Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][O:7][C:8]2[C:9]([O:25][CH2:26][CH2:27][F:28])=[C:10]([CH:14]([C:16]3[C:24]4[C:19](=[N:20][CH:21]=[CH:22][CH:23]=4)[NH:18][CH:17]=3)[OH:15])[CH:11]=[CH:12][CH:13]=2)=[C:4]([F:31])[CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O1CCCC1>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][O:7][C:8]2[C:9]([O:25][CH2:26][CH2:27][F:28])=[C:10]([C:14]([C:16]3[C:24]4[C:19](=[N:20][CH:21]=[CH:22][CH:23]=4)[NH:18][CH:17]=3)=[O:15])[CH:11]=[CH:12][CH:13]=2)=[C:4]([F:31])[CH:3]=1
Reactant: OC(c1cccc(OCc2ccc(Cl)cc2F)c1OCCF)c1c[nH]c2ncccc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: O=C(c1cccc(OCc2ccc(Cl)cc2F)c1OCCF)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.9 %

Procedure:
To a solution of [3-(4-chloro-2-fluoro-benzyloxy)-2-(2-fluoro-ethoxy)-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (661, 60 mg, 0.1 mmol) in tetrahydrofuran (10 mL) was added Dess-Martin periodinane (69 mg, 0.16 mmol) at 0° C. The reaction mixture was stirred at room temperature for 3 hours. The reaction was quenched with a saturated solution of sodium thiosulfate, extracted with ethyl acetate, washed with sodium bicarbonate, brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexanes to provide the compound as a white solid (P-2086, 15 mg, 20%). MS (ESI) [M+H+]+=441.06.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17]CC)=[O:16])=[CH:10][CH:9]=1.Br>O1CCOCC1>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[CH:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:12][CH:13]=1
Reactant: CCOC(=O)Cc1ccc(C=C2CCCC2=O)cc1
Agent: Br
Solvent: C1COCCO1
Product: O=C(O)Cc1ccc(C=C2CCCC2=O)cc1

Procedure:
A mixture of 0.4 g of ethyl 4-(2-oxo-1-cyclopentylidenemethyl)phenylacetate in 100 ml of a 10% aqueous solution of hydrobromic acid and 10 ml of dioxane was heated under reflux for 1 hour. After cooling, the reaction mixture was extracted with ether, an ether layer was washed with water and dried. The ether was distilled off and the residual oily substance was distilled under reduced pressure to give 0.1 g of an oily substance having a boiling point of 205°-210° C./0.25 mmHg.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][O:14][CH2:15][C:16]2[CH:21]=[C:20]([Br:22])[CH:19]=[CH:18][C:17]=2[NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])=[O:31])=[C:26]([Cl:39])[CH:25]=2)(=O)=O)=CC=1.[Na+].[I-:41]>CC(C)=O.O>[Br:22][C:20]1[CH:19]=[CH:18][C:17]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])=[O:31])=[C:26]([Cl:39])[CH:25]=2)=[C:16]([CH2:15][O:14][CH2:13][CH2:12][I:41])[CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOCc2cc(Br)ccc2Nc2ccc(C(=O)c3ccccc3C)c(Cl)c2)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2COCCI)cc1Cl

Procedure:
Compound 164 (1.72 g, 2.73 mmol) was dissolved in dry acetone (2.7 mL) and dry NaI (0.82 g, 5.47 mmol) was added. The suspension was stirred in a light protected flask at room temperature for 20 h after which the reaction mixture was diluted with water and the water phase was extracted three times with EtOAc. The combined organic phases were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. This afforded the title compound as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([N:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1ccc2c(c1)CCC21CCNCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(CN2CCC3(CCc4ccccc43)CC2)cc1
Temperature: 100 °C
Yield: 18.9 %

