Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:15])[C:7]3[N:8]([CH:12]=[CH:13][CH:14]=3)[NH:9][C:10]=2[CH:11]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24][CH3:25].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:15])[C:7]3[N:8]([CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:23][CH2:24][CH3:25])[C:10]=2[CH:11]=1
Reactant: O=c1c2ccc(Cl)cc2[nH]n2cccc12
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c2cc(Cl)ccc2c(=O)c2cccn21
Temperature: 25 °C
Reaction time: 48 h
Yield: 59 %

Procedure:
7-Chloropyrrolo[1,2-b]cinnolin-10(5H)-one (9.0 g) was taken up in 100 ml of DMF and milled K2CO3 (11.33 g) was added. 1-Bromopropane (10.09 g) was then added dropwise and the solution was stirred at room temperature for 48 h. Water was added and the solution was extracted into dichloromethane and washed several times with H2O and dilute hydrochloric acid. The organics were then dried (MgSO4), charcoaled, filtered and concentrated to an orange oil. The oil was purified by HPLC (silica, dichloromethane) and concentrated to give 6.33 g of an orange powder which was recrystallized from ether to yield 3.4 g of yellow-orange microcrystals, mp 107°-108°.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([C:12](=O)[CH:13]([CH3:18])[CH2:14][C:15](O)=[O:16])=[CH:11][C:5]=2[O:4][CH2:3]1.[NH2:20][NH2:21]>C(O)C>[O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]3[CH:13]([CH3:18])[CH2:14][C:15](=[O:16])[NH:20][N:21]=3)=[CH:11][C:5]=2[O:4][CH2:3]1
Reactant: NN
Reactant: CC(CC(=O)O)C(=O)c1ccc2c(c1)OCC(=O)N2
Solvent: CCO
Product: CC1CC(=O)NN=C1c1ccc2c(c1)OCC(=O)N2
Yield: 91.6 %

Procedure:
4-(3,4-Dihydro-3-oxo-1,4(2H)-benzoxazin-7-yl)-4-oxo-3-methylbutyric acid (31 g, 0.12 moles) was dissolved in ethanol (300 ml) and anhydrous hydrazine (4.7 ml, 0.15 moles) was added. The mixture was heated at reflux overnight. White crystals formed after the mixture was cooled. The crystals were collected by filtration and washed well with ethanol. The solid was dried under vacuum giving 28.5 g (93%) of the titled compound, mp 299°-302° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4]2([CH2:11][CH2:10][C@@H:9]([C:12]([O:14]CC3C=CC=CC=3)=[O:13])[CH2:8]2)[NH:3]1>CO.[Pd]>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4]2([CH2:11][CH2:10][C@@H:9]([C:12]([OH:14])=[O:13])[CH2:8]2)[NH:3]1
Reactant: O=C1NC(=O)C2(CC[C@@H](C(=O)OCc3ccccc3)C2)N1
Agent: [Pd]
Solvent: CO
Product: O=C1NC(=O)C2(CC[C@@H](C(=O)O)C2)N1
Reaction time: 3 h
Yield: 93.4 %

Procedure:
To (7R)-benzyl 2,4-dioxo-1,3-diazaspiro[4.4]nonane-7-carboxylate (from step A, 0.14 g, 0.486 mmol) in methanol (10 mL) was added Pd—C (0.030 g, 0.282 mmol) under a nitrogen atmosphere. The contents were hydrogenated at 10 psi for 3 hours. The reaction mixture was filtered over a whatman filter (FN MB 25 MM 0.45 uM) paper and washed with methanol (2×5 mL). The filtrate was concentrated under reduced pressure to yield a solid (0.09 g, 0.454 mmol, 94% yield). It was used as such for the subsequent step without further purification. MS m/z 197.3 (M−H)+
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](C2OC3=CC=CC3=CC=2)[C:9]=1[NH:23][C:24](=[O:36])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=1)=O)(C)(C)C.[C:38]([OH:44])([C:40](F)(F)F)=O>C(Cl)Cl>[O:44]1[C:38]2[C:40]([CH:10]=[CH:11][CH:12]=2)=[CH:13][CH:8]=[C:9]1[CH:25]1[C:26]([C:28]2[CH:29]=[C:30]([CH:31]=[CH:32][CH:33]=2)[C:34]#[N:35])=[N:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:23][C:24]1=[O:36]
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc3cccc-3o2)c1NC(=O)CC(=O)c1cccc(C#N)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccccc3NC(=O)C2c2ccc3cccc-3o2)c1

