Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C@@:5]1([OH:13])[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1.C([O-])([O-])=O.[Cs+].[Cs+].[N:20]([C:23]1[N:24]=[CH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:21]=S.C(N=C=NC(C)C)(C)C>CN(C)C=O>[CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[C:23]([NH:20][C:21]2[O:13][C@:5]3([CH2:4][N:3]=2)[CH:10]2[CH2:9][CH2:8][N:7]([CH2:12][CH2:11]2)[CH2:6]3)[N:24]=1
Reactant: S=C=Nc1cc2ccccc2cn1
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: c1ccc2cc(NC3=NC[C@@]4(CN5CCC4CC5)O3)ncc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.2 g, 0.873 mmol) in N,N-dimethylformamide (20 mL) was added Cs2CO3 (0.711 g, 2.182 mmol) and 3-isothiocyanatoisoquinoline (0.163 g, 0.873 mmol). The suspension was stirred at room temperature for 30 minutes. N,N′-Diisopropylcarbodiimide (0.408 mL, 2.62 mmol) was then added and the mixture was stirred at room temperature for 18 hours. The mixture was concentrated and purified by silica gel chromatography (5-25% [9:1 methanol:ammonium hydroxide]-ethyl acetate) to afford (R)—N-(isoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.16 g, 0.508 mmol, 58% yield) as an off-white solid. M.P. 196-200° C. 1H NMR (400 MHz, MeOD) δ ppm 9.00 (1H, s), 7.92 (1H, d), 7.71 (1H, d), 7.59 (1H, t), 7.20-7.45 (2H, m), 3.96 (1H, d), 3.65 (1H, d), 3.22 (1H, d), 3.08 (1H, d), 2.66-3.00 (4H, m), 2.05-2.23 (2H, m), 1.50-1.86 (3H, m). R.T.=1.37; [M+H]+=309.31.
Reaction SMILES: Cl.[C:2]1([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH3:9].C(N(CC)CC)C.[Br:23][CH2:24][C:25](Br)=[O:26]>ClCCl>[Br:23][CH2:24][C:25]([N:13]1[CH2:14][CH2:15][N:10]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=2[CH3:9])[CH2:11][CH2:12]1)=[O:26]
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: O=C(Br)CBr
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(N2CCN(C(=O)CBr)CC2)c1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-(2,3-Xylyl)piperazine hydrochloride (5 g; 25 mmol) is suspended in dichloromethane and triethylamine (7.6 ml; 54 mmol) is added. The mixture is cooled to 0° C. and bromoacetyl bromide (2.4 ml; 27 mmol) is added dropwise. The reaction is stirred for 30 minutes and then diluted in dichloromethane, washed with half-saturated sodium bicarbonate solution and dried over magnesium sulfate. The final product is purified by flash chromatography with a gradient of eluents (30/70 to 50/50; EtOAc-Pet. ether).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23]C3C=CC(C)=CC=3C(O)=O)=[C:19]([O:34][CH3:35])[CH:18]=2)=[CH:13][C:12]=1[O:36][CH3:37])([OH:3])=[O:2].[CH3:38]OC1C=C(C2C=CC(N)=C(OC)C=2)C=CC=1N.IC1C=CC=CC=1C(O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[CH:15]=[CH:16][C:11]([NH:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:1]([O:3][CH3:38])=[O:2])=[C:12]([O:36][CH3:37])[CH:13]=2)=[CH:18][C:19]=1[O:34][CH3:35]
Reactant: COc1cc(-c2ccc(N)c(OC)c2)ccc1N
Reactant: COc1cc(-c2ccc(Nc3ccc(C)cc3C(=O)O)c(OC)c2)ccc1Nc1ccccc1C(=O)O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C(O)c1ccccc1I
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1Nc1ccc(-c2ccc(N)c(OC)c2)cc1OC

