Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11](NC2C=CC(S(CC)(=O)=O)=C(C#N)C=2)=[O:12])=[C:4](C)[CH:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([S:37]([C:40]([CH3:43])([CH3:42])[CH3:41])(=[O:39])=[O:38])=[C:33]([CH:36]=1)[C:34]#[N:35].BrC1C=CC(CCCC(Cl)=O)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([S:37]([C:40]([CH3:43])([CH3:42])[CH3:41])(=[O:39])=[O:38])=[C:33]([C:34]#[N:35])[CH:36]=2)=[O:12])=[CH:6][CH:7]=1
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(Br)cc2C)cc1C#N
Reactant: CC(C)(C)S(=O)(=O)c1ccc(N)cc1C#N
Agent: O=C(Cl)CCCc1ccc(Br)cc1
Product: CC(C)(C)S(=O)(=O)c1ccc(NC(=O)CCCc2ccc(Br)cc2)cc1C#N
Yield: 100 %

Procedure:
Using a procedure analogous to that used to prepare 8B, 10B (250 mg, 1.05 mmol) was reacted with 4-(4-bromophenyl)butyric acid chloride to give 10C (493 mg, 100%). MS (ESI) m/z 461.2, 463.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.C(Cl)(Cl)Cl.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(-c2ccccc2)c1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1cccc(-c2ccccc2)c1
Reaction time: 4 h
Yield: 94.6 %

Procedure:
A mixture of 3-nitrobiphenyl (20 g, 100 mmol) and 10% Pd/C (2 g) in MeOH/CHCl3 (300 mL, 1:1) is hydrogenated at 40 psi for 4 hours. The mixture is suction filtered through a layer of diatomaceous earth and washed with MeOH. The filtrate is evaporated to dryness and the solid is further dried under vacuum to give 16 g (95%) of 3-aminobiphenyl.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[N:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=2)[N:3]=1.O.NN>[Ni].C(O)C>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[N:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CC#N)cn2)c(C)c1-c1ccccc1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1nn(-c2ccc(CCN)cn2)c(C)c1-c1ccccc1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
A mixture of [6-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)pyridin-3-yl]acetonitrile (step 3, 633 mg, 2.20 mmol), Raney Ni (W2, 0.5 g), hydrazine monohydrate (1.1 mL, 22.0 mmol), and ethanol (20 mL) was stirred at 60° C. for 6 h. After cooling to room temperature, the mixture was filtered through a bed of celite. The filtrate was evaporated to afford 642 mg (quant.) of title compound: MS (ESI) m/z 293 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]([S:13][CH3:14])[CH:10]=[CH:9][C:5]=1[C:6](O)=O)[CH3:2].[ClH:15].[NH2:16][C:17]1[C:22]([NH2:23])=[CH:21][N:20]=[CH:19][N:18]=1>P(Cl)(Cl)(Cl)=O>[ClH:15].[CH2:1]([O:3][C:4]1[CH:12]=[C:11]([S:13][CH3:14])[CH:10]=[CH:9][C:5]=1[C:6]1[NH:23][C:22]2[C:17](=[N:18][CH:19]=[N:20][CH:21]=2)[N:16]=1)[CH3:2]
Reactant: CCOc1cc(SC)ccc1C(=O)O
Reactant: Nc1cncnc1N
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOc1cc(SC)ccc1-c1nc2ncncc2[nH]1

