Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[F:33][C:34]([F:45])([F:44])[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42]N)=[CH:38][CH:37]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:42][C:39]3[C:40]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:41][C:36]([O:35][C:34]([F:33])([F:44])[F:45])=[CH:37][CH:38]=3)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(F)cc3)CC2)c1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(F)cc4)[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS m/e: 582.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:15]=[C:14]([C:16]([OH:18])=O)[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[CH:12][C:8]=2[C:9](O)=[O:10])=[CH:4][CH:3]=1.P(=O)(O)(O)O.CO>O>[CH3:1][C:2]1[CH:28]=[CH:27][C:5]2[NH:6][C:7]3[C:8]([C:9](=[O:10])[C:4]=2[CH:3]=1)=[CH:12][C:13]1[NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=2[C:16](=[O:18])[C:14]=1[CH:15]=3
Reactant: Cc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(C)cc3)cc2C(=O)O)cc1
Agent: O=P(O)(O)O
Solvent: CO
Solvent: O
Product: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1
Temperature: 92 °C
Reaction time: 5 h
Yield: 98.8 %

Procedure:
To 720 g of polyphosphoric acid (117%) heated at 92° C. were added 160 g of 2,5-di(4-methylanilino)terephthalic acid over a period of approximately 65 minutes, the temperature being maintained below 105° C. by adjustment of the addition rate. The reaction mixture was held at 105° C. for five hours and then cooled to 92° C. To this mixture was added 107.9 g of phosphoric acid (75%) dropwise over a period of approximately 30 minutes. The resultant melt was allowed to stir for 15 minutes at 90° C. and then poured slowly into 1120 g of methanol, the temperature being maintained below reflux using a water bath. The slurry was allowed to cool to room temperature and stand for 16 hours. The pigment slurry was heated at reflux for one hour, cooled below 65° C., diluted with water, collected by filtration, and washed with water until free of acid. The resultant presscake was reslurried in water and heated to 45° C. After the slurry was acidified to pH 2.6, an emulsion of 4.7 g of an anionic surfactant, 69.7 g of a petroleum distillate, and 160 g of water was added, and the slurry was stirred for three hours. The resultant slurry was collected by filtration and washed with water. The wet cake can be dried or used as is for specific applications. Here, the wet cake was dried in an oven at 60° C. to give approximately 143 g of 2,9-dimethylquinacridone as a magenta pigment.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[F:11]/[C:12](=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]([C:34]([F:37])([F:36])[F:35])([C:30]([F:33])([F:32])[F:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)/[CH2:13][OH:14].C(N(CC)CC)C>ClCCl>[F:11]/[C:12](=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]([C:30]([F:31])([F:32])[F:33])([C:34]([F:37])([F:35])[F:36])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)/[CH:13]=[O:14]
Reactant: OC/C(F)=C/CCCCCCOC(c1ccccc1)(C(F)(F)F)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C/C(F)=C/CCCCCCOC(c1ccccc1)(C(F)(F)F)C(F)(F)F
Reaction time: 1 h

Procedure:
Dimethyl sulphoxide (293 mg) in dry dichloromethane (3 ml) was added to oxalyl chloride (162 mg) in dichloromethane (14 ml) at -60° C. After 10 minutes the above alcohol (0.73 g) in dichloromethane (3 ml) was added and the mixture kept at -60° C. for 1 hour. Triethylamine (1.01 ml) was added and the whole allowed to reach 0° C. gradually. Conventional work-up gave (Z)-2-fluoro-9-(bistrifluoromethylbenzyloxy)non-2-ene-1-al.
Reaction SMILES: [N:1]1([C:5]([C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3Cl)[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:17][O:18][C:19](=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[Cl:28].C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CS(C)=O.O>[CH3:17][O:18][C:19](=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:13]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:8]=[C:7]([C:5]([N:1]4[CH2:4][CH2:3][CH2:2]4)=[O:6])[S:15][C:14]=23)=[CH:23][C:22]=1[Cl:28]
Reactant: COC(=O)Cc1ccc(O)cc1Cl
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)Cc1ccc(Oc2ccnc3cc(C(=O)N4CCC4)sc23)cc1Cl
Temperature: 100 °C
Yield: 41.5 %

