Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)[CH:17]=2)[N:12]=[C:11]([NH:24][NH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:10]1=[O:31])C1C=CC=CC=1>CN(C)C=O.O.[Pd]>[CH2:29]([O:28][C:26]([NH:25][NH:24][C:11]1[C:10](=[O:31])[N:9]([OH:8])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)[CH:17]=2)[N:12]=1)=[O:27])[CH3:30]
Reactant: CCOC(=O)NNc1nc2ccc(-n3ccnc3)cc2n(OCc2ccccc2)c1=O
Agent: [Pd]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)NNc1nc2ccc(-n3ccnc3)cc2n(O)c1=O
Yield: 92.3 %

Procedure:
A solution of 4-benzyloxy-2-(2-ethoxycarbonylhydrazino)-6-(1H-imidazol-1-yl)-quinoxalin-3(4H)-one (10.9 g; ~25.9 mmol) in a mixture of 200 ml N,N-dimethylformamide and 100 ml water was hydrogenated at atmospheric pressure and room temperature by using 1 g 5% Pd-C as a catalyst. The catalyst was removed by filtration, and the residue was stirred with acetone to give the title compound (7.9 g; 92%). M.p. 216°-218° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[N:12]=[CH:11][C:10]2[O:9][CH2:8][CH2:7][N:6]3[CH:13]=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:5]3[C:4]=2[CH:3]=1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:12]=[CH:11][C:10]2[O:9][CH2:8][CH2:7][N:6]3[CH:13]=[C:14]([C:16]([N:18]=[CH:21][N:22]([CH3:24])[CH3:23])=[O:17])[N:15]=[C:5]3[C:4]=2[CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1cn2c(n1)-c1cc(Cl)ncc1OCC2
Solvent: Cc1ccccc1
Product: CN(C)C=NC(=O)c1cn2c(n1)-c1cc(Cl)ncc1OCC2

Procedure:
A mixture of 10-chloro-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine-2-carboxamide (1.290 g, 4.875 mmol) and 1,1-Dimethoxy-N,N-dimethylmethanamine (3.238 mL, 24.37 mmol) in 70 ml of toluene was heated under reflux for 1 hour. After cooling the product precipitated from the reaction mixture, collected, washed with ethyl ether and dried on air. Weight 0.705 g (85%). MS (ESI+): 320.1
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.[CH2:13]([NH:15][CH3:16])[CH3:14]>>[CH2:13]([N:15]([CH3:16])[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2)[CH3:14]
Reactant: O=C1NCCc2cc(F)ccc21
Reactant: CCNC
Product: CCN(C)c1ccc2c(c1)CCNC2=O
Temperature: 150 °C
Yield: 85.1 %

Procedure:
6-Fluoro-3,4-dihydro-2H-isoquinolin-1-one (2.00 g, 12.1 mmol) was deposited in a sealed tube with N-ethylmethylamine (4.0 mL, 47 mmol). This was heated at 150° C. for 24 hours. This was concentrated in vacuo and purified by flash chromatography (elution with ethylacetate) to yield 6-(Ethyl-methyl-amino)-3,4-dihydro-2H-isoquinolin-1-one (2.10 g, 10.3 mmol). MS (ESI) 205.1 (M+H)+.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][C:38](=[O:40])[NH2:39])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:20]([O:22]CC4C=CC([N+]([O-])=O)=CC=4)=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].C(O)(=O)C.CO.O>[C].[Pd].O1CCCC1>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][C:38](=[O:40])[NH2:39])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: NC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(NC=O)n1
Agent: [Pd]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Reaction time: 3 h
Yield: 49.7 %

