Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([N:20]3[CH2:24][CH2:23][C@@H:22]([OH:25])[CH2:21]3)=[CH:14][C:15]([CH3:19])=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26]C(C)([O-])C.[K+].CI>C1COCC1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([N:20]3[CH2:24][CH2:23][C@@H:22]([O:25][CH3:26])[CH2:21]3)=[CH:14][C:15]([CH3:19])=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[O-]
Reactant: Cc1cc(N2CC[C@@H](O)C2)c2ccc(OCc3ccccc3)cc2n1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CO[C@@H]1CCN(c2cc(C)nc3cc(OCc4ccccc4)ccc23)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100.6 %

Procedure:
A suspension of 3.2 g (9.5 mmol) of (R)-1-(7-benzyloxy-2-methyl-quinolin-4-yl)-pyrrolidin-3-ol, product of example 86, in THF (275 ml) was treated at RT under nitrogen with 1.42 g (12.4 mmol) of potassium tert-butoxide. The suspension was stirred for 20 minutes at RT then 0.72 ml (11.4 mmol) of methyl iodide were added. After 25 minutes of stirring further 0.284 g (2.48 mmol) of potassium tert-butoxide were added followed by 0.144 ml (2.28 mol) of methyl iodide (10 minutes later) for completion of the reaction. Stirring was continued for 20 minutes, the reaction mixture was then concentrated in vacuo and the residue partitioned between water and AcOEt. The layers were separated the aqueous layer once extracted with AcOEt, the combined organic layers washed with brine, dried over magnesium sulphate and concentrated in vacuo to give 3.33 g (94.5%) (R)-7-benzyloxy-4-(3-methoxy-pyrrolidin-1-yl)-2-methyl-quinoline as an orange viscous oil. ISP mass spectrum, m/e: 349.5 (M+1 calculated for C22H24FN2O2: 349).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:12][C:11](=O)[CH2:10][O:9][C:8]=2[CH:14]=1)([O-:3])=[O:2].B.C1COCC1.CO>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:12][CH2:11][CH2:10][O:9][C:8]=2[CH:14]=1)([O-:3])=[O:2]
Reactant: O=C1COc2cc([N+](=O)[O-])ccc2N1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)OCCN2

Procedure:
A suspension of 7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (300 mg, 1.545 mmol) in THF (3 mL) was treated with BH3-THF complex (15.45 mL, 15.45 mmol, 1.0 M in THF), and the resulting orange solution was refluxed overnight. The reaction was cooled in an ice-bath. MeOH (15 mL) was added, and the reaction was then concentrated. A second portion of MeOH (20 mL) was added, and the solution was refluxed for 2 hours. At this time, the reaction was concentrated, and the residue was subjected to flash chromatography on silica gel (10% EtOAc:90% hexane followed by 30% EtOAc:70% hexane). An orange solid was obtained after drying under reduced pressure. (240 mg, 86%). 1H-NMR (DMSO-d6) δ 7.68 (dd, J=2.4, 8.9 Hz, 1H), 7.54 (s, 1H), 7.47 (d, J=2.4 Hz, 1H), 6.63 (d, J=9.0 Hz, 1H), 4.15 (t, J=4.2 Hz, 2H), 3.45-3.40 (m, 2H).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][O:24][CH2:25][CH2:26][N:27]1[C:31]([CH2:32][OH:33])=[N:30][C:29]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:28]1>C(Cl)Cl>[CH3:23][O:24][CH2:25][CH2:26][N:27]1[C:31]([CH:32]=[O:33])=[N:30][C:29]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:28]1
Reactant: COCCn1nc(-c2ccccc2)nc1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COCCn1nc(-c2ccccc2)nc1C=O

