Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:11][C:12]([CH:14]([C:20]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[O:21])[N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9].[Br:33]Br>C(Cl)(Cl)(Cl)Cl>[CH2:23]([O:22][C:20]([C:14]([N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)([C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])=[O:13])[Br:33])=[O:21])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31]
Reactant: BrBr
Reactant: CC(C)CCCCCCCOC(=O)C(C(=O)OCCCCCCCC(C)C)n1cncn1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)CCCCCCCOC(=O)C(Br)(C(=O)OCCCCCCCC(C)C)n1cncn1
Reaction time: 2 h
Yield: 107.7 %

Procedure:
1-[bis(isodecyloxycarbonyl)methyl]-1,2,4-triazole (51.8 g, 86% strength) was stirred and boiled under reflux at 78° with carbon tetrachloride (100 cm3) whilst bromine (16.0 g) was added slowly beneath the liquid surface during 30 minutes. Stirring and heating at 78°-80° was continued for a further period of 2 hours, the extent of bromination being followed by disappearance of the resonance due to the methine proton at delta=5.8 ppm from tetramethylsilane in the nmr spectrum. The solution was then cooled, washed with dilute aqueous sodium sulphite solution and with water, and the solvent was distilled yielding 57.2 g of 1-[1',1'-bis(isodecyloxycarbonyl)-1'-bromomethyl]-1,2,4-triazole of strength 76% as measured by non-aqueous titration with perchloric acid. This compound was evaluated as an extractant for copper using the procedure of Example 1 and the results are presented in Table 1.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=1[O:21][CH3:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)(=O)C>[CH2:5]([O:12][C:13]1[CH:20]=[C:19]([N+:1]([O-:4])=[O:2])[C:16]([C:17]#[N:18])=[CH:15][C:14]=1[O:21][CH3:22])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COc1cc(C#N)ccc1OCc1ccccc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1cc(C#N)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 23 °C
Reaction time: 20 h
Yield: 84.6 %

Procedure:
Acetic acid (17 ml) was added slowly to nitric acid (40 ml, 440 mmol) at 5° C. Powdered 4-benzyloxy-3-methoxybenzonitrile (10 g, 42 mmol) was added and the mixture warmed to 23° C. over 10 minutes. An exotherm occurred and the temperature was controlled at <30° C. using an ice bath. The mixture was stirred at 23° C. for 20 hours then poured into ice/water (1000 ml). After stirring for two hours the yellow solid was collected by suction filtration, washed with water and dried to yield 4-benzyloxy-3-methoxy-6-nitrobenzonitrile (10.1 g, 85% yield) as a yellow solid:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:23][CH:24]2[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([Cl:22])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[BH4-].[Na+]>CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:23][CH:24]2[CH2:25][CH2:26][CH:27]([OH:30])[CH2:28][CH2:29]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([Cl:22])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)Nc2cnc(Cl)cn2)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCC(O)CC2)C(=O)Nc2cnc(Cl)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.9 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-chloro-pyrazin-2-yl)-3-(4-oxo-cyclohexyl)-propionamide (prepared as in Example 61, 30.0 mg, 0.064 mmol) in methanol (0.5 mL) was treated with sodium borohydride (6.03 mg, 0.16 mmol). The reaction mixture was stirred at 25° C. for 5 min. The reaction was then diluted with ethyl acetate (5 mL) and quenched by the dropwise addition of water. The reaction was then diluted with more water (5 mL) and concentrated in vacuo to remove methanol. The resulting slurry was extracted with ethyl acetate (3×5 mL), and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12S, Silica, 3/7 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-chloro-pyrazin-2-yl)-3-(4-hydroxy-cyclohexyl)-propionamide (29.0 mg, 96.3%) as a light yellow foam: EI-HRMS m/e calcd for C20H23Cl2N3O4S (M+H)+ 472.0859, found 472.0866.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([S:28]([CH3:31])(=[O:30])=[O:29])[C:5]1[C:6]([CH:25]2[CH2:27][CH2:26]2)=[CH:7][C:8]2[C:12]([CH:13]=1)=[N:11][N:10]([C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)[C:9]=2[C:21]([NH:23][CH3:24])=[O:22].[NH:32]1[C:36]([CH2:37][C:38](O)=[O:39])=[N:35][N:34]=[N:33]1.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>CN(C=O)C.C(OCC)(=O)C>[Br:20][C:17]1[CH:16]=[CH:15][C:14]([N:10]2[C:9]([C:21]([NH:23][CH3:24])=[O:22])=[C:8]3[C:12]([CH:13]=[C:5]([N:4]([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:3][CH2:2][NH:1][C:38](=[O:39])[CH2:37][C:36]4[N:32]=[N:33][NH:34][N:35]=4)[C:6]([CH:25]4[CH2:26][CH2:27]4)=[CH:7]3)=[N:11]2)=[CH:19][CH:18]=1
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCN)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Reactant: O=C(O)Cc1nnn[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCNC(=O)Cc3nn[nH]n3)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 41.2 %

