Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:5]1[O:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH:16]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=4)[C:14]=3[CH:29]=2)=[N:8][N:9]=1)(=O)=O.[N:30]#[C:31][NH2:32]>>[F:26][C:25]([F:28])([F:27])[O:24][C:20]1[CH:19]=[C:18]([C:15]2[C:14]3[CH:29]=[C:10]([C:7]4[O:6][C:5]([NH:32][C:31]#[N:30])=[N:9][N:8]=4)[CH:11]=[CH:12][C:13]=3[O:17][CH:16]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CS(=O)(=O)c1nnc(-c2ccc3occ(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Reactant: N#CN
Product: N#CNc1nnc(-c2ccc3occ(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Yield: 24 %

Procedure:
In the same manner as in Example 110 and using 2-(methylsulfonyl)-5-[3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole instead of 2-(2,3-dihydro-1-benzofuran-5-yl)-5-(methylsulfonyl)-1,3,4-oxadiazole and using cyanamide instead of 3-fluorobenzylalcohol, the title compound (yield 24%) was obtained as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][CH2:20][C:21]2[S:22][CH:23]=[CH:24][N:25]=2)[NH:12][C:11]([CH2:26][C:27](O)=[O:28])=[C:10]1[C:30]([O:32][CH3:33])=[O:31].CCN=C=NCCCN(C)C.Cl.[N:46]1([CH2:52][C:53]2([C:59]#[N:60])[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]2)[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>ClCCl>[C:59]([C:53]1([CH2:52][N:46]2[CH2:47][CH2:48][N:49]([C:27](=[O:28])[CH2:26][C:11]3[NH:12][C:13]([CH2:19][CH2:20][C:21]4[S:22][CH:23]=[CH:24][N:25]=4)=[C:14]([C:15]([O:17][CH3:18])=[O:16])[CH:9]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])[C:10]=3[C:30]([O:32][CH3:33])=[O:31])[CH2:50][CH2:51]2)[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58]1)#[N:60]
Reactant: N#CC1(CN2CCNCC2)CCCCC1
Reactant: COC(=O)C1=C(CCc2nccs2)NC(CC(=O)O)=C(C(=O)OC)C1c1c(Cl)cccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C1=C(CCc2nccs2)NC(CC(=O)N2CCN(CC3(C#N)CCCCC3)CC2)=C(C(=O)OC)C1c1c(Cl)cccc1Cl
Reaction time: 8 h

Procedure:
To a suspension of 2-[4-(2,6-dichlorophenyl)-3,5-bis(methoxycarbonyl)-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-2-pyridinyl]acetic acid (511 mg/1.0 mmol) in dichloromethane (5 ml) was added water soluble carbodiimide (288 mg/1.5 mmol) followed by 1-(1-piperazinylmethyl)cyclohexanecarbonitrile (311 mg/1.5 mmol) at ambient temperature, and then the resulting solution was stirred overnight. The solution was diluted with dichloromethane (100 ml) and the resulting solution was washed with water (10 ml) and brine (10 ml) succesively. The solution was dried over magnesium sulfate, filtered and concentrated. The residue was purified by colum chromatography (NH2 gel/20 g/dichloromethane as eluent) to give a brown amorphous (731 mg/quant.).
