Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:14]([O:16][CH3:17])=[O:15])[NH:9]2.[CH3:18]I>CCCCCC.CN(C=O)C>[CH3:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:14]([O:16][CH3:17])=[O:15])[N:9]2[CH3:18]
Reactant: CI
Reactant: COC(=O)c1cc2c(OC)cccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COC(=O)c1cc2c(OC)cccc2n1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
NaH (60% dispersion in mineral oil, 0.3 g, 7.3 mmole) was washed with hexane then suspended in anhydrous DMF (16 mL). The mixture was cooled to 0° C. and methyl 4-methoxy-1H-indol-2-carboxylate (1.0 g, 4.87 mmole) was added. The mixture was stirred under argon for 10 min, then MeI (1.3 mL, 20 mmole) was added, and the thick slurry was stirred at RT for 2.5 hr. The reaction was quenched with 10% NH4Cl (2 mL) and concentrated. The residue was partitioned between H2O and Et2O, and the organic layer was dried over MgSO4 and concentrated to yield the title compound (1.03 g, 96%) as a white solid: MS (ES) m/e 220.2 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([C:8]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([S:23][CH3:24])[CH:19]=3)[N:14]=2)([OH:12])[CH:9]([CH3:11])[CH3:10])=[N:4][CH:5]=[N:6][CH:7]=1>CCO.[Pd]>[CH3:10][CH:9]([CH3:11])[C:8]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([S:23][CH3:24])[CH:19]=2)[N:14]=1)([C:3]1[CH:2]=[CH:7][N:6]=[CH:5][N:4]=1)[OH:12]
Reactant: CSc1ccc2nc(C(O)(c3ncncc3Br)C(C)C)ccc2c1
Agent: [Pd]
Solvent: CCO
Product: CSc1ccc2nc(C(O)(c3ccncn3)C(C)C)ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.4 %

Procedure:
To a stirred solution of 1-(5-bromopyrimidin-4-yl)-2-methyl-1-(6-(methylthio)quinolin-2-yl)propan-1-ol (H) (90 mg, 0.22 mmol) in EtOH (5 mL) was added 10% Pd/C (40 mg) under inert atmosphere and stirred at RT for 16 h under H2 atmosphere (balloon pressure). After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 10% EtOAc/hexane to afford 2 (12 mg, 0.036 mmol, 16.6%) as an off-white solid. 1H NMR (500 MHz, CDCl3): δ 9.18 (s, 1H), 8.64 (d, J=5.0 Hz, 1H), 8.10 (d, J=9.0 Hz, 1H), 8.04 (d, J=8.5 Hz, 1H), 7.96-7.94 (m, 2H), 7.59 (dd, J=2.0, 9.0 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 6.60 (s, 1H), 3.19-3.16 (m, 1H), 2.58 (s, 3H), 0.84 (d, J=7.0 Hz, 3H), 0.67 (d, J=7.0 Hz, 3H). HPLC: 91.02%. MS (ESI): m/z 326 [M++1].
Reaction SMILES: CO.[NH3:3].Cl[C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[Cl:18])[NH:10][C:9]=2[N:8]=[C:7]([NH:19][C:20](=[O:25])[C:21](C)(C)[CH3:22])[N:6]=1.C(Cl)(Cl)Cl.CO>C(=O)=O.CC(C)=O>[C:20]([NH2:19])(=[O:25])[CH2:21][CH3:22].[Cl:18][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[C:17]1[C:5]([NH2:3])=[N:6][C:7]([NH2:19])=[N:8][C:9]=1[NH:10]2
Reactant: N
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)c2c(n1)[nH]c1cccc(Cl)c12
Agent: O=C=O
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CCC(N)=O
Product: Nc1nc(N)c2c(n1)[nH]c1cccc(Cl)c12
Temperature: 130 °C
Reaction time: 48 h
Yield: 39 %

