the general procedures described in Parts H and I of Example 1 and purified by chromatography on silica gel (8% methanol in CH2Cl2 to 10% methanol in CH2Cl2 gradient) followed by recrystallization from 1/1 ethyl acetate/hexane to afford 2-butyl-7-(2,4-dimethoxyphenyl)-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine as a pale orange solid, m.p. 187–189° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([CH:12]([CH3:14])[CH3:13])[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1.[CH2:15]=[CH:16][C:17](C)([CH3:19])[CH3:18].[CH2:21]1CCCCC1>>[CH3:13][C:12]1([CH3:21])[C:5]2[C:10](=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=2)[C:17]([CH3:19])([CH3:18])[CH:16]([CH3:15])[CH2:14]1
Reactant: C1CCCCC1
Reactant: C=CC(C)(C)C
Reactant: Cc1ccc(C(C)C)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc2c(c1)C(C)(C)C(C)CC2(C)C
Temperature: 16 °C
Reaction time: 0.5 h

Procedure:
The starting material 1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene (HMT) was prepared by substantially following the procedures of Frank, U.S. Pat. No. 4,877,913. Specifically, a 100 ml, four-necked, round bottom flask was charged with cyclohexane (7.17 g) and anhydrous aluminum chloride (1.004 g), and cooled to about 16° C. A 60 ml addition funnel was charged with para-cymene (39.87 g), diisobutylene-2 (8.34 g), and neohexene (6.25 g) and connected to the flask. The funnel mixture was added to the flask over a period of about one hour and the flask mixture stirred 30 minutes following addition, while maintaining the temperature at about 16° C. The reaction was then quenched with deionized water (15 ml), and the organic phase separated and washed with, in order, 5% HCl, 10% Na2CO3, and 50% brine. The aqueous layers were then dried over K2CO3, filtered, and evaporated to yield a crude product (41.13 g) containing 28.16 weight % HMT.
Reaction SMILES: S(C)C.[CH3:4][Li].[CH2:6]([N:13]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@@H:14]([CH2:17][CH3:18])[CH:15]=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCOCC>[CH2:19]([N:13]([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C@@H:14]([CH2:17][CH3:18])[C@H:15]([OH:16])[CH3:4])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: [Li]C
Reactant: CC[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Solvent: CSC
Solvent: CCOCC
Product: CC[C@@H]([C@@H](C)O)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
To a stirred suspension of CuBr.SMe2 (1.54 g, 7.5 mmol) in anhydrous ether under an argon atmosphere at −78° C., was added methyllithium (1.6M in ether, 9.4 ml, 15 mmol) dropwise. After the addition was complete, the reaction was allowed to warm to room temperature. The reaction was recooled to −78° C. and a solution of (S)-2-(dibenzylamino)butanal (1 g, 3.75 mmol) in ether (20 ml) was added dropwise. After the addition, continued stirring for 2 h The reaction was then quenched with a saturated aqueous solution of NH4Cl (10 ml). The reaction mixture was extracted with ether (2×30 ml) and the combined organic phase washed with brine (20 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by flash silica gel gradient column chromatography, eluted with hexane:ethyl acetate (100:0→80:20) to afford the product as a light yellow oil (0.95 g, 89%) as the only isomer. δH (250 MHz, CDCl3) 1.05 (3 H, t, J 7.5, CHCH2CH3), 1.25 [3 H, d, J 7.5, CH(CH3)OH], 1.6-1.49 (1 H, m, CHHCH3), 1.88-1.73 (1 H, m, CHHCH3), 2.41 (1 H, s, br, OH), 2.66-2.59 (1 H, m, CHCH2CH3), 3.85-3.65 (4 H, m, 2×CH2Ph), 4.05-3.9 (1 H, m, CHOH), 7.41-7.25 (10 H, m, ArH) δC (250 MHz, CDCl3) 140.05 (2×C), 128.98 (4×CH), 128.37 (4×CH), 127.3 (2×CH), 66.81 (CH), 63.65 (CH), 55.41 (CH2), 20.63 (CH3) 18.44 (CH2), 12.5 (CH3)
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:4]([N:6]1[CH2:17][CH2:16][CH2:15][C@H:7]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:5])[CH3:3].[H][H].C(Cl)(Cl)Cl.CO>CO.[Pd]>[NH2:1][C@H:2]([C:4]([N:6]1[CH2:17][CH2:16][CH2:15][C@H:7]1[C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])=[O:5])[CH3:3]
Reactant: [H][H]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C

