Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH:8]([O:11][C:12]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH3:24])[N:22]=2)[CH:17]([NH:25][CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[CH2:16][CH:15]1[CH2:41][CH3:42])=[O:13])([CH3:10])[CH3:9].N1C=CC=CC=1>ClCCl>[CH:8]([O:11][C:12]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH3:24])[N:22]=2)[CH:17]([N:25]([C:1](=[O:3])[CH3:2])[CH2:26][C:27]2[CH:28]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=2)[CH2:16][CH:15]1[CH2:41][CH3:42])=[O:13])([CH3:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CCC1CC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(C)nc2N1C(=O)OC(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC1CC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(C)=O)c2ccc(C)nc2N1C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.9 %

Procedure:
Inject acetic anhydride (0.250 ml, 2.65 mmol) dropwise to a solution of crude 4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-7-methyl-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid isopropyl ester (0.090 g, 0.199 mmol) and pyridine (0.250 ml, 3.10 mmol) in dichloromethane (1 ml) at room temperature. Stir the mixture at room temperature for 16 h. Evaporate the solvents and purify using silica gel column chromatography (gradient eluent, 0-40% ethyl acetate in hexane) to provide the title compound (0.0650 g, 66%). MS (ES+): 546 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:16][CH2:17][C:18]([O:20]C)=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].BrC1C=C(C=CC(O)=O)C=CC=1O.OC1C=CC(C=O)=CC=1.N1C=CN=C1.[Si:49](Cl)([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]([O:20][Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][Si:9]([C:12]([CH3:14])([CH3:13])[CH3:15])([CH3:10])[CH3:11]
Reactant: COC(=O)CCc1ccc(O[Si](C)(C)C(C)(C)C)c(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C(O)C=Cc1ccc(O)c(Br)c1
Agent: O=Cc1ccc(O)cc1
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)OC(=O)C=Cc1ccc(O[Si](C)(C)C(C)(C)C)c(Br)c1

Procedure:
According to the procedure described in the synthesis method of Intermediate 43, 3-[3-bromo-4-hydroxylphenyl]acrylic acid (12.01 g) obtainable from 4-hydroxybenzaldehyde (TCI) by a method known from literature (Y. Nagao et al., Tetrahedron Lett., 1980, p. 4931) was reacted with imidazole (16.01 g) and t-butyldimethylsilyl chloride (7.43 g) and treated to obtain the title compound (Intermediate Ac-1, 17.43 g).
Reaction SMILES: OS(O)(=O)=O.[C:6]([OH:15])(=[O:14])[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH2:9].[N+]([C:19]1[CH:28]=[CH:27][C:22]([CH:23]=[CH:24][CH:25]=O)=[CH:21][CH:20]=1)([O-])=O.[OH-].[K+]>CC(O)=O.O>[C:22]1([C:23]2[CH:24]=[CH:25][C:10]3[C:8](=[C:7]([C:6]([OH:15])=[O:14])[CH:13]=[CH:12][CH:11]=3)[N:9]=2)[CH:27]=[CH:28][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=CC=Cc1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cccc2ccc(-c3ccccc3)nc12
Temperature: 105 °C

Procedure:
A mixture of conc. H2SO4 (45 mL), water (5 mL), AcOH (5 mL), anthranilic acid (XI; R2 =H) (20.5 g) and H3AsO4 (80% w/w; 32 g) was heated with stirring to 105° C., and then treated with cinnamaldehyde (VIII; R1 =H) (25 g) at the rate which maintained the temperature at 105°-110° C. The reaction mixture was stirred for a further 3 h at 110°-115° C., then cooled and strongly basified with aqueous KOH. The aqueous layer was decanted from a quantity of tar, washed with CHCl3 and then acidified with AcOH. The resulting precipitate was chromatographed on SiO2 and eluted with a gradient of MeOH in CH2Cl2 to give a low yield of the desired acid, mp 160°-161° C., identical in all respects to the compound obtained in Example A. This compound was elaborated to compound 1 of Table I by the method outlined in Example A.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](C3C4C(=CC=CC=4)C(=O)N3C)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br[C:23]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[C:28]2[C:24]=1[CH2:25][N:26]([CH3:36])[C:27]2=[O:35].O1C2(CCC(B3OC(C)(C)C(C)(C)O3)=CC2)OCC1>>[O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:23]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[C:28]4[C:24]=3[CH2:25][N:26]([CH3:36])[C:27]4=[O:35])=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CN1Cc2c(Br)ccc([N+](=O)[O-])c2C1=O
Reactant: CN1C(=O)c2ccccc2C1C1=CCC2(CC1)OCCO2
Agent: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Product: CN1Cc2c(C3=CCC4(CC3)OCCO4)ccc([N+](=O)[O-])c2C1=O