Reaction SMILES: [CH:1]12[CH2:10]C3CC(CC(C3)[CH:2]1OCC1C(Cl)=CC(C(NS(C)(=O)=O)=O)=C(F)C=1)C2.[C:28]12([O:38][CH2:39][C:40]3[C:55](Cl)=[CH:54][C:43]([C:44]([NH:46][S:47]([N:50]4[CH2:53][CH2:52][CH2:51]4)(=[O:49])=[O:48])=[O:45])=[C:42]([F:57])[CH:41]=3)[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2>>[C:28]12([O:38][CH2:39][C:40]3[C:55]([CH:10]4[CH2:1][CH2:2]4)=[CH:54][C:43]([C:44]([NH:46][S:47]([N:50]4[CH2:53][CH2:52][CH2:51]4)(=[O:49])=[O:48])=[O:45])=[C:42]([F:57])[CH:41]=3)[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2
Reactant: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(COC23CC4CC(CC(C4)C2)C3)cc1F
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(COC2C3CC4CC(C3)CC2C4)cc1F
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(COC23CC4CC(CC(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 49 and making variations as required to replace 4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide with 4-((adamantan-1-yloxy)methyl)-N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluorobenzamide, the title compound was obtained as a colorless solid (0.135 g, 83%): 1H NMR (300 MHz, CDCl3) δ8.82-8.68 (m, 1H), 7.76-7.68 (m, 1H), 7.44-7.34 (m, 1H), 4.72 (s, 2H), 4.33-4.18 (m, 4H), 2.35-2.15 (m, 5H), 1.90-1.60 (m, 13H), 1.02-0.89 (m, 2H), 0.73-0.62 (m, 2H); MS (ES+) m/z 463.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:23](=[CH:24][CH:25]=1)[C:7]1=[CH:8][C:9]3[C:10](=O)[C:11]4[CH:12]=[CH:13][C:14](Br)=[CH:15][C:16]=4[C:17](=O)[C:18]=3[CH:19]=[C:6]1[C:5]2([CH3:27])[CH3:26].I.O.II>C(O)(=O)C>[CH3:26][C:5]1([CH3:27])[C:6]2[C:7](=[CH:8][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][C:18]=3[CH:19]=2)[CH:15]=[CH:14][CH:13]=[CH:12]4)[C:23]2[C:4]1=[CH:3][CH:2]=[CH:25][CH:24]=2
Reactant: CC1(C)c2cc(Br)ccc2-c2cc3c(cc21)C(=O)c1cc(Br)ccc1C3=O
Agent: I
Agent: II
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)c2ccccc2-c2cc3cc4ccccc4cc3cc21
Reaction time: 48 h
Yield: 58.6 %

Procedure:
2,9-dibromo-13,13-dimethyl-6H-indeno[1,2-b]anthracene-6,11(13H)-dione (19 g, 0.058 mol) was dissolved in acetic acid (200 ml), and added with 57% HI (50 ml), followed by reflux-stirring for 48 hours. After the reaction was completed, the resultant solution was added with distilled water (500 ml). The produced solid was filtered and dissolved in toluene (200 ml) and iodine (4.56 g, 0.018 mol) was added thereto, followed by reflux-stirring for 3 hours. After the reaction was completed, through extraction and column chromatography, 13,13-dimethyl-13H-indeno[1,2-b]anthracene (10 g, yield 54%) was obtained.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@H:5]2[CH2:14][S:15][C:16](=[C:17]([CH2:21][CH2:22][CH3:23])[C:18]([OH:20])=[O:19])[C@H:4]2[N:3]1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH-].[Na+].[H][H]>O.[Pd]>[O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:5]2[CH2:14][S:15][CH:16]([CH:17]([CH2:21][CH2:22][CH3:23])[C:18]([OH:20])=[O:19])[C@H:4]2[N:3]1[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: [H][H]
Reactant: CCCC(C(=O)O)=C1SC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCC(C(=O)O)C1SC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Yield: 95.5 %

Procedure:
100 g of (3aS, 6aR)hexahydro2-oxo-1,3-dibenzylthieno[3,4-d]imidazol-4-ylidenepentanoic acid (formula I) are dissolved in 340 ml of water at 40° C., where the pH is set to 8.7 using aqueous sodium hydroxide solution. 25% by weight of 5% Pd/C are added to the solution. The mixture is subsequently hydrogenated at an H2 pressure of 3 bar and 100° C. until the takeup of hydrogen is complete. The catalyst is filtered off after cooling. The solution is set to pH=6.0 using hydrochloric acid and extracted with 300 ml of xylene. The aqueous phase is subsequently extracted again with 100 ml of xylene. The organic phases are combined, and the solvents are evaporated, leaving 96 g of (3aS, 6aR)-hexahydro-2-oxo-1,3-dibenzylthieno[3,4-d]imidazol-4-ylpentanoic acid (formula II) as a pale-yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[SH:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=1.[Cl:18][C:19]([Cl:33])([Cl:32])[CH2:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29]Br.O>CN(C=O)C>[Cl:18][C:19]([Cl:32])([Cl:33])[CH2:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][C:15]([OH:17])=[O:16])[CH:9]=1
