Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14]C(=O)OC(C)(C)C)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:22]([NH:24][CH2:25][C:26]12[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2)=[O:23].Cl.CO>O1CCOCC1>[ClH:1].[NH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:4]=2)[C:22]([NH:24][CH2:25][C:26]23[CH2:35][CH:30]4[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]4)[CH2:27]2)[CH2:33]3)=[O:23])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC1CCN(c2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1

Procedure:
Prepared as described in example 5d) above using [1-[4-chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]phenyl]-4-piperidinyl]-carbamic acid, 1,1-dimethylethyl ester (Example 6c), hydrochloric acid (0.5 ml of a 4N solution in dioxane) and methanol (10 ml). The mixture was heated at reflux for 15 min. to complete the reaction. After evaporation to two-thirds of the original volume, a solid crystallised on standing which was collected by filtration and dried in vacuo to give the title compound as a solid (0.025 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[C:21]([C:25]1[O:29][N:28]=[C:27]([NH2:30])[CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:25]1[O:29][N:28]=[C:27]([NH:30][C:14]([C:12]2[S:13][C:9]([S:8][C:7]3[C:6]([Cl:20])=[CH:5][N:4]=[CH:3][C:2]=3[Cl:1])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[O:16])[CH:26]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CC(C)(C)c1cc(N)no1
Product: CC(C)(C)c1cc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)no1

Procedure:
Prepared according to the procedure described for example 50 from 5-((3,5-dichloropyridin-4-yl)thio)-4-nitrothiophene-2-carboxylic acid (200 mg, 0.57 mmol) and 5-tert-butylisoxazol-3-amine (95 mg, 0.68 mmol). The title compound was obtained as a yellow solid (45 mg, 17% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.78 (1H, s), 9.01 (2H, s), 8.75 (1H, m), 8.01 (2H, m), 7.82 (2H, m), 2.51 (3H, s). MS m/z: 466.03, 468.03 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[Br-].[CH2:37]([O:39][C:40](=[O:44])[CH2:41][CH2:42][Zn+])[CH3:38].C1COCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:34][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([F:33])[C:27]=1[S:24]([NH:23][C:19]1[C:18]([F:35])=[C:17]([C:9]2[N:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH2:42][CH2:41][C:40]([O:39][CH2:37][CH3:38])=[O:44])[N:7]=2)[CH:22]=[CH:21][CH:20]=1)(=[O:26])=[O:25]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: CCOC(=O)CC[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1
Temperature: 25 °C
Yield: 64 %

Procedure:
To solid N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (1 g, 1.85 mmol) was added 3-ethoxy-3-oxopropylzinc bromide 0.5M solution in THF (31.5 ml, 15.77 mmol) at RT. Bis(tri-t-butylphosphine)palladium (0) (0.095 g, 0.186 mmol) was added to reaction mixture. The reaction was stirred at RT for several hours. The reaction was check by LCMS. The reaction mixture was quenched into sat'd NH4Cl and stirred for several hours. A white/grey ppt was filtered. The EtOAc was added to filtrate. The EtOAc was separed contained form the water layer. The water layer was rewashed with EtOAc and the organic extracts combined, dried over MgSO4, filtered, and concentrated to dryness to give an orange oil. The crude product was added to a silica gel column and eluted with EtOAc with DCM (20% to 60%) and collected fractions to obtain ethyl 3-{4-[4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinyl}propanoate (1.12 g, 64%). MS (ESI): 605 [M+H]+.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[C:14]([C:15]([O:17]C)=[O:16])=[CH:13][C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[C:5]=1[F:19].Cl>C1COCC1>[F:3][C:4]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[C:5]=1[F:19]
Reactant: COC(=O)c1cc2c(c(F)c1F)OCC(=O)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1COc2c(cc(C(=O)O)c(F)c2F)N1
Reaction time: 3 h
Yield: 79.6 %

