Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[C:8]2[CH2:13][CH2:12][CH2:11][NH:10][C:9]2=[O:14])=[CH:5][CH:4]=1.CO>[Ir].ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][C:9]2=[O:14])=[CH:15][CH:16]=1
Reactant: COc1ccc(C=C2CCCNC2=O)cc1
Agent: [Ir]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CC2CCCNC2=O)cc1
Yield: 87.4 %

Procedure:
This example describes the preparation of I where n=2 and R1=p-methoxyphenyl. In a nitrogen-filled glove box, a Fisher-Porter tube was charged with iridium catalyst prepared as in Example 1 (10 mg, 0.012 mmol) and 3-(p-methoxybenzylidene)-2-piperidone (250 mg, 1.2 mmol). Methanol (3 mL) and dichloromethane (3 mL) were added and the system was flushed 4 times with hydrogen and pressured to 60 psi (0.5 MPa) H2. After 18 h the reaction mixture was filtered through a short pad of silica. The solvent was removed at reduced pressure to afford 3-p-methoxybenzyl-2-piperidone (230 mg, 92%) as a white crystalline solid. Chiral HPLC analysis (Chiralpak AS, 60% heptane, 39.2% isopropanol, 0.4% trifluoroacetic acid, 0.4% n-hexylamine, 40° C.) indicated that conversion was 100% and the enantiomeric excess was 83%. 13C NMR: δ 21.32, 25.49, 36.72, 42.56, 43.11, 55.40, 113.93, 130.37, 131.99, 158.18, 174.93; 1H NMR: δ 1.44 (m, 1H), 1.62 (m, 1H), 1.68-1.75 (m, 2H), 2.50 (m, 1H), 2.64 (app. dd, 1H), 3.20-3.37 (m, 3H), 3.79 (s, 3H), 6.82 (d, J=9 Hz, 2H), 7.09 (br s, 1H), 7.12 (d, J=9 Hz, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:21]=[CH:20][C:6]([N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.CO.O>C(Cl)Cl>[C:8]1([N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][C:3]([OH:2])=[CH:4][CH:5]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 4-methoxy-N,N-diphenylaniline (6.0 g, 21.8 mmol) in DCM (40 mL) was slowly added BBr3 (23 mL, 23 mmol) at about −78° C. The mixture was then stirred overnight under argon while it slowly warmed up to room temperature. To the resulting mixture, methanol (70 mL) was added slowly, then stirred for about 3 hours. The mixture was then poured into water and extracted with DCM (2×200 mL). The organic phases were then combined and washed with brine, dried over Na2SO4, loaded on silica gel, and purified by short plug using hexane/ethyl acetate (9:1 to 8:1). The desired fraction was concentrated and washed with hexanes to give a white solid (Compound 7) (4.59 g, in 81% yield).
Reaction SMILES: C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.[OH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[C:30](=[O:34])[CH:29]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:28]2.COC1C=CC(C=O)=CC=1>C(O)C>[OH:34][C@@H:30]1[C:31]2[C:27](=[CH:26][C:25]([OH:24])=[CH:33][CH:32]=2)[CH2:28][C@H:29]1[C:35]([O:37][CH2:38][CH3:39])=[O:36]
Reactant: CCOC(=O)C1Cc2cc(O)ccc2C1=O
Agent: COc1ccc(C=O)cc1
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: CCO
Product: CCOC(=O)[C@@H]1Cc2cc(O)ccc2[C@H]1O
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
Twenty grams of bakers' yeast (Sigma Chemical Company, type II) are suspended in an aqueous solution containing 30 grams of sucrose in a conical flask, and the mixture is placed on an orbital shaker (220 rpm) at 30° C. for 30 minutes to initiate fermentation. Two grams of 5-hydroxy-2-carboethoxy-1-indanone is dissolved in 2 ml of 95% ethanol, the resulting solution is added to the fermenting yeast, and shaking is resumed. The reaction is followed by TLC (staining with anisaldehyde) to monitor the consumption of starting material and the production of product alcohol. After approximately 48 hours the reaction is judged complete, and the reaction is terminated by removing from the shaker and adding 20-30 grams of Celite. The resulting suspension is suction filtered through a pad of Celite and the clear yellow filtrate is extracted with ethyl acetate (4×200 ml). The extracts are combined, dried over MgSO4, filtered, and rotary evaporated to leave 1.5 grams of (1S,2R)-1-hydroxy-2-carboethoxy-5-hydroxyindane as a yellowish oil (>95% enantiomeric excess as judged by chiral chromatography).
Reaction SMILES: CO[C:3](=[O:20])[C@@H:4]([N:6]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:7][CH:8]=O)[CH3:5].Cl.[CH3:22][O:23][C:24](=[O:31])[C:25]([CH3:30])([CH3:29])[CH2:26][CH2:27][NH2:28]>>[CH2:13]([O:12][C:10]([N:6]1[CH2:7][CH2:8][N:28]([CH2:27][CH2:26][C:25]([C:24]([O:23][CH3:22])=[O:31])([CH3:30])[CH3:29])[C:3](=[O:20])[C@@H:4]1[CH3:5])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)C(C)(C)CCN
Reactant: COC(=O)[C@H](C)N(CC=O)C(=O)OCc1ccccc1
Agent: Cl
Product: COC(=O)C(C)(C)CCN1CCN(C(=O)OCc2ccccc2)[C@@H](C)C1=O
Yield: 90 %