Procedure:
To a stirred solution of spiro[indane-1,4'-piperidine] (110 mg, 0.59 mmol), in anhydrous DMF (10 ml), under an atmosphere of nitrogen, was added potassium carbonate (98 mg, 0.71 mmol) followed by benzyl bromide (0.08 ml, 0.65 mmol) dropwise. The mixture was heated at 100° C. for 2 hours, after which time the solution was cooled to ambient temperature. The solvent was removed in vacuo, then ether (20 ml) was added to the residue and the mixture was washed with water (2×20 ml). The organic layer was separated, dried (MgSO4) and the solvent evaporated in vacuo. The crude residue was chromatographed using 1:1 petrol (60/80):ether, to give 1'-benzylspiro[indane-1,4'-piperidine] as a viscous colourless oil (31 mg, 20%).
Reaction SMILES: Cl[CH2:2][S:3]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].[F:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.CC(C)([O-])C.[K+].C(O)(=O)C>C1COCC1>[F:16][C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[C:21]([CH2:2][S:3]([C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][CH:7]=2)(=[O:5])=[O:4])[CH:22]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=S(=O)(CCl)c1cccc2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1CS(=O)(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a chilled mixture of 1-chloromethanesulfonyl-naphthalene (19.7 g, 81.8 mmol) and 1-fluoro-4-nitrobenzene (8.7 mL, 82 mmol) in dry THF (197 mL) was dropwise added 1.0M potassium t-butoxide in THF (205 mL, 205 mmol). The reaction mixture was stirred at ambient temperature under nitrogen for 1.5 hours. Glacial acetic acid (16 mL, 280 mmol) was then added. After stirring at ambient temperature for 1 hour, 40 minutes, the reaction mixture was concentrated and partitioned in warm ethyl acetate and brine. The organic phase was dried with anhydrous magnesium sulfate, filtered and concentrated. The solid residue was stirred in ether, filtered and dried at 82° C. in vacuo for 1 hour. This yielded 1-(5-fluoro-2-nitro-phenylmethanesulfonyl)-naphthalene as a brown/rust-colored solid (19.9 g, 70.6%): MP: 155-160° C.; Mass Spectrum (−EI, [M−H]−) m/z 344. 1HNMR (300 MHz, DMSO-d6): δ8.50-8.52 (m, 1H), 8.33 (d, 1H, J=8.30 Hz), 8.06-8.14 (m, 2H), 7.97 (dd, 1H, J=7.32 Hz and 1.22 Hz), 7.62-7.74 (m, 3H), 7.44-7.48 (m, 1H), 7.23-7.26 (m, 1H), 5.23 ppm (s, 2H). Elemental Analysis for C17H12FNO4S: Calcd: C, 59.12; H, 3.50; N, 4.06; Found: C, 58.77; H, 3.30; N, 3.92.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[Na].Cl[CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13]>CO.C[O-].[Na+]>[OH:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[O:4][CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C(C)Cl
Reactant: Oc1ccccc1O
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)C(C)Oc1ccccc1O
Yield: 15.3 %

Procedure:
Catechol (55 g) was dissolved in a methanol solution of sodium methoxide prepared from metallic sodium (11.5 g). Methyl 2-chloropropionate (62 g) was added thereto and refluxed. Extraction with ether and purification on a silica gel column afforded 15 g of methyl 2-(2-hydroxyphenoxy)propionate. This product and 3,4-dichlorobenzylcyanide were dissolved in an ethanol solution of sodium ethoxide prepared from metallic sodium (7 g), and the mixture was refluxed with heat for 3 hours. Extraction with ether and purification on a silica gel column afforded 3 g of 2-(3,4-dichlorophenyl)-4-(2-hydroxyphenyl)-3-oxopentanonitrile. This compound (1 g), 2,3-dichloro-5-trifluoromethylpyridine (0.6 g), and potassium carbonate (0.4 g) were dissolved in dimethylformamide, and the mixture was stirred for 2 hours at 120° C. Extraction with ether and purification on a silica gel column afforded 0.6 g of 4-[2-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy]-2-(3,4-dichlorophenyl)-3-oxopentanonitrile (Compound 18).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([O:15]CC)=[O:14].Cl[Sn]Cl.[CH3:21][CH2:22]O>>[CH2:21]([CH:12]([C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[C:7]([F:8])[C:2]=1[F:1])[C:13]([OH:15])=[O:14])[CH3:22]
Reactant: CCO
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])c(F)c1F
Agent: Cl[Sn]Cl
Product: CCC(C(=O)O)c1ccc(N)c(F)c1F
Reaction time: 18 h
Yield: 38 %