Procedure:
A mixture of azetidin-1-yl-(7-chloro-thieno[3,2-b]pyridin-2-yl)-methanone (21a) (930 mg, 3.70 mmol), (2-chloro-4-hydroxy-phenyl)-acetic acid methyl ester (49e) (740 mg, 3.70 mmol), and Cs2CO3 (1.82 g, 7.40 mmol) in 7 mL of DMSO was heated at 100° C. for overnight and cooled to room temperature. EtOAc and water were added. The organic layer was washed three times with water, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography eluting with EtOAc:CHCl3:MeOH (1:1:0.04) to provide 640 mg of white solid as the intermediate 49f. 1H NMR (300 MHz, CD3OD) δ 8.47 (d, 1H, J=5.46 Hz), 7.74 (s, 1H), 7.43 (d, 1H, J=8.48 Hz), 7.32 (d, 1H, J=2.45 Hz), 7.15–7.10 (m, 1H), 6.73 (d, 1H, J=5.47 Hz), 4.67–4.54 (m, 2H), 4.24–4.13 (m, 2H), 3.80 (s, 3H), 3.65 (s, 2H), 2.48–2.33 (m, 2H). LCMS (ESI+) [M+H]/z Calc'd 417, found 417.
Reaction SMILES: [CH2:1]([C:5]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:25]=[C:24]([Cl:26])[S:23][C:22]=3[C:27]3[N:31](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].Cl.[OH-].[Na+]>O1CCOCC1>[CH2:1]([C:5]1[N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:25]=[C:24]([Cl:26])[S:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:19][CH:20]=2)[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cccnc2n1Cc1ccc(-c2cc(Cl)sc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCc1nc2cccnc2n1Cc1ccc(-c2cc(Cl)sc2-c2nnn[nH]2)cc1
Yield: 96.5 %

Procedure:
2-Butyl-3-[4-[5-chloro-2-(1-trityl-1H-tetrazol-5-yl)-3-thienyl]benzyl]-3H-imidazo[4,5-b]pyridine (1.02 g) was dissolved in 1,4-dioxane (10 ml) and treated with 1N hydrochloric acid at ambient temperature for 10 hours. The reaction mixture was neutralized with 1N aqueous sodium hydroxide and concentrated in vacuo. The residue was extracted with dichloromethane-methanol (4:1) and the extract was evaporated in vacuo. The residue was purified by silica gel column chromatography to afford 2-butyl-3-[4-[5-chloro-2-(1H-tetrazol-5-yl)-3-thienyl]benzyl]-3H-imidazo[4,5-b]pyridine (640 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][CH2:11][CH2:12]Cl)=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1.[C:17]1([CH:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][CH2:11][CH2:12][N:27]2[CH2:28][CH2:29][N:24]([CH:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:25][CH2:26]2)=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1NCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)c(Cl)cc1NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 6.5 parts of 4,5-dichloro-N-(3-chloropropyl)-2-nitrobenzenamine, 5.6 parts of 1-(diphenylmethyl)piperazine, 5.3 parts of sodium carbonate, 0.1 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. The reaction mixture is cooled to room temperature and water is added. The organic phase is separated, dried, filtered and evaporated, yielding N-(4,5-dichloro-2-nitrophenyl)-4-(diphenylmethyl)-1-piperazinepropanamine as a residue.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].I[CH2:10][CH2:11][CH2:12][CH:13]1[S:17][C:16]2[C:18]([CH3:28])=[C:19]([O:24][CH2:25][O:26][CH3:27])[C:20]([CH3:23])=[C:21]([CH3:22])[C:15]=2[O:14]1.O>CN(C)C=O>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][O:5][CH2:10][CH2:11][CH2:12][CH:13]1[S:17][C:16]2[C:18]([CH3:28])=[C:19]([O:24][CH2:25][O:26][CH3:27])[C:20]([CH3:23])=[C:21]([CH3:22])[C:15]=2[O:14]1
Reactant: CN(C)CCO
Reactant: COCOc1c(C)c(C)c2c(c1C)SC(CCCI)O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1c(C)c(C)c2c(c1C)SC(CCCOCCN(C)C)O2
Temperature: 50 °C