Procedure:
The title product was prepared according to the procedure for 7-amino-4-(1,4-dioxaspiro[4,5]dec-7-ene-8-yl-2-methyl-2,3-dihydro-1H-isoindol-1-one using 4-bromo-2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one and 1,4-dioxaspiro[4,5]dec-7-ene-8-boronic acid pinacol ester.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[N:9]=[CH:8][C:7]=1[O:14][CH2:15][C:16]1[C:17](C(=O)/C(/C)=C/N(C)C)=[N:18][CH:19]=[CH:20][CH:21]=1.Cl.[CH:31]([NH:34][NH2:35])([CH3:33])[CH3:32]>CCO>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:7]([O:14][CH2:15][C:16]2[C:17]([C:2]3[N:34]([CH:31]([CH3:33])[CH3:32])[N:35]=[CH:7][C:6]=3[CH3:11])=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:8][N:9]=[C:10]([O:12][CH3:13])[CH:11]=1
Reactant: CC(C)NN
Reactant: COc1cc(C2OCCO2)c(OCc2cccnc2C(=O)/C(C)=C/N(C)C)cn1
Agent: Cl
Solvent: CCO
Product: COc1cc(C2OCCO2)c(OCc2cccnc2-c2c(C)cnn2C(C)C)cn1
Temperature: 80 °C
Yield: 40.3 %

Procedure:
To (E)-1-(3-((4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-yloxy)methyl)pyridin-2-yl)-3-(dimethylamino)-2-methylprop-2-en-1-one (crude, 230 mg, 0.58 mmol, 1 eq.) in EtOH (5 mL) was added isopropylhydrazine hydrochloride (128 mg, 1.16 mmol, 2 eq.) at rt. The mixture was heated at 80° C. for 2 h, cooled to rt, concentrated, and diluted with a mixture of EtOAc (50 mL) and NaHCO3(sat) (10.0 mL) solution. The layers were separated and aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 4-(1,3-dioxolan-2-yl)-5-((2-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxypyridine (48 mg, 20% for two steps). 1H NMR (400 MHz, CDCl3) δ 8.75 (dd, J=4.7, 1.4 Hz, 1H), 8.12 (d, J=8.1 Hz, 1H), 7.62 (s, 1H), 7.49-7.44 (m, 2H), 6.91 (s, 1H), 6.11 (s, 1H), 4.85-5.01 (m, 2H), 4.30-3.98 (m, 5H), 3.88 (s, 3H), 1.94 (s, 3H), 1.50 (d, J=6.7 Hz, 3H), 1.39 (d, J=6.7 Hz, 3H). LRMS (M+H+) m/z 411.2.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4](O)=[O:5].C(N(CC)CC)C.CN([C:21]([O:25][N:26]1N=NC2C=CC=N[C:27]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CNOC>CC#N.CCOC(C)=O>[F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4]([N:26]([O:25][CH3:21])[CH3:27])=[O:5]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C(=O)O)C(F)(F)F
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CON(C)C(=O)C(C)(C)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.4 %