Reactant: O=C(O)Cc1cccc(S)c1
Reactant: O=C(OCC(Cl)(Cl)Cl)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)Cc1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
Cesium carbonate (1.69 g, 5.20 mmol) was added to a mixture of 3-mercapto-phenylacetic acid (0.73 g, 4.33 mmol) and 2-bromomethyl-benzoic acid 2,2,2-trichloro-ethyl ester (1.50 g, 4.33 mmol) in DMF (25 mL). The mixture was stirred for 1 h at rt. Water was added and the mixture was washed with diethyl ether. The aqueous phase was made acidic (pH5-3) with 2M HCl and thereafter extracted with diethyl ether. The combined organic phases were dried (Na2SO4) and concentrated to give the titled compound (1.88 g, 100%); 1H NMR (400 MHz, CDCl3): δ 3.50 (s, 2H), 4.46 (s, 2H), 4.88 (s, 2H), 7.01-7.08 (m, 1H), 7.10-7.16 (m, 4H), 7.22-7.35 (m, 2H), 8.00 (d, 1H); Mass spectrum: M−H+ 432.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1[C:17]2[C:18](=[O:27])[NH:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[S:22][C:16]=2[CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH:12]1[C:17]2[C:18](=[O:27])[NH:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[S:22](=[O:9])[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1Nc2ccccc2Sc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C1Nc2ccccc2S(=O)c2ccccc21

Procedure:
A solution of MCPBA (1 eq) in chloroform (5 ml) was added to a stirred solution of 10,11-dihydrodibenzo[b,f][1,4] thiazepin-11-one (114 mg, 0.5 mmol) in chloroform (30 ml). After 0.5 hr the reaction mixture was poured into sodium bicarbonate solution (5%, 30 ml), separated and the aqueous layer washed with chloroform (30 ml). The combined organic fractions were dried (MgSO4) and evaporated. Recrystallisation from toluene gave the title compound as off-white crystals (76 mg, m.p. 308°-310° C., Rf 0.16, CH2Cl2 /MeOH 50:1).
Reaction SMILES: [C:1]([O:5]O)([CH3:4])([CH3:3])C.[Cl-].[Na+].[C:9]([O:26][CH:27]1[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]1)(=[O:25])[CH2:10][CH2:11][C:12]([O:14][CH:15]1[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]1)=[O:13]>[Mo](=O)(=O)=O.C1CCCCC1>[C:9]([O:26][CH:27]1[CH2:32][C:31]([CH3:34])([CH3:33])[N:30]([O:5][CH:1]2[CH2:4][CH2:20][CH2:15][CH2:16][CH2:3]2)[C:29]([CH3:36])([CH3:35])[CH2:28]1)(=[O:25])[CH2:10][CH2:11][C:12]([O:14][CH:15]1[CH2:16][C:17]([CH3:24])([CH3:23])[N:18]([O:5][CH:1]2[CH2:4][CH2:11][CH2:10][CH2:9][CH2:3]2)[C:19]([CH3:22])([CH3:21])[CH2:20]1)=[O:13]
Reactant: CC(C)(C)OO
Reactant: CC1(C)CC(OC(=O)CCC(=O)OC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Agent: O=[Mo](=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCCCC1
Product: CC1(C)CC(OC(=O)CCC(=O)OC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)CC(C)(C)N1OC1CCCCC1
Temperature: 140 °C
Reaction time: 4 h
Yield: 137.6 %

Procedure:
A two-phase mixture of 70% aqueous t-butyl hydroperoxide (103.9 g, 807 mmol), cyclohexane (200 ml) and sodium chloride (15 g) is shaken in a separatory funnel. The organic phase is dried over magnesium sulfate, filtered, and added to 40.0 g (101 mmol) of di-(2,2,6,6-tetramethylpiperidin-4-yl) succinate. Molybdenum trioxide (2.0 g) is added, and the mixture is refluxed for one hour. Water is collected in a Dean-Stark trap. The entire reaction mixture is then transferred to a Fischer-Porter bottle and heated at 140° C. for 6 hours. Additional t-butyl hydroperoxide (90%, 10.1 g, 101 mmol) is added and heating is resumed for another 4 hours. The colorless reaction mixture is filtered, concentrated, and dissolved in heptane (200 ml). The heptane solution is passed through a short column of silica gel with heptane. Subsequent evaporation affords an oil which is crystallized from ethanol to yield 41.2 g (69%) of a white powder, m.p. 122°-6° C.