Procedure:
5 mL methanol was saturated with ammonia in the plastic container (of the sealed tube reaction apparatus), which was cooled in dry ice and acetone. 10 (200 mg, 0.6 mmol) was added to this methanol saturated with ammonia. The solution was stirred at 130° C. for 2 days. Silica gel was added to the reaction mixture and methanol was removed under reduced pressure to make a plug. The plug was transferred on top of a column packed with silica gel, ten times the weight of plug, eluted with chloroform and 1% methanol in chloroform. Fractions containing the product 10 (TLC) were pooled and evaporated to give a solid. The overall yield was 39%. TLC Rf 0.43 (chloroform-methanol 5:1), m.p. 245.2-246.3° C., 1H NMR: δ 6.15 (bs, 2H, 4-NH2, exch); 6.85 (bs, 2H, 2-NH2, exch), 7.03-7.24 (m, 3H, phenyl); 11.54 (bs, 1H, 9-NH, exch). Anal. Calculated (C10H8ClN5): C, 51.40; H, 3.38; N, 29.97; Cl, 15.17. Found: C, 51.58; H, 3.46; N, 29.86; Cl, 15.05.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N:10]1C=CC=CC=1.[NH2:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O.N1CCCC1>CCO>[NH2:10][C:2]1[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N:16][C:17]2[C:18]([CH:19]=1)=[CH:21][CH:22]=[CH:23][CH:24]=2
Reactant: c1ccncc1
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1ccccc1C=O
Solvent: C1CCNC1
Solvent: CCO
Product: CCOC(=O)c1nc2ccccc2cc1N
Temperature: 65 °C

Procedure:
A solution of ethyl bromopyruvate (1.69 g, 1.09 mL, 8.68 mmol) in dry EtOH (16 mL) was added dropwise over 20 min to a stirred solution of pyridine (684 mg, 699 μL, 8.68 mmol) in dry EtOH (24 mL). The resulting solution was heated at 60-70° C. for 1 h and cooled to room temperature. 2-Aminobenzaldehyde (1.00 g, 8.26 mmol) and pyridine (1.6 mL) were added and the resulting yellow solution was heated at reflux for 4½ h. Pyrrolidine (1.40 g, 1.64 mL, 19.7 mmol) was added and the resulting mixture was heated at reflux for 3 h and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 65×160 mm, 0-40% EtOAc in hexanes gradient) to afford ethyl 3-aminoquinoline-2-carboxylate, as a yellow solid. Rf=0.31 (20% EtOAc/hexanes). LCMS calc.=217.1; found=217.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.04-8.02 (m, 1H); 7.53-7.51 (m, 1H); 7.44-7.38 (m, 2H); 7.32 (s, 1H); 4.53 (q, J=7.1 Hz, 2H); 1.48 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21](C1C=CC(B(O)O)=CC=1)=[O:22]>>[CH:21]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)=[CH:6][CH:5]=1)=[O:22]
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: O=Cc1ccc(B(O)O)cc1
Product: O=Cc1ccc(-c2[nH]c3cccc4c3c2CCNC4=O)cc1

Procedure:
In a manner similar to that described above for Compound 12, the tricyclic bromide (168 mg, 0.63 mmol) and 4-formylbenzeneboronic acid (142 mg, 0.95 mmol) were coupled to yield 2-(4-formylphenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one, 141 mg (77%), as a yellow solid. mp 238-240° C. (dec.); 1H NMR (300 MHz, d6-DMSO) δ3.12 (m, 2H), 3.42 (m, 2H), 7.28 (t, 1H, J=7.6 Hz), 7.59 (d, 1H, J=7.6 Hz), 7.62 (d, 1H, J=7.6 Hz), 7.88 (d of ABq, 2H, J=7.7 Hz), 8.05 (d of ABq, 2H, J=7.7 Hz), 8.11 (br t, 1H), 10.07 (s, 1H), 11.75 (br s, 1H); HRMS (FAB, MH+) Calcd for C18H15N2O2: 291.1134, Found: 291.1132.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH:10]([CH3:23])[N:9]=1.[CH2:24]([N:27]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]1=2)[C:25]#[CH:26].C(O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:26]#[C:25][CH2:24][N:27]3[C:40](=[O:41])[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:33]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]3=4)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH:10]([CH3:23])[N:9]=1
Reactant: C#CCn1c(=O)c2ccccc2c2ccccc21
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2C
Solvent: CCO
Solvent: ClCCl
Product: Cc1nnc2n1-c1sc(C#CCn3c(=O)c4ccccc4c4ccccc43)cc1C(c1ccccc1Cl)=NC2C

