Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[H-].[Na+].Br[CH2:15][C:16]([O:18][CH3:19])=[O:17].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:7]=[CH:6]2
Reactant: COC(=O)CBr
Reactant: COc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cn1ccc2cc(OC)ccc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 5-methoxy-1H-indole (500 mg, 3.40 mmol) in dry DMF (8 ml), cooled at 0° C., sodium hydride (60% w/w dispersion in mineral oil, 136 mg, 3.40 mmol) was slowly added portionwise and the reaction was stirred at 0° C. for 45 minutes; then methyl 2-bromoacetate (315 μl, 3.40 mmol) was added dropwise, and the reaction was stirred at room temperature for 15 hours. Water was slowly added, and the product was extracted with Et2O and then with ethyl acetate. The combined organic layers were washed with water, dried over Na2SO4 and evaporated to dryness. The title compound was obtained and used for the next step without further purification (745 mg, 3.40 mmol, quantitative yield). MS/ESI+ 220.1 [MH]+.
Reaction SMILES: C(OC(=O)C(CS(N1CCN(C2C=CC(Br)=CC=2)CC1)(=O)=O)C(C)C)(C)(C)C.Cl.Cl.[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:39]=[CH:40][C:41]([N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[N:42][CH:43]=2)=[CH:34][CH:33]=1.[CH2:50]([C@@H:57]1[CH2:61][O:60][C:59](=[O:62])[N:58]1[C:63](=[O:73])[C@H:64]([CH2:68][S:69](Cl)(=[O:71])=[O:70])[CH:65]([CH3:67])[CH3:66])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>>[CH2:50]([C@@H:57]1[CH2:61][O:60][C:59](=[O:62])[N:58]1[C:63](=[O:73])[C@H:64]([CH2:68][S:69]([N:47]1[CH2:46][CH2:45][N:44]([C:41]2[CH:40]=[CH:39][C:38]([C:35]3[CH:34]=[CH:33][C:32]([F:31])=[CH:37][CH:36]=3)=[CH:43][N:42]=2)[CH2:49][CH2:48]1)(=[O:71])=[O:70])[CH:65]([CH3:67])[CH3:66])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: Fc1ccc(-c2ccc(N3CCNCC3)nc2)cc1
Agent: CC(C)C(CS(=O)(=O)N1CCN(c2ccc(Br)cc2)CC1)C(=O)OC(C)(C)C
Agent: Cl
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 85.9 %

Procedure:
Prepared according to the method for the preparation of 2-[4-(4-bromophenyl)-piperazine-1-sulfonylmethyl]-3-methyl-butyric acid tert-butyl ester, from 4-[5-(4-fluorophenyl)pyridin-2-yl]piperazine dihydrochloride (0.108 g) and 4-(R)-benzyl-3-(2-(R)-chlorosulfonylmethyl-3-methylbutyryl)oxazolidin-2-one (0.147 g), to yield the title compound as a pale green gum (0.167 g, 85%).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[O:7][C:6]2[CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[CH:16][CH:15]=3)=[CH:11][C:5]=2[C:4](=[O:32])[O:3]1.[CH:34](=O)[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>>[CH2:34]([N:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]#[C:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=2)=[CH:18][CH:19]=1)[C:10]1[CH:9]=[CH:8][C:6]2[O:7][C:2]([CH3:33])([CH3:1])[O:3][C:4](=[O:32])[C:5]=2[CH:11]=1)[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCC=O
Reactant: CC1(C)OC(=O)c2cc(NCc3ccc(C#Cc4ccc(C(F)(F)F)cc4)cc3)ccc2O1
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(C(F)(F)F)cc2)cc1)c1ccc2c(c1)C(=O)OC(C)(C)O2
Yield: 77.6 %

