Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.[C:6]([C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[CH:12][CH:13]=1)#[CH:7].[F:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[O:20][C:21]1[N:26]=[CH:25][C:24]([CH2:27][C:28](Cl)=[N:29][OH:30])=[CH:23][CH:22]=1.C(N(CC)CC)C>O>[F:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[O:20][C:21]1[N:26]=[CH:25][C:24]([CH2:27][C:28]2[CH:7]=[C:6]([C:8]3[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[CH:12][CH:13]=3)[O:30][N:29]=2)=[CH:23][CH:22]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(Oc2cccc(F)c2)nc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1ccc(-c2cc(Cc3ccc(Oc4cccc(F)c4)nc3)no2)c(N)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
To a tetrahydrofuran (2 mL) solution of 3-ethynyl-pyridin-2,6-diamine (10 mg, 75 μmol) described in Manufacturing Example 13-1-3 and (6-(3-fluoro-phenoxy)-pyridin-3-yl)-acetohydroximoyl chloride (42 mg, 0.15 mmol) described in Manufacturing Example 71-1-4 was added triethylamine (21 μL, 0.15 mmol), which was stirred for 1 hour at 50° C. under nitrogen atmosphere. Water was added at room temperature to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=20:1) to obtain the title compound (27 mg, 95%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[N+:9]([O-])=O.O.O.[Cl:14][Sn]Cl.O>Cl>[Cl:14][C:5]1[C:4]([NH2:9])=[C:3]([NH:2][CH3:1])[CH:8]=[CH:7][N:6]=1
Reactant: CNc1ccncc1[N+](=O)[O-]
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: O
Product: CNc1ccnc(Cl)c1N
Temperature: 90 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
10 g of (10) were dissolved in 50 ml of 12N HCl and the temperature brought to 90° C. 72.5 g di SnCl2.2H2O were added in five portions over the course of 1 minute. This was left stirring at 90° C. for 1 hour. After cooling the solution to room temperature, 100 ml of water were added and evaporated at reduced pressure. The residue was taken up in 100 ml of water, cooled to 0° C. and concentrated aqueous ammonia added, until the formation of a white, gelatinous precipitate. The pH was adjusted to 8.5-9 and the resulting emulsion centrifuged. The remaining solid residues were again taken up in water and centrifuged. The operation was repeated three times. The combined solid residues were left under stirring overnight in 50 ml of methylene chloride. The centrifuged aqueous phases were extracted three times with methylene chloride, then all the organic phases combined, then dried over anhydrous sodium sulphate and subsequently evaporated under vacuum, giving 6.2 g of (11) in the form of pink crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[C:17]4[CH:24]=[CH:23][N:22]([CH3:25])[C:18]4=[CH:19][CH:20]=3)[O:15][CH:14]([OH:26])[CH2:13]2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].N1C=CC=CC=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>ClCCl.CN(C)C1C=CN=CC=1>[C:33]([O:26][CH:14]1[CH2:13][CH:12]([C:4]2[CH:5]=[C:6]([O:10][CH3:11])[C:7]([O:8][CH3:9])=[C:2]([Br:1])[CH:3]=2)[C:21]2[C:16](=[C:17]3[CH:24]=[CH:23][N:22]([CH3:25])[C:18]3=[CH:19][CH:20]=2)[O:15]1)(=[O:35])[CH3:34]
Reactant: COc1cc(C2CC(O)Oc3c2ccc2c3ccn2C)cc(Br)c1OC
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(C2CC(OC(C)=O)Oc3c2ccc2c3ccn2C)cc(Br)c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
To a solution of 4-(3-bromo-4,5-dimethoxyphenyl)-2-hydroxy-7-methyl-pyrrolo[2,3-h]chroman (37 mg, 0.089 mmol) in dichloromethane (0.5 ml) at 0° C. was added pyridine (0.010 ml, 0.133 mmol), 4-dimethylaminopyridine (1.0 mg, 0.0082 mmol) and acetic anhydride (0.010 ml, 0.111 mmol) and the resulting solution was stirred at 0° C. for 0.5 h. The solution was then stirred at room temperature for 1.5 h. The reaction mixture was diluted with dichloromethane and the organic solution was extracted with water and a saturated aqueous solution of sodium bicarbonate. The organic layer was dried and concentrated in vacuo. The residue was purified by flash chromatography (20% ethyl acetate/hexane) to give 39 mg (90%) of the title compound. 1H NMR (CD3CN): 7.10 (dd, 1H); 7.02 (m, 1H); 6.94-6.84 (m, 2H); 6.72-6.60 (m, 1H); 6.53 (m, 1H); 6.43 (m, 1H); 4.38-4.19 (m, 1H); 3.80-3.74 (m, 9H); 2.56-2.40 (m, 1H); 2.32 (m, 1H); 1.96 (s, 3H).
Reaction SMILES: C(N1[C:8](=[O:9])[C:7]2=[C:10]([F:17])[C:11]([F:16])=[C:12]([F:15])[C:13]([F:14])=[C:6]2[C:5]1=[O:18])(C)C.S(=O)(=O)(O)[OH:20].C(O)(=O)C>O>[F:17][C:10]1[C:11]([F:16])=[C:12]([F:15])[C:13]([F:14])=[C:6]2[C:5](=[O:18])[O:9][C:8](=[O:20])[C:7]=12
Reactant: CC(C)N1C(=O)c2c(F)c(F)c(F)c(F)c2C1=O
Reactant: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Yield: 66.4 %