Procedure:
This compound was prepared by reacting rac-4-(2-chloro-phenyl)-2-iodo-6,9-dimethyl-6H-thieno-[3,2-f][1,2,4]triazolo[4,3a][4,1]diazepine (from example 108) with 5-(2-propynyl)-6(5H) phenanthridinone under the conditions described in example 37. The product was isolated by chromatography over the 50 -fold amount of silica gel using 5% (v/v) of ethanol in methylene chloride. The product was crystallized from ethanol to give yellowish crystals of the title compound with mp, 182°-186° with foaming. These crystals contained according to analytical data molar amounts of water.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:21]=[N:22][C:23]([O:26]C)=[CH:24][CH:25]=1)[CH2:9][C:10]([C:12]1[CH:13]=[N:14][C:15]([O:18]C)=[CH:16][CH:17]=1)=[O:11].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:25]=[CH:24][C:23](=[O:26])[NH:22][CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[NH:14][CH:13]=1)=[O:11]
Reactant: COc1ccc(C(=O)CC(c2ccc(OC)nc2)c2ccccc2Cl)cn1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CC(c1ccc(=O)[nH]c1)c1ccccc1Cl)c1ccc(=O)[nH]c1

Procedure:
In analogy to example 162, step 2, 3-(2-chloro-phenyl)-1,3-bis-(6-methoxy-pyridin-3-yl)-propan-1-one was reacted with concentrated aqueous HCl in 1,4-dioxane to give the title compound as an off-white solid, MS (ESI+): m/z=355.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[C:9]([N+:18]([O-:20])=[O:19])[CH:10]=[C:11]4[C:17]=3[C@H:14]([CH2:15]2)[CH2:13][NH:12]4)[CH2:5][C@H:4]([NH:21][C:22](=[O:28])[N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH2:3]1.ClOC(C)(C)C.N>O1CCCC1.C(N(CC)CC)C>[CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[C:9]([N+:18]([O-:20])=[O:19])[CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@H:4]([NH:21][C:22](=[O:28])[N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH2:3]1
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc([N+](=O)[O-])cc4c3[C@@H](CN4)C[C@H]2N(C)C1
Agent: CC(C)(C)OCl
Agent: N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc([N+](=O)[O-])cc4[nH]cc(c34)C[C@H]2N(C)C1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
Under argon, 382 mg (1 mmol) of 3-(2,3β-dihydro-6-methyl-13-nitro-8α-ergolinyl)-1,1-diethylurea is dissolved in 30 ml of absolute, freshly distilled tetrahydrofuran in the presence of 0.5 ml of triethylamine and cooled to -40° C. At this temperature, 0.16 ml (1.34 mmol) of tert-butyl hypochlorite, dissolved in 10 ml of absolute, freshly distilled tetrahydrofuran, is added dropwise thereto. After 30 minutes of agitation at -40° C., the batch is stirred into 50 ml of ice and adjusted to be alkaline with 25% strength ammonia solution. Extraction is performed with methylene chloride. The combined organic phases are dried over magnesium sulfate and concentrated. The crude product is chromatographed under pressure on silica gel, with methylene chloride/methanol/diisopropyl ether in a ratio of 80:5:15 (yield 351 mg) and subsequently crystallized from ethyl acetate/diisopropyl ether, thus obtaining 272 mg of 3-(6-methyl-13-nitro-8α-ergolinyl)-1,1-diethylurea (71.7% yield).
Reaction SMILES: Br.Br[CH2:3][C:4]1[N:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]2[NH2:15].[CH3:16][NH:17][C:18]1[CH:39]=[CH:38][C:21]([C:22]([NH:24][C@H:25]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:23])=[CH:20][CH:19]=1>>[CH3:32][CH2:31][O:30][C:28]([CH2:27][CH2:26][C@H:25]([NH:24][C:22]([C:21]1[CH:38]=[CH:39][C:18]([N:17]([CH2:3][C:4]2[N:5]=[C:6]3[C:7]([NH2:15])=[N:8][C:9]([NH2:14])=[N:10][C:11]3=[N:12][CH:13]=2)[CH3:16])=[CH:19][CH:20]=1)=[O:23])[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29]
Reactant: Nc1nc(N)c2nc(CBr)cnc2n1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(NC)cc1)C(=O)OCC
Agent: Br
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(N(C)Cc2cnc3nc(N)nc(N)c3n2)cc1)C(=O)OCC