Procedure:
210 mg of 2-dimethylaminoethanol were dissolved in 3 ml of dimethylformamide, and then 100 mg of a 50% w/w oily suspension of sodium hydride were added to the solution. This reaction mixture was then heated for 1 hour at 50° C. The reaction mixture was then cooled with ice, and a solution of 900 mg of 2-(3-iodopropyl)-5-methoxymethoxy-4,6,7-trimethyl-1,3-benzoxathiole (prepared as described in Example 86) in 2 ml of dimethylformamide was added dropwise, while stirring. After completion of the dropwise addition, the temperature of the reaction mixture was gradually raised, and then the mixture was heated for a further 2 hours at 50° C. The reaction mixture was then poured into water, and the resulting precipitate was extracted with benzene. The extract was washed with water and dried over anhydrous sodium sulfate. The benzene was distilled off under reduced pressure. The residual crude oily reaction product was separated by silica gel column chromatography. The fraction eluted with benzene was removed, while the fraction eluted with a 20:1 by volume mixture of ethyl acetate and triethylamine was subjected to silica gel Lobar column chromatography, eluted with the same eluent, to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[CH:40][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:15][C@@H:14]([S:16][C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][C@H:12]2[CH2:36][N:37]=[N+]=[N-])=[O:10])=[CH:5][CH:4]=1.CO.[C:44]([OH:47])(=[O:46])[CH3:45]>C(OCC)(=O)C.[Pd]>[C:44]([OH:47])(=[O:46])[CH3:45].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:15][C@@H:14]([S:16][C:17]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][C@H:12]2[CH2:36][NH2:37])=[O:10])=[CH:40][CH:41]=1
Reactant: COc1ccc(COC(=O)N2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2CN=[N+]=[N-])cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(COC(=O)N2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2CN)cc1
Yield: 94.5 %

Procedure:
A solution of (2S,4S)-1-p-methoxybenzyloxycarbonyl-2-azidomethyl-4-tritylthiopyrrolidine (17.27 g: 30.64 mmole) in a mixture of ethyl acetate (150 ml), methanol (200 ml), and acetic acid (2.63 ml: 46 mmole) is subjected to conventional hydrogenation over 5% palladium on carbon (5 g). After the reaction, the catalyst is filtered off and the filtrate is concentrated in vacuo to give (2S,4S)-1-p-methoxybenzyloxycarbonyl-2-aminomethyl-4-tritylthiopyrrolidine acetate (17.33 g) as a residue. The residue is dissolved in dichloromethane, washed with aqueous sodium hydrogen carbonate, and concentrated to give (2S,4S)-2-aminomethyl-1-p-methoxybenzyloxycarbonyl-4-tritylthiopyrrolidine (16.82 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[I:9].[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[OH:18].C1CCN2C(=NCCC2)CC1.[OH-].[Na+]>CN1C(=O)CCC1>[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[O:18][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[I:9]
Reactant: Oc1cc(F)ccc1F
Reactant: Nc1nccc(Cl)c1I
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nccc(Oc2cc(F)ccc2F)c1I
Temperature: 170 °C
Reaction time: 6 h
Yield: 62.1 %

