Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@@:8]2([CH3:19])[NH:13][C:12](=O)[C:11]([CH3:16])([CH3:15])[S:10](=[O:18])(=[O:17])[CH2:9]2)[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@@:8]2([CH3:19])[NH:13][C:12](=[S:30])[C:11]([CH3:16])([CH3:15])[S:10](=[O:18])(=[O:17])[CH2:9]2)[CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)C(=O)N[C@](C)(c2cc(Br)ccc2F)CS1(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)C(=S)N[C@](C)(c2cc(Br)ccc2F)CS1(=O)=O
Temperature: 80 °C
Reaction time: 10 h
Yield: 89.1 %

Procedure:
To a solution of (R)-5-(5-bromo-2-fluoro-phenyl)-2,2,5-trimethyl-1,1-dioxo-1λ6-thiomorpholin-3-one (1.4 g, 3.84 mmol, Eq: 1.00) in dioxane (29.5 ml) was added Lawesson's reagent (3.10 g, 7.68 mmol, Eq: 2.00). The reaction mixture was stirred at 80° C. for 10 hours. The reaction mixture was poured into sat. NaHCO3-solution and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to give a light yellow oil. The residue was chromatographed on 20 g silica gel with ethyl acetate in heptane to give (R)-5-(5-bromo-2-fluoro-phenyl)-2,2,5-trimethyl-1,1-dioxo-1λ6-thiomorpholin-3-thione (1.3 g, 3.42 mmol, 88.9% yield) as a light yellow foam. MS (ISP): m/z=380.0 [M+H]+ and 382.3 [M+2+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.[N+]([O-])([O-])=O.[K+].[N+:17]([O-])(O)=O.[C:21]([OH:24])(=O)[CH3:22]>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:17][C:21](=[O:24])[CH3:22])=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc2ccncc12
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Product: CC(=O)Nc1ccc(C)c2cnccc12

Procedure:
In Scheme 12, the 8-methylisoquinoline (obtained as described above) is nitrated with a suitable nitrating agent such as potassium nitrate in sulfuric acid or a mixture of nitric acid, sulfuric acid and acetic acid to yield 5-nitro-8-methylsioquinoline, which is reduced and then acetylated to give the N-(8-methyl-isoquinolin-5-yl)-acetamide. This amide may be brominated by a radical brominating agent such as N-bromosuccinimide/benzoyl peroxide to give the dibromo isoquinoline acetamide. The dibromo intermediate may then be hydrolyzed in the presence of base to yield the deprotected aldehyde aminoisoquinoline, which may be further elaborated by the chemistry illustrated in Schemes 5 and 6 to the target ureas.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[F:16][C:17]([F:50])([F:49])[C:18]1[CH:19]=[C:20]([CH2:28][O:29][C@@H:30]2[CH2:35][CH2:34][CH2:33][N:32](CC3C=[NH+]C=CC=3)[C@@H:31]2[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1>CN(C)C=O.O>[F:26][C:24]([F:25])([F:27])[C:22]1[CH:21]=[C:20]([CH2:28][O:29][C@H:30]2[CH2:35][CH2:34][CH2:33][N:32]([CH2:2][C:3]3[CH:8]=[N:7][CH:6]=[CH:5][N:4]=3)[C@H:31]2[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:19]=[C:18]([C:17]([F:50])([F:16])[F:49])[CH:23]=1
Reactant: FC(F)(F)c1cc(CO[C@@H]2CCCN(Cc3ccc[nH+]c3)[C@@H]2c2ccccc2)cc(C(F)(F)F)c1
Reactant: ClCc1cnccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(CO[C@H]2CCCN(Cc3cnccn3)[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Temperature: 60 °C