Procedure:
Dess-Martin periodinane (1530 mg, 3.60 mmol) was added to a stirred suspension of [2-(2-Methoxy-ethyl)-5-phenyl-2H-1,2,4-triazol-3-yl]-methanol (840 mg, 3.6 mmol) dissolved in Methylene chloride (36.0 mL) at rt under Ar. The solution was stirred ON. Some solid was filtered off and discarded. Sat NaHCO3 (35 ml) and more DCM (35 ml) were added to the DCM solution. The solvent was evaporated off and the crude product was purified by silica gel chromatography (Eluent: 50% EtOAc in heptane). Yield: 0.76 g of the title compound as an oil. H-NMR: (CDCl3) δ10.04 (s, 1H), 8.13 (m, 2H), 7.45 (m, 3H), 4.82 (t, 2H), 3.83 (t, 2H), 3.32 (s, 3H).
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].CN(C)CCN(C)C.[Li]CCCC.[I:27]I>C1COCC1>[CH3:3][C:2]([CH3:5])([CH3:4])[C:1]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[I:27])=[O:6]
Reactant: II
Reactant: CC(C)(C)C(=O)Nc1cccnc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1cnccc1I
Temperature: -78 °C
Reaction time: 2 h
Yield: 20.9 %

Procedure:
The 3-(Pivaloylamino)pyridine 15 (1.9 g, 11 mmol) and tetramethylethylene-diamine (4.0 mL, 26 mmol) were dissolved in dry THF (60 mL) and cooled to −78° C. While maintaining the temperature between −78° C. and −65° C., nBuLi (2.5 M solution in hexanes, 10.6 mL, 26.5 mmol) was added dropwise. The reaction was allowed to warm to −10° C. for 2 h, and then cooled back down to −78° C. Iodine (6.73 g, 26.5 mmol) dissolved in dry THF (20 mL) was added slowly. After stirring for 2 h at −78° C., the reaction was quenched with ice. Excess iodine was destroyed with addition of saturated potassium thiosulfate solution. The product was extracted with CH2Cl2, and the organic layers were washed with brine. The mixture was concentrated in vacuo to a black oil which was chromatographed (1:1 EtOAc/Hexanes; 2:1 EtOAc/Hexanes) to give 700 mg (23%) of 2,2-dimethyl-N-(4-iodo-3-pyridinyl)propanamide as a yellow solid. 1H NMR (DMSO-d6 300 MHz) δ 9.24 (s, 1 H), 8.35 (s, 1 H), 8.04 (d, 1 H), 7.95 (d, 1 H), 1.26 (s, 9 H). MS (ES+)=305.
Reaction SMILES: I[C:2]1[C:10]2[O:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].[CH3:14][C:15]([N:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)([C:17]#[CH:18])[CH3:16]>C(N(CC)CC)C.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.[Cu]I>[CH3:13][O:12][C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[CH2:8][O:9][C:10]=2[C:2]=1[C:18]#[C:17][C:15]([N:19]1[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]1)([CH3:16])[CH3:14]
Reactant: COc1ccc2c(c1I)OCC2=O
Reactant: C#CC(C)(C)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1C#CC(C)(C)N1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 50 °C
Reaction time: 7.5 h
Yield: 30.4 %

Procedure:
A solution of 7-iodo-6-methoxybenzofuran-3(2H)-one (0.290 g, 1.00 mmol) synthesized in Example B46, Step 2, dichlorobis(triphenylphosphine)palladium(II) (0.0702 g, 0.100 mmol) and copper(I) iodide (0.0190 g, 0.100 mmol) in triethylamine (4 mL) was added with a solution of tert-butyl 4-(2-methylbut-3-yn-2-yl)piperazine-1-carboxylate (Journal of Medicinal Chemistry, Vol. 47, p. 2833, 2004, 0.252 g, 1.00 mmol) in triethylamine (4 mL), and the mixture was stirred at 50° C. for 7.5 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl 4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)-2-methylbut-3-yn-2-yl]piperazine-1-carboxylate (0.126 g, 30%).
Reaction SMILES: CN(C=O)C.[NH2:6][C@H:7]([C:9]([NH:11][C@H:12]([C:16]([NH:18][C@H:19]([C:28]([NH:30][C@H:31]([C:39]([NH:41][C@H:42]([C:49]([NH:51][C@H:52]([C:59]([NH:61][C@H:62]([C:72]([O:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)=[O:73])[CH2:63][CH2:64][C:65](=[O:71])[O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:60])[CH2:53][O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:50])[CH2:43][O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:40])[C@@H:32]([CH3:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:29])[CH2:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[CH3:8].[NH:81]([C:116]([CH3:118])=[O:117])[C@H:82]([C:89]([NH:91][C@H:92]([C:101]([NH:103][C@H:104]([C:106](ON1C(=O)CCC1=O)=[O:107])[CH3:105])=[O:102])[CH2:93][C:94](=[O:100])[O:95][C:96]([CH3:99])([CH3:98])[CH3:97])=[O:90])[CH2:83][O:84][C:85]([CH3:88])([CH3:87])[CH3:86].CCN(CC)CC>O>[NH:81]([C:116]([CH3:118])=[O:117])[C@H:82]([C:89]([NH:91][C@H:92]([C:101]([NH:103][C@H:104]([C:106]([NH:6][C@H:7]([C:9]([NH:11][C@H:12]([C:16]([NH:18][C@H:19]([C:28]([NH:30][C@H:31]([C:39]([NH:41][C@H:42]([C:49]([NH:51][C@H:52]([C:59]([NH:61][C@H:62]([C:72]([O:74][C:75]1[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=1)=[O:73])[CH2:63][CH2:64][C:65](=[O:71])[O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:60])[CH2:53][O:54][C:55]([CH3:56])([CH3:57])[CH3:58])=[O:50])[CH2:43][O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:40])[C@@H:32]([CH3:38])[O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:29])[CH2:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:17])[CH:13]([CH3:14])[CH3:15])=[O:10])[CH3:8])=[O:107])[CH3:105])=[O:102])[CH2:93][C:94](=[O:100])[O:95][C:96]([CH3:97])([CH3:98])[CH3:99])=[O:90])[CH2:83][O:84][C:85]([CH3:87])([CH3:88])[CH3:86]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)Oc1ccccc1)[C@@H](C)OC(C)(C)C
Reactant: CC(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)Oc1ccccc1)[C@@H](C)OC(C)(C)C)C(C)C
Reaction time: 17 h