Procedure:
In a 500 ml three neck distillation flask were placed 47 g (0.18 mol) of N-isopropyl-tetrafluorophthalimide, 71 ml of concentrated sulfuric acid, 43 ml of acetic acid, and 13 ml of water, and the mixture was reacted for 5 hours at 140° to 150° C. with stirring. After cooling, the reaction mixture was extracted three times with 200 ml of toluene, and the toluene layers thus formed were collected and concentrated by distillation under a reduced pressure to provide 26.3 g (yield 66.4%) of tetrafluorophthalic anhydride as white crystals.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[C:14]#[N:15].O=[CH:17][C:18]1[CH:26]=[CH:25][C:23]([OH:24])=[C:20]([O:21][CH3:22])[CH:19]=1>CCO.N1CCCCC1>[OH:24][C:23]1[CH:25]=[CH:26][C:18]([CH:17]=[N:1][C:2]2[NH:6][N:5]=[C:4]([NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:3]=2[C:14]#[N:15])=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: N#Cc1c(Nc2ccccc2)n[nH]c1N
Reactant: COc1cc(C=O)ccc1O
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cc(C=Nc2[nH]nc(Nc3ccccc3)c2C#N)ccc1O
Yield: 38.8 %

Procedure:
5-amino-3-(phenylamino)-1H-pyrazole-4-carbonitrile (100 mg) was suspended in EtOH (4 mL) and Vanillin (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain A21 as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr (65 mg, 38.8% yield).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]([CH:21]=[O:22])=[C:19]([Cl:23])[N:18]=[C:17]2[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:24]([C:17]1[N:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:10][CH:11]=2)[C:20]([CH:21]=[O:22])=[C:19]([Cl:23])[N:18]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(S(=O)(=O)NC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(S(N)(=O)=O)cc1

Procedure:
Intermediate (2b) was dissolved into 60 mL of 1:1 DCM:TFA and heated to 40° C. for 16 hours. The mixture was concentrated under reduced pressure to yield intermediate (2c) as a yellow oil in a quantitative yield. MS m/z: [M+H+] calcd for C15H18ClN3O3S 356.1; found 356.3.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[CH3:49][N:50]1[CH:54]=[CH:53][C:52]([NH2:55])=[N:51]1.N1C=CC=CC=1>C(Cl)Cl.O>[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:55][C:52]2[CH:53]=[CH:54][N:50]([CH3:49])[N:51]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: Cn1ccc(N)n1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Yield: 47.7 %

