Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH2:15][C:16](=[O:18])[CH3:17])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH3:2].[Li+].CC([N-]C(C)C)C.[CH:28]1([CH2:33]I)[CH2:32][CH2:31][CH2:30][CH2:29]1>COC1SC(=O)N(CSP(OC)(OC)=S)N=1.C1COCC1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([C:6]1[CH:7]=[CH:8][C:9]([S:12]([CH2:15][C:16](=[O:18])[CH3:17])(=[O:14])=[O:13])=[CH:10][CH:11]=1)[CH2:33][CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(S(=O)(=O)CC(C)=O)cc1
Reactant: ICC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: COc1nn(CSP(=S)(OC)OC)c(=O)s1
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC1CCCC1)c1ccc(S(=O)(=O)CC(C)=O)cc1
Temperature: -78 °C

Procedure:
A solution of the title B compound, [4-(2-oxo-propylsulfonyl)-phenyl]-acetic acid ethyl ester (8 g, 0.028 mol) in 5 mL of DMTP and 80 mL of THF is cooled to −78 g and then treated with 15 mL of LDA (2 M solution in THF/hexane, 0.030 mol). The reaction is maintained at −78° C. for 20 min and then treated with a solution of 5.91 g (0.028 mL) of cyclopentylmethyl iodide in a mixture of THF (10 mL) and DMTP (3 mL), and the reaction is maintained at −78° C. for 6 h and subsequently at RT for another 6 h. The reaction is quenched with saturated ammonium chloride solution (20 mL). The organic layer is separated and aqueous layer then extracted with ethyl acetate (2×50 mL). Both the organic layers are combined and then washed with water. The organic layer is dried over sodium sulfate, filtered and evaporated under vacuum to give a brown oil as a crude product which is purified by column chromatography over Silica gel (60-120 mesh) using 80/20—hexane/ethyl acetate as an eluent to give 3-cyclopentyl-2-[4-(2-oxo-propylsulfonyl)-phenyl]-propionic acid ethyl ester as a white solid.
Reaction SMILES: BrC1N=C(C(=O)NC)C(NC2C(C(F)(F)F)=CN=C(NC3C=CC(CP(=O)(O[C@@H](CCN4C=C(B5OC(C)(C)C(C)(C)O5)C=N4)C)OCC)=CC=3OC)N=2)=CC=1.[Br:57][C:58]1[N:63]=[C:62]([C:64](=[O:67])[NH:65][CH3:66])[C:61]([NH:68][C:69]2[C:74]([C:75]([F:78])([F:77])[F:76])=[CH:73][N:72]=[C:71]([NH:79][C:80]3[CH:91]=[CH:90][C:83]([CH2:84][CH2:85][CH2:86][PH:87](=[O:89])[OH:88])=[CH:82][C:81]=3[O:92][CH3:93])[N:70]=2)=[CH:60][CH:59]=1.[CH3:94][C:95]1([CH3:113])[C:99]([CH3:101])([CH3:100])[O:98][B:97]([C:102]2[CH:103]=[N:104][N:105]([CH2:107][C:108]3([CH2:111]O)[CH2:110][CH2:109]3)[CH:106]=2)[O:96]1>>[Br:57][C:58]1[N:63]=[C:62]([C:64](=[O:67])[NH:65][CH3:66])[C:61]([NH:68][C:69]2[C:74]([C:75]([F:78])([F:76])[F:77])=[CH:73][N:72]=[C:71]([NH:79][C:80]3[CH:91]=[CH:90][C:83]([CH2:84][CH2:85][CH2:86][PH:87](=[O:88])[O:89][CH2:111][C:108]4([CH2:107][N:105]5[CH:106]=[C:102]([B:97]6[O:96][C:95]([CH3:113])([CH3:94])[C:99]([CH3:101])([CH3:100])[O:98]6)[CH:103]=[N:104]5)[CH2:110][CH2:109]4)=[CH:82][C:81]=3[O:92][CH3:93])[N:70]=2)=[CH:60][CH:59]=1
Reactant: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCC[PH](=O)O)cc2OC)ncc1C(F)(F)F
Reactant: CC1(C)OB(c2cnn(CC3(CO)CC3)c2)OC1(C)C
Agent: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1)O[C@H](C)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCC[PH](=O)OCC3(Cn4cc(B5OC(C)(C)C(C)(C)O5)cn4)CC3)cc2OC)ncc1C(F)(F)F
Yield: 43.8 %