Procedure:
The DMF-containing solution of H-Ala-Val-Asp(OtBu)-Thr(tBu)-Ser(tBu)-Ser(tBu)-Glu(OtBu)-OC6H5 (~16.8 mmol) from the preceeding step was cooled to 0° and Ac-Ser(tBu)-Asp(OtBu)-Ala-OSu, VII, (10.92 g, 20.16 mm, 1.2 eq.) added. Stirring proceeded at 0° for 30 min and 25° for 17 h while the pH was maintained at ~8 by addition of Et3N. Water (2.4 L) was added with stirring and the product was collected by filtration and dried in vacuo. The solid was crushed and washed with CH3OH (3×200 mL) and dried in vacuo. Yield: 23.0 g (91.7%); mp 255°-256°; Rf 0.48 (CHCl3 :CH3OH:AcOH; 80-5-1); [α]D25 -25.60° (c 1, TFE). Anal. calc. for C73H122N10O22 (1491.86): C, 58.77; H, 8.24; N, 9.39. Found: C, 58.54; H, 8.23; N, 9.43.
Reaction SMILES: [C:1]1([N:11]2[CH2:17][CH2:16][C:15]3[C:18]([OH:22])=[N:19][CH:20]=[N:21][C:14]=3[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][N:2]=1.N1C2CCNCCC=2C(O)=NC=1.[Cl:35]C1C2C(=CC=CC=2)C(Cl)=NN=1.CCN(CC)CC>CN(C=O)C.O>[Cl:35][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]([N:11]2[CH2:17][CH2:16][C:15]3[C:18]([OH:22])=[N:19][CH:20]=[N:21][C:14]=3[CH2:13][CH2:12]2)=[N:2][N:3]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: Oc1ncnc2c1CCN(c1nncc3ccccc13)CC2
Agent: Oc1ncnc2c1CCNCC2
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Oc1ncnc2c1CCN(c1nnc(Cl)c3ccccc13)CC2
Temperature: 25 °C
Yield: 55 %