Procedure:
A 2M solution of aqueous sodium hydroxide (30 mL) was added to a suspension of 7,8-difluoro-6-methoxycarbonyl-4H-benzo[1,4]oxazine-3-one (4.8 g, 19.88 mmoL) in THF (100 mL). The mixture was allowed to stir for 3 hours and the total volume was then reduced in vacuo to half. It was treated with 2M hydrochloric acid to caused a solid precipitate which was filtered, washed with water three times and then dried in vacuo to give the title compound (3.6 g, 80%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:21][CH3:22])[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[O:10])=[C:4]([F:23])[CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][NH:11][C:9](=[O:10])[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[O:25][CH3:24])=[CH:3][C:4]=2[F:23])[O:21][CH3:22])=[CH:14][CH:15]=1)#[N:20]
Reactant: COc1ccccc1B(O)O
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(Br)cc1F
Product: COc1ccccc1-c1ccc(C(OC)C(=O)NCc2ccc(C#N)cc2)c(F)c1

Procedure:
In analogy to example 57.1, (RS)-2-(4-bromo-2-fluoro-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide (example 41.2) was reacted with 2-methoxyphenylboronic acid to give (RS)-N-(4-cyano-benzyl)-2-(3-fluoro-2′-methoxy-biphenyl-4-yl)-2-methoxy-acetamide. Light yellow gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH:19]=[CH:18][N:17]=[C:16]1[CH2:20]O.[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH:19]=[CH:18][N:17]=[C:16]1[CH2:20][N:27]1[C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]2[C:23]1=[O:33]
Reactant: O=C(c1ccccc1Cl)c1ccccc1-n1ccnc1CO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(c1ccccc1Cl)c1ccccc1-n1ccnc1CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 17, 2'-chloro-2-[2-(hydroxymethyl)imidazol-1-yl]benzophenone is treated with phthalimide and triphenylphosphine and finally with diethyl azodicarboxylate to give 2'-chloro-2-[2-(phthalimidomethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:5][CH:4]=1)=O.[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:18][C:19]1[CH:25]=[CH:24][C:22](/[N:23]=[CH:1]/[C:3]2[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:5][CH:4]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(C=O)cc1
Reactant: Nc1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)COc1ccc(/C=N/c2ccc(F)cc2)cc1