Procedure:
2-(Chloromethyl)pyrazine (0.17 g), potassium carbonate (0.6 g) and the compound of Description 3 (0.35 g) were suspended in dimethylformamide (3 ml); the reaction mixture was heated at 60° C. for 12 h. The mixture was cooled, diluted with water (30 ml) and extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford a brown oil. The product was purified by column chromatography on silica gel using a gradient elution of 15-35% ethyl acetate in hexane. This afforded the product as a white solid, which was recrystallised from pentane to give colourless crystals: mp 108°-110° C. 1H NMR (360 MHz, DMSO-d6) d 1.42-1.60 (2H, m NCH2CH2CH2), 1.77-1.92 (1H, m, NCH2CHH), 2.13-2.25 (2H, m, NCHH+NCH2CHH), 2.84-2.92 (1H, m, NCHH), 3.12 (1H, d, J=14.0 Hz, NCHH-pyrazine), 3.55 (1H, m, CHO), 3.63 (1H, m, CHPh), 3.78 (1H, d, 14.0 Hz, NCHH-pyrazine), 4.11 (1H, d, J=13.0 Hz, OCHHAr), 4.64 (1H, d, J=13.0 Hz, OCHHAr), 7.20-7.33 (3H, m, ArH), 7.49-7.56 (2H, m, ArH), 7.71 (2H, s, ArH), 7.93 (1H, s, ArH), 8.48-8.63 (3H, m, ArH); MS (CI+) 496 (M+ +1, 60%). Found: C, 60.90; H, 4.86; N, 8.48. Calcd. for C25H23F6N3O: C, 60.60; H, 4.68; N, 8.48%.
Reaction SMILES: C(C1C=C(CCC2C=CN3C(=O)C(/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27])=C(N4CCOCC4)N=C3C=2)SC=1)C.[CH:32]([O:34][C@H:35]1[CH2:40][CH2:39][CH2:38][N:37]([C:41]2[N:42]=[C:43]3[CH:53]=[C:52]([C:54]([NH:56][C:57]4[S:58][CH:59]=[C:60]([C:62]([CH3:65])([CH3:64])[CH3:63])[N:61]=4)=[O:55])[CH:51]=[CH:50][N:44]3[C:45](=[O:49])[C:46]=2C=O)[CH2:36]1)=[O:33]>>[C:62]([C:60]1[N:61]=[C:57]([NH:56][C:54]([C:52]2[CH:51]=[CH:50][N:44]3[C:45](=[O:49])[C:46](/[CH:24]=[CH:25]/[C:26]([O:28][C:52]([CH3:54])([CH3:53])[CH3:51])=[O:27])=[C:41]([N:37]4[CH2:38][CH2:39][CH2:40][C@H:35]([O:34][CH:32]=[O:33])[CH2:36]4)[N:42]=[C:43]3[CH:53]=2)=[O:55])[S:58][CH:59]=1)([CH3:65])([CH3:64])[CH3:63]
Reactant: CCc1csc(CCc2ccn3c(=O)c(/C=C/C(=O)O)c(N4CCOCC4)nc3c2)c1
Reactant: CC(C)(C)c1csc(NC(=O)c2ccn3c(=O)c(C=O)c(N4CCC[C@H](OC=O)C4)nc3c2)n1
Product: CC(C)(C)OC(=O)/C=C/c1c(N2CCC[C@H](OC=O)C2)nc2cc(C(=O)Nc3nc(C(C)(C)C)cs3)ccn2c1=O
Yield: 100 %

Procedure:
Reactions were performed in the same manner as in Example 1, (J) by using (3S)-1-[8-({[4-(tert-butyl)-1,3-thiazol-2-yl]amino}carbonyl)-3-formyl-4-oxo-4H-pyrido-[1,2-a]pyrimidin-2-yl]hexahydro-3-pyridinyl formate (524 mg, 1.083 mmol), and the resulting residue was purified by silica gel column chromatography (chloroform→chloroform:methanol=100:1→70:1→50:1) to obtain 742 mg (100% or more) of the title compound as a brown oily substance in a mixture containing byproducts.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]3[C:26]4[CH2:25][CH2:24][N:23]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:22][C:21]=4[C:20]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)=[N:19]3)[CH2:11][CH2:10]2)=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.C[Si]([N:45]=[C:46]=[O:47])(C)C.CO.C(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]3[C:26]4[CH2:25][CH2:24][N:23]([S:27]([CH3:30])(=[O:28])=[O:29])[CH2:22][C:21]=4[C:20]([C:31]4[CH:32]=[CH:33][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:35][CH:36]=4)=[N:19]3)[CH2:11][CH2:10]2)=[C:4]([NH:8][C:46]([NH2:45])=[O:47])[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCN(c3c(N)cccc3Cl)CC2)C1
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCN(c3c(Cl)cccc3NC(N)=O)CC2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 22.5 %