Procedure:
Three grams of 2-ethoxy-4-methylmercapto-benzoic acid and 2.2 g of 4,5-diamino-pyrimidine hydrochloride were refluxed in 30 ml of phosphorus oxychloride for three hours. The reaction mixture was poured on ice and then made ammoniacal, and the supernatant solution was decanted from the semicrystalline residue. After dissolution in methanol and filtering off from the insoluble products, the residue was purified over a silicagel column (eluate: methylene chloride/ethanol in volume ratio of from 100:0 to 98:2). The hydrochloride was precipitated from acetone with ethereal hydrochloric acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH3:56][Si:57]([CH3:62])([CH3:61])[CH2:58][CH2:59]O>C1COCC1>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([O:22][CH2:59][CH2:58][Si:57]([CH3:62])([CH3:61])[CH3:56])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21]
Reactant: C[Si](C)(C)CCO
Reactant: COC(=O)CCC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
To a solution of 6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoic acid methyl ester (222 mg, 0.66 mmol), triphenylphosphine (260 mg, 0.996 mmol), and diethyl azodicarboxylate (173 mg, 0.996 mmol) in THF (3 mL) at 0° C. was added a solution of 2-trimethylsilylethanol (142 μL, 0.996 mmol) in THF (3 mL). The resulting yellow solution was allowed to warm to room temperature and stirred overnight. The reaction was concentrated to dryness and ether and hexanes were added. Triphenyiphosphine oxide was removed by filtration and the filtrate was concentrated and purified by silica gel chromatography to provide 248 mg of the desired product as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 0.03 (s, 9H), 1.18-1.30 (m, 2H), 1.81 (s, 3H), 2.18 (s, 3H), 2.25-2.33 (m, 2H), 2.37-2.45 (m, 2H), 3.42 (d, 2H, J=7 Hz), 3.62 (s, 3H), 3.77 (s, 3H), 4.25-4.35 (m, 2H), 5.13 (s, 2H), 5.12-5.22 (m, 1H) ppm.
Reaction SMILES: [O:1]=[C:2]([CH3:8])/[CH:3]=[CH:4]/[C:5](Cl)=[O:6].[CH2:9]([NH:11][CH2:12][CH3:13])[CH3:10]>CCOCC>[CH2:9]([N:11]([CH2:12][CH3:13])[C:5](=[O:6])/[CH:4]=[CH:3]/[C:2](=[O:1])[CH3:8])[CH3:10]
Reactant: CCNCC
Reactant: CC(=O)/C=C/C(=O)Cl
Solvent: CCOCC
Product: CCN(CC)C(=O)/C=C/C(C)=O
Temperature: -15 °C
Reaction time: 2 h

Procedure:
To flame dried flask containing (E)-4-oxo-2-pentenoyl chloride (1.16 g, 8.76 mmol) in ether cooled to -15° C. is added diethylamine (1.41 g, 19.28 mmol) in ether (5 ml) and stirred for 2 hours while being warmed to ambient temperature. The solvents are removed in vacuo, and chromatographed on silica gel (230-400 mesh, 100 ml), eluting with hexane/ethyl acetate (75/25). The appropriate fractions are combined (Rf =0.31, TLC, hexane/ethyl acetate, 25/75) and concentrated in vacuo to give the title compound, NMR (CDCl3) 7.15, 7.04, 3.45, 3.40, 2.33, 1.20, 1.15.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]2[O:8][C@@H:4]([CH2:5][CH2:6]2)[C@@H:3]1[C:9]([NH2:11])=[O:10].Cl[C:13]1[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([NH2:20])[C:14]=1[N+:21]([O-:23])=[O:22].CCN(C(C)C)C(C)C>CC(O)C>[NH2:20][C:15]1[C:14]([N+:21]([O-:23])=[O:22])=[C:13]([NH:1][C@@H:2]2[C@@H:7]3[O:8][C@@H:4]([CH2:5][CH2:6]3)[C@@H:3]2[C:9]([NH2:11])=[O:10])[C:18]([Cl:19])=[CH:17][N:16]=1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Reactant: NC(=O)[C@@H]1[C@H](N)[C@H]2CC[C@@H]1O2
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2[N+](=O)[O-])[C@H]2CC[C@@H]1O2
Temperature: 60 °C
Yield: 100.7 %

Procedure:
(1S,2R,3S,4R)-3-amino-7-oxabicyclo[2.2.1]heptane-2-carboxamide (15) (170 mg, 0.67 mmol), 4,5-dichloro-3-nitropyridin-2-amine (127 mg, 0.6 mmol), DIPEA (5.5 eq) were taken in IPA and heated at 60° C. for 15 h when a yellow precipitate appeared. The precipitate was filtered, washed well with IPA and dried to afford the desired product, (198 mg, 34%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]=[N:10][S:11](=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:14]>ClC(Cl)C>[Cl:14][C:9]1[C:8]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=2[S:11][N:10]=1
Reactant: COc1cccc2c1C=NS2=O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: COc1cccc2snc(Cl)c12
Yield: 60 %