Procedure:
Compound Ic-7 can be synthesixed by reacting commercially available 3,3′-dimethoxy-[1,1′-biphenyl]4,4′-diamine (1 equivalent) with 1.2 equivalents of the commercially available methyl ester of iodobenzoic acid in the presence of Pd2(dba)3/DPPP (0.1-0.5 equiv) and 1.2 equivalents Cs2CO3 in toluene at 110° C. for 20 h with vigorous stirring. The intermediate compound methyl 2-((4′-amino-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)amino)benzoate is isolated by flash chromatography on a C18 column. The product is then reacted by addition of 1.2 equivalent of methyl 2-iodo-5-methylbenzoate in the presence of catalytic (0.1-0.5 equiv) Pd2(dba)3/DPPP and 1.2 equivalents anhydrous, finely powdered Cs2CO3 in toluene at 110° C. for 20 h to yield methyl 2-((3,3′-dimethoxy-4′-((2-(methoxycarbonyl)phenyl)amino)-[1,1′-biphenyl]-4-yl)amino)-5-methylbenzoate. The methyl esters can then be hydrolyzed under basic conditions followed by acidification to yield compound Ic-7, 2-((4′-((2-carboxyphenyl)amino)-3,3′-dimethoxy-[1, 1′-biphenyl]-4-yl)amino)-5-methylbenzoic acid.
Reaction SMILES: [C:1]([C:3]1[C:4]([Cl:14])=[N:5][C:6](Cl)=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10])#[N:2].[NH2:15][CH:16]([CH:19]([CH3:21])[CH3:20])[CH2:17][OH:18].C(NC(C)C)(C)C.ClCl>>[Cl:14][C:4]1[C:3]([C:1]#[N:2])=[C:8]([C:9]([F:12])([F:11])[F:10])[CH:7]=[C:6]([NH:15][CH:16]([CH2:17][OH:18])[CH:19]([CH3:21])[CH3:20])[N:5]=1
Reactant: N#Cc1c(C(F)(F)F)cc(Cl)nc1Cl
Reactant: CC(C)C(N)CO
Agent: ClCl
Solvent: CC(C)NC(C)C
Product: CC(C)C(CO)Nc1cc(C(F)(F)F)c(C#N)c(Cl)n1

Procedure:
Neat 3-cyano-2,6-dichloro-4-trifluoromethylpyridine (0.641 g, 6 mmol) (Compound 14) was added by pipette at a dropwise rate over 3 minutes to 2-amino-3-methyl-butan-1-ol (1.5 g, 6 mmol) (Compound 15). Di-isopropylamine (0.9 g, 7 mmol) was added after 10 minutes and the resultant mixture was heated in a sealed tube at 70° C. for 30 minutes to selectively displace the chlorine at position 6 before quenching in ice-cold water and extracted with dichloromethane. Organic extracts were washed twice with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was washed with diethylether and the resultant solid was used in the next step without further purification. 2-Chloro-6-[[1-(hydroxymethyl)-2-methyl-propyl]amino]-4-(trifluoromethyl) pyridine-3-carbonitrile (Compound 13) was isolated in 50% yield.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C([Li])CCC.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C>>[CH2:9]([C:3]1[CH:4]=[CH:5][C:6]([B:22]([OH:27])[OH:23])=[C:7]([F:8])[C:2]=1[F:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCCCCCc1cccc(F)c1F
Agent: [Li]CCCC
Product: CCCCCCCCc1ccc(B(O)O)c(F)c1F

Procedure:
Quantities: compound from Example 25 (31 g, 0.14 mol), n-butyllithium (14 cm3, 10.0M in hexanes, 0.14 mol) and triisopropyl borate (52.7 g, 0.28 mol). The experimental procedure was as described in Example 28.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([C:7]1[C:8]([CH3:17])=[C:9]2[N:14]([CH:15]=1)[N:13]=[CH:12][NH:11][C:10]2=[O:16])=[O:6]>O.C1COCC1.CO>[CH3:17][C:8]1[C:7]([C:5]([OH:6])=[O:4])=[CH:15][N:14]2[C:9]=1[C:10](=[O:16])[NH:11][CH:12]=[N:13]2
Reactant: COC(=O)c1cn2nc[nH]c(=O)c2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(=O)O)cn2nc[nH]c(=O)c12
Temperature: 65 °C
Yield: 90.6 %