Procedure:
4-chloro-3-iodopyridin-2-amine (3.00 g, 11.79 mmol), 2,5-difluoro phenol (4.60 g, 35.4 mmol), DBU (1.777 ml, 11.79 mmol) were combined in NMP (15 mL) and solution was stirred at 170° C. for 6 h under microwave irradiation. The crude reaction mixture was poured into 1N NaOH solution (70 mL), the resultant suspension was filtered, washed with water (5×10 mL) and dried to afford crude product which was purified by silica gel chromatography (EtOAc-hexanes) to afford 4-(2,5-difluorophenoxy)-3-iodopyridin-2-amine as white solid. (2.55 g, 62.1% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.74 (d, J=7.6 Hz, 1H), 7.47 (m, 1H), 7.28 (m, 1H), 7.18 (On, 1H), 6.25 (br s, 2H), 5.88 (dd, J=5.6 Hz, 1H); MS (ESI) m/z: 349.03 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[CH:15]N(C)C)[C:10](OCC)=[O:11])=[C:5]([O:19][CH3:20])[CH:4]=1)#[N:2].[NH:21]([C:23]1[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH2:30][CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:28])=[CH:25][N:24]=1)[NH2:22]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:15]=[N:22][N:21]([C:23]3[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH2:30][CH:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[O:28])=[CH:25][N:24]=3)[C:10]=2[OH:11])=[C:5]([O:19][CH3:20])[CH:4]=1)#[N:2]
Reactant: CCOC(=O)C(=CN(C)C)c1ccc(C#N)cc1OC
Reactant: NNc1ccc(C(=O)NCC2CCOCC2)cn1
Product: COc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCC3CCOCC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 188 using ethyl 2-(4-cyano-2-methoxyphenyl)-3-(dimethylamino)acrylate and 6-hydrazinyl-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (t, J=7.1 Hz, 11 H) 1.22 (d, J=9.6 Hz, 3 H) 1.62 (d, J=12.1 Hz, 2 H) 3.19 (dd, J=11.6, 5.6 Hz, 4 H) 3.86 (d, J=9.6 Hz, 2 H) 3.97 (s, 3 H) 7.38-7.57 (m, 2 H) 8.43 (br. s., 2H) 8.72 (br. s., 1 H) 8.92 (s, 1 H). MS m/z [M+H]+ 434.4.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]#[C:20][CH2:21][CH2:22][NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:13]=[CH:12]2)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]#[C:20][CH2:21][CH2:22][NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH:13]=[CH:12]2
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc(C#CCCNC(=O)OCc3ccccc3)ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(NCCC#Cc1ccc2cc(O)ccc2c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of benzyl 4-[6-(tert-butyldimethylsilyloxy)naphthalen-2-yl]but-3-ynylcarbamate (29, 578 mg, 1.26 mmol) in anhydrous THF (60 mL) was added dropwise tetrabutylammonium fluoride (1 M in THF, 1.38 mL) and the mixture was stirred for 2 h at room temperature. The resulting solution was concentrated in vacuo and the residue was purified by column chromatography (silical gel, 95:5 CH2Cl2/MeOH) to afford carbamate 30 (418 mg, 96%) as a pale yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.82 (s, 1H), 7.67 (d, J=9.6 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.37-7.29 (m, 6H), 7.11-7.08 (m, 2H), 5.30 (br s, 2H), 5.14 (s, 2H), 3.48 (q, J=6.3 Hz, 2H), 2.68 (t, J=6.6 Hz, 2H).
Reaction SMILES: Cl.O.[Cl-].[NH4+].[Cl:5][C:6]1[CH:7]=[C:8]([C:28]([O:30][CH3:31])=[O:29])[C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)=[C:10]([N+:18]([O-])=O)[C:11]=1[C:12]#[C:13][Si:14]([CH3:17])([CH3:16])[CH3:15]>CO.[Fe]>[NH2:18][C:10]1[C:11]([C:12]#[C:13][Si:14]([CH3:16])([CH3:15])[CH3:17])=[C:6]([Cl:5])[CH:7]=[C:8]([C:28]([O:30][CH3:31])=[O:29])[C:9]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1
Reactant: COC(=O)c1cc(Cl)c(C#C[Si](C)(C)C)c([N+](=O)[O-])c1-c1cccc(F)c1
Agent: [Fe]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(Cl)c(C#C[Si](C)(C)C)c(N)c1-c1cccc(F)c1
Temperature: 60 °C
Yield: 83.1 %