Procedure:
reacting this 6-bromomethyl-2,4-diaminopteridine hydrobromide with diethyl N-[4-(N-methylamino)-benzoyl]glutamate to give diethyl methotrexate, and
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].C(N(CC)CC)C.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CC(O)C.O>[CH2:25]([NH:1][CH2:2][C:3]([OH:5])=[O:4])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: CCCCCCCCCCCCBr
Reactant: NCC(=O)O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCCNCC(=O)O
Yield: 26.3 %

Procedure:
Glycine was dissolved in a 2:1 mixture by volume of IPA and water. Triethylamine and 1-bromododecane were added to the solution successively and the mixture was kept stirring for more than 7 days. After the solvent was removed, THF was added to the remaining material. Triethylamine hydrobromide was removed by filtration and the filtrate was concentrated. N-n-dodecylglycine was obtained from the concentrated solution by separation and purification by column chromatography with the yield of 26.3%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]2[C:11](=[CH:12][C:13]([C:27]#[N:28])=[CH:14][CH:15]=2)[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].OS(O)(=O)=O.C1C(=O)N([Br:41])C(=O)C1.CCOCC>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:16]2[C:11](=[CH:12][C:13]([C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]=1[Br:41])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCc2ccccc2)c2ccc(C#N)cc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1cc(OCc2ccccc2)c2ccc(C#N)cc2c1Br
Temperature: -60 °C
Reaction time: 4 h
Yield: 87.4 %