Procedure:
A suspension of 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-carbamoylmethoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 2.4 g.), 10% palladium-carbon (0.96 g.), acetic acid (0.17 ml.), methanol (9.6 ml.), water (1.7 ml.) and tetrahydrofuran (24 ml.) was subjected to catalytic reduction under ordinary pressure for 3 hours. After filtration, the filtrate was concentrated in vacuo. Water and ethyl acetate were added to the residue and adjusted to pH 7.5 with sodium bicarbonate. After filtration, the filtrate was washed with ethyl acetate and diethyl ether in turn, adjusted to pH 1.0 with 10% hydrochloric acid and stirred under ice-cooling for 20 minutes. The precipitates were collected by filtration, washed with water, and dried to give 7-[2-(2-formamidothiazol-4-yl)-2-carbamoylmethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.92 g.).
Reaction SMILES: [C:1]([C:8]1[C:9]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][NH:11][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:19]SC1C(C2C=NC=CC=2)=NNC=1>>[C:1]([C:8]1[C:9]([C:13]2[CH2:14][N:15]([CH3:19])[CH2:16][CH2:17][CH:18]=2)=[N:10][NH:11][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CSc1c[nH]nc1-c1cccnc1
Reactant: CCCCCC#Cc1c[nH]nc1-c1cccnc1
Product: CCCCCC#Cc1c[nH]nc1C1=CCCN(C)C1
Yield: 44 %

Procedure:
Compound 44B was converted to compound 45B, using the methodology described for the conversion of 21A to 22A (see Scheme 3). Yield: 44% (amorphous). LCMS (method A); Rt: 1.84 min, ([M+H]+=258). 1H-NMR (400 MHz, CDCl3): δ 7.57 (s, 1H), 6.78-6.66 (bs, 1H), 3.42-3.38 (m, 2H), 2.59 (bt, J=7 Hz, 2H), 2.45 (s, 3H), 2.44-2.37 (m, 2H), 1.62-1.43 (m, 4H), 0.94 (t, J=7 Hz, 3H).
Reaction SMILES: [C:1]([O-:10])(=[O:9])[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5].[Mg+2:11].[OH:12][C@H:13]([CH2:19][C:20](=[O:22])[O-:21])[CH2:14][N+:15]([CH3:18])([CH3:17])[CH3:16].C([O-])(=O)C(CCC)CCC.O[C@H](CC(=O)[O-])C[N+](C)(C)C.C(O)(=O)C(CCC)CCC>O>[OH:12][C@H:13]([CH2:19][C:20](=[O:21])[O-:22])[CH2:14][N+:15]([CH3:18])([CH3:16])[CH3:17].[Mg:11].[C:1]([O-:10])(=[O:9])[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5]
Reactant: [Mg+2]
Agent: CCCC(CCC)C(=O)O
Agent: CCCC(CCC)C(=O)[O-]
Agent: C[N+](C)(C)C[C@H](O)CC(=O)[O-]
Solvent: O
Product: [Mg]

Procedure:
As we discovered and disclose in Example 2, L-carnitine magnesium valproate, another embodiment of the present invention, is a white solid having a melting point of 77.2° C., different from the melting point of L-carnitine. The 1H-NMR spectrum of L-carnitine magnesium valproate (FIG. 3) differs from that of the starting materials (i.e., L-carnitine and valproic acid) and confirms the structure. L-carnitine magnesium valproate is nearly odorless and free from objectionable taste. L-Carnitine magnesium valproate is soluble in water, and aqueous solutions of this salt provide bioavailable L-carnitine, magnesium, and valproate.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[C:15]([O:23][C:24]([F:27])([F:26])[F:25])[CH:14]=1>C1COCC1.[OH-].[Na+]>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][CH2:2][C@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]2)(=[O:21])=[O:20])=[C:15]([O:23][C:24]([F:26])([F:25])[F:27])[CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)[C@H]1CC[C@H](CNS(=O)(=O)c2ccc(Br)cc2OC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of trans-4-aminomethyl-cyclohexanecarboxylic acid (3.14 g, 20 mmol) in THF (20 mL) and 1 M aqueous sodium hydroxide (42 mL) was added a solution of 4-bromo-2-trifluoromethoxy benzenesulfonyl chloride (6.9 g, 20.4 mmol) in THF (20 mL) and the mixture was stirred for 2 hr at ambient temperature. The resulting mixture was concentrated and 1 M aqueous HCl (45 mL) was added. The resulting precipitate was filtered, washed with water and hexanes to give trans-4-[(4-bromo-2-trifluoromethoxy-benzenesulfonylamino)-methyl]-cyclohexanecarboxylic acid (7.18 g, 78%) as a white powder.
Reaction SMILES: C([C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1)C.C(C1C2C(=O)C3C(=CC=CC=3)C(=O)C=2CCC1)C.C(N(CCCC)C(=O)N(CCCC)CCCC)CCC.[H][H]>>[CH:12]1[CH:13]=[C:14]2[C:15]([OH:17])=[C:16]3[C:7](=[C:8]([OH:18])[C:9]2=[CH:10][CH:11]=1)[CH:6]=[CH:5][CH:4]=[CH:3]3
Reactant: [H][H]
Reactant: CCc1cccc2c1C(=O)c1ccccc1C2=O
Agent: CCC1CCCC2=C1C(=O)c1ccccc1C2=O
Agent: CCCCN(CCCC)C(=O)N(CCCC)CCCC
Product: Oc1c2ccccc2c(O)c2ccccc12