Procedure:
7-Phthalazin-1-yl-6,7,8,9-tetrahydro-5H-pyrimido-[4,5-d]azepin-4-ol. A solution of 6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol (50 mg, 0.33 mmol), 1,4-dichlorophthalazine (55 mg, 0.28 mmol), and Et3N (0.11 mL, 0.81 mmol) in DMF (5 mL) was heated at 120° C. for 2 h. The mixture was cooled to rt, diluted with water, and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated to give 7-(4-chloro-phthalazin-1-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol (50 mg, 55%), of which 23 mg (0.14 mmol) was treated with ammonium formate (116 mg, 1.85 mmol) and Pd(OH)2/C (14 mg, 0.08 mmol) in MeOH/dioxane (1:1; 4 mL). After 1 h at 100° C., the mixture was cooled rt, filtered through diatomaceous earth, and concentrated to give the title compound, which was carried on to Step D as in Example 1. MS (ESI−): mass calcd. for C26H28N6, 424.24; m/z found, 423.2 [M−H]−. 1H NMR (CDCl3): 9.13 (s, 1H), 8.51 (s, 1H), 8.08-8.04 (m, 1H), 7.91-7.80 (m, 3H), 7.48-7.36 (m, 4H), 6.56 (s, 1H), 4.04-3.97 (m, 2H), 3.96-3.89 (m, 2H), 3.37-3.30 (m, 2H), 3.20-3.08 (m, 2H), 1.32 (s, 9H).
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[F:16][C:17]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:18]=1[NH2:19]>>[F:16][C:17]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:18]=1[NH:19][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Nc1cc(F)ccc1F
Reactant: CCOC(=O)c1cnc2ccnn2c1O
Product: CCOC(=O)c1cnc2ccnn2c1Nc1cc(F)ccc1F
Yield: 62.2 %

Procedure:
Using ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylate (2.0 g, 9.65 mmol) and 2,5-difluoroaniline (1.12 g, 8.69 mmol) instead of 4-fluoro-2-methylaniline, and in the same manner as in Example 1 step 1, the title compound (1.72 g, 56%) was obtained.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:10]([O:16][CH2:17][C:18]([N:20]2[CH2:25][C@H:24]([CH3:26])[N:23]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:22][C@H:21]2[CH3:35])=[O:19])=[N:11][CH:12]=[C:13]([Cl:15])[CH:14]=1)C.CO.O.[OH-].[Li+].Cl>[Cl-].[Na+].O.O.O1CCCC1>[Cl:15][C:13]1[CH:14]=[C:9]([NH:8][CH2:7][CH2:6][CH2:5][C:4]([OH:36])=[O:3])[C:10]([O:16][CH2:17][C:18]([N:20]2[CH2:25][C@H:24]([CH3:26])[N:23]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:22][C@H:21]2[CH3:35])=[O:19])=[N:11][CH:12]=1
Reactant: CCOC(=O)CCCNc1cc(Cl)cnc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ncc(Cl)cc1NCCCC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-ylamino)-butyric acid ethyl ester (0.034 g, 0.065 mmol) in 2:2:1 methanol:tetrahydrofuran:water (1 mL) was added lithium hydroxide monohydrate (0.010 g, 0.24 mmol). The reaction was stirred at ambient temperature for 3 hours. The pH of the solution was adjusted to ˜4 by the addition of 0.2 M hydrochloric acid, then diluted with brine and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The product was purified by anion exchange chromatography to give the title compound as its acetic acid addition salt (0.020 g, LRMS: 493.1, 495.3)
Reaction SMILES: C(O)C.CS[C:6](SC)=[CH:7][N+:8]([O-:10])=[O:9].[CH2:13]([NH:20][CH2:21][CH2:22][NH2:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CO>C(Cl)(Cl)Cl>[CH2:13]([N:20]1[CH2:21][CH2:22][NH:23][C:6]1=[CH:7][N+:8]([O-:10])=[O:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCCNCc1ccccc1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CO
Product: O=[N+]([O-])C=C1NCCN1Cc1ccccc1
Yield: 74.1 %