Procedure:
The 4-methoxy benzisothiazolone (0.065 mole) was dissolved in 200 mL of dichloroethane and PCl5 (1.05 mole equiv.) was added neat. The reaction was refluxed-monitored by tlc. An additional 0.25 mole equiv. and 2×0.10 mole equiv. of PCl5 was added after 1 hour, 21/2 hours, and 3 hours before the reaction was judged complete by tlc. The reaction was cooled and the solvent and excess reagent removed by house vacuum distillation. The residue was flash chromatographed (30% CH2Cl2 /70% hexane) affording the 3-chloro-4-methoxy-1,2-benzisothiazole in 60% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl[C:11]1(Cl)[CH2:16][O:15][CH2:14][CH2:13][O:12]1>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:1]2[CH2:14][CH2:13][O:12][CH2:11][C:16]2=[O:15])=[CH:3][CH:4]=1)#[N:7]
Reactant: ClC1(Cl)COCCO1
Reactant: N#Cc1ccc(N)cc1
Product: N#Cc1ccc(N2CCOCC2=O)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of 959 mg (8.12 mmol) of 4-aminobenzonitrile and 1.12 g of a mixture of 2-chlorodioxene and 2,2-dichlorodioxane (molar ratio 89:11) is heated at 80° C. with stirring for 18 hours. On cooling to room temperature, the product crystallises: 1.9 g of 2-(2-chloroethoxy)-N-(4-cyanophenyl)acetamide as yellowish crystals. 1H-NMR (d 6-DMSO): δ=3.82 (m; 4H), 4.19 (s; 2H), 7.78 (d, J=8 Hz, 2H), 7.85 (d, J=8 Hz, 2H), 10.22 (s, 1H).
Reaction SMILES: C(O[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([N:19]2[C:23]([CH3:24])=[CH:22][N:21]=[CH:20]2)=[C:16]([F:18])[CH:17]=1)=O)C1C=CC=CC=1.C([Li])CCC.[CH2:30]([O:34][C:35](=[O:39])CCC)[C@@H:31]1[O:33]C1.C(=O)(O)[O-].[Na+]>O1CCCC1.CO>[F:18][C:16]1[CH:17]=[C:12]([N:11]2[CH2:9][C@H:30]([CH2:31][OH:33])[O:34][C:35]2=[O:39])[CH:13]=[CH:14][C:15]=1[N:19]1[C:23]([CH3:24])=[CH:22][N:21]=[CH:20]1
Reactant: CCCC(=O)OC[C@H]1CO1
Reactant: Cc1cncn1-c1ccc(NC(=O)OCc2ccccc2)cc1F
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cncn1-c1ccc(N2C[C@H](CO)OC2=O)cc1F
Reaction time: 0.33 h
Yield: 30 %

Procedure:
5-Benzyloxycarbonylamino-2-(5-methyl-imidazol-1-yl)fluorobenzene (3.2 g, 9.85 mmol) was dissolved in dry tetrahydrofuran (40 ml) under nitrogen, cooled to −70°, and treated with a solution of n-butyllithium (1.6 M in isohexane, 6.81 ml). After stirring for 20 minutes at −70°, (R)-glycidylbutyrate (1.57 g, 10.09 mmol) was added at −70°. Stirring was continued for 16 hours allowing the temperature to rise to ambient. The mixture was treated MeOH (10 ml), stirred 15 minutes, then poured into aqueous sodium bicarbonate (5%, 100 ml) and extracted with EtOAc (3×40 ml). The combined extracts were washed with brine (20 ml), dried (magnesium sulfate) and evaporated. and the residue purified by chromatography on a 20 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 5 to 10% MeOH in dichloromethane. Relevant fractions were combined and evaporated, to give the desired product (0.86 g). MS (ESP): 292 (MH+) for C14H14FN3O3.
Reaction SMILES: C([S:4][C@H:5]1[CH2:9][C@@H:8]([CH2:10][C:11]2[S:15][C:14]3=[CH:16][N:17]=[CH:18][N:13]3[C:12]=2[CH3:19])[N:7]([C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])[CH2:6]1)(=O)C.C1(OP(O[C:43]2[C@H:44]([CH3:60])[C@@H:45]3[C@@H:55]([C@H:56]([OH:58])[CH3:57])[C:54](=[O:59])[N:46]3[C:47]=2[C:48]([O:50][CH2:51][CH:52]=[CH2:53])=[O:49])(OC2C=CC=CC=2)=O)C=CC=CC=1>>[CH2:23]([O:22][C:20]([N:7]1[C@H:8]([CH2:10][C:11]2[S:15][C:14]3=[CH:16][N:17]=[CH:18][N:13]3[C:12]=2[CH3:19])[CH2:9][C@H:5]([S:4][C:43]2[C@H:44]([CH3:60])[C@@H:45]3[C@@H:55]([C@H:56]([OH:58])[CH3:57])[C:54](=[O:59])[N:46]3[C:47]=2[C:48]([O:50][CH2:51][CH:52]=[CH2:53])=[O:49])[CH2:6]1)=[O:21])[CH:24]=[CH2:25]
Reactant: C=CCOC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1Cc1sc2cncn2c1C
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3sc4cncn4c3C)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 40 %