Procedure:
Prepared from {4-benzofuran-2-yl-2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-phenyl}-carbamic acid tert.-butyl ester (Example K28) (255 mg, 0.51 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (260 mg).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:17][C:16]2[CH:18]=[C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[CH:28]=[C:27]([C:32]3[NH:36][C:35]([C@@H:37]5[CH2:41][CH2:40][CH2:39][N:38]5C(OC(C)(C)C)=O)=[N:34][CH:33]=3)[CH:26]=[CH:25]4)[CH:20]=[CH:21][C:15]=2[N:14]=1)=O)(C)(C)C.C(OC(N1CCC[C@H]1C1NC2C=C(C3C=C4C(C=CC(C5NC([C@@H]6CCCN6C(OC(C)(C)C)=O)=NC=5)=C4)=CC=3)C=CC=2N=1)=O)(C)(C)C.[C:97]([OH:103])([C:99]([F:102])([F:101])[F:100])=[O:98]>C(Cl)Cl>[C:97]([OH:103])([C:99]([F:102])([F:101])[F:100])=[O:98].[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:17][C:16]2[CH:18]=[C:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:32]5[NH:36][C:35]([C@@H:37]6[CH2:41][CH2:40][CH2:39][NH:38]6)=[N:34][CH:33]=5)[CH:28]=4)[CH:23]=3)[CH:20]=[CH:21][C:15]=2[N:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc5nc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]c5c4)ccc3c2)[nH]1
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc3ccc(-c4ccc5nc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]c5c4)cc3c2)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc2cc(-c3cnc([C@@H]4CCCN4)[nH]3)ccc2cc1-c1ccc2nc([C@@H]3CCCN3)[nH]c2c1
Reaction time: 4 h
Yield: 31 %

Procedure:
A mixture of (S)-tert-butyl 2-(5-(6-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate and (S)-tert-butyl 2-(5-(7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate as TFA salts (74 mg) and TFA (2 mL) in CH2Cl2 (10 mL) was stirred at ambient conditions for 4 hours. The volatile component was removed in vacuo. The crude material was purified by a reverse phase HPLC (0 to 50% water/acetonitrile/TFA) to provide a TFA salt of 2-((S)-pyrrolidin-2-yl)-6-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-benzo[d]imidazole (32 mg, 31%) as yellow oil and a TFA salt of 2-((S)-pyrrolidin-2-yl)-6-(7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)-1H-benzo[d]imidazole (16 mg) as yellow oil.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)=[O:5].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH2:15]([NH:22][C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][C:4]([O:3][CH2:2][CH3:1])=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Solvent: O
Product: CCOC(=O)C=C(CC(=O)OCC)NCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.4 %

Procedure:
To 50.00 g (0.247 mol) of diethyl acetonedicarboxylate was added dropwise 31.79 g (0.297 mol) of benzylamine at such a rate that reaction temperature was kept below 50° C. The reaction mixture was stirred at room temperature for 12 hours and poured into H2O, extracted twice with ether, dried (MgSO4) and concentrated in vacuo affording 60.00 g of a yellow-green oil. Crude was purified by HPLC using 10% ethyl acetate/cyclohexane affording 46.2 g of a yellow semi solid. This was kugelrohr distilled at 53 Pa and collected at a pot temperature of 148°-150° C. to give 39.4 g (55%) of enamine diester as a beige crystalline solid; mp 34°-36° C.
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH2:7][CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[ClH:16]>O1CCOCC1>[ClH:16].[NH:8]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCCNC(=O)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1CNCCCN1