Procedure:
To a mixture of Compound (7) (34 mg, 67 μmol) and tetrazole acetic acid (10 mg, 81 μmol) in DMF (3 mL) at 0° C. was added HATU (31 mg, 81 μmol) and DIPEA (18 μL, 0.1 mmol). The mixture was stirred at RT for 40 min. Ethyl acetate (5 mL) was added and the mixture was washed with 1M hydrochloric acid and saturated sodium bicarbonate. The combined aqueous phase was neutralised to pH 7 (by addition of 6M hydrochloric acid) and lyophilised. The crude material was then purified by reverse phase flash column chromatography eluting with ACN/water (5-100%) to give Compound (8) (17 mg, 41%). ESI-MS m/z calculated for [M+H]+: 616.11/618.11; found: 615.96/617.96. 1H NMR (400 MHz, d4-MeOH) δ 9.42 (s, 1H), 9.27 (d, J=8.7 Hz, 2H), 9.10 (d, J=8.7 Hz, 2H), 8.87 (s, 1H), 5.55-5.37 (m, 2H), 5.37-5.14 (m, 2H), 5.01 (t, J=6.5 Hz, 2H), 4.70 (s, 3H), 4.52 (s, 3H), 3.95-3.73 (m, 1H), 2.69-2.41 (m, 3H), 2.27-2.10 (m, 1H).
Reaction SMILES: I[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[C:5]([S:15][C:16]#[N:17])=[CH:4][CH:3]=1.NC1C2C(=C([N+]([O-])=O)C=CC=2)C(SC#N)=CC=1>>[N+:12]([C:7]1[C:6]2[C:11](=[CH:2][CH:3]=[CH:4][C:5]=2[S:15][C:16]#[N:17])[CH:10]=[CH:9][CH:8]=1)([O-:14])=[O:13]
Reactant: N#CSc1ccc(I)c2cccc([N+](=O)[O-])c12
Agent: N#CSc1ccc(N)c2cccc([N+](=O)[O-])c12
Product: N#CSc1cccc2cccc([N+](=O)[O-])c12