Procedure:
In a 1.75-liter continuously stirred tank-type reactor with internal filters to retain the catalyst inside the reactor, operating at a volume of 1.25 liters, a temperature of 43°-45° C. and pressure of 15 psig, a working solution was circulated at a flow rate of 50 ml/min. The working solution initially contained 18 wt % ethylanthraquinone, of which 45 wt % was tetrahydroethylanthraquinone, 58 wt % of an aromatic solvent (alkylated benzenes - heavy naphtha fraction, Aromatic 150), and 24 wt % tetra-n-butylurea. The hydrogen feed rate was controlled to give a maximum reduction level (anthrahydroquinone or HQ titer) of 0.408 g mol/l. 2.254 g of a 2.6 wt % palladium on gamma alumina catalyst was added to the reactor.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12](Cl)=[O:13])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[N:20][CH:21]=1.N1C=CC=CC=1.O>ClCCl>[Cl:1][C:2]1[C:3]([C:12]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[N:20][CH:21]=2)=[O:13])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc(N)cn1
Reactant: O=C(Cl)c1nc2ccccc2nc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(NC(=O)c2nc3ccccc3nc2Cl)cn1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A solution of 3-chloroquinoxaline-2-carbonyl chloride (3.5 g, 15.45 mmol) in dichloromethane (32.3 mL) was added dropwise to a mixture of methyl 5-aminopyridine-2-carboxylate (2.35 g, 15.45 mmol), pyridine (3.75 mL, 46.35 mmol) and dichloromethane (48.38 mL) at 0° C. The mixture was stirred and allowed to warm up to room temperature overnight. To the reaction, water (40 mL) was added and the product precipitated. The solid was isolated by filtration, washed with water (1×40 mL) and hexanes (2×50 mL) to yield methyl 5-[(3-chloroquinoxaline-2-carbonyl)amino]pyridine-2-carboxylate (4.31 g, 81%) as a cream colored solid. 1H NMR (400 MHz, DMSO-d6) δ 11.61 (s, 1H), 9.00 (d, J=2.5 Hz, 1H), 8.46 (dd, J=8.6, 2.6 Hz, 1H), 8.36-8.26 (m, 1H), 8.24-8.12 (m, 2H), 8.12-7.95 (m, 2H), 3.89 (s, 3H) ppm. ESI-MS m/z calc. 342.05, found 343.4 (M+1)+; Retention time: 1.25 minutes (3 minutes run).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:12][CH:13]=[C:14]2[C:19](=[O:20])OC(C)(C)OC2=O)=[CH:4][C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.C(OCC)(=O)C.CCCCCC>CO>[Br:1][C:2]1[CH:11]=[C:6]2[O:7][CH2:8][CH2:9][O:10][C:5]2=[C:4]2[C:3]=1[NH:12][CH:13]=[CH:14][C:19]2=[O:20]
Reactant: CC1(C)OC(=O)C(=CNc2cc3c(cc2Br)OCCO3)C(=O)O1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1cc[nH]c2c(Br)cc3c(c12)OCCO3
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
5-[(7-Bromo-2,3-dihydro-benzo[1,4]dioxin-6-ylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione (22.9 g, 59.6 mmol) was added portionwise to refluxing Dowtherm A® (45 mL) over 3 minutes. After a further 3 minutes at reflux the mixture was cooled to room temperature. Ethyl acetate/hexane (10 mL/20 mL) was added and a black solid isolated by filtration. This residue was dissolved in hot methanol (400 mL) and filtered through Keiselguhr. Water (800 mL) was added and the mixture stored at 5° C. overnight. Filtration and drying afforded a pale yellow solid (10.3 g, 61%).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C:2]1=[O:7].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[O:18]1[C:22]2([CH2:27][CH2:26][C:25](C3C(O)=CC=CN=3)=[CH:24][CH2:23]2)[O:21][CH2:20][CH2:19]1>CN(C=O)C>[O:18]1[C:22]2([CH2:27][CH2:26][CH:25]([N:1]3[C:5](=[O:6])[CH2:4][CH2:3][C:2]3=[O:7])[CH2:24][CH2:23]2)[O:21][CH2:20][CH2:19]1
Reactant: Oc1cccnc1C1=CCC2(CC1)OCCO2