Procedure:
To a stirred solution of 3-chloro-2-(4-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenylamine (0.062 g, 0.104 mmol) in CH2Cl2 (0.52 mL) was added trimethylsilyl isocyanate (0.017 mL, 0.125 mmol). The reaction mixture was allowed to stir for 48 h at room temperature. The reaction had not gone to completion, so an additional 0.017 mL (0.125 mmol) of trimethylsilyl isocyanate was added and the reaction was heated to 45° C. for 10 h. Column chromatography (silica, 3-10% MeOH/CH2Cl2) afforded 1-[3-chloro-2-(4-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenyl]-urea (0.015 g, 22%). MS (electrospray): exact mass calculated for C28H33CIF3N7O3S, 639.2; m/z found, 640.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.26 (br s, 1H), 8.05 (d, J=8.2 Hz, 1H), 7.73 (d, J=8.2 Hz, 2H), 7.66 (d, J=8.2 Hz, 2H), 7.09 (t, J=8.2 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 4.65 (s, 2H), 4.55 (s, 2H), 4.15 (t, J=6.7 Hz, 2H), 3.65-3.73 (m, 4H), 2.96 (t, J=5.6 Hz, 2H), 2.87-2.92 (m, 2H), 2.91 (s, 3H), 2.70 (d, J=11.4 Hz, 2H), 2.40 (t, J=6.7 Hz, 2H), 2.09-2.22 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:24][CH3:25])=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[N:6][CH:7]=1.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1B(O)O>>[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:16]1([O:24][CH3:25])[C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:19]2[N:11]([C:9](=[O:10])[NH:8][C:4]3[CH:5]=[N:6][CH:7]=[CH:2][CH:3]=3)[CH2:12][CH2:13][C:14]=2[CH2:15]1
Reactant: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cncc(Br)c1)CC2
Reactant: OB(O)c1ccco1
Product: COC1(c2ccco2)CC2=C(C=C1C(F)(F)F)N(C(=O)Nc1cccnc1)CC2
Yield: 80 %

Procedure:
This was prepared from 1-(5-bromopyrid-3-ylcarbamoyl)-5-methoxy-6-trifluoromethylindoline and 2-furylboronic acid by the same method as for Example 10, affording the title compound as a pale brown crystalline solid in 80% yield, m.p. 92-94° C.
Reaction SMILES: [Si:1]([O-])([O-:4])([O-:3])[O-:2].[Na+:6].[Na+].[Na+].[Na+].O=[Al-:11]=O.[Na+].[OH-].[Na+]>O>[O-:3][Si:1]([O-:4])=[O:2].[O-:3][Si:1]([O-:4])=[O:2].[Na+:6].[Al+3:11]
Reactant: O=[Al-]=O
Reactant: [O-][Si]([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[Si]([O-])[O-]
Product: [Al+3]

Procedure:
Sodium aluminosilicate gel was prepared from 519 grams of N brand sodium silicate solution, 205 grams of sodium aluminate crystals, 40 grams of sodium hydroxide pellets and 500 milliliters of deionized water. The particular sodium silicate solution used analyzed 29.0% by weight SiO2 and 9.1% by weight Na2O, with the balance water. The gel was prepared by first dissolving the sodium hydroxide, then the sodium aluminate, in the deionized water. The sodium silicate solution was placed in a beaker outfitted with an overhead stirrer. While the sodium silicate solution was stirring, the caustic sodium aluminate solution was poured in. This caused the creation of a stiff white gel from the two generally clear solutions. The stiff gel was finally homogenized by mixing in a WARING BLENDER mixer for one minute on the lowest speed setting.
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][N:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:26])[C:4]([O:6][CH3:7])=[O:5].[Cl-].[NH4+].O>CCO.C(OCC)(=O)C.[Fe]>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:12]2[CH:11]=[C:10]3[C:15]([CH2:16][N:8]([C@@H:3]([CH:2]([CH3:27])[CH3:1])[C:4]([O:6][CH3:7])=[O:5])[C:9]3=[O:26])=[CH:14][CH:13]=2)=[N:18][CH:19]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc([N+](=O)[O-])cn3)cc2C1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cn3)cc2C1=O