Procedure:
The title compound was prepared following procedure described in Example 32, step c) from 2,2-dimethyl-6-[(4-{[4-(trifluoromethyl)phenyl]ethynyl}benzyl)amino]-4H-1,3-benzodioxin-4-one (427 mg; 0.95 mmol) and hexanal (Aldrich, 170 μl; 1.42 mmol) to give 560 mg of crude. Purification by flash chromatography on silica gel (EtOAc/c-Hexe 5:90 then 10:90) gave 395 mg (78%) of the title compound as a brown powder. HPLC, Rt: 6.21 min (purity: 68.5%). 1H NMR (CDCl3) δ: 7.59 (brs, 4H), 7.47 (m, 2H), 7.30.(m 3H), 6.76-6.83 (m, 2H), 4.50 (s, 2H), 3.38 (m, 2H), 1.68 (s, 6H), 1.61 (m, 2H), 1.28 (m, 6H), 0.86 (m, 3H).
Reaction SMILES: [NH:1]([C:8]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:9][C:10]([C:12]1[C:13](Cl)=[N:14][C:15]([Cl:22])=[CH:16][C:17]=1[C:18]([F:21])([F:20])[F:19])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+]>O1CCOCC1>[NH:1]([C:8]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:13]2[C:12]([C:10](=[O:11])[CH:9]=1)=[C:17]([C:18]([F:21])([F:19])[F:20])[CH:16]=[C:15]([Cl:22])[N:14]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C=C(Nc1ccccc1)Nc1ccccc1)c1c(C(F)(F)F)cc(Cl)nc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nc(Cl)cc(C(F)(F)F)c12
Yield: 94.5 %

Procedure:
A mixture of 3,3-dianilino-1-[2,6-dichloro-4-(trifluoromethyl)-3-pyridinyl]-2-propen-1-one (12.9 g, 28.5 mmol) and t-BuOK (28.5 mL, 28.5 mmol, 1M in THF) in dioxane (200 mL) was heated at reflux overnight. The reaction was cooled, concentrated in vacuo, treated with saturated NH4Cl and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. Silica gel flash chromatography of the residue using 6:1 Hex:EtOAc provided 2-anilino-7-chloro-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one (11.2 g, 95%) as an off-white solid: LCMS RT: 3.00 min, MH+: 416.7, Rf=0.25 (3:1 Hex:EtOAc). This transformation can be accomplished by using the combination of other aprotic solvents such as DMF, and THF with other bases such as NaH.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:9]2[NH:10][C:11]([CH3:13])=[N:12][C:8]=2[CH:7]=[C:6]([C:14]([O:16]C)=[O:15])[CH:5]=1>CO>[Cl:3][C:4]1[C:9]2[NH:10][C:11]([CH3:13])=[N:12][C:8]=2[CH:7]=[C:6]([C:14]([OH:16])=[O:15])[CH:5]=1
Reactant: COC(=O)c1cc(Cl)c2[nH]c(C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2cc(C(=O)O)cc(Cl)c2[nH]1
Temperature: 65 °C
Reaction time: 16 h
Yield: 71.8 %

Procedure:
Add 2N sodium hydroxide (5 mL, 5 mmol) to a solution of methyl 7-chloro-2-methyl-1H-benzo[d]imidazole-5-carboxylate (280 mg, 1.25 mmol) in methanol (7.5 mL). Stir at 65° C. for 16 hours. The methanol was concentrated in vacuo and the remaining aqueous layer was extracted with ethyl acetate (10 mL). Acidify the aqueous layer to pH ˜4 with 1N hydrochloric acid (˜5 mL). A colorless precipitate was filtered and dried under high vacuum to yield the title compound (189 mg, 72%). 1H NMR (400 MHz, CD3OD) δ ppm 2.61 (s, 3H), 7.86 (d, J=1.37 Hz, 1H), 8.08 (d, J=1.17 Hz, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C:8]1[S:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([C:30](O)=[O:31])=[N:26][N:27]([CH3:29])[CH:28]=2)=[CH:20][CH:19]=1>>[S:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][N:1]1[C:30]([C:25]1[C:24]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)=[CH:28][N:27]([CH3:29])[N:26]=1)=[O:31]
Reactant: Cn1cc(-c2ccc(F)cc2)c(C(=O)O)n1
Reactant: c1ccc2sc(CC3CCCCN3)nc2c1
Product: Cn1cc(-c2ccc(F)cc2)c(C(=O)N2CCCCC2Cc2nc3ccccc3s2)n1