Procedure:
Other compounds of formula (I) within the scope of the invention may be obtained by conventional methods of organic chemistry. For example, halogen atoms may be introduced by diazotisation of an appropriate amino derivative followed by application of the Sandmeyer reaction. In this way 1-iodo-5-nitro-4-thiocyanatonaphthalene may be prepared from 1-amino-5-nitro-4-thiocyanatonaphthalene. Elimination of the amino group from the latter compound via its diazonium derivative gives 1-nitro-8-thiocyanatonaphthalene, which may also be prepared by diazotisation of 1-amino-8-nitronaphthalene followed by reaction with an alkali metal thiocyanate. Similarly, 1-amino-8-chloronaphthalene gives 1-chloro-8-thiocyanatonaphthalene. Acylamino derivatives may be obtained by acylation of the corresponding amino compounds. Thus, reaction of 1-amino-5-nitro-4-thiocyanatonaphthalene with acetic anhydride in acetic acid gives the 1-acetylamino derivative. 1-Amino-5-nitro-4-thiocyanatonaphthalene may itself be obtained by direct thiocyanation of 1-amino-5-nitronaphthalene; bis-thiocyanation gives 1-amino-2,4-dithiocyanato-5-nitronaphthalene, which may be converted into 2-amino-6-nitro-5-thiocyanatonaphtho[1,2-d]thiazole by refluxing in an alcoholic solvent containing a small quantity of a mineral acid. Likewise, thiocyanation of 1-amino-5-cyanonaphthalene gives 1-amino-5-cyano-4-thiocyanatonaphthalene; diamination of this compound via its diazonium derivative yields 1-cyano-8-thiocyanatonaphthalene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][C:16]([CH2:17][NH:18][C@H:19]([C@@H:23]([CH3:26])[CH2:24][CH3:25])[C:20](O)=[O:21])=[C:11]2[C:10]([C:27]([O:29][CH3:30])=[O:28])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=N[C:41]2[CH:42]=[CH:43][CH:44]=[N:45][C:40]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CCCC1.CN1CCOCC1>C1COCC1>[CH:40]1([NH:45][C:20](=[O:21])[C@H:19]([NH:18][CH2:17][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH:9]=[C:10]([C:27]([O:29][CH3:30])=[O:28])[C:11]=23)[C@@H:23]([CH3:26])[CH2:24][CH3:25])[CH2:41][CH2:42][CH2:43][CH2:44]1
Reactant: CC[C@H](C)[C@@H](NCc1ccnc2c1c(C(=O)OC)cn2C(=O)OC(C)(C)C)C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCCC1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC[C@H](C)[C@@H](NCc1ccnc2c1c(C(=O)OC)cn2C(=O)OC(C)(C)C)C(=O)NC1CCCC1
Temperature: 43 °C
Reaction time: 36 h

Procedure:
To (2R,3S)-2-((1-(tert-butoxycarbonyl)-3-(methoxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methylamino)-3-methylpentanoic acid was added THF (2 mL), followed by HATU (94 mg, 0.246 mmol), cyclopentanamine (70.0 mg, 0.822 mmol) and 4-methylmorpholine (83 mg, 0.822 mmol). The suspension was stirred at 43° C. for 36 h to afford the title compound, which was used in the next step without further purification. [M+H] calc'd for C26H38N4O5, 487; found, 487.7.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[Cl:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][NH2:38].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[Cl:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][NH:38][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:31])([F:1])[F:32])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:30]
Reactant: NCc1cccc(Cl)c1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1cccc(Cl)c1)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (50 mg, 0.11 mmol) was combined with 3-chlorobenzylamine (16 mg, 0.11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 0.14 mmol), 1-hydroxybenzotriazole (17 mg, 0.13 mmol), and triethylamine (0.064 ml, 0.46 mmol) in 1 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 30 ml of ethyl acetate, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to afford 56 mg of the title compound as a colorless solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[CH:2]1.C([Li])CCC.[Cl:19][C:20]1[N:21]=[C:22]2[N:26]([C:27]=1[S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:24][S:23]2>C1COCC1>[Cl:19][C:20]1[N:21]=[C:22]2[N:26]([C:27]=1[S:28]([N:1]1[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[CH:2]1)(=[O:30])=[O:29])[CH:25]=[CH:24][S:23]2
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: O=S(=O)(Cl)c1c(Cl)nc2sccn12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)Cc1cn(S(=O)(=O)c2c(Cl)nc3sccn23)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of 3-indolylacetic acid (175 mg, 1.00 mmol) in THF is cooled to −78° C. under nitrogen and treated portionwise with 2.5 M n-butyllithium in hexanes (0.84 mL, 2.10 mmol) over a 10 min. period. After 1 h at −78° C., the reaction mixture is treated with (6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl chloride (257 mg, 1.00 mmol) in THF, allowed to warm to ambient temperature, stirred for 24 h and concentrated in vacuo. The resultant residue is treated with 1 M aq HCl (˜2 mL) and water (3 mL) and extracted with dichloromethane. The extracts are combined, dried (MgSO4) and concentrated in vacuo. Chromatography of this residue, eluting with ethyl acetate, affords the title compound as a light tan solid, 32 mg, mp 220-222° C. (darkens>200° C.), identified by mass spectral and NMR analyses.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][S:15][C:13]1[O:14][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=2)=[N:11][N:12]=1)[CH3:22]
Reactant: Sc1nnc(-c2ccc3c(c2)CCO3)o1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CSc1nnc(-c2ccc3c(c2)CCO3)o1
Yield: 54 %