Procedure:
A solution of LiOH (25 gm, 10 equiv) in water (416 mL) was added to a solution of 5-methyl-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester (23.0 gm, 0.104 mol) in a mixture of THF (1.2 L) and MeOH (0.4 L). This was heated at 65° C. for 20 h and then concentrated in vacuo to about 200 mL. Water (400 mL) was added and the pH was adjusted to 4 using conc. aqueous HCl. The precipitate was collected, washed with water, and dried to give the acid (18.2 gm, 90%). 1H NMR (MeOH-D4) δ 2.67 (s, 3H), 7.63 (s, 1H), 7.84 (s, 1H). HPLC Ret Time: 0.97 min (YMC C18 S5, 4.6×50 mm column, 3 min gradient, 4 mL/min).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][NH:3][C:2]1=[O:11].[C:12]1([O:22][CH2:23][CH:24]2[O:26][CH2:25]2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.CO>C1(C)C=CC=CC=1>[C:12]1([O:22][CH2:23][CH:24]([OH:26])[CH2:25][N:8]2[CH2:7][CH2:6][C:5]3([O:1][C:2](=[O:11])[NH:3][CH2:4]3)[CH2:10][CH2:9]2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc2c(OCC3CO3)cccc2c1
Reactant: O=C1NCC2(CCNCC2)O1
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C1NCC2(CCN(CC(O)COc3cccc4ccccc34)CC2)O1
Yield: 73.4 %

Procedure:
A mixture of 2 g 1-oxa-3,8-diazaspiro[4.5]-decan 2-one, 3.12 g 2,3-epoxypropyl 1-naphthyl ether, 5 ml methanol and 10 ml toluene is heated at reflux for 5 hours. The solvent is removed by evaporation in vacuum. The residue is filtered through 20 g silica gel with 5% methanol/methylene chloride. Evaporation of solvent and recrystalization from ethyl acetate affords 3.35 g 8-[3-(1-naphthyloxy)-2-hydroxypropyl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one, mp 178°-179°.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].S(Cl)(Cl)=O.[CH3:18]O>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:18])=[O:5]
Reactant: CO
Reactant: O=C([O-])c1cccc([N+](=O)[O-])c1Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Reaction time: 8 h
Yield: 98 %

Procedure:
To a stirred solution of 2-chloro-3-nitrobenzoate (1.0 g, 5.0 mmol) in anhydrous methanol (10 mL) at 0° C. was added thionyl chloride (0.5 mL, 7.4 mmol) dropwise and the reaction mixture was stirred overnight at reflux. The mixture was diluted with methanol and concentrated under reduced pressure to remove the excess thionyl chloride and then re-dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate, re-extracted with ethyl acetate, dried (Na2SO4), filtered, and concentrated under reduced pressure to give methyl 2-chloro-3-nitrobenzoate (1.1 g, 98%) as a white foam that was used in the next step without further purification: 1H NMR (300 MHz, DMSO-d6) δ 8.21 (d, J=1.5 Hz, 1H), 8.07 (dd, J=7.8, 1.5 Hz, 1H), 7.73 (t, J=8.1 Hz, 1H), 3.91 (s, 3H).
Reaction SMILES: FC(F)(F)C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O.[Cl:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3[CH:36]=[N:37][N:38]([CH2:40][C:41](O)=[O:42])[CH:39]=3)=[N:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1.N1C=CC=CC=1.[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.Cl>CN(C)C=O>[Cl:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3[CH:36]=[N:37][N:38]([CH2:40][C:41]([NH:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)=[O:42])[CH:39]=3)=[N:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1
Reactant: O=C(O)Cn1cc(Nc2ncnc3cc(OCCCCl)ccc23)cn1
Reactant: Nc1ccccc1
Agent: Cl
Agent: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cn1cc(Nc2ncnc3cc(OCCCCl)ccc23)cn1)Nc1ccccc1
Reaction time: 0.08 h
Yield: 53.9 %