Procedure:
Ethanol (200 mL) was added to a solution of 1,1-bis-methylsulfanyl-2-nitro-ethene (14.5 g, 0.0878 mol) and N1-benzyl-ethane-1,2-diamine (12 g, 0.080 mol). The resulting mixture was heated to reflux for 2 hours. The reaction mixture was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was concentrated and the concentrate was dissolved in ethylacetate. The precipitate formed was collected and washed with ethylacetate to afford 13 g of the product (74.7% yield).
Reaction SMILES: [N+](C1C=C(S(CC[O:15][C:16](=[O:61])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:60])[CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([N:35]3[C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[N:37]=[C:36]3[S:44]([CH2:46][C:47]3[C:52]([CH3:53])=[C:51]([O:54][CH2:55][C:56]([F:59])([F:58])[F:57])[CH:50]=[CH:49][N:48]=3)=[O:45])(=[O:34])=[O:33])=[CH:28][CH:27]=2)(=O)=O)C=CC=1)([O-])=O.C([O-])(O)=O.[Na+]>CC#N.O.CC(O)C>[CH3:53][C:52]1[C:47]([CH2:46][S:44]([C:36]2[N:35]([S:32]([C:29]3[CH:28]=[CH:27][C:26]([O:25][CH2:24][C:23]([NH:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:16]([OH:61])=[O:15])=[O:60])=[CH:31][CH:30]=3)(=[O:34])=[O:33])[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[N:37]=2)=[O:45])=[N:48][CH:49]=[CH:50][C:51]=1[O:54][CH2:55][C:56]([F:58])([F:57])[F:59]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2n1S(=O)(=O)c1ccc(OCC(=O)NCCCCCC(=O)OCCS(=O)(=O)c2cccc([N+](=O)[O-])c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: CC#N
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2n1S(=O)(=O)c1ccc(OCC(=O)NCCCCCC(=O)O)cc1
Yield: 43.1 %

Procedure:
A solution of 6-[2-(4-{2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]-benzimidazole-1-sulfonyl}-phenoxy)acetylamino]hexanoic acid 2-(3-nitro-benzenesulfonyl)ethyl ester (Intermediate 20, 450 mg, 0.50 mmol) and of NaHCO3 (50 mg, 0.60 mmol, 1.2 eq) in CH3CN-H2O-iPrOH (2 mL:1 mL:1 mL) was heated to 70° C. for 1.5 h. Thereafter volatile materials were removed by evaporation, the residual gummy oil was dissolved in CH2Cl2, and the mixture was filtered to remove undissolved solid. The filtrate was dried and concentrated under reduced pressure. The residual oil was purified by silica gel column to yield 150 mg of Compound 7 as a light brown foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH2:10].C(N(CC)CC)C.[C:18]([C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]1[C:18]([OH:25])([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:26]2[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:28]1=[O:29]
Reactant: NCCc1ccccc1F
Reactant: O=C(Cl)c1ccccc1C(=O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(O)(c2ccccc2)N1CCc1ccccc1F

Procedure:
At room temperature, 0.31 g (2.2 mmol) of 2-(2-fluorophenyl)ethylamine and 0.22 g (2.2 mmol) of triethylamine in 10 ml of absolute toluene were admixed dropwise with a solution of 0.49 g (2.0 mmol) of 2-benzoylbenzoyl chloride in 10 ml of absolute toluene. The reaction mixture was heated under eflux for 3 h. After cooling, the turbid solution was admixed with 20 ml of water. The organic phase was separated off, diluted with 20 ml of toluene and washed three times with 1 M hydrochloric acid. To complete the extraction, the combined aqueous phases were extracted with diethyl ether. The combined organic phases were washed three times with 1 M aqueous sodium hydroxide solution and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness using a rotary evaporator. The residue was recrystallized from toluene. The resulting colorless crystalline product was filtered off with suction and dried. Yield: 53 g. M.p.: 208° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([N:12]1[C:17]2[CH:18]=[C:19]([C:22]([NH:24][C:25]3[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=3)=[O:23])[CH:20]=[CH:21][C:16]=2[O:15][CH2:14][CH2:13]1)(=[O:11])=[O:10].F[C:35]1C=CC(F)=C[C:36]=1S(Cl)(=O)=O>>[CH2:35]([O:30][C:29](=[O:31])[C:28]1[CH:32]=[CH:33][C:25]([NH:24][C:22]([C:19]2[CH:20]=[CH:21][C:16]3[O:15][CH2:14][CH2:13][N:12]([S:9]([C:3]4[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=4[F:1])(=[O:10])=[O:11])[C:17]=3[CH:18]=2)=[O:23])=[CH:26][CH:27]=1)[CH3:36]
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Reactant: O=C(O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(F)ccc2F)CCO3)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(F)ccc2F)CCO3)cc1