Procedure:
The title compound (0.210 g) was prepared from 2-piperidin-2-ylmethyl-benzothiazole, D30 (0.135 g) and 4-(4-fluorophenyl)-1-methyl-1-H-pyrazol-3-carboxylic acid (0.135 g) using the procedure described in Example 60.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cl:14][CH2:15][C:16](O)=[O:17].S(=O)(=O)(O)O>C1C=CC=CC=1>[Cl:14][CH2:15][C:16]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:17]
Reactant: O=C(O)CCl
Reactant: CCCCCCCCCCCCO
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CCCCCCCCCCCCOC(=O)CCl
Yield: 90 %

Procedure:
The mixture of 1-dodecanol (0.2 mol, 37.27 g), chloroacetic acid (0.2 mol, 18.9 g), benzene (200 ml) and sulfuric acid (2 ml) was refluxed for 12 hrs. After the reaction, the mixture was washed with 25% Na2CO3 (100 ml). The organic layer was dried with magnesium sulfate and then evaporated, the remaining liquid was distilled under vacuum to provide a colorless oil (bp 150° C./3 mmHg) in 90% yield.
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[S:4][CH:3]=1.[Li]CCCC.CCCCCC.[CH2:22]([CH:24]([C:27]1[C:28]2[N:29]([C:34](I)=[C:35]([CH3:37])[N:36]=2)[N:30]=[C:31]([CH3:33])[CH:32]=1)[CH2:25][CH3:26])[CH3:23]>C1COCC1.[Cl-].[Cl-].[Zn+2]>[CH2:22]([CH:24]([C:27]1[C:28]2[N:29]([C:34]([C:3]3[S:4][C:5]4[C:6](=[N:7][CH:8]=[CH:9][CH:10]=4)[C:2]=3[CH3:1])=[C:35]([CH3:37])[N:36]=2)[N:30]=[C:31]([CH3:33])[CH:32]=1)[CH2:25][CH3:26])[CH3:23]
Reactant: Cc1csc2cccnc12
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc4cccnc4c3C)c(C)nc12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 34.8 %

Procedure:
190 mg of 3-Methyl-thieno[3,2-b]pyridine (1.28 mmol) is dissolved in 3.0 ml of dry THF and cooled to −78° C. 0.62 ml of n-BuLi 2.5M in hexane (1.54 mmol) is added at −78° C. and stirred at −78° C. for 10 min and room temperature for 10 min. The reaction vessel is cooled to −78° C. again and 3.3 ml of 0.5 M ZnCl2 in THF (1.66 mmol) is added at −78C and stirred at room temperature for 15 min. 343 mg of 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (1.0 mmol) and 41 mg of PdCl2(pddf) (0.05 mmol) are added and the tube is capped. The tube is heated at 80° C. for overnight. The reaction is quenched by NH4Claq. and extracted by CH2Cl2, dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt:2 M NH3 in MeOH=10:3:1) to give 127 mg of the title compound. Yield 35%. mass spectrum (m/e): 365 (M+1); 1H-NMR (CDCl3): 8.79 (dd, 1H, J=4.8 Hz, 1.4 Hz), 8.21 (dd, 1H, J=7.9 Hz, 1.4 Hz), 7.33 (dd, 1H, J=7.9 Hz, 4.8 Hz), 6.76 (s, 1H), 3.38 (m, 1H), 2.55 (s, 6H), 2.47 (s, 3H), 1.89 (m, 4H), 0.92 (t, 6H, J=7.5 Hz) ppm.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:16]=[C:15]1[C:8]2=[CH:7][C:6]3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:10]=3[N:9]2[CH2:11][CH2:12][CH2:13][NH:14]1
Reactant: OB(O)c1ccccc1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: N#Cc1cc(-c2ccccc2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, light grey solid (66 mg, 88%), MS (ISP) m/z=302.5 [(M+H)+], mp 237.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available phenylboronic acid (39.6 mg, 0.325 mmol).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1Br)(=[O:3])[CH3:2].[FH:25].[F-].[K+]>C(#N)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[F:25])(=[O:3])[CH3:2]
Reactant: F
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](F)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
10.0 g (24.3 mmol) of 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide were heated under reflux in 100 ml of anhydrous acetonitrile with 10.0 g (128 mmol) of potassium hydrogen difluoride for 6 hours. The mixture was then filtered, the solvent was stripped off in vacuo and the residue was taken up in methylene chloride. After filtration over a short silica gel column and concentration of the solution, it was possible to crystallize the product from ether. Yield 6.1 g (72%), melting point 100° C., [α·D20 =+17.5 (c=1.03 in CHCl3) [F. Micheel et al., Chem. Ber. 88, 475 (1955), melting point 98°-99° C., [α]D18 =+22 (CH3OH)]. 1H NMR (CDCl3): δ=5.26 (dd, 1-H), J1.2 =7.0, J1,F =50.0 Hz.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([OH:17])=O)=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[F:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]2([OH:62])[CH2:61][CH2:60][NH:59][CH2:58]2)=[CH:53][C:52]=1[CH3:63]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([N:59]3[CH2:60][CH2:61][C:57]([C:54]4[CH:55]=[CH:56][C:51]([F:50])=[C:52]([CH3:63])[CH:53]=4)([OH:62])[CH2:58]3)=[O:17])=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: Cc1cc(C2(O)CCNC2)ccc1F
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2nocc2C(=O)N2CCC(O)(c3ccc(F)c(C)c3)C2)cc1Cl
Yield: 40.6 %