Procedure:
A suspension of iron (<10 micron) (1.6 g, 29 mmol) in methanol (24 mL) was treated with 6 M hydrogen chloride in water (0.4 mL, 2.4 mmol) and heated at 60° C. for 2 hours. The reaction mixture was treated with 5 M ammonium chloride in water (4.1 mL, 21 mmol) followed by methyl 4-chloro-3′-fluoro-6-nitro-5-[(trimethylsilyl)ethynyl]biphenyl-2-carboxylate (1.9 g, 4.8 mmol) and heated at 60° C. for 16 hours. The reaction mixture was filtered over celite, washed with methanol, and the filtrate was concentrated to a solid. The solid was diluted with ethyl acetate (200 mL) and saturated sodium bicarbonate (100 mL) and stirred for a few minutes. The organic layer was separated, washed with brine, dried with sodium sulfate, filtered, and concentrated to a crude residue. Purification by flash column chromatography using ethyl acetate in hexanes (0%-10%) gave the desired product (1.5 g, 86%). LCMS for C19H20ClFNO2Si (M+H)+: m/z=376.1; Found: 376.1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.Br[CH:12]([CH:19]=O)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][C:12]1[S:7][C:6]([C:5]2[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)=[N:8][CH:19]=1)[CH3:18]
Reactant: CCOC(=O)CC(Br)C=O
Reactant: NC(=S)c1ccc(Br)cc1
Solvent: CCO
Product: CCOC(=O)Cc1cnc(-c2ccc(Br)cc2)s1

Procedure:
A mixture of 4-bromothiobenzamide (2.16 g., 0.01 mole) and ethyl 3-bromo-4-oxobutyrate (3.2 g., 0.015 mole) in ethanol (50 ml.) is heated at reflux for 6 hours. On cooling and partial evaporation there is obtained 2-(4-bromophenyl)thiazol-5-ylacetic acid ethyl ester. Reaction of this product with ammonia according to the procedure of Example 3 gives 2-(4-bromophenyl)thiazol-5-ylacetamide, which on reaction with diethyl oxalate and base in dimethylformamide, according to the general procedure of Example 6, affords the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:30]=[C:21]3[CH2:22][N:23]([CH:26]4[CH2:29][O:28][CH2:27]4)[CH2:24][CH2:25][N:20]3[N:19]=2)[C:3]1=[O:31].Cl[C:33]1[C:38]([CH:39]=[O:40])=[C:37]([N:41]2[CH2:54][CH2:53][N:44]3[C:45]4[CH2:46][CH2:47][CH2:48][CH2:49][C:50]=4[C:51]([F:52])=[C:43]3[C:42]2=[O:55])[N:36]=[CH:35][CH:34]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[F:52][C:51]1[C:50]2[CH2:49][CH2:48][CH2:47][CH2:46][C:45]=2[N:44]2[CH2:53][CH2:54][N:41]([C:37]3[N:36]=[CH:35][CH:34]=[C:33]([C:6]4[CH:5]=[C:4]([NH:17][C:18]5[CH:30]=[C:21]6[CH2:22][N:23]([CH:26]7[CH2:29][O:28][CH2:27]7)[CH2:24][CH2:25][N:20]6[N:19]=5)[C:3](=[O:31])[N:2]([CH3:1])[CH:7]=4)[C:38]=3[CH:39]=[O:40])[C:42](=[O:55])[C:43]=12
Reactant: O=Cc1c(Cl)ccnc1N1CCn2c3c(c(F)c2C1=O)CCCC3
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2cc3n(n2)CCN(C2COC2)C3)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: Cn1cc(-c2ccnc(N3CCn4c5c(c(F)c4C3=O)CCCC5)c2C=O)cc(Nc2cc3n(n2)CCN(C2COC2)C3)c1=O
Temperature: 100 °C
Yield: 60 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1-methyl-3-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 163a (354 mg, 0.83 mmol), 4-chloro-2-(10-fluoro-1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)nicotinaldehyde 134c (289 mg, 0.83 mmol), PdCl2(dppf) (68 mg, 0.08 mmol), K3PO4 (352 mg, 1.66 mmol), sodium acetate (136 mg, 1.66 mmol), acetonitrile (50 mL), and water (3 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 166a (305 mg, 60%) as a brown solid. MS-ESI: [M+H]+: 613.6.
Reaction SMILES: [H][H].C=O.C[N:6]([CH2:11][CH2:12][C:13]#[N:14])[CH2:7][CH2:8][C:9]#[N:10]>[Pd].CO.[Cr].[Co]>[NH:6]([CH2:11][CH2:12][C:13]#[N:14])[CH2:7][CH2:8][C:9]#[N:10]
Reactant: [H][H]
Reactant: CN(CCC#N)CCC#N
Agent: [Co]
Agent: [Cr]
Agent: [Pd]
Solvent: CO
Product: N#CCCNCCC#N
Temperature: 95 °C