Procedure:
In the same manner as in Example 1 and using 5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and ethyl bromoacetate instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 54%) was obtained as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:10]=2)[C:5]([CH3:21])=[N:4][C:3]=1[C:22](OC)=[O:23].[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+]>CO>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[CH:10]=2)[C:5]([CH3:21])=[N:4][C:3]=1[C:22]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:23]
Reactant: COC(=O)c1nc(C)c2ccc(Oc3ccc(OC)cc3)cc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Oc2ccc3c(C)nc(C(=O)NCC(=O)O)c(O)c3c2)cc1
Temperature: 110 °C

Procedure:
A pressure glass reaction flask which included top threads for a screw cap lid can be fitted with a magnetic stirrer, charged with 6e, glycine (about 3 molar equivalents), methanol, and a sodium methoxide solution (with 1.2 molar eqivalents NaOCH3) and sealed. The reaction can then be heated to 110° C. for at least 6 h during which time the reaction forms a yellow suspension. The reaction can then be cooled to 20-25° C. and evaluated by HPLC. The reaction can be continued until less than 1% 6e remains as determined by HPLC, filtered, washed with methanol, dried under vacuum, dissolved in water and extracted with ethyl acetate to remove impurities to below 0.1%. The ethyl acetate can be removed and an acetic acid solution (with 3 molar eqivalents acetic acid) can be added over one hour. The suspension can be stirred at room temperature for at least 3 hours, filtered, and the solid washed with water (3×), cold acetone (5-10° C., 2×) and evaluated for impurities by HPLC. If acetone removable impurities are present, the flask can be charged with acetone and refluxed for at least 8 h, slowly cooled to 5-10° C., stirred for at least 2-3 h, filtered, washed with cold acetone (5-10° C., 3×) and dried under vacuum to obtain 2-[4-hydroxy-1-methyl-6-(4-methoxy-phenoxy)-isoquinoline-3-carboxamido]acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:14][OH:15])=[CH:12][N:11]=[C:10]([NH:16][C:17](=[O:19])[CH3:18])[CH:9]=2)=[C:4](F)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:13](=[CH:12][N:11]=[C:10]([NH:16][C:17](=[O:19])[CH3:18])[CH:9]=3)[CH2:14][O:15][C:4]=2[CH:3]=1
Reactant: CC(=O)Nc1cc(-c2ccc(Cl)cc2F)c(CO)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc2c(cn1)COc1cc(Cl)ccc1-2
Temperature: 95 °C
Yield: 84 %