Procedure:
A solution of 3-(3-chloro-4-methoxyphenyl)isoxazole-4-carboxylic acid (10 mg, 0.04 mmol), N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.08 mmol, 2 equ.) and TBTU (15 mg, 0.046 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 3-(4-fluoro-3-methylphenyl)pyrrolidin-3-ol hydrochloride (9 mg, 0.04 mmol). After 1 h at rt the crude product was purified by RP-HPLC, evaporated and dried in vacuum to yield the title compound (7 mg). MS (ESI, pos. ion) m/z: calcd for C22H20ClFN2O4: 430.1096, found 430.1094.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6](CCNS(CC1C(Br)=CC=CC=1Br)(=O)=O)=[C:5]2CCCC1C=CC(C(O)=O)=CC=1.[H-].[Na+].C(Br)(C1C=CC=CC=1)C1C=CC=CC=1.O>CN(C=O)C>[CH:11]([N:7]1[C:8]2[C:4](=[CH:3][CH:2]=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)c1ccc(CCCc2c(CCNS(=O)(=O)Cc3c(Br)cccc3Br)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: BrC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(C(c2ccccc2)n2ccc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.7 %

Procedure:
To a solution of the product from step 2 (1.66 g, 4.86 mmol) in DMF (20 mL) was added NaH (60% in mineral oil, 0.24 g, 5.83 mmol) under N2 atmosphere. The mixture was stirred for 1 h at room temperature, followed by the dropwise addition of benzhydryl bromide (1.8 g, 7.29 mmol) in DMF (5 mL). This reaction mixture was stirred overnight at room temperature. Water (500 mL) was added, and the mixture was extracted with EtOAc, washed with brine, dried (Na2SO4), and concentrated under reduced pressure to a brown syrup, which was purified by silica-gel chromatography using 10% EtOAc/hexanes as eluent to isolate the N-benzhydrylindole as a white solid (1.47 g) in 59% yield.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[C:20]([CH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][NH2:29])[CH2:24][CH2:23]1)#[N:21]>>[C:20]([CH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][NH:29][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])[CH2:24][CH2:23]1)#[N:21]
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: N#CC1CCC(CN)CC1
Product: CCc1cc(-c2cncc(C(=O)NCC3CCC(C#N)CC3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and (4-cyano-cyclohexylmethyl)-amine to afford the title compound. MS: m/e=379 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:20][N:21]([CH2:34][CH3:35])S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C1(S)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:20][NH:21][CH2:34][CH3:35])[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CCN(C[C@H](CC(=O)OC(C)(C)C)Nc1ccc(C#N)c(Cl)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC[C@H](CC(=O)OC(C)(C)C)Nc1ccc(C#N)c(Cl)c1