Procedure:
Racemic Compound 71A was prepared analogously to Compound 69A using (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)ethylphosphinic acid (Compound 67B, 206 mg, 0.341 mmol) and (1-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]methyl}cyclopropyl)methanol (Compound 63B, 400 mg, 2 mmol) to afford 129 mg of the title compound (48%). MS (ESI): m/z=879.92/881.81 [M+H]+. UPLC: tR=1.61 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:32]4[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=4)=[CH:19][CH:18]=3)=[O:24])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(I)cc3)cc2s1
Product: COc1ccc(-c2ccc(C(=O)Nc3ccc4nc(N(C)CCN(C)C)sc4c3)cc2)cc1

Procedure:
The title compound is prepared by following a procedure analogous to Example 113, Step 1, using N-{2-[(2-dimethylamino-ethyl)-methyl-amino]-benzothiazol-6-yl}-4-iodo-benzamide (0.15 g, 0.31 mmol) and 4-methoxyphenyl boronic acid (0.057 g, 0.38 mmol) to give 0.025 g (16%). LC/MS, Retention time=4.45 min; (m/z): calcd for C26H28N4O2S (M+H)+: 461.6; found: 461.0.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[CH:4]=[C:5]([C:7]#[N:8])[CH:6]=1.[I:21]N1C(=O)CCC1=O>C(#N)C.O>[NH2:1][C:2]1[N:3]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:17])[F:18])=[CH:11][C:10]=2[Cl:20])[CH:4]=[C:5]([C:7]#[N:8])[C:6]=1[I:21]
Reactant: N#Cc1cc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CC#N
Product: N#Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-1-(2,6-dichloro4-trifluoromethylphenyl)4-cyanopyrrole (EP-372982 A2) in acetonitrile (20 ml) was added N-iodosuccinimide (703 mg). The reaction was stirred at room temperature for 30 minutes, diluted with water (100 ml) and extracted with ether (100 ml). The organic fraction was separated, dried over MgSO4, filtered and evaporated to dryness, the residue was purified by column chromatography (silica, 20 g) eluted with dichloromethane:hexane (7:3) to give the title compound as a yellow crystaline material, m.p. 130-132° C.
Reaction SMILES: [O-]CC.[K+:4].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.[Cl:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[C:20]([CH3:25])[CH:19]=[CH:18][N:17]=1>C(OCC)C>[Cl:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[C:20](/[CH:25]=[C:6](\[O-:8])/[C:5]([O:12][CH2:13][CH3:14])=[O:11])[CH:19]=[CH:18][N:17]=1.[K+:4]
Reactant: Cc1ccnc(Cl)c1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCOC(=O)/C([O-])=C/c1ccnc(Cl)c1[N+](=O)[O-]
Reaction time: 0.08 h
Yield: 81.6 %

Procedure:
To a heterogeneous solution of potassium ethoxide (6.56 g, 77.9 mmol) in diethyl ether (55 mL), was slowly added diethyl oxalate (10.6 mL, 77.9 mmol). A slight exotherm resulted. After stirring 5 min, a homogeneous yellow solution resulted, but after 10 min, a heterogeneous yellow slurry was observed. Addition of 2-chloro-4-methyl-3-nitropyridine (13.45 g, 77.9 mmol) as a solid, with a diethyl ether rinse (23 mL), resulted in a dark violet solution with a dark precipitate. The mixture was stirred at room temperature overnight (21 h). The solid precipitate was filtered, rinsed thoroughly with diethyl ether, and air-dried to give potassium (1Z)-1-(2-chloro-3-nitropyridin-4-yl)-3-ethoxy-3-oxoprop-1-en-2-olate (19.8 g, 63.6 mmol, yield 81%) as an orange solid. The crude product was used directly without further purification or identification.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1
Reactant: COC(=O)c1cc(Br)oc1C
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(-c2ccccc2OC)oc1C
Reaction time: 8 h
Yield: 93 %