Procedure:
Triphenylphosphine (1.190 g, 4.54 mmol) was dissolved in methylene chloride (40 mL) and cooled to 0° C. To this solution was added N-bromosuccinimide (914 mg, 5.14 mmol) and was stirred at 0° C. until it was completely dissolved and became light purple in color. The 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 1.00 g, 3.02 mmol) was then added and it was stirred at 0° C. for 20 min and then warmed to 25° C. and stirred for 30 min. After such time, 1-methyl-1H-pyrazol-3-ylamine (441 mg, 4.54 mmol) and pyridine (740 μL, 4.53 mmol) were added and it was stirred at 25° C. for 16 h. The reaction was then diluted with water (30 mL) and then extracted with methylene chloride (3×15 mL). The organic layers were then combined and dried over magnesium sulfate, filtered and concentrated in vacuo. Flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/hexanes) followed by reverse phase preparative HPLC purification (Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 30% acetonitrile/water to 100% acetonitrile/water; 30 mL/min flow rate for 15 min run) afforded 3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-1-methyl-pyrazole (590 mg, 48%) as a white solid: ESI-LRMS m/e calcd for C19H24ClN3O3S [M+] 409.1. found 410.1 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 0.96-1.18 (m, 2H, CH2), 1.35-1.86 (m, 8H, 4×CH2), 2.10-2.21 (m, 1H, CH), 3.24 (s, 3H, SO2CH3), 3.57 (t, J=7.6 Hz, 1H, CH), 3.73 (s, 3H, NCH3), 6.59 (d, J=2.3 Hz, 1H, Ar), 7.21 (d, J=2.3 Hz, 1H, Ar), 7.38 (dd, Jo=8.2, Jm=1.7 Hz, 1H, Ar), 7.50 (d, Jm=1.7 Hz, 1H, Ar), 7.96 (d, Jo=8.2 Hz, 1H, Ar), 8.82 (s, 1H, NH).
Reaction SMILES: [CH2:1]1[C@H:9]2[C@H:4]([CH2:5][CH2:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)[N:3]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[C:23](=O)[C:22]3=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]3[C:20]2=[O:29])[CH2:2]1.[H][H].[C:32](O)(=[O:34])C>[Pd]>[CH3:32][O:34][C:13]1[C:7]2[CH2:6][CH2:5][C@H:4]3[C@H:9]([CH2:1][CH2:2][N:3]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:23][C:22]4[C:21](=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:20]3=[O:29])[C:8]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)O
Reactant: [H][H]
Reactant: O=C1c2ccccc2C(=O)N1CCCCCN1CC[C@@H]2c3ccccc3CC[C@@H]21
Agent: [Pd]
Product: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCCCN1Cc2ccccc2C1=O
Yield: 27 %

Procedure:
A solution of 3.10 g (0.007 mol) of rac-N-[5-(cis-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)pentyl]phthalimide in 100 ml of glacial acetic acid was treated with 1.0 g of 10% palladium/charcoal and hydrogenated at 60° for 6 hours at 20 bar hydrogen pressure. The acetic acid was distilled off and the residue was taken up in methylene chloride. The solution was washed with 2N sodium hydroxide solution, dried with sodium sulphate and concentrated. Chromatography over silica gel with ethyl acetate/methanol 19:1 yielded 0.80 g (27%) of rac-cis-2-[5-(6-methoxy-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-3-yl)pentyl]isoindolin-1-one as a yellow oil [MS: m/e (% basis peak)=404 (M+, 6), 216 (100), 202 (8), 185 (6), 146 (7)] as well as 1.64 g (55%) of rac-2-[5-(6-methoxy-2,3,3a,4,5,9b-hexahydro-1H-cis-benzo[e]indol-6-yl)pentyl]octahydro-cis-isoindole-1,3-dione as a yellow oil [MS: m/e (% basis peak)=424 (M+ , 7), 216 (100), 185 (5)].
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[NH:17])=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1>CC(=O)CC>[BrH:1].[Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:10]=3[N:9]([CH2:21][CH2:22][CH2:23][O:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[C:8]2=[NH:17])=[CH:4][CH:3]=1
Reactant: Cc1ccc2[nH]c(=N)n(Cc3ccc(Br)cc3)c2c1
Reactant: Fc1ccc(OCCCBr)cc1
Solvent: CCC(C)=O
Product: Br
Product: Cc1ccc2c(c1)n(Cc1ccc(Br)cc1)c(=N)n2CCCOc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.1 %