Procedure:
4-{[4-(2,5-Difluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid, MS (ISP): m/e=472.9 (M−H), was prepared as described for example 14, steps 1 to 8. Step 7 was performed using 2,5-difluoro-benzenesulfonyl chloride and yielded 4-{[4-(2,5-difluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 8.
Reaction SMILES: CS(C)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:18][C:19]1[CH:20]=[C:21]([CH:26]([OH:35])[CH:27]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[OH:28])[CH:22]=[CH:23][C:24]=1[Cl:25].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[Cl:18][C:19]1[CH:20]=[C:21]([C:26](=[O:35])[C:27]([CH:29]2[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]2)=[O:28])[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: OC(c1ccncc1)C(O)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CS(C)=O
Product: O=C(C(=O)C1CCNCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 71.8 %

Procedure:
To a stirring solution of methyl sulfoxide (38.3 g, 35 mL, 490 mmol) in dichloromethane (750 mL) at -78° C. was added trifluoroacetic anhydride (77 g, 52 mL, 368 mmol) dropwise. After ten minutes, 1-(3,4-dichlorophenyl)-2-pyridin-4-yl-ethane-1,2-diol (31.7 g, 112 mmol) in dichloromethane (500 mL) was added dropwise. After another ten minutes, triethylamine (70 g, 96 mL, 690 mmol) was added dropwise and the reaction mixture immediately warmed to 0° C. and poured into saturated aqueous sodium hydrogen carbonate (300 mL). The aqueous layer was extracted with ethyl acetate (3×200 mL) and the organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated at reduced pressure. The resulting solid was triturated with ethyl acetate to give the dione as a yellow solid (23 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[C:37]([O:38][CH3:39])=[CH:36][C:26]2[CH2:27][CH2:28][N:29]([CH2:32][CH:33]([OH:35])[CH3:34])[CH2:30][CH2:31][C:25]=2[CH:24]=1>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:22][C:23]2[C:37]([O:38][CH3:39])=[CH:36][C:26]3[CH2:27][CH2:28][N:29]([CH2:32][CH:33]([OH:35])[CH3:34])[CH2:30][CH2:31][C:25]=3[CH:24]=2)=[N:3][CH:4]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CC(C)O)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)CCN(CC(C)O)CC2
Yield: 62 %

Procedure:
In an analogous manner to Example 1534, the product was prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide and 1-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-propan-2-ol. The product was isolated as off-white needles (60 mg, 62%). mp: 183-185° C., MS (ESI+): 561 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.35 (s, 1H), 8.55 (d, J=8 Hz, 1H), 8.16 (s, 1H), 8.03 (s, 1H), 7.91 (d, J=8 Hz, 1H), 7.58 (t, 1H), 7.53 (s, 1H), 7.26 (m, 1H), 6.68 (s, 1H), 3.89 (s, 3H), 3.89 (m, 1H), 2.86-2.52 (m, 15H), 1.18 (d, J=6 Hz, 3H).
Reaction SMILES: Cl.[OH:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7](=[O:20])[C:8]([CH3:19])=[C:9]([C@H:14]3[CH2:18][CH2:17][CH2:16][NH:15]3)[O:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.Br[CH2:29][CH2:30][O:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1>CN(C)C=O>[OH:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7](=[O:20])[C:8]([CH3:19])=[C:9]([C@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3[CH2:29][CH2:30][O:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[O:10]2)=[CH:5][CH:4]=1
Reactant: Cc1c([C@H]2CCCN2)oc2c(C)c(O)ccc2c1=O
Reactant: BrCCOC1CCCCO1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c([C@H]2CCCN2CCOC2CCCCO2)oc2c(C)c(O)ccc2c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 73.6 %

Procedure:
To a solution of 7-hydroxy-3,8-dimethyl-2-[(2R)-pyrrolidin-2-yl]-4H-chromen-4-one hydrochloride (70 mg, 0.27 mmol) obtained in Example 2-3 and triethylamine (56 μL, 0.40 mmol) in dimethylformamide (1.5 mL), 2-(2-bromoethoxy)tetrahydro-2H-pyran (163 μL, 1.08 mmol) was added dropwise, and then the mixture was stirred at room temperature for 20 hours. Triethylamine (38 μL, 0.27 mmol) and 2-(2-bromoethoxy)tetrahydro-2H-pyran (41 μL, 0.27 mmol) were further added dropwise thereto, and then the mixture was stirred at room temperature for 27 hours. The reaction solution was concentrated, and then the obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/0→90/10) to obtain 77 mg of the title compound (yield: 74%).