Procedure:
To a stirred solution of ethyl 2,3-difluoro-4-nitrophenylacetate (5.85 g, 23.9 mol) in EtOH (100 mL), was added SnCl2 (16.1 g, 71.6 mmol) at rt. The stirring was continued for 18 hours at reflux. After removal of the solvent, the residue was dissolved in CHCl3 (100 mL) and poured into ice water-4M NaOH (40 mL of 4M NaOH in 300 mL of ice-water), extracted with CHCl3 (100 mL×2), dried over anhydrous MgSO4, and concentrated under a reduced pressure. The residue was chromatographed on silica gel (middle pressure chromatography system YAMAZEN YFLC-5404, linear gradient of hexane-EtOAc from 9:1 to 7:3, φ50 mm×500 mm, 15 ml/min) to give ethyl 4-amino-2,3-difluorophenylacetic acid (1.94 g, 38%) as a colorless oil. 1H-NMR (CDCl3) δ1.25 (t, J=7.3 Hz, 3H), 3.55 (d, J=1.0H, 2H), 3.78 (brs, 2H), 4.15 (dd, J=7.2 Hz, 14.2 Hz, 2H), 6.49 (dt, J=1.8, 8.2 Hz, 1H), 6.78 (m, 1H); MS (FAB) m/z 216 (M++1).
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.OC(C(F)(F)F)=O.[C:40]([C:44]1[CH:49]=[CH:48][C:47]([CH2:50][CH2:51][CH2:52][CH:53]2[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)=[CH:46][CH:45]=1)([O:42][CH3:43])=[O:41]>>[C:40]([C:44]1[CH:49]=[CH:48][C:47]([CH2:50][CH2:51][CH2:52][CH:53]2[CH2:54][CH2:55][N:56]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:6][N:5]([C@H:14]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[C:15]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[O:16])[CH2:4]3)[CH2:57][CH2:58]2)=[CH:46][CH:45]=1)([O:42][CH3:43])=[O:41]
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: COC(=O)c1ccc(CCCC2CCNCC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(CCCC2CCN(C[C@H]3CN([C@@H](C(=O)OCc4ccc(OC)cc4)C4CCCCC4)C[C@@H]3c3ccccc3)CC2)cc1
Yield: 44.1 %

Procedure:
The title compound was prepared from 50 mg (0.11 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, (4-methoxy)benzyl ester (from EXAMPLE 33, Step E) and 0.1 mol of 4-(3-((4-carbomethoxy)phenyl) propyl)piperidine TFA (from EXAMPLE 29, Step B) using a procedure analogous to that described in EXAMPLE 1, Step J to afford 33 mg (48%) of the title compound: 1H NMR (500 MHz), 0.60-1.28 (9H), 1.46-1.80 (11H), 1.95 (app d, J=13.0, 1H),2.18-2.36 (3H), 2.54 (dd, J=6.5,9.0, 1H), 2.60-2.64 (m, 2H), 2.66 (t, J=8.5, 2H), 2.77-2.82 (m, 2H), 3.13-3.21 (3H), 3.80 (s, 3H), 3.90 (s, 3H), 5.09 (ABq, J=12.0, 2H), 6.87 (d, J=9.0, 2H), 7.15-7.23 (5H), 7.25 (d, J=7.0, 2H), 7.32 (d, J=9.0,21), 7.93 (d, J=7.0, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1([CH:28]=[CH:27][CH:26]=[CH:25][CH2:24]1)[CH2:10][N:11]1[CH2:16][CH2:15][NH:14][C:13](=O)[CH:12]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(N1CCNC(=O)C1C1C=CC=CC=1)C)C>>[CH2:1]([O:8][C:9]1([CH:24]=[CH:25][CH:26]=[CH:27][CH2:28]1)[CH2:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH:12]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NCCN(CC2(OCc3ccccc3)C=CC=CC2)C1c1ccccc1
Agent: CCN(CC)C(C)N1CCNC(=O)C1c1ccccc1
Product: C1=CCC(CN2CCNCC2c2ccccc2)(OCc2ccccc2)C=C1