Procedure:
The procedure of Example 23-a) is repeated to prepare 362.4 mg of a mercaptan compound as a yellow oil from 474.5 mg of (3S,5S)-3-acetylthio-1-allyloxycarbonyl-5-(3-methylimidazo[5,1-b]thiazol-2-yl)methylpyrrolidine described in Synthesis Example 10. Allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-(3-methylimidazo[5,1-b]thiazol-2-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate (255.4 mg) is prepared as a colorless amorphous material from this mercaptan compound and 544.2 mg of allyl(1R,5R,6S)-2-(diphenylphosphono)oxy-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[C:14]([NH2:15])=[CH:13][C:12]([CH:16]([CH3:18])[CH3:17])=[N:11]3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.N1C=CC=CC=1.[C:25](Cl)([O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[O:26]>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[C:14]([NH:15][C:25](=[O:26])[O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[CH:13][C:12]([CH:16]([CH3:18])[CH3:17])=[N:11]3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)c1cc(N)n(-c2ccc3ncsc3c2)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc3ncsc3c2)n1
Reaction time: 2 h
Yield: 23.1 %

Procedure:
To a stirring solution of 1-(benzo[d]thiazol-6-yl)-3-isopropyl-1H-pyrazol-5-amine (0.80 g, 3.1 mmol) and pyridine (0.51 ml, 6.2 mmol) in CH2Cl2 (30 ml) at RT was added Troc-Cl (0.51 ml, 3.7 mmol). After 2 h, the completed reaction was washed with 10% CuSO4 (2×), H2O (1×), brine (1×), dried (MgSO4), evaporated and purified by flash column chromatography (EtOAc/hexanes) to afford 2,2,2-trichloroethyl 1-(benzo[d]thiazol-6-yl)-3-isopropyl-1H-pyrazol-5-ylcarbamate (0.31 g, 23% yield) as an oil. MS (ESI) m/z: 433.0 (M+H+), 435.0 (M+2+H+).
Reaction SMILES: ClC[CH2:3][CH2:4][N:5]([CH3:7])[CH3:6].[CH2:8]([O:10][C:11](=[O:23])[C:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)=[O:13])[CH3:9].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH2:8]([O:10][C:11](=[O:23])[C:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH2:3][CH2:4][N:5]([CH3:7])[CH3:6])[CH:15]=1)=[O:13])[CH3:9]
Reactant: CN(C)CCCCl
Reactant: CCOC(=O)C(=O)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)C(=O)c1cn(CCN(C)C)c2ccccc12
Yield: 63.3 %

Procedure:
The general procedure 1 was then followed using 1-chloro-3-dimethylaminopropane (7 mmol, 0.75 g), ethyl-2-(1H-indol-3-yl)-2-oxoacetate (6 mmol, 1.3 g) and Cs2CO3 (6.6 mmol, 2.15 g). The purification was achieved by column chromatography (petro-lether:ethylacetate:diethylamine 6:3:1) to yield ethyl-2-{1-[2-(dimethylamino)ethyl]-1H-indol-3-yl}-2-oxoacetate (3.8 mmol, 63%) as an pale yellow oil. IR {tilde over (ν)} [cm−1]=3023; 2962; 2917; 1732; 1630. EI-MS m/z (rel. int.)=302 (8.21%; M+•.). 1H NMR (300 MHz, CDCl3) 8.43 (m; 1H; indole-H); 8.39 (s; 1H; indole-H); 7.33 (m; 3H; indole-H); 4.40 (q; 3J=7.1 Hz; 2H; OCH2CH3); 4.27 (t; 3J=6.8 Hz; 2H; indole-CH2CH2CH2N); 2.22 (s; 6H; N(CH3)2); 2.20 (m; 2H; indole-CH2CH2CH2N); 2.00 (quint; 3J=6.7 Hz; 2H; indole-CH2CH2CH2N); 1.42 (t; 3J=7.1 Hz; 3H OCH2CH3).
Reaction SMILES: [CH:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1.[CH2:6](Cl)Cl>[Pd]>[CH:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:6][CH:1]1[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: ClCCl
Agent: [Pd]
Agent: C1=CCCC1
Product: CC1C=CCC1
Reaction time: 96 h