Procedure:
9.36 g of Z-Ala-Pro-OtBu are hydrogenated in 100 ml of methanol in the presence of 500 mg of Pd on charcoal (10 %) at room temperature. The hydrogen uptake has ended after 90 minutes. The solution is freed of catalyst by filtration and evaporated in a waterpump vacuum at 30°C to give an oil. This proves to be homogeneous in a thin layer chromatogram on silica gel. Rf = 0.35 in the system chloroform-methanol (1:1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]([OH:14])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:16][NH:17][O:18][CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:19][O:18][N:17]([CH3:16])[C:12]([C:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11]1)=[O:14]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: CNOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CON(C)C(=O)C1(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(tert-butoxycarbonylamino)cyclopropanecarboxylic acid (11.00 g, 54.7 mmol, 1.0 eq) in methylene chloride at 0° C. was added N,O-dimethyl hydroxylamine HCl (5.9 g, 60.4 mmol, 1.1 eq), TEA (13.82 g, 13.6 mmol, 2.5 eq) and HATU (22.90 g, 60.2 mmol, 1.1 eq). The resulting reaction mixture was stirred at room temperature under an N2 atmosphere overnight. After TLC showed reaction was completed, the reaction mixture was concentrated, diluted with water and extracted with diethyl ether. The organic layer was washed with brine, dried over Na2SO4 and concentrated to get the desired product as a white solid. Yield: 13.00 g (97.52%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1.[CH2:20]([NH:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C1C=CN=CC=1)C1C2C(=NC=CN=2)N=C(C2C=C(Br)C=CC=2F)N=1)CCC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[N:17]=[C:16]([N:28]([CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1
Reactant: O=c1[nH]c(-c2cc(Br)ccc2F)nc2nccnc12
Reactant: c1ccc(CCNc2ccncc2)cc1
Agent: CCCCN(c1ccncc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12
Product: Fc1ccc(Br)cc1-c1nc(N(CCc2ccccc2)c2ccncc2)c2nccnc2n1

Procedure:
The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 4-(phenethylamino)pyridine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH2:6].C(O)(=[O:12])C.BrN1C(=O)CCC1=O.[OH-].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[CH2:6][O:12]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)O
Reactant: C=Cc1cccc(Cl)c1
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Clc1cccc(C2CO2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of m-chlorostyrene (5.70 g, 41.0 mmol) and acetic acid (2.33 mL, 40.9 mmol) in dioxane (33 mL) and H2O (78 mL) at 0° C. was added N-bromosuccinimide (8.02 g, 45.0 mmol) in three portions. The reaction was allowed to warm to RT After 4 hours, 2N NaOH (60 mL) was added and the reaction was allowed to stir at RT overnight. The reaction mixture was partitioned between water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give 6.20 g of a slightly tinted oil which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][CH2:13][OH:14])[C:5]#[N:6].C1(C)C=CC=CC=1.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl.C(OCC)(=O)C>Cl.[Cl-].[Na+].O>[OH:14][CH2:13][CH2:12][CH2:11][N:10]1[C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[NH:1][C:23]1=[O:25]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: N#Cc1ccc(NCCCO)c(N)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(c1)[nH]c(=O)n2CCCO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
100 mg (0.52 mmol) of 3-amino-4-[(3-hydroxypropyl)amino]benzonitrile (Intermediate 12) are dissolved in 2.5 ml of 2N aqueous HCl and 1.5 ml of toluene are added. 150 mg (0.51 mmol) of triphosgene are added and the system is stirred at rt for 18 hr. After adding 75 additional mg of triphosgene and prosecuting the stirring for 1 hour 5 ml of brine and 25 ml of ethyl acetate are added and the system is stirred for 10 minutes. The organic layer is isolated and the aqueous one is extracted with 4×10 ml of ethyl acetate. The combined organic phases are washed with brine, dried and concentrated to give 106 mg (93% yield) of 100 pure (UPLC) title compound.
Reaction SMILES: [CH3:1][C:2](=[O:23])[C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C@H:10]([CH2:11][C:12](=[O:22])[CH2:13][CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[CH3:24][Mg]Cl>COC(C)(C)C>[CH3:1][C:2]([C@@H:3]1[C@@:20]2([CH3:21])[CH2:19][CH2:18][C@@H:17]3[C@@:15]4([CH3:16])[CH2:14][CH2:13][C@:12]([OH:22])([CH3:24])[CH2:11][C@@H:10]4[CH2:9][CH2:8][C@H:7]3[C@@H:6]2[CH2:5][CH2:4]1)=[O:23]
Reactant: C[Mg]Cl
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: COC(C)(C)C
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
Reaction time: 6 h