Procedure:
Compound from Step B was treated with 4 N hydrogen chloride in dioxane at ambient temperature for 2.5 h. Concentration gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:15]=[CH:16][C:17]3[CH:22]=[CH:21][N:20]([C:23]4[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=4)[C:26](Cl)=[O:27])[C:18]=3[N:19]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:32][NH2:33]>ClCCl>[CH3:32][NH:33][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([N:20]2[C:18]3[N:19]=[C:14]([NH:13][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=4)[N:15]=[CH:16][C:17]=3[CH:22]=[CH:21]2)[CH:24]=1
Reactant: COc1cc(Nc2ncc3ccn(-c4cccc(C(=O)Cl)c4)c3n2)cc(OC)c1OC
Reactant: CN
Solvent: ClCCl
Product: CNC(=O)c1cccc(-n2ccc3cnc(Nc4cc(OC)c(OC)c(OC)c4)nc32)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-[2-(3,4,5-trimethoxy-phenylamino)-pyrrolo[2,3-d]pyrimidin-7-yl]-benzoyl chloride in dichloromethane is added 5 equivalents of methylamine solution (2.0 M in tetrahydrofuran). After stirring at room temperature for 1 hour, the reaction is quenched with water. Removal of the solvent followed by purification with reverse phase HPLC gives N-methyl-3-[2-(3,4,5-trimethoxy-phenylamino)-pyrrolo[2,3-d]pyrimidin-7-yl]-benzamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:45])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:34][CH3:35])([C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[O:28])[CH2:25][CH3:26])[CH2:14][C:13](=[O:36])[NH:12][CH:11]3[C:37]3[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:38]=3[CH3:44])[C:5]2=[CH:4][CH:3]=1.[C:46](OC(=O)C)(=[O:48])[CH3:47]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:46]([N:8]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:7]=2)[C:10]2([CH:15]([C:16]3[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=3[O:23][C:24]([CH2:34][CH3:35])([C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[O:28])[CH2:25][CH3:26])[CH2:14][C:13](=[O:36])[NH:12][CH:11]2[C:37]2[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:38]=2[CH3:44])[C:9]1=[O:45])(=[O:48])[CH3:47]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)NS(C)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)N(C(C)=O)c1cc(Cl)ccc12)C(=O)NS(C)(=O)=O
Reaction time: 2 h
Yield: 23.5 %

Procedure:
At room temperature, to a mixture of racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-ethyl-1-methanesulfonylaminocarbonyl-propoxy)-phenyl]-2′-(5-chloro-2-methyl-phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (400 mg, 0.58 mmol) and acetic anhydride (71 mg, 0.69 mmol) in DCM (20 mL) was added DMAP (7 mg, 0.06 mmol) slowly. After the mixture was stirred for 2 h, the solution was washed by 0.5N HCl solution twice, dried over anhydrous Na2SO4 and concentrated. The residue was purified by Prep-HPLC to give the title compound as a white solid (100 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:15][NH2:16]>N1C=CC=CC=1>[NH:15]([C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)[NH2:16]
Reactant: COC(=O)C1(c2ccc(Cl)nc2)CC1
Reactant: NN
Solvent: c1ccncc1
Product: COC(=O)C1(c2ccc(NN)nc2)CC1
Temperature: 90 °C
Yield: 86.9 %

Procedure:
To a solution of methyl 1-(6-chloropyridin-3-yl)cyclopropanecarboxylate (1 g, 0.005 mol) in pyridine (2 mL) was added hydrazine (0.30 mL, 0.0094 mol). The solution was heated at 90° C. overnight. The reaction solution was cooled to RT, and then diluted with a small amount of ice-water. The precipitate was collected by filtration, and dried under vacuum to afford the desired compound (0.9 g, 90%). Analytical LCMS: (M+H)+=208.0.
Reaction SMILES: CNC(C1[N:6](CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)[N:7]=CN=1)=O.[F:28][C:29]1[CH:30]=[CH:31][C:32]2[N:33]([C:35]([CH2:45][N:46]3[C:50]([C:51](OC)=[O:52])=[N:49][CH:48]=[N:47]3)=[C:36]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[N:37]=2)[CH:34]=1.O.NN>>[F:28][C:29]1[CH:30]=[CH:31][C:32]2[N:33]([C:35]([CH2:45][N:46]3[C:50]([C:51]([NH:6][NH2:7])=[O:52])=[N:49][CH:48]=[N:47]3)=[C:36]([C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)[N:37]=2)[CH:34]=1
Reactant: COC(=O)c1ncnn1Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12
Reactant: CNC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Agent: NN
Solvent: O
Product: NNC(=O)c1ncnn1Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12