Procedure:
To a clear solution of 3,3,3-trifluoro-2,2-dimethylpropionic acid (5.000 g, 32.0 mmol) in MeCN (22.88 ml) was added triethylamine (9.82 ml, 70.5 mmol) followed by HATU (12.79 g, 33.6 mmol) and the mixture was stirred at room temperature. After 15 min, to the dark clear mixture was added N,O-dimethylhydroxylamine hydrochloride (3.44 g, 35.2 mmol) and the mixture was stirred at room temperature. After 18 h, the reaction mixture was diluted with EtOAc (100 mL) and washed with 1 N HCl (2×100 mL), and sat. NaCl (5×100 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a orange solid. The orange solid was absorbed onto a plug of silica gel and purified by silica gel chromatography eluting with a gradient of 0% to 25% EtOAc in heptane to provide 3,3,3-trifluoro-N-methoxy-N,2,2-trimethylpropanamide (5.0503 g, 25.4 mmol, 79% yield) as yellow liquid. 1H NMR (300 MHz, CDCl3) δ 3.71 (3H, s), 3.22 (3H, s), 1.51 (6H, d, J=0.7 Hz); LCMS (ESI) m/z 200.1 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][C:19]=2[O:28][CH2:29][CH3:30])=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH2:29]([O:28][C:19]1[CH:20]=[CH:21][C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:17])[CH3:30]
Reactant: CCOC(=O)C1(NC(=O)c2c(OCC)ccc3ccccc23)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1ccc2ccccc2c1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
The mixture of 2-[(2-ethoxy-naphthalene-1-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (45) (270 mg, 0.67 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (10 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until pH ˜4. The precipitate is filtered to give a pure product (46) as white solid (170 mg, 68%).
Reaction SMILES: C[C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][NH:5][CH:6]=1.Br[CH:14]([CH2:20][CH3:21])[C:15]([N:17]([CH3:19])[CH3:18])=[O:16].Cl[CH:23](C)C(N(C)C)=O>>[CH2:20]([CH:14]([N:5]1[CH:6]=[CH:2][C:3]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[CH3:23])=[N:4]1)[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[CH3:21]
Reactant: CCC(Br)C(=O)N(C)C
Reactant: Cc1c[nH]nc1-c1ccccc1
Reactant: CC(Cl)C(=O)N(C)C
Product: CCC(C(=O)N(C)C)n1ccc(-c2ccccc2C)n1

Procedure:
Following the procedure of Example 1, but substituting 3-(o-tolyl)pyrazole for 4-methyl-3-phenylpyrazole and 2-bromo-N,N-dimethylbutyramide for 2-chloro-N,N-dimethylpropionamide there was obtained α-ethyl-N,N-dimethyl-3-(o-tolyl)-pyrazole-1-acetamide having a melting point of 48°-51° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC([O:44][C:45]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])=[O:46])COC(CCCCCCCCCCCCCCCCC)=O)=[O:19]>CC(C)=O>[C:45]([OH:44])(=[O:46])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57]/[CH:58]=[CH:59]\[CH2:60][CH2:61][CH2:62][CH2:63][CH2:1][CH2:2][CH2:3][CH3:4].[C:18]([OH:20])(=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCCCC
Solvent: CC(C)=O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O
Product: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)O
Yield: 62 %
Yield: 30 %

Procedure:
A spread was prepared in a manner similar as described in Example I, except that the mixture to be interesterified comprised 57 parts of the palm oil stearin and 43 parts of the palmkernel stearin. The margarine fat blend comprised 8% of the stearin fraction obtained from fractionation in acetone of the randomly interesterified mixture, 62% low erucic acid rapeseed oil and 30% of a high oleic acid residue containing variety of linseed oil. A very good product was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:12](O)[CH2:13][OH:14]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2([CH3:10])[O:14][CH2:13][CH2:12][O:11]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OCCO
Reactant: CC(=O)c1ccc(F)c(Br)c1
Solvent: Cc1ccccc1
Product: CC1(c2ccc(F)c(Br)c2)OCCO1