Procedure:
A mixture of methyl 5-bromo-2-methyl-3-furancarboxylate (2.2 g), 2-methoxyphenylboronic acid (1.8 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (2.3 g, 92%) as a white solid.
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9].C1(C)C=CC=CC=1.[S:19]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)(=[O:22])(=[O:21])[NH2:20].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:7][C:6]1[C:2]([C:26]2[CH:27]=[CH:28][C:23]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:24][CH:25]=2)=[C:3]([C:8]([O:10][CH3:11])=[O:9])[S:4][CH:5]=1
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1scc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1scc(C)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 105 °C
Reaction time: 15 h
Yield: 74.4 %

Procedure:
To a stirred suspension of methyl 3-bromo-4-methylthiophene-2-carboxylate (compound 7a, 9.0 g, 38.0 mmol) in ethanol: toluene (100:30 ml) in sealed tube, (4-sulfamoylphenyl)boronic acid (8.46 g, 42.0 mmol) and potassium carbonate (10.57 g, 76.0 mmol) were added under a nitrogen atmosphere at room temperature (about 25° C.). Nitrogen gas was purged to this suspension for further 15 minute at room temperature (about 25° C.) and tetrakis(triphenyl phosphine)palladium(0) (2.21 g, 1.9 mmol) was added at 25° C. and sealed tube was closed. The reaction mixture was stirred at 105° C. for 15 hr and the progress of the reaction was monitored by TLC. Reaction mixture was filtered and washed with ethyl acetate (2×100 ml). Organic layer was concentrated under reduced pressure to obtain crude product as semi-solid (11.2 g); which was purified by column chromatography over silica gel (100-200 mesh) using 50% ethyl acetate in hexanes as an eluent to obtain the title compound (20% ethyl ester as trans esterified product was observed) (8.8 g, 70.70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:23])[C:9]([N:11]2[CH2:22][CH2:21][CH2:20][C@H:12]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[CH:5]=[CH:6][CH:7]=1.Br[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1.[Li]CCCC>C1COCC1.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([OH:23])([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[C:9]([N:11]2[CH2:22][CH2:21][CH2:20][C@H:12]2[C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)C(=O)c1cccc(Cl)c1
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)C(O)(c1cccnc1)c1cccc(Cl)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
tert-Butyl 1-[(3-chlorophenyl)(oxo)acetyl]-L-prolinate (2.2 g, 6.46 mmol) was dissolved in THF (10 mL) and cooled to −78° C. under a nitrogen atmosphere (Vessel A). In a separate vessel containing 3-bromopyridine (0.68 mL, 7.1 mmol) in ethyl ether (50 mL) cooled to −78° C. was added n-BuLi (2.5M in hexanes, 3.1 mL, 7.7 mmol) and the mixture was stirred for one hour (Vessel B). The contents of Vessel B were added to Vessel A via cannula at −78° C. The temperature was increased to 0° C. and the mixture stirred for 2.5 hours. The mixture was then quenched with saturated ammonium chloride solution (40 mL) and extracted with EtOAc. The EtOAc was evaporated in vacuo, and the residue dried and purified on silica gel using a 1:1 then 2:1 mixture of EtOAc to hexane as mobile phase. Pooled fractions were dried to yield: Nonpolar isomer of tert-butyl 1-[(3-chlorophenyl)(hydroxy)pyridin-3-ylacetyl]-L-prolinate (0.43 g, HPLC RT=3.01 min, Method A; LCMS m/z=417). Polar isomer of ten-butyl 1-[(3-chlorophenyl)(hydroxy)pyridin-3-ylacetyl]-L-prolinate (0.12 g, HPLC RT=2.96 min, Method A; LCMS m/z=417).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH:6]1[CH2:8][CH2:7]1)[OH:5].O.[NH2:11][NH2:12]>CO>[CH:6]1([CH:4]([OH:5])[C:3]([NH:11][NH2:12])=[O:2])[CH2:8][CH2:7]1
Reactant: COC(=O)C(O)C1CC1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)C(O)C1CC1
Yield: 69 %