Procedure:
Inside a nitrogen purged drybox, the palladium catalyst, {[(2,6-iPr2Ph)2DABMe2]Pd(CH2CH2CH2CO2Me)}BAF (77 mg, 0.053 mmol) was dissolved in CH2Cl2 (2 ml) and cyclopentene (2 ml) and 3-MeCyp (1 ml) added. The solution was stirred for 4 days after which the volatiles were removed. MeOH was added and the polymer filtered, washed well with MeOH and finally with 2% Irganox® 1010/acetone solution and dried. Yield=1.06 g. Tm (DSC)=210.5° C., Tg (DSC)=73° C. 13C-NMR (TCB, 120° C.) indicated ˜5% 3-MeCyp incorporation.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:35]([C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1)#[N:36]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:41]5[CH:40]=[CH:39][CH:38]=[C:37]([C:35]#[N:36])[CH:42]=5)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Reactant: N#Cc1cccc(B(O)O)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccc(C#N)c5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 3-cyano-phenylboronic acid.
Reaction SMILES: C[Mg]Br.[C:4]([C:7]1[CH:8]=[CH:9][C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:11]([CH:21]=1)[C:12]([NH:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:13])(=[O:6])[CH3:5].OS(O)(=O)=O.[C:35]([O-])(O)=O.[Na+]>O1CCCC1.C(OCC)(=O)C>[OH:6][C:4]([C:7]1[CH:8]=[CH:9][C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:11]([CH:21]=1)[C:12]([NH:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:13])([CH3:35])[CH3:5]
Reactant: O=C([O-])O
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Agent: C[Mg]Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Reaction time: 0.75 h

Procedure:
3M Methylmagnesium bromide (0.10 ml, 0.29 mmol) was added to a solution of 5-acetyl-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in Example 72; 100 mg, 0.29 mmol) in tetrahydrofuran (3 ml) at 0° C. The solution was stirred for 45 minutes. Another 3 equivalents of 3M methylmagnesium bromide (300 ul) were added at 0° C. and solution was stirred for 18 hours. 1N H2SO4 (5 ml) was then added, the mixture was stirred for 3 minutes, then ethyl acetate (10 ml) was added. The acid layer was basified to pH 9 using saturated NaHCO3 solution. The organic layer was washed with saturated NaHCO3 solution (5 ml), dried (MgSO4) and the solvent was removed in vacuo. The residue was purified by MDAP to give the title compound as a white solid. 61 mg.
Reaction SMILES: CCN(CC)CC.[C:8]1([CH:14]=O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[CH2:17]([O:19][C:20]([C:22]1[N:23]=[C:24]2[CH2:29][NH:28][CH2:27][CH2:26][N:25]2[CH:30]=1)=[O:21])[CH3:18].[BH3-]C#N.[Na+]>CCO>[CH2:17]([O:19][C:20]([C:22]1[N:23]=[C:24]2[CH2:29][N:28]([CH2:14][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:27][CH2:26][N:25]2[CH:30]=1)=[O:21])[CH3:18]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)c1cn2c(n1)CNCC2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cn2c(n1)CN(Cc1ccccc1)CC2
Reaction time: 3 h

Procedure:
Et3N (6.27 mL), PhCHO (4.92 mL) were added successively to the EtOH (81 mL) solution of 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid ethyl ester, hydrochloride (9.47 g) at room temperature and stirred for 3 h under a nitrogen atmosphere. Then NaBH3CN (2.97 g) was added to the reaction mixture and stirred for 19 h. The mixture was filtered through a pad of Celite and diluted with CH2Cl2 and washed with 50% K2CO3 aq. The organic layer was dried (K2CO3) and filtered. The filtrate was concentrated under reduced pressure. The residue was applied to silica gel column chromatography, then the column was eluted with CHCl3-acetone (1/0˜9/1) and CHCl3-MeOH (19/1˜9/1). The titled compound was obtained as pale yellow crystals (4.16 g, 36%).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:18]([CH3:20])=[C:17]([CH3:21])[N:16]=[C:15]([NH2:22])[C:14]=2[N:13]=[C:12]1[CH2:23][O:24][CH2:25][CH3:26]>>[NH2:22][C:15]1[C:14]2[N:13]=[C:12]([CH2:23][O:24][CH2:25][CH3:26])[N:11]([CH2:10][CH2:9][CH2:8][NH:7][C:3](=[O:4])[N:2]([CH3:6])[CH3:1])[C:19]=2[C:18]([CH3:20])=[C:17]([CH3:21])[N:16]=1
Reactant: CN(C)C(=O)Cl
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1CCCN
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCCNC(=O)N(C)C