Procedure:
The title compound was prepared according to the procedure described for compound 68 from methyl 1-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-5-carboxylate and hydrazine hydrate. m/e+ 370 for C17H14F2N7O (M+H)+.
Reaction SMILES: BrC1C=C2C(C(C)(C)CCC2=O)=CC=1.[Br:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23](OCC)=[O:24])[CH:19]=[CH:20][CH:21]=1.[H-].C([Al+]CC(C)C)C(C)C>>[Br:15][C:16]1[CH:17]=[C:18]([CH2:22][CH:23]=[O:24])[CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)Cc1cccc(Br)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: CC1(C)CCC(=O)c2cc(Br)ccc21
Agent: [H-]
Product: O=CCc1cccc(Br)c1

Procedure:
Compound G can be obtained as described in J. Med. Chem. 1995, 38, 4764-4767, and as shown in Reaction Scheme 1. Thus, referring now specifically to Reaction Scheme 1, ethyl 3-bromophenylacetate (Compound B, made by esterification of 3-bromophenylacetic acid) is reduced with diisobutylaluminum hydride (DIBAL H) to yield (3-bromophenyl)acetaldehyde. (3-Bromophenyl)acetaldehyde is reacted in a Wittig reaction with (carbethoxymethylene)triphenylphosphorane to provide a mixture of E and Z ethyl 4-(3-bromophenyl)but-2-enoates. The latter compounds are hydrogenated to yield ethyl 4-(3-bromophenyl)butanoate (Compound D). Compound D is reacted with the Grignard reagent derived from methylbromide to give the tertiary alcohol 5-(3-bromophenyl)-2-methylpentan-2-ol (Compound E) (It should be apparent to those skilled in the art, that the choice of the Grignard reagent used in this reaction step determines the nature of the R1 substituent in the resulting compounds of the invention.) Compound E is then treated with acid to cyclize it and to form 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F). Compound F is oxidized with chromium trioxide to yield 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G). The isomeric compound, 6-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H) can be obtained, starting with ethyl (4-bromophenyl)acetate, in accordance with the sequence of reactions illustrated in Reaction Scheme 1 for Compound G.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[C:21]([C:27](O)=[O:28])=[N:22][CH:23]=[C:24]([F:26])[CH:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:21]3[C:20]([Cl:19])=[CH:25][C:24]([F:26])=[CH:23][N:22]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)c1ncc(F)cc1Cl
Product: C[C@]1(c2cc(NC(=O)c3ncc(F)cc3Cl)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 3-chloro-5-fluoro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=417.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[F:8].[Li]CCCC.[F:21][C:22]1[CH:32]=[CH:31][C:25]([C:26](OCC)=[O:27])=[CH:24][CH:23]=1>C1COCC1>[F:1][C:2]1[C:3]([C:26](=[O:27])[C:25]2[CH:31]=[CH:32][C:22]([F:21])=[CH:23][CH:24]=2)=[C:4]([NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: CC(C)(C)C(=O)Nc1ccc(F)c(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ccc(F)c(F)c1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a −78° C. solution of 2.5 g (11.724 mmol) N-(3,4-difluorophenyl)-2,2-dimethylpropanamide in 39 ml anhydrous THF was added drop wise over 15 mins 18 mL (28.136 mmol) n-BuLi (1.6M solution in cyclohexanes). After 1 hr at −78° C., 4 mL (26.966 mmol) ethyl 4-fluorobenzoate was added dropwise and the reaction mixture stirred from −78° C. to rt. After 45 mins, the reaction mixture was cooled to 0 C and quenched with saturated ammonium chloride and poured into a 1:1 mixture of ether:water and warmed to room temperature. The organic phase was isolated, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to yield N-[3,4-difluoro-2-(4-fluorobenzoyl)phenyl]-2,2-dimethylpropanamide (6-3). A solution of 3.5 g (10.706 mmol) N-[3,4-difluoro-2-(4-fluorobenzoyl)phenyl]-2,2-dimethylpropanamide in 43 mL 6N HCl and 8.6 mL DME was heated to 100° C. After 24 h at 100° C., the reaction mixture was cooled to room temperature and sodium carbonate was added until reaction mixture was basic. The reactions was diluted with water, extracted three times with ether, and washed with brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography (1×14 cm silica gel, linear gradient 0-20% EtOAc:hexane) afforded (6-amino-2,3-difluorophenyl)(4-fluorophenyl)methanone. 1H NMR (CDCl3, 400 MHz) δ 7.85-7.80 (m, 2H, ArH); 7.17-7.11 (m, 3H, ArH); 6.47 (ddd, J=2.01 Hz, 3.66 Hz, 9.16 Hz, 1H, ArH); 4.84 (br s, 2H, ArNH2). ES MS+1=252.1.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[F:6][C:7]([F:25])([C:21]([F:24])([F:23])[F:22])[C:8]([F:20])([F:19])[O:9][C:10]([F:18])([F:17])[C:11]([F:16])([F:15])[CH2:12][CH2:13]O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:15][C:11]([F:16])([C:10]([F:17])([F:18])[O:9][C:8]([F:19])([F:20])[C:7]([F:6])([F:25])[C:21]([F:22])([F:24])[F:23])[CH2:12][CH2:13][O:4][C:1](=[O:5])[CH:2]=[CH2:3]
Reactant: C=CC(=O)O
Reactant: OCCC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C=CC(=O)OCCC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)F