Procedure:
A solution of 15 (137 mg, 0.366 mmol) in freshly distilled THF (7.3 mL) and cooled to -78° C. under Ar was treated with 10 μL of a 1 μL/mL solution of H2SO4 in THF and the solution was stirred for 20 min before the addition of NBS (78 mg, 439 mmol, 1.2 equiv). The reaction mixture was allowed to warm to -60° C. and was stirred for 4 h at which time the reaction was complete by TLC. Et2O (7.3 mL) was added and the resulting organic phase was washed with 5% aqueous NaHCO3 (1×10 mL), saturated aqueous NaCl (1×10 mL), dried (MgSO4), and concentrated in vacuo. Chromatography (SiO2, 2×20 cm, 10% EtOAc-hexane) afforded 16 (145 mg, 166 mg theoretical, 87%) as a white crystalline solid: mp 179° C. dec (white needles, 10% EtOAc-hexane); 1H NMR (CDCl3, 250 MHz) δ8.40 (s, 1H, C8-H), 8.26 (d, 1H, J=8.5 Hz), 8.23 (s 1H, C3-H), 7.5-7.3 (m, 6H), 5.23 (s, 2H), 1.58 (s, 9H); 13C NMR (CDCl3, 75 MHz) δ154.4, 152.4, 137.0, 136.0, 132.2, 132.0, 128.7, 128.6, 128.4, 128.0, 124.9, 124.8, 124.2, 119.1, 111.9, 102.0, 81.9, 70.8, 28.3; IR (KBr) vmax 3416, 2978, 2230, 1738, 1623, 1603, 1570, 1498, 1405, 1364, 1335, 1229, 1158, 990, 970, 878, 850, 823, 758, 696 cm-1 ; FABHRMS (NBA-CsI) m/z 584.9793 (M+ +Cs, C23H21BrN2O3 requires 584.9790).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][C:3]=1[F:14].S(Cl)(Cl)=O.[C:19]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].[Mg+2].[Cl-].[Cl-]>C(#N)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19]([O:27][CH2:28][CH3:29])=[O:26])=[O:11])=[CH:4][C:3]=1[F:14]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C(=O)O)c1ccc(Cl)c(F)c1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
A solution of 2-(4-chloro-3-fluorophenyl)-2-methylpropanoic acid (2.05 g, 9.46 mmol) in thionyl chloride (40.0 mL, 548 mmol) in a 500 mL round bottom flask was stirred at 95° C. for 2 hours. The reaction was concentrated in vacuo and azeotroped in toluene (50 mL) to give the crude acid chloride. A solution of diethyl malonate (1.43 mL, 9.46 mmol) in ACN (20 mL) was cooled to 0° C. MgCl2 (0.901 g, 9.46 mmol) and then TEA (2.76 mL, 19.9 mmol) were added, and the mixture was stirred at 25° C. for 2 hours. A solution of the acid chloride in ACN (30 mL) was added, and the mixture was stirred at 50° C. for 16 hours. The reaction was cooled, diluted with water (75 mL), and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (75 mL) and brine (75 mL). The organic layer was dried over MgSO4, concentrated, and dried in vacuo to give diethyl 2-(2-(4-chloro-3-fluorophenyl)-2-methylpropanoyl)malonate (2.95 g). MS m/e=359.4 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][C:9]=1[NH:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[NH:16][S:17]([C:20]([F:23])([F:21])[F:22])(=[O:19])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Oc2ccccc2)c(NS(=O)(=O)C(F)(F)F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: O=S(=O)(Nc1cc(O)ccc1Oc1ccccc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
34.7 g of 4-phenoxy-3-trifluoromethylsulfonylaminoanisole and 31 g of ethanethiol were dissolved in 350 ml of methylene chloride. The resulting solution was then ice-cooled. Thereto was added 27 g of aluminum chloride at the same temperature in 30 minutes. Stirring was conducted for 30 minutes at 5°-10° C. The reaction mixture was poured into 300 ml of ice water and the resulting organic layer was separated. The organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, dried with anhydrous magnesium sulfate, and subjected to distillation under reduced pressure to remove the solvent. The resulting crystal was recrystallized from toluene to obtain 28.5 g (yield: 85.6%) of 4-phenoxy-3-trifluoromethylsulfonylaminophenol having a melting point of 97°-99° C.
Reaction SMILES: [Li+].[BH4-].C[Si](Cl)(C)C.[C:8]([O:12][C:13]([N:15]1[CH2:19][C@H:18]([OH:20])[CH2:17][C@H:16]1[C:21](O)=[O:22])=[O:14])([CH3:11])([CH3:10])[CH3:9]>C1COCC1>[OH:20][C@H:18]1[CH2:19][N:15]([C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:14])[C@H:16]([CH2:21][OH:22])[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a 0° C. suspension of LiBH4 (2.0 equiv) in THF (0.67 M) was slowly added TMSCl (4.0 equiv) by syringe. After stirring at room temperature for 30 minutes, (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (1.0 equiv) was then added, and the resulting mixture was stirred at room temperature overnight. The reaction was quenched by the careful addition of sat'd. aq. NaHCO3, and the mixture was diluted with EtOAc, and the organice layer was washed twice with sat'd. aq. NaHCO3, once with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The title compound was isolated in 65% yield and used without further purification.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41](O)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[CH3:48][N:49]1[C:53]([CH3:54])=[CH:52][CH:51]=[C:50]1[CH2:55][NH2:56]>>[CH3:48][N:49]1[C:53]([CH3:54])=[CH:52][CH:51]=[C:50]1[CH2:55][NH:56][C:41]([C:39]1[S:40][C:36]([N:33]2[CH2:34][CH2:35][N:31]([CH2:30][C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:47][CH:46]=3)[C:32]2=[O:45])=[CH:37][C:38]=1[CH3:44])=[O:42]
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: Cc1ccc(CN)n1C
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccc(C)n1C
Yield: 57 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (1,5-dimethyl-1H-pyrrol-2-yl)methanamine, the title compound was obtained as a beige solid in 57% yield: 1H NMR (300 MHz, CDCl3) δ 7.30-7.23 (m, 2H), 7.07-6.98 (m, 2H), 6.08 (s, 1H), 6.00 (d, J=3.2 Hz, 1H), 5.81 (d, J=3.2 Hz, 1H), 5.67 (t, J=4.4 Hz, 1H), 4.53 (d, J=4.4 Hz, 2H), 4.42 (s, 2H), 3.83-3.74 (m, 2H), 3.49-3.39 (m, 5H), 2.48 (s, 3H), 2.21 (s, 3H); MS (ES+) m/z 463.1 (M+23).
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH2:10][C:11](=[O:24])[CH:12]([C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C(=O)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].O.OS(O)(=O)=O>C(OCC)C>[CH2:1]([S:8][CH2:9][CH2:10][C:11](=[O:24])[CH2:12][C:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C(C(=O)CCSCc1ccccc1)C(=O)c1ccccc1
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=C(CCSCc1ccccc1)CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
34.0 g (0.1 mol) of 1-benzylthio-4-benzoyl-3,5-hexanedione (see Example 17) are initially placed in a 100 ml flask equipped with a thermometer, a stirrer, a dropping funnel and a reflux condenser. 19.8 g (0.11 mol) of sodium methylate solution (30% in methanol) are added dropwise, with stirring, in the course of 40 minutes. In the course of this the reaction temperature rises from room temperature to approx. 32° C. The mixture is stirred for a further hour at room temperature and for a further 3 hours at approx. 45° C. and is then cooled to room temperature and stirred into 200 ml of water and 12 g of concentrated H2SO4. 180 ml of diethyl ether are added and the organic phase is separated off. The aqueous phase is washed with a further 50 ml of diethyl ether. The combined organic phases are washed with water, sodium bicarbonate and water again and are then dried, concentrated and fractionated. The resulting product, which has a boiling point of 180°-183° C. at 0.001 bar, is recrystallized from 20 ml of isopropanol.
Reaction SMILES: [F:1][C:2]1[C:9]([I:10])=[C:8]([CH3:11])[CH:7]=[CH:6][C:3]=1C#N.S(=O)(=O)(O)[OH:13].[CH3:17][OH:18]>>[F:1][C:2]1[C:9]([I:10])=[C:8]([CH3:11])[CH:7]=[CH:6][C:3]=1[C:17]([OH:13])=[O:18]
Reactant: Cc1ccc(C#N)c(F)c1I
Reactant: CO
Reactant: O=S(=O)(O)O
Product: Cc1ccc(C(=O)O)c(F)c1I
Temperature: 115 °C
Reaction time: 8 h