Procedure:
The crude 1,1-dimethylethyl (3S)-3-[(3-chloro-4-cyanophenyl)amino]-4-{ethyl[(2-nitrophenyl)sulfonyl]amino}butanoate from the previous step (16.2 mmol), phenyl hydrosulfide (1.0 equiv., 1.78 g, 16.2 mmol), and K2CO3 (325 mesh, 3 equiv., 6.71 g, 48.6 mmol) in DMF (60 mL) were stirred at room temperature for 90 min. The reaction mixture was diluted with H2O (200 mL) and extracted with Et2O (3×). The organic extracts were washed with H2O, and 10% aq. Na2CO3, dried, and concentrated to give the titled product which was contaminated with the 2-nitrophenyl phenyl sulfide by-product. This contaminated product was used directly in the next step.
Reaction SMILES: [Br-].CS([NH:6][C:7]([CH2:9][CH2:10][CH2:11][CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:8])(=O)=O.[Na].[C:33](OCC)(=O)[CH3:34].Cl>CS(C)=O>[C:7]([NH2:6])(=[O:8])[CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:33]\[CH3:34]
Reactant: CS(=O)(=O)NC(=O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Br-]
Agent: [Na]
Solvent: CS(C)=O
Product: C/C=C\CCCC(N)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 27.0 g. (52.0 mmoles) of (4-methanesulfonylaminocarbonyl-n-butyl)triphenylphosphonium bromide in 46 ml. of dimethyl sulfoxide is added dropwise 49.3 ml. (98.6 mmoles) of a 2.0M solution of sodium methylsulfonylmethide in dimethyl sulfoxide. To the resultant red solution is added over the course of 15 minutes a solution of 6.6 g. (20.8 mmoles) of the hemiacetal prepared in Example IV in 63 ml. of dimethyl sulfoxide. After being stirred for an additional 2.0 hours, the reaction is poured onto 600 ml. of ice-water. The cold aqueous layer is covered with ethyl acetate and acidified to pH~3 with 10% hydrochloric acid. The acidified aqueous layer is further extracted with ethyl acetate (2 × 200 ml.) and the combined organic extracts are washed with water followed by brine. Drying the organic layer over anhydrous sodium sulfate and concentration affords the crude product which is triturated with ether. Concentration of the ether provides N-methanesulfonyl 7-[2β-(1,3-oxathialan-2-yl)-3α -(tetrahydropyran-2-yloxy)-5α-hydroxycyclopent-1α-yl)]-cis-5-heptenamide (VI).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[C:17]([OH:25])(=[O:24])[C:18]([CH2:20][C:21](O)=[O:22])=[CH2:19]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:21](=[O:22])[CH2:20][CH:18]([C:17]([OH:25])=[O:24])[CH2:19]3)=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(CCc2cccc(F)c2)cc1
Reactant: C=C(CC(=O)O)C(=O)O
Product: O=C(O)C1CC(=O)N(c2ccc(CCc3cccc(F)c3)cc2)C1