Procedure:
As described for example 112a, (rac.)-2-cyclopropyl-2-hydroxy-acetic acid methyl ester (Newall, Christopher Earle; Foxton, Michael Walter; Hartley, Charles David; Looker, Brian Edgar. Cephalosporin antibiotics. Eur. Pat. Appl. (1985), 57 pp) in methanol was reacted with hydrazine hydrate (1.0 equivalent) at rt for 76 h. All volatiles were evaporated and the residue was triturated with hexane to afford the title compound as a white solid (yield: 69%). MS: m/e=112.2 [M−H2O]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([C@@H:31]3[CH2:35][CH2:34][CH2:33][C@H:32]3[C:36]([O:38]C)=[O:37])=[O:30])=[CH:25][CH:24]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:14][C:12]=2[N:13]=1>C1COCC1.O1CCOCC1.[OH-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([C@@H:31]3[CH2:35][CH2:34][CH2:33][C@H:32]3[C:36]([OH:38])=[O:37])=[O:30])=[CH:25][CH:24]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][C:19]([F:21])([F:20])[F:22])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(OC(F)(F)F)cc4s3)c(F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(OC(F)(F)F)cc4s3)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
In 250-mL round-bottom flask, methyl (1R,2R)-2-[(3′-fluoro-4′-{[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]amino}-1,1′-biphenyl-4-yl)carbonyl]cyclopentanecarboxylate (2.53 g, 4.53 mmol) was dissolved in 100 mL of 1:1 THF/dioxane containing 5.0 molar equivalents of 1 N aqueous NaOH. The mixture was stirred at rt overnight. The mixture was concentrated under reduced pressure to a volume of about 20 mL. Ethyl acetate (100 mL), water (30 mL), and 5.1 molar equivalents of 1 N aqueous HCl were added to the mixture. The mixture was transferred to a separation funnel. The organic layer was washed with water (1×50 mL), dried (Na2SO4), and concentrated under reduced pressure. The solid was ultrasonicated in 30 mL acetonitrile and filtered to give the desired compound as a white solid (1.96 g, 80%, 94.5% ee). 1H NMR (400 MHz, DMSO-d6) δ 12.20 (br s, 1H), 10.60 (bs, 1H), 8.70 (t, 1H), 7.60-8.20 (m, 8H), 7.30 (d, 1H), 4.70 (q, 1H), 3.20 (q, 1H), 2.20 (m, 1H), 2.00 (m, 1H), 1.50-1.90 (m, 4H); LC-MS m/z 545.3 (MH+), ret. time 3.93 min.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:13])[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:14]F>C(#N)C.ClC(Cl)(Cl)C(F)(F)F>[C:1]1([CH:7]([F:14])[C:8](=[O:13])[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: FF
Reactant: COC(=O)C(=O)Cc1ccccc1
Solvent: FC(F)(F)C(Cl)(Cl)Cl
Solvent: CC#N
Product: COC(=O)C(=O)C(F)c1ccccc1