Procedure:
The compound of example 391 (1.5 g, 0.0040 mol), iron (0.533 g, 0.0095 mol) and ammonium chloride (0.930 g, 0.0174 mol) in EtOH: H2O (22.5 mL, 15:7.5) was refluxed for about 16 h. After completion of the reaction, the reaction mixture was filtered through celite. The filtrate was concentrated to obtain a residue which was dissolved in ethyl acetate and washed with water and brine, dried over anhydrous sodium sulfate and concentrated to obtain a residue, which was purified by column chromatography (silica gel, 30% ethyl acetate in petroleum ether) to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:29][OH:30].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:29]\[OH:30])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)CC(c2ccc(Br)cc2)c2ccc(Cl)cc2F)ccc1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(Br)cc2)c2ccc(Cl)cc2F)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-phenyl)-3-(4-chloro-2-fluoro-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing 12% of the corresponding Z isomer as an off-white foam, MS (ESI+): m/z=463.0 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]2[CH:8]=[N:7][N:6]=[C:5]2[C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.[CH2:15]=[O:16]>>[CH:1]1([N:4]2[C:5]([C:9]3[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=3)=[N:6][N:7]=[C:8]2[CH2:15][OH:16])[CH2:3][CH2:2]1
Reactant: C=O
Reactant: c1cc(-c2nncn2C2CC2)ccn1
Product: OCc1nnc(-c2ccncc2)n1C1CC1
Temperature: 135 °C
Yield: 85 %

Procedure:
4-(4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine (6.85 g, 36.8 mmol) was mixed with 37% formaldehyde (30 mL) in a sealed vial and heated at 135° C. o.n. The reaction mixture was concentrated with silica gel and then mixed with MeOH. The mixture was filtered and washed with MeOH. The filtrate was concentrated with silica gel again and loaded on a flash column and eluted with 10% MeOH (2 M NH3) in DCM to give the title compound (6.8 g, 85%). 1H-NMR(DMSO-d6): 8.75(d, 2H), 7.84 (d, 2H), 5.63 (t, 1H), 4.72 (d, 2H), 3.66 (m, 1H), 1.04 (m, 2H), 0.73 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][C:16](=O)[CH2:15][CH2:14]1)(=[O:12])=[O:11].[CH2:25]([SH:28])[CH2:26][SH:27].B(F)(F)F.CCOCC.[OH-].[Na+]>ClCCl.CCCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[CH2:14][CH2:15][C:16]2([S:28][CH2:25][CH2:26][S:27]2)[CH:17]=[C:18]1[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:12])=[O:11]
Reactant: SCCS
Reactant: CCOC(=O)C1=CC(=O)CCC1S(=O)(=O)Nc1ccc(F)cc1Cl
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C1=CC2(CCC1S(=O)(=O)Nc1ccc(F)cc1Cl)SCCS2
Yield: 266.3 %

Procedure:
100 mg (0.27 mmol) of ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3-oxo-1-cyclohexene-1-carboxylate obtained in Example 7 was dissolved in 1 ml of dichloromethane and 0.034 ml (0.405 mmol) of ethane-1,2-dithiol and 0.025 ml (0.203 mmol) of boron trifluoride diethyl etherate were added thereto with stirring under ice-cooling, followed by stirring at room temperature for 1 hour. To the reaction solution was added a 1N aqueous sodium hydroxide solution and the mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The resulting solid was washed with diethyl ether and then with hexane to give 325 mg of the title compound as a white powder (76% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][C:7](=[O:16])[N:6]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:5]2=[O:22].CO[CH:25]1[CH:29]([CH2:30][O:31][CH:32]2[CH2:37]CCC[O:33]2)[CH2:28][CH:27](OC)O1>C(O)(=O)C>[CH3:21][S:18]([NH:17][N:6]1[C:5](=[O:22])[C:4]2[C:9](=[CH:10][C:11]([C:12]([F:13])([F:15])[F:14])=[C:2]([N:1]3[CH:27]=[CH:28][C:29]([CH2:30][O:31][C:32](=[O:33])[CH3:37])=[CH:25]3)[CH:3]=2)[NH:8][C:7]1=[O:16])(=[O:20])=[O:19]
Reactant: COC1CC(COC2CCCCO2)C(OC)O1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(N)cc2c1=O
Solvent: CC(=O)O
Product: CC(=O)OCc1ccn(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2C(F)(F)F)c1