Reactant: O=C1CCC(=O)N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCC(=O)N1C1CCC2(CC1)OCCO2
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A solution of pyrrolidine-2,5-dione (210 mg, 2 mmol) in DMF was treated with sodiumhexamethyldisilazid (1.5 eq), stirred for 30 min and treated with 4-dioxaspiro[4.5]decan-8-yl methanesulfonate (250 mg, 1 mmol) from example 1, step A, and heated at 80° C. for 18 h. DMF was removed under vacuum and the residue was purified by silica column chromatography to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:29])[CH2:9][CH2:10][C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH:26]([CH3:28])[CH3:27])=[CH:4][CH:3]=1.[CH:30]1[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[C:33]([S:39](Cl)(=[O:41])=[O:40])=[CH:32][CH:31]=1.O>N1C=CC=CC=1>[CH:26]([C:12]1[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[S:15][C:11]=1[CH2:10][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:39]([C:33]2[CH:32]=[CH:31][CH:30]=[CH:35][C:34]=2[N+:36]([O-:38])=[O:37])(=[O:40])=[O:41])=[CH:3][CH:4]=1)=[O:29])([CH3:27])[CH3:28]
Reactant: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)sc1CCC(=O)c1ccc(N)cc1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)sc1CCC(=O)c1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
The obtained 1-(4-aminophenyl)-3-[4-isopropyl-2-[4-(trifluoromethyl)phenyl]thiazol-5-yl]-propan-1-one (250 mg, 0.597 mmol) was dissolved in anhydrous pyridine (5 mL). O-nitrophenylsulfonyl chloride (146 mg, 0.659 mmol) was added to the solution. The mixture was stirred at room temperature for 1 hour. The outer temperature was heated to 80° C., and the mixture was further stirred for 16 hours. The mixture was cooled to room temperature. Water was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated brine, and dried with anhydrous sodium sulfate to remove the solvent. The obtained residue was purified by silica gel column chromatography with hexane/ethyl acetate (8:2, v/v) to give the desired compound (265 mg) as yellow crystalline product (yield 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:4]=1[CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:10]=2[NH:9][C:8](=O)[CH2:7]1.CN(C)C1C=CC(C)=CC=1.P(Cl)(Cl)([Cl:38])=O>C1(C)C=CC=CC=1>[Cl:38][C:8]1[CH2:7][N:6]([CH2:5][C:4]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:3]=2[O:2][CH3:1])[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:10]=2[N:9]=1
Reactant: COc1ccc(CN2CC(=O)Nc3ccc(C)cc3C2=O)c(OC)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccc(N(C)C)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CN2CC(Cl)=Nc3ccc(C)cc3C2=O)c(OC)c1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
4-(2,4-Dimethoxy-benzyl)-7-methyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (34.0 g, 100 mmol) and N,N-dimethyl-p-toluidine (28.9 mL, 200 mmol) were mixed in toluene (100 mL) and heated to 100° C. Then phosphorus oxychloride (10.1 mL, 110 mmol) was added dropwise and heating at 100° C. was continued for 2.5 h. The resulting dark red solution was used directly in the subsequent step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([N+:19]([O-])=O)=[CH:17][C:6]2[N:7]([CH3:16])[C:8](=[O:15])[CH2:9][N:10]([CH2:12][C:13]#[N:14])[CH2:11][C:5]=2[CH:4]=1.O.NN.C(O)C>[Pd]>[NH2:19][C:18]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][C:13]#[N:14])[CH2:9][C:8](=[O:15])[N:7]([CH3:16])[C:6]=2[CH:17]=1
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C)C(=O)CN(CC#N)C2
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1cc2c(cc1N)N(C)C(=O)CN(CC#N)C2
Yield: 16.1 %