Procedure:
In the same manner as in Example 1, methyl 3-phenylpyruvate (35.62 g; 0.2 mol) is dissolved in a mixture of acetonitrile (240 g) and trichlorotrifluoroethane (1.6 L) and reacted with fluorine at -10° C. After the same work-up as in Example 1, the residue is rectified to give methyl 3-phenyl-3-fluoropyruvate (11.8 g). The silyl enol ether obtained by the treatment of the above product with bis-(trimethylsilyl)acetamide (BSA) in methylene chloride shows boiling point 93°-95° C./1 mmHg and 19F NMR (CDCl3), δ (int. C6F6)+31.5 (s).
Reaction SMILES: [CH2:1](I)C.[NH2:4][CH2:5][CH2:6][CH2:7][C@:8]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:12]([C:13](=[O:18])[C@@H:14]([O:16][CH3:17])[CH3:15])[N:11]=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[S:9]1>>[NH2:4][CH2:5][CH2:6][CH2:7][C@:8]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:12]([C:13](=[O:18])[C@@H:14]([O:16][CH2:17][CH3:1])[CH3:15])[N:11]=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[S:9]1
Reactant: CO[C@@H](C)C(=O)N1N=C(c2cccc(F)c2)S[C@@]1(CCCN)c1ccccc1
Reactant: CCI
Product: CCO[C@@H](C)C(=O)N1N=C(c2cccc(F)c2)S[C@@]1(CCCN)c1ccccc1

Procedure:
Prepared as described in Example 64 using ethyl iodide in place of methyl iodide. MS (+) m/z 416 (M+1) detected; 1H NMR (400 MHz, 10:1 CDCl3:CD3OD) δ 7.39 (m, 7H), 7.30 (m 1H), 7.20 (m, 1H), 4.85 (br q, 1H, J=6.3 Hz), 3.68-3.53 (m, 2H), 3.27 (m, 1H), 3.11 (m, 2H), 2.58 (m, 1H), 2.21 (m, 1H), 1.72 (m, 1H), 1.47 (d, 3H, J=6.3 Hz), 1.24 (m, 3H). Stereochemistry was assigned by inference from (S)-1-((S)-2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3 (2H)-yl)-2-methoxypropan-1-one.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[N:8]1.Br[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([Cl:30])[CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:30][C:24]1[CH:23]=[C:22]([C:11]2[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=[CH:9][CH:10]=2)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]
Reactant: N#Cc1ccc(Br)cc1Cl
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(-c2ccnn2C2CCCCO2)cc1Cl
Temperature: 35 °C
Reaction time: 2.5 h
Yield: 69.6 %

Procedure:
1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.5 g; 23.28 mmol) and 4-bromo-2-chlorobenzonitrile (4 g; 18.48 mmol) were dissolved in THF (65 ml). To this mixture bis(triphenylphosphine)-palladium(II) chloride (0.65 g; 0.92 mmol), sodium carbonate (4.7 g; 44.3 mmol) and 18 ml of water were added and the reaction mixture was stirred at 35° C. for 2.5 h. The solvents were distilled to almost dryness and water (48 ml) was added. After 30 min of stirring the precipitated product was filtered and 32 ml of ethanol was added to the precipitation. The suspension was stirred for 15 min at RT and 30 min at −10° C. before filtering to give 3.7 g of the product. 1H-NMR (400 MHz; d6-DMSO): δ 1.63-1.54 (m, 3H), 1.84-1.80 (m, 1H), 1.97-1.94 (m, 1H), 2.39-2.35 (m, 1H), 3.63-3.57 (m, 1H), 3.99 (m, 1H), 5.32-5.27 (m, 1H), 6.72 (d, 1H), 7.65 (d, 1H), 7.72 (m, 1H), 7.92 (d, 1H), 8.14 (d, 1H).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8](=[O:28])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([N:22]2[CH2:27][CH2:26][S:25][CH2:24][CH2:23]2)=[N:11][CH:10]=1.[OH:39]OS([O-])=O.[K+]>CO>[F:38][C:2]([F:37])([F:1])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8](=[O:28])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([N:22]2[CH2:27][CH2:26][S:25](=[O:39])[CH2:24][CH2:23]2)=[N:11][CH:10]=1
Reactant: Cc1ccccc1-c1cc(N2CCSCC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Product: Cc1ccccc1-c1cc(N2CCS(=O)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 159.9 %