Procedure:
Pentafluorophenyl trifluoroacetate (0.867 g, 3.10 mmol) was added dropwise, at room temperature, to a stirred suspension of (4-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-1-yl)acetic acid (0.800 g, 2.21 mmol) and pyridine (0.245 g, 3.10 mmol) in dimethylformamide (8 ml). After stirring for 5 minutes, aniline (0.412 g, 4.43 mmol) was added and the reaction mixture was stirred for 2 hours. The mixture was poured into dilute hydrochloric acid (0.2N, 25 ml) and the resultant solid filtered and then washed with water. The residue was stirred in dilute aqueous sodium hydroxide solution and filtered and the residue washed successively with water, methanol and diethylether to give 2-(4-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-1-yl)-N-phenylacetamide (0.520 g, 54% yield): MS (+ve ESI): 437 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:9]2[O:13][C:12]([CH2:14][N:15]3[CH:19]=[C:18]([C:20]([O:22]CC4C=CC=CC=4)=[O:21])[CH:17]=[N:16]3)=[N:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1>C(OCC)(=O)C.[C].[Pd]>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([C:9]2[O:13][C:12]([CH2:14][N:15]3[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[CH:17]=[N:16]3)=[N:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)c1cnn(Cc2nnc(-c3cccc(C(F)(F)F)c3)o2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)c1cnn(Cc2nnc(-c3cccc(C(F)(F)F)c3)o2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
The compound (0.08 g) obtained in Example 122b was dissolved in ethyl acetate (2 ml), palladium carbon (5 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature overnight. Palladium carbon was removed by filtration, and the solvent was evaporated from the filtrate under reduced pressure to give the title compound (0.06 g) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[C:12](Cl)(=[O:14])[CH3:13].[Al+3].[Cl-].[Cl-].[Cl-]>[N+](C1C=CC=CC=1)([O-])=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12](=[O:14])[CH3:13])[CH:6]=[CH:5]2
Reactant: CC(=O)Cl
Reactant: Brc1ccc2ccccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)c1ccc2cc(Br)ccc2c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 45.2 %

Procedure:
A mixture of 2-bromonaphthalene (41.4 g, 200 mmol), acetyl chloride (11.3 mL, 160 mmol), nitrobenzene (250 mL) and AlCl3 (28 g, 210 mmol) was stirred for 4 hours at 100° C. (oil bath temperature). The resulting reaction mixture was cooled, poured onto ice/water (100 mL) and filtered. The filtrate was washed with water (100 mL). The solvent (nitrobenzene) was removed by distillation. The resulting residue was crystallized from hexane to afford 18 g of desired product (36% yield).
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].CC(=CC)C.[C:16]([Si:20]([CH3:35])([CH3:34])[O:21][CH2:22][CH:23]([CH3:33])[O:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=[O:28])([CH3:19])([CH3:18])[CH3:17]>O.O1CCOCC1>[C:16]([Si:20]([CH3:35])([CH3:34])[O:21][CH2:22][CH:23]([CH3:33])[O:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[C:27]([OH:6])=[O:28])([CH3:18])([CH3:19])[CH3:17]
Reactant: O=P([O-])(O)O
Reactant: CC(CO[Si](C)(C)C(C)(C)C)Oc1ccccc1C=O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(CO[Si](C)(C)C(C)(C)C)Oc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
A solution of sodium chlorite (1.17 g; 12.9 mmol; 5.5 eq.) and sodium dihydrogenphosphate (1.01 g; 8.44 mmol; 3.6 eq.) in water (10 mL) was added dropwise to a mixture of 2-methyl-2-butene (2 mL) and 2-[2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethoxy]-benzaldehyde (690 mg; 2.34 mmol; 1 eq.) in 1,4-dioxane (10 mL). The reaction mixture was stirred at room temperature for 1.5 hour. After dilution with EA, the solution was washed with 1M HCl, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (690 mg, 95%) as a white solid. UPLC/MS: (MS−) 309.1 ([M−H]−).
Reaction SMILES: Br[C:2]1[C:3]([F:24])=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:7]=1.[C:25]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:26]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH:25]([C:2]1[C:3]([F:24])=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:7]=1)=[CH2:26]
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1NC1CCN(C2CCOCC2)CC1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(NC2CCN(C3CCOCC3)CC2)c([N+](=O)[O-])cc1F
Temperature: 130 °C
Yield: 314.8 %