Procedure:
To a solution of 130 mg (0.39 mmol) of N-(6-amino-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide in 5 ml of acetic acid a solution of 95 mg (0.39 mmol) of 2-(2,5-dimethoxy-tetrahydro-furan-3-ylmethoxy)-tetrahydro-pyran (prepared according to Frydman, Benjamin; Ojea, Maria I. 1,4-Diaminobutanes from furans: a new synthetic approach to substituted putrescines. Tetrahedron Letters (1998), 39(27), 4765-4768) is added and the reaction mixture is stirred at reflux for 3 hours. The solvent is evaporated at HV overnight to yield acetic acid 1-(3-methanesulfonylamino-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-yl)-1H-pyrrol-3-ylmethyl ester. 1H-NMR ; DMSO-d6 (400 MHz, ppm): 7.85 (s, 1H , aromatic); 7.62 (s, 1H , aromatic); 7.03 (s, 1H, N-CH═C(CH2) in pyrrol); 6.91 (m, 1H, N-CH═CH in pyrrol); 6.27 (m, 1H, CH═CH-C(CH2)-N in pyrrol); 4.96 (s, 2H, CH2-OCOCH3); 3.16 (s, 3H, SO2-CH3); 2.03 (s, 3H, CH2-OCOCH3); LC-MS: 459 [M-H]-; Agilent LC/MSD 1100 Series, LC-MS method: Column: SunFireC18, 4.6*50 mm, 3.5 μm; negative MS; water/acetonitril 95:5 to 5:95 in 5 min, flow: 1.5 ml/min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].P(Cl)(Cl)(Cl)(Cl)[Cl:15].C(Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([Cl:15])=[O:8]
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])c(C(=O)Cl)c1

Procedure:
The reaction of 36.2 g of 5-methyl-2-nitrobenzoic acid and 41.6 g of phosphorus pentachloride in 150 ml of toluene gave a crude product which was treated with methylene chloride to give 5-methyl-2-nitrobenzoyl chloride as an oil. When 30 g of this acid chloride in 50 ml of tetrahydrofuran was added to a warm solution of 30.9 g of 5-aminotetrazole monohydrate in 600 ml of tetrahydrofuran and 30 ml of water, a precipitate formed quickly. This was allowed to stand for 1 hour, the white solid was separated by filtration, washed with water and air dried to give 5-methyl-2-nitro-N-(1H-tetrazol-5-yl)benzamide melting at about 278°-279° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].Cl.N1C=CC=CC=1>C(OCCO)C>[Br:16][C:17]1[CH:18]=[C:19]([NH:20][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])[CH:21]=[CH:22][CH:23]=1
Reactant: COc1cccc2c(Cl)c(C#N)cnc12
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cccc2c(Nc3cccc(Br)c3)c(C#N)cnc12
Yield: 89.6 %

Procedure:
A solution of 328.0 mg (1.5 mmol) of 4-chloro-8-methoxy-3-quinolinecarbonitrile, 309.7 mg (1.8 mmol) of 3-bromoaniline and 173.3 mg (1.5 mmol) of pyridine hydrochloride in 15 ml of 2-ethoxyethanol was refluxed under nitrogen for 0.5 hours. The solvent was removed and the residue was diluted with water followed by neutralization to pH 7-8 with diluted sodium carbonate solution. The precipitate was collected and washed with ether and dried in vacuo to give 476.1 mg (89.6%) of the product as a yellow solid, m.p. 210-212° C.; mass spectrum (electrospray, m/e): M+H 353.8, 355.8.
Reaction SMILES: [CH3:1][Mg]Cl.[CH3:4][C:5](=[O:26])[C@@H:6]1[C@:23]2([CH3:24])[C@H:9]([C@H:10]3[C@H:20]([CH2:21][CH2:22]2)[C@:18]2([CH3:19])[C@H:13]([CH2:14][C:15](=[O:25])[CH2:16][CH2:17]2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[CH3:4][C:5]([C@@H:6]1[C@@:23]2([CH3:24])[CH2:22][CH2:21][C@@H:20]3[C@@:18]4([CH3:19])[CH2:17][CH2:16][C@:15]([OH:25])([CH3:1])[CH2:14][C@@H:13]4[CH2:12][CH2:11][C@H:10]3[C@@H:9]2[CH2:8][CH2:7]1)=[O:26]
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
Reactant: C[Mg]Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
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: 0 °C
Reaction time: 0.33 h
Yield: 75.9 %