Procedure:
To a stirred solution of N-(4-(4-chloro-2-fluorophenyl)-5-(hydroxymethyl)pyridin-2-yl)acetamide (9 g, 23.82 mmol) in DMF (90 mL) was added potassium carbonate (9.88 g, 71.5 mmol) and the resultant mixture was sealed tightly and heated at 95° C. for 16 h. The reaction mixture was then cooled to room temperature and volatiles were removed under reduced pressure. The crude material was taken up in water (200 mL) and filtered. The residue was washed with water (2×250 mL) and dried under reduced pressure for 16 h to afford N-(8-chloro-5H-chromeno[3,4-c]pyridin-2-yl)acetamide (5.5 g, 20.02 mmol, 84% yield) as a pale brown solid. LCMS (ESI) m/e 275.2 [(M)−, calcd for C14H12ClN2O2 275.1] LC/MS retention time (method D): tR=1.77 min; 1H NMR (400 MHz, DMSO-d6) δ 10.6 (s, 1H), 8.41 (s, 1H), 8.25 (s, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.22-7.15 (m, 2H), 5.2 (s, 2H), 2.2 (s, 3H).
Reaction SMILES: C([O:4][C:5](=[O:65])[C@H:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23](=[O:64])[NH:24][C@@H:25]([CH2:54][CH2:55][NH:56][C:57](=[O:63])[O:58][C:59]([CH3:62])([CH3:61])[CH3:60])[C:26](=[O:53])[NH:27][C@H:28]([C:50](=[O:52])[NH2:51])[CH2:29][S:30][C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:18][CH:17]=1)[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])C=C.C(N(CC)CC)C.C(O)=O>O1CCCC1.O>[C:11]([O:10][C:8]([NH:7][C@H:6]([C:5]([OH:65])=[O:4])[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][C:23](=[O:64])[NH:24][C@@H:25]([CH2:54][CH2:55][NH:56][C:57](=[O:63])[O:58][C:59]([CH3:60])([CH3:62])[CH3:61])[C:26](=[O:53])[NH:27][C@H:28]([C:50](=[O:52])[NH2:51])[CH2:29][S:30][C:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:20][CH:21]=1)=[O:9])([CH3:12])([CH3:13])[CH3:14]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)N[C@@H](CCNC(=O)OC(C)(C)C)C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)cc1)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCC[C@H](NC(=O)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(N)=O
Temperature: 25 °C

Procedure:
4.91 g (5.40 mmol) of the compound from example 14A was dissolved in approx. 110 ml tetrahydrofuran. 3.8 ml (27 mmol) Triethylamine, 1.02 ml (27 mmol) formic acid and 0.62 g (0.54 mmol) tetrakis(triphenylphosphin)palladium(0) were added. The reaction mixture was stirred over night at room temperature. The reaction was diluted with approx. 60 ml water and twice extracted with approx. 50 ml dichloromethane. The combined organic phases were extracted with brine, dried over sodium sulfate and concentrated to dryness under reduced pressure. The raw product was dissolved in dichloromethane and chromatographed over approx. 500 ml silica gel. Solvents used were dichloromethane, dichloromethane/methanol 40/1 and dichloromethane/methanol 1/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. The raw product was further purified by preparative RP-HPLC on a C18 column with a water/methanol gradient to yield 1.96 g (42% of theory) product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:10]Cl)=[CH:4][CH:3]=1.C(N(CC)CC)C>O1CCCC1.C(OCC)C>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([S:12]([C:9]([S:8][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[CH2:10])(=[O:14])=[O:13])=[CH:20][CH:19]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(CCl)Sc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=C(Sc1ccc(Br)cc1)S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 40.7 %