Procedure:
A 300 cc Hastelloy C autoclave was charged with 10.0 g of 5% palladium on carbon catalyst (50 wt % water wet). The reactor was flushed several times with nitrogen and then hydrogen. Then 123 g of crude IBPN obtained as the distillation residue in Example 1 was pumped into the autoclave. The temperature of the reactor contents was raised to 95°C. and hydrogen was added to provide a pressure of 115 psig. Formaldehyde (as a 55 wt % solution in methanol) was then admitted to the autoclave at a rate of 0.2 ml/min until a total of 66.9 g had been added. The mixture was allowed to react for 3.5 hours at which time analysis by gas chromatography/mass spectroscopy revealed that the IBPN had been completely converted to methyliminobispropionitrile (MIBPN). The reactor contents containing the MIBPN were then cooled and filtered and the methanol and water were removed in vacuo to give a clear light yellow liquid. Little to no reduction of the nitrile to the amine occurred under these conditions as evidenced by the lack of terminal N-methyl derivatives in the GC mass spectrum.
Reaction SMILES: [C:1]1(=[C:7]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18]C(C)(C)C)=[O:17])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.O>C(Cl)Cl>[C:1]1(=[C:7]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=C(O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)cc1
Temperature: 0 °C
Yield: 66.2 %

Procedure:
A solution of 1,1-dimethylethyl(2E)-3-{4-[cyclohexylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoate (7) (0.24 g, 0.61 mmol) in CH2Cl2 (6 mL) was cooled in an ice-water bath and stirred under a nitrogen atmosphere. To the cold solution was slowly added trifluoroacetic acid (6 mL). The reaction mixture was stirred in the ice-water bath under a nitrogen atmosphere for 1 h. The reaction mixture was concentrated to give the crude product as a solid. The crude product was dissolved in CH2Cl2 and the solution was concentrated to give a solid. The crude product was transferred to a separatory funnel with the aid of CH2Cl2 and H2O. The organic phase was removed and the aqueous phase that contained suspended solids was extracted twice with CH2Cl2. The organic phase was removed and the aqueous suspension was filtered with the aid of H2O. The filtered white solid was dissolved in CH2Cl2 and MeOH and the solution was filtered. The filtrate was concentrated and the resulting solid was dried in a vacuum oven to give 135 mg (67%) of compound 8 as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.52 (m, 6 H), 2.15 (m, 4 H), 6.44 (d, J=15.9 Hz, 1 H), 6.66 (d, J=8.4 Hz, 2 H), 6.84 (d, J=8.4 Hz, 2 H), 7.05 (d, J=8.0 Hz, 2 H), 7.52 (d, J=15.9 Hz, 1 H), 7.57 (d, J=8.0 Hz, 2 H), 9.31 (s, 1 H), 12.31 (br s, 1 H). The sample was silated prior to EI analysis. HRMS (EI) Calcd for C28H38O3Si2: 478.2360 (M+). Found: 478.2376.