Procedure:
To a mixture of (7-Methoxy-1-methyl-8-nitro-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetonitrile (0.47 g, 0.0016 mol) and Hydrazine hydrate (2.00 mL, 0.0411 mol) in Ethanol (10 mL, 0.2 mol) was added 10% Pd/C (10:90, Palladium:carbon black, 0.047 g) and reacted in an analogous manner to example 712. The reaction was filtered and evaporated. This product was chromatographed on SiO2 (13 g) with (20-1) DCM/MeOH giving (8-Amino-7-methoxy-1-methyl-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetonitrile as a tan solid (0.067 g, 16%). Mp 128-132° C.; LCMS (m/e)) 261 (M+1); 1H-NMR (DMSO, 400 MHz) δ 6.80 (s, 1H), 6.59 (s, 1H), 4.95 (s, 2H), 3.77 (s, 3H), 3.77-3.75 (d, 2H, J=9.35 Hz), 3.62 (s, 2H), 3.18 (s, 3H), 3.06 (s, 2H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:26][C:20]5([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH2:19]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[C:29]1[N:34]=[CH:33][C:32]([CH2:35][CH3:36])=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>O>[CH2:35]([C:32]1[CH:31]=[N:30][C:29]([N:23]2[CH2:22][CH2:21][C:20]3([CH2:26][C:18]4([O:17][C:14]5=[CH:15][N:16]=[C:11]([C:8]6[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=6)[CH:12]=[C:13]5[CH2:27]4)[CH2:19]3)[CH2:25][CH2:24]2)=[N:34][CH:33]=1)[CH3:36]
Reactant: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)cc1
Reactant: CCc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1cnc(N2CCC3(CC2)CC2(Cc4cc(-c5ccc(S(C)(=O)=O)cc5)ncc4O2)C3)nc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 5-(4-methylsulfonyl-phenyl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (HCl salt; 50 mg), 2-chloro-5-ethyl-pyrimidine (18 mg), potassium carbonate (35 mg), and N-methyl-pyrrolidinone (2 ml) is stirred at 80° C. for 4 h. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The combined extracts are dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 1:1→1:9) to give the title compound. LC (method 1): tR=1.16 min; Mass spectrum (ESI+): m/z=491 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21](NC2C=CC(C3(CC(O)=O)CC4C(=CC=CC=4)C3)=CC=2)=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9]C(NC1C=CC=CC=1C)=O.C([O-])=O.[NH4+].[CH2:47]([OH:49])[CH3:48]>[Pd]>[CH2:47]([O:49][C:21](=[O:22])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH2:9])=[C:3]([OH:2])[CH:4]=1)[CH3:48]
Reactant: CCO
Reactant: COc1cc(CC(=O)Nc2ccc(C3(CC(=O)O)Cc4ccccc4C3)cc2)ccc1NC(=O)Nc1ccccc1C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: CCOC(=O)Cc1ccc(N)c(O)c1
Temperature: 50 °C