Reaction SMILES: [CH:1]1([N:4]([CH2:15][CH3:16])[CH2:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]#[CH:13])=[CH:8][C:7]=2[CH3:14])[CH2:3][CH2:2]1.C(O)(=O)C1C=CC=CC=1.[CH2:26]([O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][C:33](I)=[CH:32][CH:31]=1)[CH3:27]>C(N(CC)CC)C.[Cu]I.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>[CH:1]1([N:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:33]3[CH:34]=[CH:35][C:30]([C:29]([O:28][CH2:26][CH3:27])=[O:37])=[CH:31][CH:32]=3)=[CH:8][C:7]=2[CH3:14])[CH2:15][CH3:16])[CH2:3][CH2:2]1
Reactant: C#Cc1ccc(CN(CC)C2CC2)c(C)c1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(CN(CC)C3CC3)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure F; cyclopropyl-ethyl-(4-ethynyl-2-methyl-benzyl)-amine (Intermediate 161, 190.0 mg, 0.89 mmol) and ethyl-4-iodo benzoate (Reagent A, 245.0 mg, 0.89 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (56.0 mg, 0.30 mmol) and sparged with argon for 15 minutes. Dichlorobis(triphenylphosphine)-palladium(II) (208 mg, 0.30 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (3-5% EtOAc-hexanes) afforded the title compound.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>ClCCl>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N+:23]=1[O-:9]
Reactant: BrCCCCCCOCCc1ccccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1ccccc1CCOCCCCCCBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
m-Chloroperbenzoic acid (1.13 g) was added in one portion to a solution of 2-[2-[(6-bromohexyl)oxy]ethyl]pyridine (1.0 g) in dichloromethane (50 ml). The solution was stirred at room temperature overnight. The mixture was quenched with 10% w/v sodium sulphite solution (50 ml) and the organic layer washed with 8% sodium bicarbonate solution (50 ml). The organic layer was dried and evaporated to leave the title compound as a pale yellow oil (980 mg) used without further purification. A portion (100 mg) was purified by FCC eluting with System A (80:20:1) to give a pale yellow oil (20 mg), t.l.c. (System A 80:20:1) Rf 0.48.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[CH3:28][C:29]1[CH:30]=[CH:31][C:32]([NH2:35])=[CH:33][CH:34]=1>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH:35][C:32]3[CH:33]=[CH:34][C:29]([CH3:28])=[CH:30][CH:31]=3)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Br)ccc2F)N=C1NC(=O)OC(C)(C)C
Reactant: Cc1ccc(N)cc1
Product: Cc1ccc(Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)cc1

Procedure:
The coupling of [(S)-4-(5-bromo-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate E8) and p-tolylamine according to procedure A followed by deprotection yielded the title compound as an off white solid. MS (ESI): m/z=369.2 [M+H]+.