Procedure:
A solution of N-(5-bromo-4-fluoro-2-nitrophenyl)-1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine (D78, 800 mg, ˜75% purity) and n-tributylvinyltin (0.697 ml, 2.3 mmol) in toluene (30 ml) was treated, under a positive flow of argon, with triphenylphosphine (129.8 mg, 0.5 mmol) and bis(dibenzylideneacetone)palladium(0) (170.1 mg, 0.297 mmol), then stirred and heated under argon atmosphere at 130° C. for 1.5 h. The mixture was filtered through a celite pad. The organic layer was washed with NH4OH (10% aq) and water, then dried over MgSO4 and concentrated. The mixture was purified on silica column (100 g of silica, methanol/dichloromethane, 5% to 20%, 15CV) to afford 550 mg of title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([C:22](=[O:24])[CH3:23])[CH:19]=[C:18]([CH:25]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[CH3:26])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[BH4-].[Na+].CC(C)=O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([CH:22]([OH:24])[CH3:23])[CH:19]=[C:18]([CH:25]([O:27][CH2:28][C:29]([F:30])([F:31])[F:32])[CH3:26])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(Nc2nc(C(C)=O)cc(C(C)OCC(F)(F)F)n2)ccc1-n1cnc(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Product: COc1cc(Nc2nc(C(C)O)cc(C(C)OCC(F)(F)F)n2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(2-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-6-(1-(2,2,2-trifluoroethoxy)-ethyl)pyrimidin-4-yl)ethanone (90 mg, 0.20 mmol) was dissolved in ethanol (5 mL). Sodium borohydride (30.3 mg, 0.80 mmol) was added in portions. The mixture was stirred at rt for 10 min. Acetone (2 mL) was added and the mixture was stirred for 20 min. The mixture was filtered, the volatiles were removed in vacuum, and the residue was purified by preparative HPLC to yield the title compound consisting of four stereoisomers, 64 mg (71%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([CH2:27]Br)=[CH:21][C:22](=[O:26])[O:23]2)=[CH:18][CH:17]=1.C(=O)(O)[O-].[K+]>O1CCCC1>[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([CH2:27][N:11]3[CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9][CH2:10]3)=[CH:21][C:22](=[O:26])[O:23]2)=[CH:18][CH:17]=1
Reactant: COc1ccc2c(CBr)cc(=O)oc2c1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc2c(CN3CCN(Cc4ccccc4)CC3)cc(=O)oc2c1

Procedure:
0.03 mol of 1-benzylpiperazine, 0.03 mol of 7-methoxy-2-oxo-4-bromomethyl-3-chromene and 0.03 mol of potassium bicarbonate are introduced into an Erlenmeyer flask containing 150 ml of tetrahydrofuran. The mixture is brought to reflux for 24 hours. The reaction is brought to an end and, after cooling, the solution is filtered and evaporated under reduced pressure. The residue is then purified by chromatography on a column of silica gel, methylene chloride generally being used as eluent. The final product is thus obtained in the base form.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:10]([NH:12][C@H:13]([C:29](=[O:31])[NH2:30])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]2)=[CH:17][CH:16]=1)=[O:11].[CH2:39]([O:41][P:42]([C:47]([F:59])([F:58])[C:48]1[CH:53]=[CH:52][C:51]([CH2:54][C:55](O)=[O:56])=[CH:50][CH:49]=1)([O:44][CH2:45][CH3:46])=[O:43])[CH3:40]>>[CH2:39]([O:41][P:42]([C:47]([C:48]1[CH:49]=[CH:50][C:51]([CH2:54][C:55](=[O:56])[NH:8][C@H:9]([C:10](=[O:11])[NH:12][C@H:13]([C:29](=[O:31])[NH2:30])[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH:21]3[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]3)=[CH:19][CH:20]=2)[CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:52][CH:53]=1)([F:59])[F:58])(=[O:43])[O:44][CH2:45][CH3:46])[CH3:40]
Reactant: NC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)cc1)NC(=O)[C@@H](N)Cc1ccccc1
Reactant: CCOP(=O)(OCC)C(F)(F)c1ccc(CC(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(OCC)C(F)(F)c1ccc(CC(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccc(C3CC(=O)NS3(=O)=O)cc2)C(N)=O)cc1