Procedure:
To a solution of 1-(4-bromo-benzyl)-6-methyl-1,3-dihydro-benzoimidazol-2-ylideneamine (0.14 g, 0.44 mmol) in 2-butanone (5 ml) at rt was added 1-(3-bromo-propoxy)-4-fluoro-benzene (0.15 g, 0.66 mmol). The reaction was stirred for 10 min and then additional 2-butanone (5 ml) was introduced. The mixture was heated to reflux where it was maintained for 48 h. After this time, the reaction was cooled to rt and additional 1-(3-bromo-propoxy)-4-fluoro-benzene (0.05, 0.22 mmol) was added. The reaction was then heated to reflux for a further 15 h. It was then cooled to rt and filtered. The collected solid was dried to provide 3-(4-bromo-benzyl)-1-[3-(4-fluoro-phenoxy)-propyl]-5-methyl-1,3-dihydrobenzoimidazol-2-ylideneamine, hydrobromide salt (0.04 g, 16%). HPLC-MS 468, 470 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:35])=[C:6]([CH:34]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][C:24]=2[O:32][CH3:33])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2.[Sn](Cl)(Cl)(Cl)Cl.CN(C)C=O.C(O)C>C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([C:10]2[C:9]([CH2:8][O:7][C:6]3[CH:34]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:35])=[C:18]3[C:13]([NH:14][C:15]([CH3:22])([CH3:21])[C:16](=[O:20])[N:17]3[CH3:19])=[CH:12][CH:11]=2)=[C:24]([O:32][CH3:33])[CH:25]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1cc(N)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Temperature: 80 °C
Reaction time: 72 h
Yield: 49.5 %

Procedure:
A mixture of 8-(5-fluoro-2-methylphenoxymethyl)-7-(2-methoxy-4-nitrophenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 8-6, 26.1 mg, 0.0544 mmol) and tin chloride (II) (64.8 mg, 0.342 mmol) was suspended in mixed solvent of anhydrous N,N-dimethylformamide (0.25 ml) and anhydrous ethanol (0.5 mL), and stirred at 80° C. for 3 days. After cooling down, the reaction mixture was diluted with ethyl acetate (10 mL) and saturated aqueous sodium hydrogen carbonate solution was added thereto until the pH became 9. After the precipitated solids were filtered out, the filtrate was washed with water (50 mL) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (12.1 mg) as a brown solid. (Yield 50%)
Reaction SMILES: [OH:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][Br:4].[C:12](Cl)(=[O:14])[CH3:13]>ClCCl>[C:2]([O-:1])(=[O:14])[CH3:5].[C:12]([O:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][Br:4])(=[O:14])[CH3:13]
Reactant: OC(CBr)Cc1ccccc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)OC(CBr)Cc1ccccc1
Product: CC(=O)[O-]
Yield: 167.9 %

Procedure:
8 g (37.2 mmol) of 2-hydroxy-3-phenyl-propyl bromide are dissolved at room temperature in 80 ml of dichloromethane; with stirring, 2.64 ml (37.2 mmol) of acetyl chloride and after 3 hours a further 2.64 ml (37.2 mmol) of acetyl chloride are added dropwise thereto; the mixture is stirred for 4 hours at 60° and for 16 hours at room temperature and washed with 25 ml each of water and saturated sodium chloride solution. The aqueous phases are combined and washed with 30 ml of dichloromethane. The combined organic phases are dried over sodium sulfate and concentrated by evaporation. Chromatography on silica gel with hexanelethyl acetate (19:1) as eluant yields 8.03 g (83% of theory) of 2-acetoxy-3-phenyl-propyl bromide in the form of a colourless liquid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:12][N:13](C=O)C>C1(C)C=CC=CC=1.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:2]([C:12]#[N:13])[C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: Brc1cccc2ncccc12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: N#Cc1cccc2ncccc12
Temperature: 25 °C
Reaction time: 66 h