Procedure:
1-(3-bromo-4-fluorophenyl)ethanone (7.5 g, 34.5 mmol), ethylene glycol (10 mL) and a catalytic amount of tosyl acid was refluxed in toluene (100 mL) for 18 h with a Dean-Stark trap. The crude reaction mixture was quenched with H2O (100 mL) extracted with EtOAc (3×50 mL), washed organic layer with H2O, brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 100% EtOAc/hexanes gradient) to afford 8.8 g of Intermediate 416.1. 1H NMR (400 MHz, CDCl3) δ ppm 1.61 (s, 3H) 3.69-3.81 (m, 2H) 3.97-4.09 (m, 2H) 7.07 (t, J=8.35 Hz, 1H) 7.32-7.43 (m, 1H) 7.67 (dd, J=6.59, 2.20 Hz, 1H).
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[N:9]([CH2:10][C:11]#[C:12][CH3:13])[C:8]([C:14]([O:16]CC)=O)=[C:7]([CH:19]=O)[N:6]=1.C(O)(=O)C>C(O)C>[Br:4][C:5]1[N:9]([CH2:10][C:11]#[C:12][CH3:13])[C:8]2[C:14](=[O:16])[NH:3][N:2]=[CH:19][C:7]=2[N:6]=1
Reactant: NN
Reactant: CC#CCn1c(Br)nc(C=O)c1C(=O)OCC
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC#CCn1c(Br)nc2cn[nH]c(=O)c21
Temperature: 100 °C
Reaction time: 1 h

Procedure:
6.31 ml (0.126 mol) hydrazine hydrate were added drop-wise at ambient temperature to a solution of 35.0 g (0.117 mol) ethyl 2-bromo-3-(but-2-ynyl)-5-formyl-3H-imidazole-4-carboxylate in 400 ml of ethanol. After 30 min stirring 27 ml (0.472 mol) concentrated acetic acid were added and the solution was then stirred for 1 h at 100° C. After cooling the precipitated solid was suction filtered, washed with ethanol and diethyl ether and dried. The solid was further purified by re-crystallization from EtOH.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]2[C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[CH:22]=1)=CC=CC=2)=O.C(=O)([O-])[O-].[K+].[K+]>CS(O)(=O)=O.ClCCl>[CH:10]1[C:5]2[C:4]3[C:5]([C:4]4[C:19]([C:18]=2[CH:17]=[CH:16][CH:15]=1)=[CH:20][CH:21]=[CH:22][CH:9]=4)=[CH:6][CH:7]=[C:8]1[C:3]=3[CH:8]=[CH:7][CH:1]=[CH:3]1
Reactant: O=Cc1ccccc1-c1cc2ccccc2c2ccccc12
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: c1ccc2c(c1)ccc1c3ccccc3c3ccccc3c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
24.0 g of the resulting 9-(2-formylphenyl)phenanthrene and 100 mL of dichloromethane were placed in a flask. During stirring at room temperature, 6 drops of methanesulfonic acid were added to the flask by means of a Pasteur pipette. Stirring was conducted at room temperature for further 8 hours. After the completion of the reaction, 100 mL of a 10% aqueous solution of potassium carbonate was added. An aqueous phase was removed and an organic phase which had been separated was washed with water and saturated brine, and then dried with magnesium sulfate. After the magnesium sulfate was filtered out, the organic phase was concentrated. The resulting residue was purified by means of silica gel column chromatography, whereby 5.21 g (yield: 25%) of benzo[g]chrysene was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:3]=1.[S:27](N)([NH2:30])(=[O:29])=[O:28]>O1CCOCC1.O.C(=O)(O)[O-].[Na+]>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([NH2:30])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: NS(N)(=O)=O
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCNCC2)nc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(N)(=O)=O)CC2)nc1N

Procedure:
[4-Amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (308 mg, 0.848 mmol, Example 107) in dioxane (3 mL) and sulfamide (814 mg, 8.48 mmol, Aldrich) refluxed overnight. The mixture was diluted with water and sodium bicarbonate and extracted with dichloromethane. The organic solution was washed with water, dried (MgSO4), filtered and evaporated. Chromatography on silica gel (methanol/triethylamine/ethyl acetate 5:2:95) gave, after crystallization from ethanol/ethyl ether, 255 mg of colorless solid, MP 217-218° C. MS(ES) MH+443
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Ba+2].[OH-].COCCOC.[CH3:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[C:22]([Cl:27])[N:21]=1>O>[CH3:19][C:20]1[N:21]=[C:22]([Cl:27])[CH:23]=[C:24]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:25]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: Cc1nc(Cl)cc(-c2ccccc2)n1
Temperature: 80 °C
Reaction time: 6 h
Yield: 51.3 %