Procedure:
This compound was prepared according to the procedure of Example 1.1, Step 10, using 4.23-B of Step 2 and {4-[(diethoxy-phosphoryl)-difluoro-methyl]-phenyl}-acetic acid (Biochemistry, (2003), 42, 12792) as the starting materials. LCMS found for C34H40F2N4O9PS (M+H)+: m/z=749.
Reaction SMILES: O[CH2:2][C:3]([CH3:14])([CH3:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[NH:15]1[C:19]2=[N:20][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:23]=[C:18]2[CH:17]=[C:16]1[C:29]([O:31][CH2:32][CH3:33])=[O:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:8]([O:7][C:6]([NH:5][CH2:4][C:3]([CH3:14])([CH3:13])[CH2:2][N:15]1[C:19]2=[N:20][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:23]=[C:18]2[CH:17]=[C:16]1[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:12])([CH3:11])([CH3:10])[CH3:9]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2n1
Reactant: CC(C)(CO)CNC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC(C)(C)CNC(=O)OC(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
To a solution of tert-butyl (3-hydroxy-2,2-dimethylpropyl)carbamate (2.13 g, 10.5 mmol), diethyl 1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylate (Intermediate D, 2.50 g, 9.53 mmol), and triphenylphosphine (5.00 g, 19.1 mmol) in THF (15 mL) is added diisopropyl azodicarboxylate (3.95 mL, 19.1 mmol). The reaction is stirred at room temperature for 64 h. The solvent is removed in vacuo and the crude material is purified via silica gel chromatography using a gradient elution of 0-30% ethyl acetate/hexanes to afford the title compound as a yellow oil which crystallized upon standing (4.20 g, 99%). LCMS: 478.86 (M+Na+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[O:12])=[N:8][C:7]=2[C:19]=1[N+:20]([O-])=O>[Pd].CO>[CH3:1][O:2][C:3]1[C:19]([NH2:20])=[C:7]2[N:8]=[C:9]([C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[O:12])[S:10][C:6]2=[CH:5][CH:4]=1
Reactant: COc1ccc2sc(C(=O)N3CCOCC3)nc2c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1ccc2sc(C(=O)N3CCOCC3)nc2c1N
Reaction time: 18 h
Yield: 90.7 %

Procedure:
20 mg of 10% palladium on activated carbon is added to 210 mg (0.65 mmol) of 5-methoxy-2-(morpholin-4-ylcarbonyl)-4-nitro-1,3-benzothiazole in solution in 10 ml of methanol. The reaction medium is then placed under stirring under a hydrogen atmosphere for 18 hours. The catalyst is then filtered out and the solvent evaporated off. 173 mg of the expected product (crude yield=91%) is obtained in the form of a yellow oil and is used in the following stage without other purification.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[CH3:21][C:22]1[CH:23]=[C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:25]=[C:26]([N+:28]([O-:30])=[O:29])[CH:27]=1>C(Cl)(Cl)(Cl)Cl>[Br:8][CH2:21][C:22]1[CH:23]=[C:24]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:25]=[C:26]([N+:28]([O-:30])=[O:29])[CH:27]=1
Reactant: Cc1cc(-c2ccccc2)cc([N+](=O)[O-])c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc(CBr)cc(-c2ccccc2)c1
Temperature: 80 °C

Procedure:
NBS (184 mg, 1.032 mmol) and AIBN (15.4 mg, 0.04 mmol) were added to a solution of 3-methyl-5-nitrobiphenyl (200 mg, 0.938 mmol) in carbon tetrachloride (1.88 mL) and then the reaction mixture was heated to 80° C. for 3 hours. Additional AIBN (15.4 mg, 0.04 mmol) was added to the reaction mixture and was heated for additional 1 hour. The mixture was purified directly by silica gel column chromatography (ethyl acetate/hexanes) to yield 3-(bromomethyl)-5-nitrobiphenyl.