Procedure:
1-Benzyloxy benzyl-2-phenyl-3-keto piperazine prepared according to Example 12, is reduced by following the procedure described hereinabove in Example 8a whereby, in place of 1-diethylamino ethyl-3-keto-2-phenyl piperazine, the equimolecular amount of said 1-benzyloxy benzyl-2-phenyl-3-keto piperazine is used. The resulting 2-phenyl piperazine compound is obtained in the form of white crystals melting at 140°-141° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:39][C@H:40]([CH2:48][O:49][CH3:50])[C:41]([N:43]1[CH2:46][CH:45]([F:47])[CH2:44]1)=[O:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(#N)C>[F:47][CH:45]1[CH2:46][N:43]([C:41](=[O:42])[C@H:40]([NH:39][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH:19]=2)=[O:22])[CH2:48][O:49][CH3:50])[CH2:44]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reactant: COC[C@@H](N)C(=O)N1CC(F)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COC[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
A 10 mL round-bottomed flask was charged with 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (75 mg, 0.16 mmol), (R)-2-amino-1-(3-fluoro-azetidin-1-yl)-3-methoxy-propan-1-one trifluoroacetate (63 mg, 0.21 mmol), and HATU (63 mg, 0.21 mmol). Then added acetonitrile (1 mL) followed by N,N-diisopropylethylamine (0.55 mL, 3.15 mmol). The light yellow reaction mixture was stirred at room temperature overnight then quenched with water. The mixture was extracted with dichloromethane. The organic layers were combined, dried over Na2SO4, and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/heptanes (gradient: 5-90% EtOAc) to afford 47 mg (47%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-fluoro-azetidin-1-yl)-1-methoxymethyl-2-oxo-ethyl]-amide as an off-white solid. MS: [M+H]+=616.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=5)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:35]=[CH:36][CH:37]=[CH:38][C:6]=2[N:5]=1.C(N(CC)CC)C.[NH2:46][S:47]([C:50]1[CH:51]=[C:52]([CH:56]=[CH:57][C:58]=1[Cl:59])[C:53](Cl)=[O:54])(=[O:49])=[O:48]>ClCCl>[Cl:59][C:58]1[CH:57]=[CH:56][C:52]([C:53]([N:22]2[CH2:23][CH2:24][C:19]([CH2:18][CH2:17][N:16]3[C@H:11]4[CH2:12][CH2:13][C@@H:14]3[CH2:15][CH:9]([N:8]3[C:7]5[CH:35]=[CH:36][CH:37]=[CH:38][C:6]=5[N:5]=[C:4]3[CH3:3])[CH2:10]4)([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[CH:26]=3)[CH2:20][CH2:21]2)=[O:54])=[CH:51][C:50]=1[S:47]([NH2:46])(=[O:49])=[O:48]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2cccc(C(F)(F)F)c2)CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(C(F)(F)F)c2)CCN(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 2-methyl-1-[8-(2-{4-[3-(trifluoromethyl)phenyl]piperidin-4-yl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-1H-benzimidazole dihydrochloride (0.1 g, 0.2 mmol), triethylamine (0.056 mL, 0.4 mmol) and 3-(aminosulfonyl)-4-chlorobenzoyl chloride (0.056 g, 0.22 mmol) in dichloromethane (2 mL) was stirred at rt for 1.5 h. The reaction mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, dried, concentrated and purified by three successive chromatographies on silica gel eluting with mixtures of methanol in dichloromethane to give 2-chloro-5-({4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-[3-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)benzenesulfonamide as a wax (0.002 g, 2%). 1H NMR (400 MHz, CD3OD3) δ 7.79-7.94 (m, 2H), 7.57-7.71 (m, 5H), 7.40-7.54 (m, 2H), 7.15-7.21 (m, 2H), 4.73 (m, 1H), 4.15 (m, 1H), 3.39-3.55 (m, 4H), 3.16-3.22 (m, 1H), 2.52 (s, 3H), 2.34-2.50 (m, 3H), 2.22-2.32 (m, 1H), 1.94-2.12 (m, 10H), 1.68-1.74 (m, 2H). HRMS C36H39ClF3N5O3S m/z 714.2492 (M+H)Cal., 714.2496 (M+H)Obs..
Reaction SMILES: Cl[CH:2]([C:15]1[CH:19]=[C:18]([Si:20]([CH3:23])([CH3:22])[CH3:21])[O:17][CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:24]1([OH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C[O-].[K+]>O1CCCC1>[O:30]([CH:2]([C:15]1[CH:19]=[C:18]([Si:20]([CH3:23])([CH3:22])[CH3:21])[O:17][CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Oc1ccccc1
Reactant: CCCCCCCCCCCCC(Cl)c1coc([Si](C)(C)C)c1
Agent: C[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(Oc1ccccc1)c1coc([Si](C)(C)C)c1
Temperature: 25 °C