Procedure:
To a solution of 0.1810 g (0.870 mmol) 10 in 5 mL DMF was added 0.0630 g (0.54 mmol) zinc cyanide and 0.0640 g (0.055 mmol) tetrakis(triphenylphosphine)palladium(0). After 66 h under argon at 80° C., the reaction mixture was cooled to room temperature, diluted with 40 mL toluene and washed with 10 mL 2N NH4H. The aqueous layer was extracted with 10 mL toluene. The combined organic layers were washed with 10 mL brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (25×130 mm silica gel, linear gradient 2-3% (10% NH4OH:MeOH):CH2Cl2) afforded 11. 1NMR (CDCl3, 400 MHz) 69.065 (dd, 1H, J=1.65, 4.21 Hz, ArH); 8.567 (d, 1H, J=8.50 Hz, ArH); 8.377 (d, 1H, J=8.50 Hz, ArH); 8.005 (dd, 1H, J=1.09, 7.22 Hz, ArH); 7.796 (dd, 1H, J=7.22, 8.59 Hz, ArH); 7.636 (dd, 1H, J=4.21, 8.51 Hz, ArH); MS (Electrospray): m/z 155.0 (M+H).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:17])[CH2:6][CH:7]([CH:11]2[CH2:16][CH2:15][CH2:14][S:13][CH2:12]2)[CH2:8][C:9]=1[OH:10])(=O)[CH3:2].[Cl:18][C:19]1[S:23][C:22]([CH2:24][O:25][NH2:26])=[CH:21][CH:20]=1>C(O)C>[Cl:18][C:19]1[S:23][C:22]([CH2:24][O:25][N:26]=[C:1]([C:4]2[C:5](=[O:17])[CH2:6][CH:7]([CH:11]3[CH2:16][CH2:15][CH2:14][S:13][CH2:12]3)[CH2:8][C:9]=2[OH:10])[CH3:2])=[CH:21][CH:20]=1
Reactant: CC(=O)C1=C(O)CC(C2CCCSC2)CC1=O
Reactant: NOCc1ccc(Cl)s1
Solvent: CCO
Product: CC(=NOCc1ccc(Cl)s1)C1=C(O)CC(C2CCCSC2)CC1=O
Reaction time: 14 h
Yield: 95 %

Procedure:
A solution containing 5.1 g (0.020 mol) of 2-acetyl-3-hydroxy-5-(tetrahydro-2H-thiopyran-3-yl)cyclohex-2-en-1-one and 3.4 g (0.021 mol) of (5-chlorothien-2-yl)methoxyamine in 200 ml of ethanol was stirred overnight (about 14 hours) at room temprature and then evaporated to remove ethanol. The concentrate was diluted with 150 ml of methylene chloride and then washed with 100 ml of water and then with 100 ml of saturated aqueous sodium chloride solution. The washed methylene chloride solution was dried over anhydrous magnesium sulfate and then evaporated to dryness under reduced pressure to afford a white solid. Recrystallation of this solid absolute ethanol afforded 7.6 g of the title compound, m.p. 154°-155° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([NH:12][CH3:13])[C:9]([N+:14]([O-:16])=[O:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:17](Cl)[C:18](=[CH2:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:19][C:18](=[CH2:17])[CH2:20][O:1][C:2]1[CH:11]=[C:10]([NH:12][CH3:13])[C:9]([N+:14]([O-:16])=[O:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=C(C)CCl
Reactant: CNc1cc(O)c(C(=O)OC)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)COc1cc(NC)c([N+](=O)[O-])cc1C(=O)OC
Yield: 70952.6 %

Procedure:
The title compound was prepared following the procedure described for Step-6 of Intermediate-1 using methyl 2-hydroxy-4-(methylamino)-5-nitrobenzoate (4.00 g, 0.0176 mmol), methallyl chloride (2.8 g, 0.0318 mmol), potassium carbonate (4.38 g, 0.037 mmol) and DMF (50.0 mL) to afford 3.500 g of desired product. 1HNMR (DMSO-d6): δ 1.81 (s, 3H), 3.00 (d, J=4.8 Hz, 3H), 3.76 (s, 3H), 4.65 (s, 2H), 5.00 (s, 1H), 5.24 (s, 1H), 6.30 (s, 1H), 8.59 (s, 2H); [M+H]+: 281.00.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][S:18]([NH:21][CH3:22])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:4]=1)#[N:2].O1CCOCC1.CCO.[H][H]>[Pd].C(N(CC)CC)C>[NH2:2][CH2:1][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([O:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][S:18]([NH:21][CH3:22])(=[O:20])=[O:19])=[CH:15][CH:16]=2)[CH:4]=1
Reactant: CNS(=O)(=O)Cc1ccc(Oc2cc(C#N)nc(C)n2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CNS(=O)(=O)Cc1ccc(Oc2cc(CN)nc(C)n2)cc1
Reaction time: 4.5 h
Yield: 52.3 %