Procedure:
5α-Pregnane 3,20-dione (10 g) is reacted with a reagent obtained by reacting FeCl3 (5.2 g) and MeMgCl (4 equiv, based on FeCl3) in t-butyl methyl ether (anhydrous, 200 mf) at −25° C. for 3h. The reaction is quenched with acetic acid (32 ml). The reaction mixture is concentrated in vacuo and the residue is stirred with 3N HCI for 6 h. The solid is collected by filtration, washed with water and dried at 50° C. under vacuum to obtain crude ganaxolone. The crude product is dissolved in THF (33 mL) at reflux and filtered not. The filtrate is added with water (45 mL) to obtain a suspension, which is collected by filtration, washed with water and dried. The dried product is further slurried in ethyl acetate (50 mL) at 70° C. for 19 h, The suspension is cooled to 0° C. and filtered. The ethyl acetate slurry step was repeated second time to obtain purified ganaxolone.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:13]=2[CH3:19])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[N:20]1([C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.CN(CCCN=C=N)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[C:16]([NH:18][C:30](=[O:31])[C:29]3[CH:28]=[CH:27][C:26]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:34][CH:33]=3)[CH:15]=[CH:14][C:13]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Reactant: CCOC(=O)c1ccc(-c2cc(N)ccc2C)cc1
Agent: CN(C)CCCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2cc(NC(=O)c3ccc(N4CCOCC4)cc3)ccc2C)cc1
Yield: 88.1 %

Procedure:
5′-Amino-2′-methyl-biphenyl-4-carboxylic acid ethyl ester (2.15 g), 4-morpholin-4-yl benzoic acid (1.27 g), N-methylmorpholine (2.05 ml), 1-hydroxybenzotriazole (826 mg) and 1-ethyl-3-(3-(dimethylaminopropyl)carbodiimide hydrochloride (1.17 g) in dry DMF (30 ml) was stirred at 20 C for 18 h. Then the DMF was evaporated and the residue partitioned between water and dichloromethane. The dried extracts were evaporated and the residue purified on silica gel. Elution with 1-2% methanol in dichloromethane gave a colourless solid (2.4 g)
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:21]([OH:30])(=[O:29])[C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)[SH:24].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][S:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[C:21]([OH:30])=[O:29])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1csc(-c2cc3cc(CCl)ccc3o2)n1
Reactant: O=C(O)c1ccccc1S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1csc(-c2cc3cc(CSc4ccccc4C(=O)O)ccc3o2)n1
Reaction time: 1 h
Yield: 52 %

Procedure:
To a solution of 4-tert-butyl-2-(5-chloromethylbenzofuran-2-yl)thiazole (0.68 g) and thiosalicylic acid (0.72 g) in N,N-dimethylformamide (5 ml), potassium carbonate (0.78 g) was added dropwise at 100° C. After being stirred for one hour, the reaction mixture was cooled, poured into a mixture of ice and diluted aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution to remove thiosalicylic acid, dried over magnesium sulfate and concentrated under reduced pressure. The residue was crystallized with ethyl acetate and filtered to give 4-tert-butyl-2-[5-(2-carboxyphenylthiomethyl)benzofuran-2-yl]thiazole (0.49 g).