Procedure:
tert-Butyl (4-formylphenoxy)acetate (93.7 g, 0.40 mol) was dissolved in dry toluene (200 mL), added 4-fluoroaniline (38.1 mL, 0.40 mol) and p-toluene sulfonic acid (cat, ±1 g). The mixture was refluxed in a Dean-Stark apparatus for 2 hours, cooled at an icebath and a precipitate was formed. The precipitate was filtered, washed with cold heptane and dried to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:41][CH:42]1[CH2:47][CH2:46][N:45]([CH2:48][C:49]2[CH:56]=[CH:55][C:52]([C:53]#[N:54])=[CH:51][CH:50]=2)[CH2:44][CH2:43]1>CN(C)C=O.O>[Br:1][C:2]1[S:3][C:4]([C:7]([NH:41][CH:42]2[CH2:47][CH2:46][N:45]([CH2:48][C:49]3[CH:56]=[CH:55][C:52]([C:53]#[N:54])=[CH:51][CH:50]=3)[CH2:44][CH2:43]2)=[O:9])=[CH:5][N:6]=1
Reactant: N#Cc1ccc(CN2CCC(N)CC2)cc1
Reactant: O=C(O)c1cnc(Br)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(CN2CCC(NC(=O)c3cnc(Br)s3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a stirred mixture of 2-bromothiazole-5-carboxylic acid (500 mg, 2.4 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added triethylamine (1.1 mL, 7.92 mmol), HATU (1 g, 2.64 mmol), and 4-((4-aminopiperidin-1-yl)methyl)benzonitrile (762 mg, 2.64 mmol). The mixture was stirred at room temperature overnight and then poured into water. The resulting solids were collected by filtration and purified by column chromatography to yield 972 mg (100%) of 2-bromo-N-(1-(4-cyanobenzyl)piperidin-4-yl)thiazole-5-carboxamide as a yellow solid. LCMS (m/z): 406 (MH+).
Reaction SMILES: ClCl.[C:3]1([CH2:9][CH2:10][CH2:11][CH2:12][PH:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[C:24]1([CH2:30][O:31][C:32]([NH:34][CH2:35][CH2:36][CH2:37][CH2:38][C@@H:39]([C:41]([N:43]2[CH2:57][CH2:56][CH2:55][C@H:44]2[C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:46])=[O:42])[NH2:40])=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C.ClCCl.CC(C)=O.O1CCCC1.C(N(CC)CC)C>[C:3]1([CH2:9][CH2:10][CH2:11][CH2:12][P:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([NH:40][C@H:39]([C:41]([N:43]2[CH2:57][CH2:56][CH2:55][C@H:44]2[C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:46])=[O:42])[CH2:38][CH2:37][CH2:36][CH2:35][NH:34][C:32]([O:31][CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:33])=[O:22])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=[PH](CCCCc1ccccc1)OCc1ccccc1
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Agent: ClCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCCCC[C@H](NP(=O)(CCCCc1ccccc1)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A half saturated solution of dry chlorine in carbon tetrachloride is added dropwise by syringe to a solution of (4-phenylbutyl)phosphinic acid, phenylmethyl ester (1.0 g., 3.47 mmole), from Example 1 (c), in 5 ml. of dry carbon tetrachloride under argon until the yellow color of excess chlorine persists. The mixture is evaporated to dryness (0.15 mm. of Hg), and the residue is taken up in 5 ml. of dry tetrahydrofuran and treated with 1-[N6 -[(phenylmethoxy)carbonyl]-L-lysyl]-L-proline, phenylmethyl ester, hydrochloride salt (1.74 g., 3.4 mmole). The resulting suspension is cooled to 0° (ice bath) under argon and treated dropwise with a solution of triethylamine (1.2 ml.) in 6 ml. of dry tetrahydrofuran over a 15 minute period. After the addition is complete, the mixture is stirred at 0° for 15 minutes, then allowed to warm to room temperature and stirred for an additional one hour. The mixture is diluted with ethyl acetate, filtered and evaporated to dryness. The residue is taken up in ethyl acetate, washed successively with 5% potassium bisulfate, water, saturated sodium bicarbonate, saturated sodium chloride, dried (Na2SO4), and evaporated. The residue (3.2 g.) is purified by flash chromatography on silica gel (120 g.) eluting with dichloromethane-hexane (5:1) to give 1.62 g. of 1-[N2 -[(4-phenylbutyl)(phenylmethoxy)phosphinyl]-N6 -[(phenylmethoxy)carbonyl]-L-lysyl]-L-proline,phenyl methyl ester as a colorless oil. Tlc (dichloromethane/acetone; 4:1) single spot at Rf 0.42.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([OH:8])=[N:6][CH:7]=1.[H-].[Na+].[CH3:15]I>CN(C)C=O>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=[O:8])[N:6]([CH3:15])[CH:7]=1
Reactant: Cc1c(Br)cnc(O)c1[N+](=O)[O-]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(Br)cn(C)c(=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
A solution of 5-bromo-4-methyl-3-nitropyridin-2-ol (15.00 g, 64.37 mmol) [Combi-Blocks, AN-1086] in N,N-dimethylformamide (250 mL) was treated with sodium hydride (3.09 g, 77.3 mmol) (60% dispersion on mineral oil) slowly and portionwise, and stirred at RT for 30 min. The reaction mixture was treated with methyl iodide (4.81 mL, 77.2 mmol) dropwise and stirred at RT for 3 h. LCMS indicated a clean peak for methylated product. The reaction mixture was poured over water/ice (˜400 mL) and allowed to stir while the ice melted. The aqueous mixture was extracted with ethyl acetate. The organic layer was washed with water (3×) and brine, dried with magnesium sulfate, filtered, and concentrated to give the desired product (14.9 g, 93%) that was used without further purification. LCMS calculated for C7H8BrN2O3 (M+H)+: m/z=247.0, 249.0. found: 247.0, 248.9.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][NH:7][CH:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[C:13]1([N:19]=[C:20]=[S:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH:8]([CH3:9])[CH3:10])[C:20]([NH:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[S:21])=[CH:11][CH:12]=1
Reactant: S=C=Nc1ccccc1
Reactant: CC(C)NCc1ccc(Br)cc1
Product: CC(C)N(Cc1ccc(Br)cc1)C(=S)Nc1ccccc1
Yield: 87.4 %