Reaction SMILES: C(N1CCN(C2N=C(Br)C=C3C=CSC=23)CC1)C.[CH2:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:28]=[C:29]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([CH3:50])([CH3:49])[CH2:43][CH2:44][O:45]C(=O)C)=[CH:38][CH:37]=3)[CH:30]=[C:31]3[CH:35]=[CH:34][S:33][C:32]=23)[CH2:23][CH2:22]1)[CH3:20].[ClH:51]>C(OCC)(=O)C>[ClH:51].[ClH:51].[CH2:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:28]=[C:29]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([CH3:49])([CH3:50])[CH2:43][CH2:44][OH:45])=[CH:38][CH:37]=3)[CH:30]=[C:31]3[CH:35]=[CH:34][S:33][C:32]=23)[CH2:23][CH2:22]1)[CH3:20]
Reactant: CCN1CCN(c2nc(-c3ccc(C(C)(C)CCOC(C)=O)cc3)cc3ccsc23)CC1
Agent: CCN1CCN(c2nc(Br)cc3ccsc23)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCN1CCN(c2nc(-c3ccc(C(C)(C)CCO)cc3)cc3ccsc23)CC1
Reaction time: 2 h

Procedure:
The resulting compound and 7-(1-ethylpiperazin-4-yl)-5-bromothieno[2,3-c]pyridine (0.20 g) were reacted in the same manner as in Example 300-4, to give a reaction solution containing 7-(4-ethylpiperazin-1-yl)-5-[4-(3-acetoxy-1,1-dimethylpropyl)phenyl]thieno[2,3-c]pyridine. Ethyl acetate and 2N hydrochloric acid were added to the reaction solution, and the resulting insoluble matters were filtered off. The aqueous layer was separated, while the organic layer was extracted with 2N hydrochloric acid. The aqueous layers were combined and washed with ethyl acetate twice. The pH of the resulting solution was adjusted to pH 10 by adding a 8N aqueous solution of sodium hydroxide thereto, and the solution was extracted with ethyl acetate twice. The extract was washed with brine, dried over magnesium sulfate, and the solvent was evaporated. Methanol (10 ml) was added to the resulting residue and dissolved, followed by the addition of a 8N aqueous solution of sodium hydroxide (0.75 ml). The resulting solution was left as it was at room temperature for 2 hr, and then the solvent was evaporated. Water was added to the resulting residue, and then the mixture was extracted with ethyl acetate thrice. The extract was washed with brine, dried over magnesium sulfate, and the solvent was evaporated. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate/n-hexane system), to give 0.16 g of the free compound of the title compound as a colorless viscous oil.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][C:13]1[CH:51]=[CH:50][C:16]([CH2:17][O:18][CH2:19][C@H:20]([CH3:49])[C@H:21]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[C@@H:22]([CH3:40])[CH2:23][CH2:24][C:25]([N:27]2[C@H:31]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:30][O:29][C:28]2=[O:39])=[O:26])=[CH:15][CH:14]=1.CI>C1COCC1>[CH3:11][O:12][C:13]1[CH:51]=[CH:50][C:16]([CH2:17][O:18][CH2:19][C@H:20]([CH3:49])[C@H:21]([O:41][Si:42]([C:45]([CH3:46])([CH3:48])[CH3:47])([CH3:44])[CH3:43])[C@@H:22]([CH3:40])[CH2:23][C@@H:24]([CH3:1])[C:25]([N:27]2[C@H:31]([CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:30][O:29][C:28]2=[O:39])=[O:26])=[CH:15][CH:14]=1
Reactant: COc1ccc(COC[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CCC(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(COC[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C[C@@H](C)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.4 %