Procedure:
To a solution of 1.24 g (2.24 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-thiomorpholin-4-yl-4-o-tolyl-nicotinamide (step a)) in 25 ml methanol were added 689 mg (1.12 mmol) Oxone® at 0° C. After completed addition the reaction mixture was allowed to warm to room temperature and stirred for 1.5 h. Quenching with 5 ml 40% aqueous sodium hydrogen sulfite solution was followed by addition of 6 ml 1N sodium hydroxide solution to adjust the pH to 7-8. The mixture was diluted with 50 ml water and extracted with 3 150-ml portions of dichloromethane. The combined extracts were dried with sodium sulfate and concentrated to give 1.20 g of crude product. Flash chromatography afforded 1.02 g (79.9%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1.[N:14]([O-])=[O:15].[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:13])[C:9](=[N:14][OH:15])[C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: CC(=O)CC(=O)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)C(=NO)C(=O)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
To a 0° C. solution of 1-(3-chlorophenyl)butane-1,3-dione (0.75 g, 3.8 mmol) in 15 mL acetic acid was slowly added sodium nitrite (0.560 g, 8.11 mmol) as a solution in 1.5 mL water. The reaction was stirred at 0° C. for 30 minutes and then warmed to room temperature. After an additional 4 hours, the reaction was poured into aqueous saturated sodium bicarbonate and extracted three times with dichloromethane. The combined extracts were dried over magnesium sulfate and concentrated to yield 765.7 mg (89%) of 1-(3-chlorophenyl)-2-(hydroxyimino)butane-1,3-dione, which was carried forward without further purification. LCMS (ESI) m+H=226; 1H NMR (400 MHz, DMSO-d6) δ: 7.81 (d, 1H), 7.80 (s, 1H), 7.75 (d, 1H), 7.62 (t, 1H), 2.60 (s, 1H), 2.48 (s, 3H).
Reaction SMILES: [S:1]1[C:5]([CH2:6][C:7]#[N:8])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.Br[CH2:14][CH2:15][CH2:16]Br.[OH-].[K+].Cl>CCOCC.CS(C)=O>[S:1]1[C:5]([C:6]2([C:7]#[N:8])[CH2:16][CH2:15][CH2:14]2)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: BrCCCBr
Reactant: N#CCc1cc2ccccc2s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CS(C)=O
Product: N#CC1(c2cc3ccccc3s2)CCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of benzo[b]thiophen-2-acetonitrile (8.05 g) and 1,3-dibromopropane (5.2 ml) in ether (50 ml) was added dropwise under nitrogen over 1 hour to a stirred, ice-cold suspension of finely-powdered potassium hydroxide (13.53 g) in dimethyl sulphoxide (100 ml). When the addition was complete, the mixture was stirred at ambient temperature for 4 hours, then it was added to ice-cold water (200 ml). The resulting mixture was acidified to pH4 by the addition of concentrated hydrochloric acid, then the product was extracted into ether (3×200 ml). The combined extracts were washed with water (500 ml), dried (MgSO4), and the solvent was removed in vacuo to give 1-(benzo[b]thiophen-2-yl)cyclobutanecarbonitrile as a red oil (8.16 g) which was used without purification.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2].Cl[C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([CH2:23][N:24]3[CH2:29][CH2:28][N:27]([C:30]([CH3:35])([CH2:33][OH:34])[CH2:31][OH:32])[CH2:26][CH2:25]3)[N:19]2[CH3:22])=[C:15]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[N:14]=1>>[CH2:1]([C:3]1[N:4]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[C:18]([CH2:23][N:24]4[CH2:25][CH2:26][N:27]([C:30]([CH3:35])([CH2:31][OH:32])[CH2:33][OH:34])[CH2:28][CH2:29]4)[N:19]3[CH3:22])=[C:15]([N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)[N:14]=2)[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: Cn1c(CN2CCN(C(C)(CO)CO)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(CO)CO)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-ethylbenzimidazole and 2-(4-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperazin-1-yl)-2-methylpropane-1,3-diol were reacted to give 440. LCMS m/z: 550.3 (MH+)