Procedure:
Following the procedure described in Example 1, process variant (a), 23 g of N-(4-bromobenzyl)-N-isopropylamine were reacted with 14 g of phenyl isothiocyanate. 32 g of N-(4-bromobenzyl)-N-isopropyl-N'-phenylthiourea were obtained. Yield: 88%. Melting point: 133.5°-134.5° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.C[Sn](C)(C)[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:19]2[O:25][CH2:26][O:27][C:18]=2[CH:17]=1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:26]1[O:27][C:18]2[C:19](=[CH:20][C:21]([N+:22]([O-:24])=[O:23])=[C:16]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[CH:8]=[C:7]([O:12][CH3:13])[CH:6]=[CH:5]4)[CH:17]=2)[O:25]1
Reactant: C[Sn](C)(C)c1cc2c(cc1[N+](=O)[O-])OCO2
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc2cc(-c3cc4c(cc3[N+](=O)[O-])OCO4)ccc2c1
Reaction time: 0.5 h
Yield: 71 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (120 mg) and cuprous bromide (20 mg) were added to a solution of 2-bromo-6-methoxynaphthalene (0.3 g, 1.27 mmol) and trimethyl(3,4-methylenedioxy-6-nitrophenyl)stannane, 62, (0.45 g, 1.37 mmol) in THF (30 mL) at room temperature and stirred for 0.5 h. The mixture was then refluxed under N2 for 16 h. After cooling, THF was evaporated and 50 mL ethyl acetate was added to the residue. The solution was washed with water. The organic layer was separated and passed through a Celite bed to remove suspended particles. The organic layer was then washed with brine, dried (anhydrous Na2SO4), and evaporated in vacuo. The residue was chromatographed using a 80:20 mixture of hexanes:ethyl acetate to give the desired product 45 (0.29 g) in 71% yield; mp 165-167° C.; IR (KBr) 2911, 1609, 1520, 1482, 1429, 1393, 1344, 1257, 1199 cm−1; 1H NMR (CDCl3) δ3.94 (3H, s), 6.14 (2H, s), 6.88 (1H, s), 7.16-7.21 (2H, m), 7.31 (1H, dd, J1=8.5, J2=1.9), 7.47 (1H, s), 7.67-7.77 (3H, m); 13C NMR δ55.89, 103.45, 105.92, 106.19, 111.69, 119.86, 126.90, 127.02, 127.55, 129.23, 130.09, 133.76, 133.85, 134.48, 143.38, 147.52, 151.47, 158.62; HRMS (EI) calcd for C18H13NO5 m/z: 323.0794; found: 323.0788.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:17][CH:16]2[C:34](O)=[O:35])[CH:12]=[CH:13][CH:14]=1.[C:37]([NH:44][CH2:45][CH2:46][CH2:47][NH2:48])([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:40]([O:39][C:37](=[O:38])[NH:44][CH2:45][CH2:46][CH2:47][NH:48][C:34]([C@H:16]1[C@H:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=2)[C@:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[C@H:18]([CH2:29][C:30]([CH3:31])([CH3:33])[CH3:32])[NH:17]1)=[O:35])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NCCCNC(=O)OC(C)(C)C)[C@H](c2cccc(Cl)c2)[C@@]1(C#N)c1ccc(Cl)cc1
Yield: 87 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid prepared in Example 25a (1 g, 1.8 mmol) was reacted with N-Boc-1,3-diaminopropane (Aldrich) (0.7 g, 4 mmol), HATU (1.4 g, 3.7 mmol) and iPr2NEt (2.8 g, 21 mmol) in CH2Cl2 (100 mL) at room temperature for 60 h to give rac-(3-{[(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester as a white solid (0.92 g, 87%).
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[N:6][C:5]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])=[N:4]1.[F:15][C:16]([F:25])([F:24])[CH2:17][CH2:18][CH:19]([C:22]#[N:23])[C:20]#[N:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:13][C:8]([F:14])([C:5]1[N:6]=[CH:7][N:3]([CH2:2][C:19]([CH2:18][CH2:17][C:16]([F:15])([F:24])[F:25])([C:20]#[N:21])[C:22]#[N:23])[N:4]=1)[C:9]([F:12])([F:11])[F:10]
Reactant: FC(F)(F)C(F)(F)c1ncn(CCl)n1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cnc(C(F)(F)C(F)(F)F)n1
Yield: 9.4 %