Procedure:
Titanium tetrachloride (350 uL, 3.2 mmol) is added in a dropwise fashion to a solution of titanium tetraethoxide (2.42 g, 10.6 mmol) in tetrahydrofuran (anhydrous, 30 mL) cooled to 0° C. After stirring for 20 min at 0° C., methyl magnesium chloride (3M, 4.3 mL 12.9 mmol) in tetrahydrofuran solution is added dropwise while maintaining the temperature below 5° C. After stirring for an additional 20 minutes at 5° C., 5α-pregnane-3,20-dione (2.53 g, 8 mmol) was added in one portion. The reaction is warmed to 40° C. and stirred for 4 hours. The reaction mixture is quenched with 20 mL of methanol and the solvent removed in vacuo. The reaction mixture is partitioned between 100 ml of 3N HCl and 100 mL of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and brine and the solvent removed in vacuo to afford crude ganaxolone as a white solid of 75.9% pure ganaxolone by HPLC (Table 1, entry 3).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[N+](=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N-]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH2:16]([O:15][C:13]([CH:12]1[CH2:7][CH:6]1[C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)=[O:14])[CH3:17]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1ccc(F)cc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CC1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 120.1 %

Procedure:
In an oven-dried two-neck round flask equipped with condenser and Argon inlet was charged with 40 mL of newly opened anhydrous chloroform. Dry Argon gas was bubbled through the chloroform. copper (I) iodide (38 mg, 1 mol %) and palladium (II) acetate (45 mg, 1 mol %) were added to the Chloroform and stirred at room temperature for 15 minutes under argon. Then 4-fluorostyrene (2.4 mL, 20 mmol) in 20 mL of dry chloroform was added to the above solution. Finally ethyl diazoacetate (8.3 mL, 80 mmol) in 10 mL of chloroform was added dropwise to the reaction mixture over 2 hour. The reaction mixture was heated at 80° C. for overnight. The reaction mixture was cooled down to room temperature and rotavaped to afford dark green oil. The residue was diluted with 200 mL of ethyl acetate and washed with saturated sodium bicarbonate aqueous solution (1×50 mL), water (1×50 mL) and brine (1×50 mL) respectively. The ethyl acetate layer was dried over Sodium sulfate and concentrated to give 5 gram of light brown oil as crude product, which was purified with flash chromatography (40 gram prepacked column by Isco, Inc., 230-400 mesh, eluants: 0-20% ethyl acetate in hexanes) to obtain 2.625 grams of the desired product as clear oil. The trans configuration of the structure was confirmed by NOE of 1H NMR, yield=62%.
Reaction SMILES: [F:1][C:2]1([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.Cl.[NH2:17][OH:18].C(N(CC)CC)C>C(O)C.O>[F:1][C:2]1([C:8]2[CH:15]=[CH:14][C:11]([C:12](=[N:17][OH:18])[NH2:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: N#Cc1ccc(C2(F)CCOCC2)cc1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=NO)c1ccc(C2(F)CCOCC2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-(4-fluorotetrahydro-2H-pyran-4-yl)benzonitrile (Step 1, 180 mg, 0.877 mmol), hydroxylamine hydrochloride (134 mg, 1.93 mmol) and triethylamine (196 mg, 1.93 mmol) in ethanol (4.5 mL) was stirred and heated at reflux for 4 h. After being cooled to rt, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate. The organic extract was successively washed with brine and dried over anhydrous magnesium sulfate. After filtration and evaporation of the solvent, the title compound was obtained (201 mg, 76%): 1H NMR (500 MHz, DMSO-d6) δ 9.64 (s, 1H), 7.70 (d, 2H), 7.44 (d, 2H), 5.81 (s, 2H), 3.88-3.83 (m, 2H), 3.73-3.67 (m, 2H), 2.23-2.06 (m, 2H), 1.87-1.81 (m, 2H); DCI(NH3)-MS m/z 239 (MH)+; HPLC RT (Method I) 3.13 min.
Reaction SMILES: Br[C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[CH2:8]([Li])[CH2:9][CH2:10]C.[CH2:13](Br)[C:14]#C>CCCCCC.O1CCCC1>[CH3:6][C:2]([CH3:7])([CH2:10][C:9]#[CH:8])[C:3]([O:5][CH2:13][CH3:14])=[O:4]
Reactant: C#CCBr
Reactant: [Li]CCCC
Reactant: CC(C)(Br)C(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C#CCC(C)(C)C(=O)OCC

Procedure:
Amounts used: 14.7 ml (0.1 m, 19.5 g) of bromoisobutyric acid, 75 ml of 1.6M n-butyllithium solution in n-hexane, 40 ml of tetrahydrofuran and 17.85 g of propargylbromide.