Procedure:
NaHMDS (1 M in THF, 14.9 mL, 14.9 mmol) was added dropwise over a 30 min period to a cooled (−78° C.) suspension of the imide 25 (7.91 g, 13.6 mmol) in THF (45 mL). After 15 min of stirring, the resulting cold solution was treated with MeI (2.53 mL, 40.8 mmol) and allowed to stir at −78° C. for 3 h before being warmed to 25° C. overnight (12 h) The reaction was quenched with H2O (100 mL), and the aqueous layer was extracted with Et2O (3×150 mL). The combined organic extracts were dried (MgSO4), concentrated in vacuo and chromatographed (EtOAc/hexane 1:9) to provide 5.97 g (74%) of 26 as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.42-7.26 (m, 7H), 6.95-6.92 (m, 2H), 4.71 (m, 1H), 4.51 (m, 2H), 4.18 (m, 2H), 3.95 (m, 1H), 3.84 (s, 3H), 3.63 (dd, J=8.9, 3.8 Hz, 1H), 3.57 (dd, J=6.4, 2.7 Hz, 1H), 3.35 (t, J=8.5 Hz, 1H), 3.28 (dd, J=13.3, 3.1 Hz, 1H), 2.83 (dd, J=13.3, 9.4 Hz, 1H), 2.10-1.95 (m, 2H), 1.68 (m, 1H), 1.38 (ddd, J=14.1, 9.8, 4.9 Hz, 1H), 1.31 (d, J=6.8 Hz, 3H), 1.04 (d, J=6.9 Hz, 3H), 0.98 (s, 9H), 0.95 (d, J=6.7 Hz, 3H), 0.14 (s, 3H), 0.13 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 176.8, 158.8, 152.8, 135.1, 130.8, 129.3, 128.9, 128.7, 127.1, 113.5, 77.6, 72.6, 72.4, 65.7, 55.0, 38.9, 38.0, 37.6, 35.3, 33.8, 26.0, 18.8, 18.3, 14.9, 13.8, −3.8, −4.2.
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C:15]3[C:18]4[CH:26]=[C:25]([N+:27]([O-])=O)[C:24]([CH3:30])=[CH:23][C:19]=4[O:20][C:21](=[O:22])[C:14]=3[CH2:13]1)[CH2:2]2.[H][H]>CN(C)C=O.[Ni]>[NH2:27][C:25]1[C:24]([CH3:30])=[CH:23][C:19]2[O:20][C:21](=[O:22])[C:14]3[CH2:13][N:12]([CH2:11][CH2:10][N:3]4[CH2:2][CH:1]5[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]5)[CH2:4]4)[CH2:17][CH2:16][C:15]=3[C:18]=2[CH:26]=1
Reactant: [H][H]
Reactant: Cc1cc2oc(=O)c3c(c2cc1[N+](=O)[O-])CCN(CCN1CC2CCC(CC2)C1)C3
Agent: [Ni]
Solvent: CN(C)C=O
Product: Cc1cc2oc(=O)c3c(c2cc1N)CCN(CCN1CC2CCC(CC2)C1)C3
Yield: 51.4 %

Procedure:
A solution of 3-[2-(3-azabicyclo[3.2.2]non-3-yl)ethyl]-1,2,3,4-tetrahydro-8-methyl-9-nitro-5H-[1]benzopyrano[3,4-c]pyridin-5-one (10.5 g, 0.026 moles) in N,N-dimethylformamide (300 ml) is hydrogenated at 50 psi at 24° C. in the presence of Raney Nickel until the required amount of hydrogen has been taken up. The catalyst is filtered off and rinsed with hot N,N-dimethylformamide until free of organic material. The filtrate is slightly concentrated and cooled to give the product. Recrystallization from ethanol gave the product (5.1 g), mp 142°-143° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH:17]3[CH2:22][CH:21](O)[C:20]4[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=4[S:18]3(=[O:29])=[O:28])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH:17]3[CH:22]=[CH:21][C:20]4[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=4[S:18]3(=[O:28])=[O:29])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=S1(=O)c2ccccc2C(O)CC1CCCN1CCN(c2ccc(F)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=S1(=O)c2ccccc2C=CC1CCCN1CCN(c2ccc(F)cc2)CC1