Procedure:
1.74 g of 1-(chloromethyl)-3-(pentafluoroethyl)-1H-1,2,4-triazole and 1.20 g of (3,3,3-trifluoropropyl)malononitrile were dissolved in 21 ml of N,N-dimethylformamide. 2.04 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for 4 hours. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexane-MTBE to obtain 0.25 g of {[3-(pentafluoroethyl)-1H-1,2,4-triazole 1-yl]methyl}(3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (34), hereinafter) shown by below formula.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].C([Li])CCC.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C.Cl>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([B:19]([OH:24])[OH:20])=[C:3]([C:10]([F:13])([F:12])[F:11])[CH:4]=1
Reactant: COc1ccc(Br)c(C(F)(F)F)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)c(C(F)(F)F)c1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 71.8 %

Procedure:
A solution of 4-bromo-3-trifluoromethylanisole (13 g, 50 mmol) in dry THF (110 mL) was treated with butyllithium solution (2.5 M in hexane, 24 mL, 60 mmol) during ca. 5 min at −78° C. under nitrogen. After 15 min, the solution was treated with triisopropyl borate (23 mL, 100 mmol) during ca. 5 min at −78° C. After a further 30 min, the cooling bath was removed and the reaction solution was warmed to 23° C. and left for 3.5 h. At this time, the resulting opaque mixture was concentrated in vacuo and the residue was treated with 1 N aqueous hydrogen chloride (110 mL, 110 mmol) and extracted with ethyl acetate (3×75 mL). The combined extracts were washed with water (2×100 mL) and brine (100 mL), dried (Na2SO4), and concentrated in vacuo to give the crude product as a tacky yellow solid (11 g) which was triturated overnight with hexane (100 mL). Vacuum filtration gave the title compound (7.9 g, 72%) as a white solid which was pure enough for further use.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[NH:23]1[CH2:27][CH2:26][C@@H:25]([NH2:28])[CH2:24]1.C(N(CC)CC)C>C(#N)C>[NH2:28][C@@H:25]1[CH2:26][CH2:27][N:23]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=3[NH:12][C:13](=[O:21])[CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[N:3]=2)[CH2:24]1
Reactant: N[C@@H]1CCNC1
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N[C@@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Temperature: 100 °C
Yield: 53.6 %

Procedure:
To a 10 mL vial was added N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1(a)) (0.166 g), (3R)-3-pyrrolidinamine (0.127 g), triethylamine (0.083 mL) and acetonitrile (5 mL). The vial was sealed and heated at 100° C. for 30 minutes within a microwave. The reaction was cooled to room temperature and the resulting solid removed by filtration. This solid was purified (Varian SCX cartridge, using methanol and 10% ammonia in methanol as eluant) to afford the title compound (0.102 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[OH:14])([O-])=O.CO>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:5]=1[OH:14]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1O
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: Nc1cc(C(F)(F)F)ccc1O

Procedure:
A solution of 2-nitro-4-(trifluoromethyl)phenol (100 mg, 0.483 mmol) in ethanol (10 mL) was pumped through an H-cube™ hydrogenator CatCart (Pd/C, 30×4 mm) at a flow rate of 1 mL/min at 40° C. and 40 psi, topping up the solution with methanol (10×1 mL) when it was running low. The collected solution was evaporated to dryness to give an off-white solid (88 mg, assume quantitative yield). The material was carried forward without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:4]=2[N:5]=[C:6](/[CH:8]=C/C2C=CC=CC=2)[N:7]=1.[O:21]1CCOCC1.O>O=[Os](=O)(=O)=O>[Cl:1][C:2]1[C:3]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:4]=2[N:5]=[C:6]([CH:8]=[O:21])[N:7]=1
Reactant: O=C1CCc2c(Cl)nc(/C=C/c3ccccc3)nc2N1
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: O=Cc1nc(Cl)c2c(n1)NC(=O)CC2
Temperature: 0 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
4-Chloro-2-[(E)-2-phenylethenyl]-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (0.18 g, 0.64 mmol) was dissolved in a 2:1 solution of 1,4-dioxane/water (6 mL) and cooled to 0° C. NalO4 (0.314 g, 1.47 mmol) and catalytic OsO4 (1 mL, 4% aq. solution) were added and the solution was then stirred at ambient temperature for 16 h. The reaction solution was concentrated under vacuum, diluted with water, and extracted with 10% MeOH/DCM (4×). The organic layers were combined, dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was then purified by column chromatography (silica gel) using a DCM/DCM-MeOH—NH4OH (90:10:1) gradient to yield the desired compound as an off-white solid (0.05 g, 44%).