Procedure:
Acrylic acid was esterified with 2-[2-(heptafluoropropoxy)-tetrafluoroethyl]-ethyl alcohol (US 2008113199 A1) in the presence catalytic amounts of p-toluene sulfonic acid to yield acrylic acid 3,3,4,4-tetrafluoro-4-heptafluoropropyloxy-butyl ester quantitatively. The ester was washed with water and distilled prior to the reaction with APTES (Aminopropyl triethoxysilane, CAS#919-30-2). A solution of one equivalent of APTES and two equivalents acrylic acid 3,3,4,4-tetrafluoro-4-heptafluoropropyloxy-butyl in absolute ethanol were allowed to stir at 60° C. for 5 h. The solvent was distilled of under reduced pressure to provide the desired twin-tail silane (tertiary amine fluorosilane) quantitatively as a colorless oil.
Reaction SMILES: O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[C:14]1([C:20]#[CH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:22](=[C:25]1[C:30](=[O:31])[O:29][C:28]([CH3:33])([CH3:32])[O:27][C:26]1=[O:34])[CH2:23][CH3:24]>O.ClCCl.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:23]([C@H:22]([CH:25]1[C:26](=[O:34])[O:27][C:28]([CH3:33])([CH3:32])[O:29][C:30]1=[O:31])[C:21]#[C:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:24]
Reactant: C#Cc1ccccc1
Reactant: CCC=C1C(=O)OC(C)(C)OC1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: O
Solvent: ClCCl
Product: CC[C@@H](C#Cc1ccccc1)C1C(=O)OC(C)(C)OC1=O
Temperature: 0 °C
Yield: 82.4 %

Procedure:
A solution of copper (II) acetate monohydrate (10 mg, 0.050 mmol) in water (0.2 ml) was treated with sodium (L)-ascorbate (20 mg, 0.10 mmol), the mixture was stirred until the mixture was turned bright orange (3 min). Subsequently, (R,M)-3-{[4-(2-diphenylphosphanyl-7-methoxy-naphthalen-1-yl)-phthalazin-1-ylamino]-phenyl-methyl}-pentan-3-ol (1st diastereomer, 33.1 mg, 0.050 mmol) and phenylacetylene (0.275 ml, 2.5 mmol) were added, the resulting mixture was stirred for 10 min at 23° C., cooled to 0° C., stirred for 5 min and treated with 5-(1-propylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (46 mg, 0.25 mmol). The reaction mixture was stirred vigorously at 0° C. for 24 hrs, diluted with dichloromethane (2 ml) and subjected directly to flash chromatography on silica gel (hexane/EtOAc 3:1-2:1) to give 59 mg of the pure title compound as a white solid. (yield: 83%)
Reaction SMILES: Cl[P:2]1(=[O:7])[O:6][CH2:5][CH2:4][O:3]1.[C:8]([O:13][CH2:14][CH2:15][OH:16])(=[O:12])[C:9]([CH3:11])=[CH2:10]>>[C:8]([O:13][CH2:14][CH2:15][O:16][P:2]1(=[O:7])[O:6][CH2:5][CH2:4][O:3]1)(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: C=C(C)C(=O)OCCO
Reactant: O=P1(Cl)OCCO1
Product: C=C(C)C(=O)OCCOP1(=O)OCCO1