Yield: 59.9 %

Procedure:
A suspension of 41.9 mg (0.1 mmol) of the Compound 23 in 10 ml of 3 N hydrochloric acid aqueous solution was refluxed for 24 hours. The reaction mixture was cooled with ice, adjusted to pH 10 with a 5 N aqueous solution of sodium hydroxide, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by silica gel column chromatography (eluent: methanol:chloroform=1:99) to obtain 24 mg (yield: 60%) of the title compound.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([C:18]4[C:19]([CH3:26])=[N:20][C:21]([CH3:25])=[CH:22][C:23]=4[CH3:24])=[N:15][C:14]=3[C:27](O)=[O:28])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:30][O:31][C:32](=[O:41])[C:33]1[CH:38]=[C:37]([NH2:39])[CH:36]=[CH:35][C:34]=1[F:40]>>[CH3:30][O:31][C:32](=[O:41])[C:33]1[CH:38]=[C:37]([NH:39][C:27]([C:14]2[N:15]=[C:16]([C:18]3[C:19]([CH3:26])=[N:20][C:21]([CH3:25])=[CH:22][C:23]=3[CH3:24])[NH:17][C:13]=2[CH2:12][CH2:11][C:1]23[CH2:10][CH:5]4[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]4)[CH2:8]2)[CH2:2]3)=[O:28])[CH:36]=[CH:35][C:34]=1[F:40]
Reactant: COC(=O)c1cc(N)ccc1F
Reactant: Cc1cc(C)c(-c2nc(C(=O)O)c(CCC34CC5CC(CC(C5)C3)C4)[nH]2)c(C)n1
Product: COC(=O)c1cc(NC(=O)c2nc(-c3c(C)cc(C)nc3C)[nH]c2CCC23CC4CC(CC(C4)C2)C3)ccc1F

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-(2,4,6-trimethyl-pyridine-3-yl)-1H-imidazole-4-carboxylic acid (Example 182) was reacted with 5-amino-2-fluoro-benzoic acid methyl ester according to the procedure of Example 20, step d to afford 5-{[5-(2-adamantan-1-yl-ethyl)-2-(2,4,6-trimethyl-pyridine-3-yl)-1H-imidazole-4-carbonyl]-amino}-2-fluoro-benzoic acid methyl ester. The ester was hydrolysed following the procedure of Example 36, step d, to afford the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO) 12.50 (1H, br s), 9.67 (1H, s), 8.15 (1H, d), 7.71 (1H, m), 7.03 (2H, m), 2.99 (2H, m), 2.42 (3H, s), 2.25 (3H, s), 2.09 (3H, s), 1.92 (3H, br s), 1.60 (6H, m), 1.50 (6H, br s), 1.42 (2H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 53.44; H, 7.81; N, 8.03%. C38H52FN5O8.7.0 mols H2O requires: C, 53.57; H, 7.81; N, 8.22%.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[Cl-].[Cl-].[Cl-].[Al+3].[C:22](Cl)(=[O:24])[CH3:23].Cl>[N+](C1C=CC=CC=1)([O-])=O>[F:1][C:2]([F:16])([F:17])[O:3][C:4]1([C:22](=[O:24])[CH3:23])[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][CH2:9]1
Reactant: CC(=O)Cl
Reactant: FC(F)(F)Oc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)C1(OC(F)(F)F)C=CC(c2ccccc2)=CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a mixture of 30 g (126 mmol) 4-(trifluoromethoxy)-1,1′-biphenyl and 21 g aluminium trichloride (157 mmol) in 120 ml nitrobenzene are added at a temperature below 20° C. 9.87 g (126 mmol) acetyl chloride. The reaction mixture is stirred for 2 h at 0° C., added to 240 ml ice-water and 42 ml conc. HCl and extracted with ethyl acetate. The organic phase is washed with water and brine and the solvents removed in vacuo. The residue is triturated with petrol ether, filtrated and dried. From the filtrate another batch can be obtained after crystallizing at 4° C. to give overall 23.5 g (66%).