Procedure:
A reaction vessel was charged with 2.19 g of tetrakistriphenylphosphine palladium, 847 mg of phenylboronic acid, and 2.99 g of barium hydroxide, to which 40 ml of 1,2-dimethoxyethane, 7 ml of water, and 1.01 g of 2-methyl-4,6-dichloropyrimidine were added, followed by stirring at 80° C. under an atmosphere of a nitrogen gas for 6 hours. The reaction mixture was then left for cooling to room temperature, and water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.65 g of 2-methyl-4-chloro-6-phenylpyrimidine.
Reaction SMILES: [Co:1]=O.[N+:3]([O-:6])([OH:5])=[O:4]>>[N+:3]([O-:6])([O-:5])=[O:4].[Co+2:1].[N+:3]([O-:6])([O-:5])=[O:4]
Reactant: O=[N+]([O-])O
Reactant: O=[Co]
Product: O=[N+]([O-])[O-]
Product: [Co+2]

Procedure:
The cobalt oxide was dissolved in 3 mol/L nitric acid solution to yield a second cobalt nitrate solution.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.Cl[CH2:21][CH2:22][CH2:23][C:24]1([CH3:29])[O:28][CH2:27][CH2:26][O:25]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:21][CH2:22][CH2:23][C:24]3([CH3:29])[O:28][CH2:27][CH2:26][O:25]3)[C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: CC1(CCCCl)OCCO1
Reactant: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Solvent: CN(C)C=O
Product: CC1(CCCN2C(=O)CN=C(c3ccccc3)c3cc(Cl)ccc32)OCCO1
Temperature: 100 °C

Procedure:
A solution of 54.2 g. of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one in 500 ml. of dimethylformamide is treated under an atomosphere of argon at 0° C. with 32.8 g. of potassium tertiary butylate and the mixture is then stirred in an ice-bath for 30 minutes. Then, at 10°-15° C. there is added a solution of 66 g. of 2-(3-chloropropyl)2-methyl-1,3-dioxolan in 100 ml. of dimethylformamide, the mixture is stirred at 20°-24° C. for 30 minutes and subsequently heated to 100° C. for 30 minutes. The mixture is cooled and poured on to 2.5 liters of ice-water. The separated oily product is extracted with methylene chloride and the organic phase washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated to dryness. The residue crystallizes upon trituration with ether, and there is obtained 7-chloro-1,3-dihydro-1-[3-(2-methyl-1,3 -dioxolan-2-yl)propyl]-5-phenyl-2H-1,4-benzodiazepin-2-one having a melting point of 152°-153° C. Recrystallization from ethanol does not increase the melting point.
Reaction SMILES: C(N[C:6]([NH:8][S:9]([C:12]1[C:13]([CH3:20])=[N:14][N:15]([CH3:19])[C:16]=1[O:17][CH3:18])(=[O:11])=[O:10])=[O:7])CCC.C(Cl)(Cl)=O>C1C=CC=CC=1>[CH3:19][N:15]1[C:16]([O:17][CH3:18])=[C:12]([S:9]([N:8]=[C:6]=[O:7])(=[O:11])=[O:10])[C:13]([CH3:20])=[N:14]1
Reactant: CCCCNC(=O)NS(=O)(=O)c1c(C)nn(C)c1OC
Agent: O=C(Cl)Cl
Solvent: c1ccccc1
Product: COc1c(S(=O)(=O)N=C=O)c(C)nn1C

Procedure:
Into a mixture of 100 ml of dry benzene and 9.12 g (0.03 mol) of N-(n-butylcarbamoyl)-1,3-dimethyl-5-methoxypyrazole-4-sulfonamide, under reflux, 8.9 g (0.09 mol) of phosgene was passed over 1.5 hours. Then, the reaction mixture was further refluxed for 30 minutes. After completion of the reaction, evaporation of benzene under reduced pressure gave crude 1,3-dimethyl-5-methoxypyrazole-4-sulfonyl isocyanate as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:24])[CH2:10][N:11]2[CH:15]=[C:14]([N+:16]([O-])=O)[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:12]2)[CH:5]=[CH:6][CH:7]=1>[Pd].CO.ClCCl>[NH2:16][C:14]1[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:12][N:11]([CH2:10][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[O:24])[CH:15]=1
Reactant: CCOC(=O)c1nn(CC(=O)Nc2cccc(F)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1nn(CC(=O)Nc2cccc(F)c2)cc1N
Yield: 88.2 %