Procedure:
Using the method of Examples 94-105, dimethylcarbamyl chloride was reacted with 1-(3-aminopropyl)-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 349.2340.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[N:5]=[C:4]([NH:15][C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([CH3:24])=[C:18]([O:25][CH3:26])[CH:17]=2)[N:3]=1.C1C(=O)N([Br:34])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C1C=CC=CC=1>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([C:11]#[N:12])=[CH:13][CH:14]=2)[N:5]=[C:4]([NH:15][C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([CH3:24])=[C:18]([O:25][CH3:26])[C:17]=2[Br:34])[N:3]=1
Reactant: COc1cc(Nc2nc(N)n(-c3ccc(C#N)cc3)n2)cc(OC)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: COc1cc(Nc2nc(N)n(-c3ccc(C#N)cc3)n2)c(Br)c(OC)c1C
Yield: 42.4 %

Procedure:
To a suspension of 4-[5-Amino-3-(3,5-dimethoxy-4-methyl-phenylamino)-[1,2,4]triazol-1-yl]-benzonitrile (155 mg, 0.44 mmol) in CCl4 (10 mL) and benzene (10 mL) was added N-bromosuccimide (100 mg, 0.56 mmol) and benzoyl peroxide (10 mg). The reaction mixture was refluxed for 16 h. Concentration. The residue was purified by HPLC to give the title compound (80 mg). FIA-MS: m/e=429.1 and 431.1 (M+H), 427.1 and 429.1 (M−H). Rt=3.89 min (Method A). 1H-NMR (500 MHz, DMSO(d6)): 7.95 (d, 2H), 7.82 (s, 1H), 7.80 (d, 2H), 7.37 (s, 1H), 6.88 (br. s, 2H), 3.80 (s, 3H), 3.69 (s, 3H), 2.08 (s, 3H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[F:13])[CH2:2][CH2:3][CH3:4].[Li]CCCC.[CH2:19]([CH:22]1[CH2:27][CH2:26][CH:25]([CH:28]2[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]2)[CH2:24][CH2:23]1)[CH2:20][CH3:21].Cl>C1COCC1>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:31]2([OH:34])[CH2:30][CH2:29][CH:28]([CH:25]3[CH2:26][CH2:27][CH:22]([CH2:19][CH2:20][CH3:21])[CH2:23][CH2:24]3)[CH2:33][CH2:32]2)=[C:8]([F:12])[C:7]=1[F:13])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cccc(F)c1F
Reactant: CCCC1CCC(C2CCC(=O)CC2)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCOc1ccc(C2(O)CCC(C3CCC(CCC)CC3)CC2)c(F)c1F
Reaction time: 2 h

Procedure:
31.0 g (0.17 mol) of 1-butoxy-2,3-difluorobenzene are initially introduced in 200 ml of THF, and 100 ml (0.16 mol) of n-BuLi (15% soln. in hexane) are added at −70° C. After 2 h at this temperature, a solution of 35.6 g (0.16 mol) of 4′-propylbicyclohexyl-4-one in 200 ml of THF is metered in, and the batch is stirred for 2.5 h. The reaction mixture is hydrolysed with ice-cooling and acidified using 2 N HCl. The solution is extracted with MTBE, and the combined organic phases are washed with sat. sodium chloride solution and dried using sodium sulfate. The solution is concentrated to dryness, and the crude product (66.3 g of yellow solid) is used directly for the following reaction.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:11]([NH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])(=[O:13])[CH3:12]
Reactant: NCC(=O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NCC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
About 200 grams of 2-aminoacetophenone were added to about 350 ml. of acetic anhydride at 0° C. After warming to ambient temperature, the reaction mixture was stirred 4 hours and, upon addition of ice water, a precipitate formed which was filtered and washed with water. The precipitate was suspended in ether and washed separately with 1 l. each of 1 N sodium hydroxide, water, 1 N hydrochloric acid, and again with 1 N sodium hydroxide. The ether suspension was dried with sodium sulfate, filtered, and concentrated. Ligroin was added and the desired product was collected by filtration. The identity of the final product was confirmed by NMR analysis; yield 215 grams, m.p. 69° C.