Procedure:
A solution of (3-hydroxy-4-nitro-phenyl)-acetic acid ethyl ester (5.0 g, Reference Example 4) was dissolved in ethanol (approximately 200 mL) was treated with ammonium formate (approximately 20 g). The mixture was warmed to 50° C. and then treated cautiously with palladium on charcoal (approximately 1 g, 5%)—effervescence was observed. After 30 minutes the mixture was filtered hot through a pad of filter-aid and the filtrate was concentrated to give the title compound (3.3 g) as a black solid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[NH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:31]1[CH:36]=[C:35]([NH2:37])[N:34]=[C:33]([NH2:38])[N:32]=1.CO>O1CCOCC1>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[NH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:31]4[N:32]=[C:33]([NH2:38])[N:34]=[C:35]([NH2:37])[CH:36]=4)=[CH:17][CH:16]=3)=[N:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Oc1ccc(-c2nnc(Nc3cccc(C(F)(F)F)c3)[nH]2)cc1
Reactant: Nc1cc(Cl)nc(N)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CO
Product: Nc1cc(Oc2ccc(-c3nnc(Nc4cccc(C(F)(F)F)c4)[nH]3)cc2)nc(N)n1

Procedure:
4-(5-{[3-(trifluoromethyl)phenyl]amino}-4H-1,2,4-triazol-3-yl)phenol (160 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous dioxane in 2-5 mL microwave vial (Personal Chemistry). Solid Cs2CO3 (163.0 mg, 0.5 mmol) was added, followed by 4-chloro-2,6,-diaminopyrimidine (79.5 mg, 0.55 mmol). The vial was capped and microwaved at 200° C. for 20 min. Then ca. 3 mL of MeOH was added to dissolve the formed suspension, the solution was transferred into a round-bottom flask and solvent was removed in vacuo. The residue was re-dissolved in 3 mL of DMF, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water system with 0.01% of TFA.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=1.[Cl:15][C:16]1[N:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[N:21]=[CH:20][C:19]([S:22]([N:12]2[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[CH:9][C:10]([CH:13]=[O:14])=[CH:11]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=Cc1c[nH]c(-c2ccccc2F)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Product: O=Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2ccc(Cl)nc2)c1

Procedure:
By a similar reaction as in Reference Example 65 and using 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (893 mg) and 6-chloropyridine-3-sulfonyl chloride (1.30 g), the title compound was obtained as a pale-red solid (yield 1.14 g, 66%). More specifically, 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (893 mg) was dissolved in tetrahydrofuran (10 mL), sodium hydride (60% in oil, 226 mg) was added and the mixture was stirred at room temperature for 15 min. 15-Crown-5 (1.1 mL) was added and the mixture was further stirred at the same temperature for 15 min. 6-Chloropyridine-3-sulfonyl chloride (1.30 g) was added. The reaction mixture was stirred at room temperature for 15 min. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→3:2) to give the title compound as a pale-red solid (yield 1.14 g, 66%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[CH2:23][C:24](O)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)C.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[CH2:23][CH2:24][OH:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCCc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 43.5 %

Procedure:
10 ml (20 mmole) 2 M borane dimethyl sulfide complex in diethyl ether was slowly added to 6.3 g (18.1 mmole) 2,4-dibenzyloxyphenyl acetic acid dissolved in 50 ml dry tetrahydrofuran cooled on an ice bath under nitrogen and then stirred for 7 days at room temperature. The reaction was quenched with water and extracted with ethyl acetate, dried with magnesium sulfate and evaporated. The crude product was purified by chromatography on silica gel using dichloromethane/methanol as eluent to give 2.63 g of the desired product and a mixture of 2,4-dibenzyloxyphenyl acetic acid and the desired product. The mixture was dissolved in 100 ml ethyl acetate, 0.152 g (4 mmole) lithium aluminum hydride was added in portions and the mixture was stirred at room temperature for 6 hours. After 4 hours some more lithium aluminum hydride was added. The reaction was quenched with 1% hydrochloric acid and the solution was filtered. The filtrate was dried with magnesium sulfate and evaporated in vacuo to give 1.3 g more of 2-[2,4-di(benzyloxy)phenyl]-1-ethanol (total yield 3.9 g, 64.4%).