Procedure:
To a 500 ml round bottom, three neck flask equipped with a condenser and magnetic stirrer, was added 2-fluoro-3-iodo-4-methyl-benzonitrile (33 g, 126.4 mmol), 70 ml of methanol, and 70 ml of 60% aqueous sulfuric acid. The flask was sealed and temperature was raised to 115° C. The reaction mixture was stirred at this temperature overnight. The precipitate that formed was filtered onto fritted filter, washed with 1 L of water, and dried under vacuum for 2 h and then in vacuum oven at 60° C. for 3 h to give 31.5 g of IXS-4-95-1. 1H NMR (DMSO-d6, 400 MHz) δ 13.2 (broad s, 1H), 7.74 (t, 1H), 7.26 (d, 1H), 2.47 (s, 3H), and MS [MH+]=280).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[Br:30][C:31]1[CH:32]=[C:33]([OH:43])[CH:34]=[C:35]([S:37]([CH2:40][CH2:41][CH3:42])(=[O:39])=[O:38])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:43][C:33]2[CH:34]=[C:35]([S:37]([CH2:40][CH2:41][CH3:42])(=[O:39])=[O:38])[CH:36]=[C:31]([Br:30])[CH:32]=2)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Reactant: CCCS(=O)(=O)c1cc(O)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCS(=O)(=O)c1cc(Br)cc(OCCCCCCc2cccc(OCCCC(=O)OCC)c2CCC(=O)OCC)c1
Yield: 96.8 %

Procedure:
A similar procedure as described in Example 40, step 6 was used, starting from 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (2.14 g, 4.53 mmol), 3-bromo-5-(propane-1-sulfonyl)-phenol (1.15 g, 4.12 mmol), and potassium carbonate (1.14 g, 8.24 mmol) to afford 4-[3-{6-[3-bromo-5-(propane-1-sulfonyl)-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (2.67 g, 97%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C32H45BrO8S (M+Na)+ 691.1911, found 691.1905.