Procedure:
Combine palladium (18.54 g, 10% on charcoal), 1-[4-(6-cyano-2-methyl-pyrimidin-4-yl)oxyphenyl]-N-methyl-methanesulfonamide (46.34 g, 141.19 mmol), 1,4-Dioxane (278 mL), EtOH (185 mL), and triethylamine (78.7 mL) in a PARR reactor. Seal the PARR reactor and charge it with hydrogen (400 psi). Shake the reactor at room temperature for 4.5 h. Open the reactor and filter the contents through CELITE®. Collect and evaporate the filtrate to provide the title compound as a yellow solid (23.8 g, 48%). MS (m/z): 323 (M+1). Wash the CELITE® pad with a mixture of 1,4-dioxane/MeOH (6×500 mL); collect the filtrate; and evaporate the solvent to provide a second crop of the title compound as a yellow solid (pinky solid, 48%). MS (m/z): 323 (M+1).
Reaction SMILES: [Br: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][N:14]=3)[C:6]=2[CH:19]=1.C[O-].[Na+].CN(C)C=O.Br[CH2:29][C:30]([O:32][CH3:33])=[O:31]>O.C1(C)C=CC=CC=1>[CH3:33][O:32][C:30](=[O:31])[CH2:29][N:11]1[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:19][C:6]=2[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:8][CH2:9][C:10]1=[O:12]
Reactant: O=C1CN=C(c2ccccn2)c2cc(Br)ccc2N1
Reactant: COC(=O)CBr
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)CN=C(c2ccccn2)c2cc(Br)ccc21
Reaction time: 0.33 h

Procedure:
A mixture of 0.1 mole of 7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepin-2-one and 0.11 mole of sodium methoxide in about 200 ml. of dimethylformamide is heated at about 95° c. for about 20 minutes. To the mixture is added a solution of 0.11 mole of methyl bromoacetate in about 200 ml. of toluene over a period of about 1 hour at about 95° C., and heating is continued for an additional period of about 6 hours. The reaction mixture is then evaporated in vacuo and the residue thus obtained is stirred with about 500 ml. of water. The resulting suspension is filtered and the solids thus obtained are crystallized from a suitable organic solvent such as ether, methanol, methylene chloride, methylene chloridemethanol and the like to obtain 7-bromo-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepin-1-acetic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[N:7]([O])[C:6]([CH3:10])([CH3:9])[CH2:5][CH2:4][CH2:3]1.[C:12]([O:16]N=O)(C)([CH3:14])[CH3:13].N[C:20]1[CH:25]=CC=C[CH:21]=1>N1C=CC=CC=1.[V]>[O:16]([N:7]1[C:2]([CH3:11])([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1([CH3:10])[CH3:9])[C:12]1[CH:14]=[CH:25][CH:20]=[CH:21][CH:13]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)ON=O
Reactant: CC1(C)CCCC(C)(C)N1[O]
Agent: [V]
Solvent: c1ccncc1
Product: CC1(C)CCCC(C)(C)N1Oc1ccccc1
Yield: 72 %

Procedure:
The procedure of Example 5 is repeated using 1.95 g (12.5 mmol) of 2,2,6,6-tetramethylpiperidine-1-oxyl, 3.09 g (30.0 mmol) of tert-butylnitrite and 217 mg (˜0.125 mmol) of vanadium polyoxometallate (H5PV2Mo10O40) in 100 mL of pyridine and 2.32 g (25 mmol) of aniline in 5 mL of pyridine. The crude is purified by vacuum flash chromatography (heptane) to give 2.10 g of a colorless oil in 72.2% yield.