Procedure:
The 2-chloro-2-oxo-1,3,2-dioxaphospholane prepared in step (a) was reacted with 2-hydroxyethyl methacrylate to give 2-(2-oxo-1,3,2-dioxaphospholan-2-yloxy)ethyl methacrylate, as follows: Into a thoroughly dried 500 cm3 three-necked round bottomed flask equipped with a mechanical stirrer, drying tube and dropping funnel were placed 2-hydroxyethyl methacrylate (20.0 g, 0.154 mol) and triethylamine (15.6 g, 0.154 mol) was added slowly to the stirred solution, maintained at -20° C. to -15° C., over a period of 0.5 hr, whereupon triethylamine hydrochloride began to precipitate from the solution.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([Cl:24])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[C:9]([CH:12]=1)C=O.N1CCCCC1.[C:31](O)(=O)[CH2:32][C:33]([OH:35])=[O:34].Cl>N1C=CC=CC=1>[Cl:24][C:16]1[CH:17]=[C:18]([C:20]([F:22])([F:23])[F:21])[CH:19]=[C:2]([Cl:1])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[C:9]([CH:31]=[CH:32][C:33]([OH:35])=[O:34])[CH:12]=1
Reactant: O=Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 5 h
Yield: 66.7 %

Procedure:
270 g of 5-(2,6-dichloro-4-trifluoromethylphenoxy)-2-nitro-benzaldehyde and 6 g of piperidine were added, at 25° C., to 89.5 g of malonic acid in 570 ml of pyridine. The reaction mixture was stirred for 5 hours at 85° to 90° C. and was then heated for 90 minutes under reflux, after which it was poured onto water, the mixture was acidified with hydrochloric acid and the product was filtered off. The crystalline product was recrystalized from n-butanol. 200 g (66% of theory) of 3-(5-(2,6-dichloro-4-trifluoromethyl-phenoxy)-2-nitrophenyl)propenoic acid, of melting point 192° C., were obtained in the form of yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:12]3[N:13]=[CH:14][C:15](=[O:17])[NH:16][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[S:20][CH3:21].[C:22]([C:26]1[CH:30]=[C:29]([N:31]=[C:32]=[O:33])[N:28]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:27]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([C:26]1[CH:30]=[C:29]([NH:31][C:32]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([O:6][C:7]3[C:12]4[N:13]=[CH:14][C:15](=[O:17])[NH:16][C:11]=4[N:10]=[CH:9][CH:8]=3)=[CH:4][C:3]=2[S:20][CH3:21])=[O:33])[N:28]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:27]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Reactant: CSc1cc(Oc2ccnc3[nH]c(=O)cnc23)ccc1N
Product: CSc1cc(Oc2ccnc3[nH]c(=O)cnc23)ccc1NC(=O)Nc1cc(C(C)(C)C)nn1-c1ccccc1
Yield: 97 %

Procedure:
Method F2 was used with 8-(4-amino-3-(methylthio)phenoxy)pyrido[3,2-b]pyrazin-3(4H)-one and 3-tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole to afford the title compound (175 mg, 97%) as a white powder.
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH2:28][OH:29])[C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[O:21][CH3:22])=[C:6]([NH:23][C:24](=[O:26])[CH3:25])[CH:5]=1)[CH3:2].[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>N1C=CC=CC=1>[CH2:1]([N:3]([CH2:27][CH2:28][O:29][S:36]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:38])=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[O:21][CH3:22])=[C:6]([NH:23][C:24](=[O:26])[CH3:25])[CH:5]=1)[CH3:2]
Reactant: CCN(CCO)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2OC)c(NC(C)=O)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: CCN(CCOS(=O)(=O)c1ccccc1)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2OC)c(NC(C)=O)c1
Reaction time: 2 h
Yield: 44 %

Procedure:
To a mixture composed of 16 g of Compound [1-g] and 70 ml of pyridine was added dropwise 13 g of benzenesulfonyl chloride under cooling with ice. The mixture was stirred at a temperature range between 10° C. and 15° C. for 2 hours and then the reaction solution was poured into cold diluted hydrochloric acid. The precipitate thus deposited was collected by filtration, washed with water and recrystallized from acetonitrile to obtain 9.5 g of Compound [1-h].