Procedure:
Thirty-five grams (82 mmoles) of 2-chloro-1-(p-chlorophenylsulfonyl)ethyl p-bromophenyl sulfide was dissolved in 100 ml of tetrahydrofuran and treated with 12 ml (86 mmoles) of triethylamine. The mixture was diluted with 100 ml of diethyl ether and allowed to stand for 15 minutes. The precipitated triethylamine hydrochloride was separated by filtration. Evaporation of solvent from the filtrate gave 35 g of crude solid m.p. 45°-95°. Recrystallization from 100 ml of ethyl acetate-pentane (45:55) gave 13 g of pure product, m.p. 97°-99°.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([C:19]([O:21]C)=O)=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][Al](C)C.CNCCNC>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:8]=[CH:9][C:10]([C:19](=[O:21])[CH3:23])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Al](C)C
Reactant: COC(=O)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Agent: CNCCNC
Solvent: Cc1ccccc1
Product: CC(=O)c1cnc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
Following General Procedure O, methyl 5,6-diphenyl-pyrazine-2-carboxylate (Compound 93, 83 mg, 0.29 mmol), Me3Al (0.4 ml, 2M in toluene), DMEDA (28 mg, 0.32 mmol) in toluene was reacted to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3](I)=[CH:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[NH2:17][C:18]1C(C(F)(F)F)=C(C=CC=1I)C(OC)=O>CN(C=O)C.[C-]#N.[Zn+2].[C-]#N.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>[NH2:1][C:2]1[C:3]([C:18]#[N:17])=[CH:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(I)c(N)c1C(F)(F)F
Reactant: COC(=O)c1cc(N)c(I)cc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N)c(C#N)cc1C(F)(F)F
Temperature: 100 °C
Reaction time: 15 h
Yield: 73 %

Procedure:
A mixture of methyl 5-amino-4-iodo-2-(trifluoromethyl)benzoate (major) and methyl 3-amino-4-iodo-2-(trifluoromethyl)benzoate (minor) in a 4:1 ratio (prepared in Example 51 Step 4) (1.08 g, 3.13 mmol) was dissolved in DMF (17 mL), and the mixture was sparged with nitrogen for 15 minutes. Zinc cyanide (257 mg, 2.19 mmol) and tetrakis(triphenylphosphine)palladium(0) (362 mg, 0.313 mmol) were added and the mixture was stirred at 100° C. for 15 h. The reaction mixture was cooled to ambient temperature and was filtered through celite. The filter cake was washed with ethyl acetate and the filtrate was washed with 5% lithium chloride. The aqueous wash was back-extracted with ethyl acetate (2×). The combined organic portion was washed with 10% lithium chloride and brine, was dried over sodium sulfate then filtered and concentrated to afford a residue which was purified by column chromatography (silica gel, 30-50% ethyl acetate in hexanes) to afford pure methyl 5-amino-4-cyano-2-(trifluoromethyl)benzoate (556 mg, 2.28 mmol, 73% yield). 1H NMR (400 MHz, CDCl3): δ 7.76 (s, 1H), 7.10 (s, 1H), 4.88 (br s, 2H), 3.93 (s, 3H); GCMS for C10H7F3N2O2: 244 (M+).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:28]=[CH:27][C:26]([S:29]([CH3:31])=[O:30])=[CH:25][CH:24]=4)=[N:21][CH:22]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:3].C(=O)=O.CO>C(Cl)(Cl)Cl>[CH3:3][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:28]=[CH:27][C:26]([S@@:29]([CH3:31])=[O:30])=[CH:25][CH:24]=4)=[N:21][CH:22]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:1]
Reactant: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc(S(C)=O)cc4)nc3)CC2)n1
Agent: O=C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc([S@@](C)=O)cc4)nc3)CC2)n1
Yield: 8.6 %

Procedure:
The racemic sulfoxide 5-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]-2-[4-(methylsulfinyl)phenyl]pyridine (prepared as in Example 171, 290 mg) was subjected to Chiral HPLC [column: Chiralcel OJ-H, column mobile phase: 80% CO2: 20% (80% MeOH: 20% CHCl3) (2 mL/min), pressure 140 bar, temperature 30° C., 254 nm] analysis and then separation to give two (R and S) enantiomers. The title compound (25 mg) was isolated a tan solid with Tr of 11.15 min (first eluting peak). The (R) absolute stereochemistry was assigned by Ab initio VCD analysis.