Procedure:
A mixture of 3-(1-chlorotridecyl)-5-trimethylsilylfuran, phenol and potassium methoxide in tetrahydrofuran is stirred at room temperature to give 3-(1-phenoxytridecyl)-5-trimethylsilylfuran. A mixture of this intermediate and Rose Bengal in tetrahydrofuran is exposed to oxygen by the procedure of Example 1 to give 4-(1-phenoxytridecyl)-5-hydroxy-2(5H)-furanone.
Reaction SMILES: [CH3:1][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]>C(Cl)Cl.O=[Mn]=O>[CH3:1][C:2]1[C:9]([C:10]([F:11])([F:12])[F:13])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Cc1c(CO)cccc1C(F)(F)F
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1c(C=O)cccc1C(F)(F)F
Reaction time: 72 h

Procedure:
To a sol. of 2-methyl-3-trifluoromethylbenzyl alcohol (0.500 g, 2.63 mmol) in CH2Cl2 (25 mL) was added activated MnO2 (2.29 g, 26.3 mmol). After stirring for 72 h, the mixture was filtered over Celite, and the solvents were removed under reduced pressure. The aldehyde is used in the next step without further purification. 1H NMR (CDCl3) δ 10.40 (s, 1H), 8.00 (d, 1H), 7.85 (d, 1H), 7.45 (t, 1H), 2.8 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.Br[CH:17]([CH3:20])[CH:18]=[CH2:19]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:15])[CH:18]([CH3:19])[CH:17]=[CH2:20])=[CH:6][CH:7]=1
Reactant: C=CC(C)Br
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Product: C=CC(C)C(O)c1c(C)noc1-c1ccc(Br)cc1

Procedure:
Prepared according to the procedure described in Example 63, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 3-bromo-but-1-ene.
Reaction SMILES: C([O:5][C:6](=[O:17])[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[N:10]=[C:9]([CH2:15][CH3:16])[CH:8]=1)(C)(C)C.[ClH:18]>>[ClH:18].[CH2:13]([C:11]1[CH:12]=[C:7]([CH:8]=[C:9]([CH2:15][CH3:16])[N:10]=1)[C:6]([OH:17])=[O:5])[CH3:14]
Reactant: CCc1cc(C(=O)OC(C)(C)C)cc(CC)n1
Agent: Cl
Product: CCc1cc(C(=O)O)cc(CC)n1