Procedure:
In an analogous manner to that described in Example 36 c), the reaction of 4-[2-(3-fluoro-phenyl)-ethyl]-phenylamine with itaconic acid yields the (RS)-1-{4-[2-(3-fluoro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid as a light brown solid; MS: m/e=326 (M−H)+.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:26]2[O:27][C:28]([CH3:31])=[CH:29][N:30]=2)[CH:13]=[C:14]([O:17]COCC[Si](C)(C)C)[C:15]=1[Br:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1COCC1.O>[CH2:2]([O:9][C:10]1[C:15]([Br:16])=[C:14]([OH:17])[CH:13]=[C:12]([C:26]2[O:27][C:28]([CH3:31])=[CH:29][N:30]=2)[CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cnc(-c2cc(OCOCC[Si](C)(C)C)c(Br)c(OCc3ccccc3)c2)o1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(-c2cc(O)c(Br)c(OCc3ccccc3)c2)o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Concentrated hydrochloric acid (3 mL) was added to a solution of 2-(3-(benzyloxy)-4-bromo-5-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-5-methyloxazole (0.60 g, 1.22 mmol) in THF (8 mL) and stirred at room temperature for three hours. The solution was diluted with water and extracted with 1:1 ethyl acetate/diethyl ether (4×). The extracts were washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated to a solid. The solid was triturated with heptane (2×) and dried under vacuum to provide 3-(benzyloxy)-2-bromo-5-(5-methyloxazol-2-yl)phenol as an off white solid (412 mg). MS (M+1)=360.2. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.52 (d, J=7.07 Hz, 2H), 7.36-7.43 (m, 2H), 7.28-7.35 (m, 2H), 7.23 (d, J=1.52 Hz, 1H), 6.86 (d, J=1.52 Hz, 1H), 5.24 (s, 2H), 4.21 (q, J=6.74 Hz, 2H), 2.41 (d, J=1.01 Hz, 3H), 1.50 (t, J=6.82 Hz, 3H).
Reaction SMILES: [CH2:1]([Zn]CC)C.FC(F)(F)C(O)=O.[CH:13]1([C:19]([O:21][CH3:22])=[O:20])[CH2:18][CH2:17][CH:16]=[CH:15][CH2:14]1>ClCCl>[CH:15]12[CH2:1][CH:16]1[CH2:17][CH2:18][CH:13]([C:19]([O:21][CH3:22])=[O:20])[CH2:14]2
Reactant: CC[Zn]CC
Reactant: COC(=O)C1CC=CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1CCC2CC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a solution of diethyl zinc (1.0 M in hexanes, 35 mL, 35.00 mmol) in anhydrous dichloromethane (34 mL) was added trifluoroacetic acid (3.99 g, 35.0 mmol) in 17.2 mL anhydrous dichloromethane at 0° C. The reaction mixture was stirred at the same temperature for 1 hour, and then added a solution of diidomethane (9.37 g, 35.00 mmol) in anhydrous dichloromethane (17 mL) at 0° C. The reaction mixture was further stirred at the same temperature for another 1 hour. To this mixture was added a solution of methyl cyclohex-3-enecarboxylate (2.45 g, 17.50 mmol) in anhydrous dichloromethane 17 mL) at 0° C. The resulting mixture was warmed to ambient temperature and further stirred for 4 hours. The mixture was quenched with a saturated solution of ammonium chloride (50 mL) and separated the organic layer. The aqueous layer was extracted with dichloromethane (15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography with ethyl acetate in hexanes (30%) to afford the title compound as yellow oil (2.56 g, 95%): 1H NMR (300 MHz, CDCl3) δ 3.64 (s, 3H), 2.31-1.92 (m, 3H), 1.84-1.65 (m, 2H), 1.54 (t, J=12.9 Hz, 1H), 1.19-1.04 (m, 1H), 0.93-0.86 (m, 2H), 0.63-0.55 (m, 1H), 0.05-0.00 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH2:11][CH2:12][O:13][CH2:14][O:15][CH3:16])[C:8]([O:17][CH3:18])=[CH:7][C:4]=1[CH:5]=O.C([O-])(=O)C.[NH4+].[N+:24]([CH2:27][CH3:28])([O-:26])=[O:25]>>[CH3:18][O:17][C:8]1[CH:7]=[C:4]([CH:5]=[C:27]([N+:24]([O-:26])=[O:25])[CH3:28])[C:3]([O:2][CH3:1])=[CH:10][C:9]=1[CH2:11][CH2:12][O:13][CH2:14][O:15][CH3:16]
Reactant: CC[N+](=O)[O-]
Reactant: COCOCCc1cc(OC)c(C=O)cc1OC
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COCOCCc1cc(OC)c(C=C(C)[N+](=O)[O-])cc1OC
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 2,5-dimethoxy-4-(2-methoxymethoxy-ethyl)-benzaldehyde (3.00 g, 11.80 mmol) and ammonium acetate (0.91 g 11.80 mmol) in nitroethane (10 mL) was stirred at 70° C. for 2 h. After allowing the reaction mixture to cool down to room temperature, the solvent was removed under vacuum. The oily residue was purified by flash chromatography using a hexane and ethyl acetate gradient to give 0.9 g of yellow oil. MS (m/z) 211. 1HNMR(CDCl3): δ ppm 2.40 (s, 3H), 2.95 (m, 2H), 3.31 (s, 3H), 3.75 (m, 2H), 3.78 (s, 3H), 3.83 (s, 3H), 4.63 (s, 2H), 6.77 (s, 1H), 6.83 (s, 1H), 8.25 (s, 1H).