Procedure:
A mixture of ethyl 1-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-4-nitro-1H-pyrazole-3-carboxylate (0.168 g, 0.5 mmol) was hydrogenated over 10% palladium on carbon (0.034 g) in a mixture of methanol (6 ml) and dichloromethane (3 ml) for 3 hours. The mixture was filtered through Celite and the filtrate was evaporated to leave ethyl 4-amino-1-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazole-3-carboxylate (0.135 g, 88% yield):
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[C:21]4[CH2:20][N:19](CC5C=CC(OC)=CC=5)[C:18](=[O:31])[NH:17][C:16]=4[N:15]=[CH:14][CH:13]=3)=[CH:8][CH:9]=2)[N:4]([CH3:32])[N:3]=1>FC(F)(F)C(O)=O>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[C:21]4[CH2:20][NH:19][C:18](=[O:31])[NH:17][C:16]=4[N:15]=[CH:14][CH:13]=3)=[CH:8][CH:9]=2)[N:4]([CH3:32])[N:3]=1
Reactant: COc1ccc(CN2Cc3c(Oc4ccc5c(N)nn(C)c5c4)ccnc3NC2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(N)c2ccc(Oc3ccnc4c3CNC(=O)N4)cc21
Temperature: 75 °C
Reaction time: 48 h
Yield: 91.3 %

Procedure:
Compound 276 (25.00 mg; 0.06 mmol; 1.00 eq.) was dissolved in trifluoroacetic acid (2.00 ml). The vessel was sealed and heated at 75 degrees C. for two days. The reaction was concentrated, redissolved in DMSO, treated with Et3N to get pH ˜8, and then purified via prep HPLC to afford 17mg (69%) of 277 as a white solid. LC-MS (M+H=311, obsd.=311).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[NH2:12][CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[C:21]([F:41])=[C:22]([C:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:30][CH:29]=3)=[CH:26][N:27]=2)[C:23]#[N:24])[CH:17]=[CH:18][CH:19]=1.[C:42](OC(=O)C)(=[O:44])[CH3:43]>ClCCl.[Cl-].[Na+].O.O>[C:23]([C:22]1[C:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:30][CH:29]=2)=[CH:26][N:27]=[C:20]([C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[CH2:13][NH:12][C:42](=[O:44])[CH3:43])[C:21]=1[F:41])#[N:24]
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)cnc(-c2cccc(CN)c2)c1F
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCc1cccc(-c2ncc(-c3ccc(Oc4ccccc4)cc3)c(C#N)c2F)c1
Reaction time: 1 h
Yield: 89.7 %

Procedure:
Hunig's base (0.045 mL, 0.256 mmol) was added to a mixture of 2-(3-(aminomethyl)phenyl)-3-fluoro-5-(4-phenoxyphenyl)isonicotinonitrile bis-HCl salt (12 mg, 0.026 mmol) and acetic anhydride (0.012 mL, 0.128 mmol) in dichloromethane (3 mL). After 1 h at room temperature, the mixture was diluted with brine (10 mL), water (10 mL) and extracted with dichloromethane (3×10 mL). The combined extracts were dried (MgSO4) and concentrated. Silica gel chromatography, loading with dichloromethane and eluting with 50-100% ethyl acetate in hexanes, gave N-(3-(4-cyano-3-fluoro-5-(4-phenoxyphenyl)pyridin-2-yl)benzyl)acetamide as off-white solid (10.2 mg, 91% yield), 1H NMR (500 MHz, CDCl3) δ ppm 8.73 (1H, s), 7.89-7.98 (2H, m), 7.57-7.66 (2H, m), 7.47-7.55 (1H, m), 7.37-7.47 (3H, m), 7.18-7.25 (1H, m), 7.14-7.18 (2H, m), 7.12 (2H, δ, J=7.70 Hz), 5.87 (1H, br. s), 4.55 (2H, δ, J=5.77 Hz), 2.07 (3H, s); MS (ES+) m/z: 438 (M+H); LC retention time: 4.388 min (analytical HPLC Method A).