Procedure:
A solution of 2,6-diethyl-isonicotinic acid tert-butyl ester (635 mg, 2.70 mmol) in 6 N aq. HCl (10 mL) is stirred at 95° C. for 15 h before the solvent is evaporated. The residue is dried under HV to give 2,6-diethyl-isonicotinic acid hydrochloride (523 mg) as a colourless solid, LC-MS: tR=0.42 min; [M+1]+=180.31; 1H NMR (D6-DMSO): δ 7.95 (s, 2H), 3.05 (q, J=7.5 Hz, 4H), 1.31 (t, J=7.5 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:31])([CH3:30])[CH2:27][O:28][CH3:29])=[CH:22][C:21]=3[O:32][CH2:33][CH3:34])=[N:9]2)=[CH:4][CH:3]=1.[C:35](Cl)([Cl:37])=[O:36]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:35]([Cl:37])=[O:36])[C:10]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:31])([CH3:30])[CH2:27][O:28][CH3:29])=[CH:22][C:21]=3[O:32][CH2:33][CH3:34])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(C(C)(C)COC)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Product: CCOc1cc(C(C)(C)COC)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Yield: 56.7 %

Procedure:
4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-methoxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-1H-imidazole (580 mg, 1.166 mmol) was reacted with phosgene (725 uL, 1.399 mmol, 20% solution in toluene) using the procedure as described in example 12 to give 4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-methoxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (370 mg, 57% yield) as white solids.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:16]=[C:15]([N:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1>[OH-].[Na+].CO.O>[CH3:13][N:9]([CH2:10][CH2:11][CH3:12])[C:7](=[O:8])[C:6]1[CH:5]=[C:4]([CH:16]=[C:15]([N:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])[CH:14]=1)[C:3]([OH:23])=[O:2]
Reactant: CCCN(C)C(=O)c1cc(C(=O)OC)cc(N2CCCC2=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(N2CCCC2=O)c1

Procedure:
Stir N-methyl-5-(2-oxopyrrolidin-1-yl)-N-propyl-isophthalamic acid methyl ester (100 mg, 0.314 mmol) in 1 N NaOH (0.5 mL) and methanol (0.5 mL) at room temperature for 3 days. Dilute the mixture with water (1 mL) and wash the aqueous solution with diethyl ether. Acidify with 1 N HCl (0.55 mL) and extract with ethyl acetate (3×2 mL). Concentrate the organic layers to give the title compound as a crude residue which is used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:9]=[C:8]([N:10]2[CH2:14][C@@:13]3([CH2:19][CH2:18][CH2:17][C@@:16]([CH2:21][N:22]4[C:26]5[CH:27]=[C:28]([C:31]#[N:32])[CH:29]=[CH:30][C:25]=5[N:24]=[CH:23]4)([CH3:20])[CH2:15]3)[O:12][C:11]2=[O:33])[O:7][N:6]=1)([CH3:4])[CH3:3].C1C(=O)N([Cl:41])C(=O)C1>C(Cl)(Cl)Cl>[Cl:41][C:9]1[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[N:6][O:7][C:8]=1[N:10]1[CH2:14][C@@:13]2([CH2:19][CH2:18][CH2:17][C@@:16]([CH2:21][N:22]3[C:26]4[CH:27]=[C:28]([C:31]#[N:32])[CH:29]=[CH:30][C:25]=4[N:24]=[CH:23]3)([CH3:20])[CH2:15]2)[O:12][C:11]1=[O:33]
Reactant: CC(C)(C)c1cc(N2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)on1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1noc(N2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)c1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 54 %

Procedure:
To a vial was added 1-({(5S,7S)-3-[3-(1,1-dimethylethyl)-5-isoxazolyl]-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1H-benzimidazole-6-carbonitrile (85 mg, 0.190 mmol) and chloroform (950 μL) at RT, followed by NCS (25.4 mg, 0.190 mmol). The reaction mixture was stirred at RT followed by 65° C. for 5 h. Ater 22 h reaction at 65° C. the crude mixture was purified by reverse phase HPLC (30-80% MeCN/H2O, 0.1% TFA modifier, 30×150 mm Sunfire 18 column), and TFA salt of 1-({(5S,7S)-3-[4-chloro-3-(1,1-dimethylethyl)-5-isoxazolyl]-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1H-benzimidazole-6-carbonitrile was obtained (62.4 mg, 54% yield). MS (m/z) 482.2 (M+H+).