Procedure:
In analogy to the procedure described in Example 12D, (S)-2-[benzyloxycarbonyl-(2-oxo-ethyl)-amino]-propionic acid methyl ester (intermediate 12C) and 4-amino-2,2-dimethyl-butyric acid methyl ester, hydrochloride (intermediate 27) gave the titled compound in 90% yield as light yellow oil. MS: 377.21 (MH+).
Reaction SMILES: [C:1]([NH:5][CH2:6][CH2:7][CH2:8][S:9]([OH:12])(=[O:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+:14]>CO>[C:1]([NH:5][CH2:6][CH2:7][CH2:8][S:9]([O-:12])(=[O:10])=[O:11])([CH3:4])([CH3:2])[CH3:3].[Na+:14]
Reactant: CC(C)(C)NCCCS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)NCCCS(=O)(=O)[O-]
Yield: 93.6 %

Procedure:
3-(tert-Butylamino)propylsulfonic acid (18 g) was added to a solution of sodium hydroxide (3.69 g, 0.092 mol) in methanol (300 mL). The mixture was stirred till become clear. The solvent was removed and the solid residue was dried in vacuum to give sodium 3-(tert-butylamino)propylsulfonate (18.7 g), as white microcrystals, decomposition at 170° C., 1H NMR (D2O) δ 1.08 (s, 9H), 1.80-1.90 (m, 2H), 2.64 (t, J=7.6 Hz, 2H), 2.91-2.96 (m, 2H); 13C NMR δ 24.4, 26.9, 39.8, 48.7, 49.6.
Reaction SMILES: [Br:1][C:2]1[S:10][C:9]2[CH:8]=[CH:7][N:6]=[C:5](Cl)[C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[N:18]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CS(C)=O>[Br:1][C:2]1[S:10][C:9]2[CH:8]=[CH:7][N:6]=[C:5]([N:21]3[CH2:22][CH2:23][CH2:24][N:18]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:20]3)[C:4]=2[CH:3]=1
Reactant: Clc1nccc2sc(Br)cc12
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCCN(c2nccc3sc(Br)cc23)CC1
Yield: 24.2 %

Procedure:
The same procedure above intermediate was used starting from 2-bromo-4-chlorothieno[3,2-c]pyridine (7.5 g, 30.45 mmol), K2CO3 (6.7 g, 33.5 mmol) and tert-butyl 1,4-diazepane-1-carboxylate (21.0 g, 152.2 mmol) in DMSO (30 mL). Purification by flash chromatography 3.04 g of the title compound (Yield 25%). HPLC purity 92%; 1H NMR (270 MHz, CDCl3) δ 1.38 (s, 4.5H), 1.43 (s, 4.5H), 1.96-2.11 (m, 2H), 3.36-3.41 (m, 1H), 3.46-3.51 (m, 1H), 3.65-3.87 (m, 6H), 7.02-7.04 (m, 1H), 7.40-7.42 (m, 1H), 7.94 (d, J=5.4 Hz, 1H). m/z=411.97 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)[CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:22](O)[CH3:23]>ClC(Cl)C.C(N)CC1C=CC=CC=1>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=3)[O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:7][CH2:6][CH2:5][C:23]3[CH:22]=[CH:4][CH:3]=[CH:2][CH:21]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3cccc(OC[C@H]4CO4)c3)noc2c1
Reactant: CCO
Agent: NCCc1ccccc1
Solvent: CC(Cl)Cl
Product: O[C@H](CNCCc1ccccc1)COc1cccc(-c2noc3cc(F)ccc23)c1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(3-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dichloroethane, phenethylamine, and ethanol, essentially as described above in Example 57. Purity by LC/MS=˜88%, [M+H]+=407.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:11]=3)([CH3:4])([CH3:3])[CH3:2].CCCCCC.C([Li])CCC.[CH2:33]([C:35]([C:39]1[CH:40]=[CH:41][C:42](=[C:44]([CH3:46])[CH3:45])[CH:43]=1)([CH3:38])[CH2:36][CH3:37])[CH3:34]>C1COCC1.CCOCC.O>[CH2:33]([C:35]([C:39]1[CH:40]=[CH:41][CH:42]([C:44]([C:11]2[C:10]3[CH2:9][C:8]4[C:16](=[CH:17][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=4)[C:15]=3[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=2)([CH3:46])[CH3:45])[CH:43]=1)([CH3:38])[CH2:36][CH3:37])[CH3:34]
Reactant: CCC(C)(CC)C1=CC(=C(C)C)C=C1
Reactant: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)ccc1C2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: CCC(C)(CC)C1=CC(C(C)(C)c2cc(C(C)(C)C)cc3c2Cc2ccc(C(C)(C)C)cc2-3)C=C1
Temperature: 25 °C
Yield: 37.1 %

Procedure:
To a solution of 1.93 g (6.9 mmol) of 3,6-di-tert-butylfluorene in 30 ml of THF, 4.7 ml (7.6 mmol) of a hexane solution of n-butyllithium was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for one night. To the resulting red solution, a solution of 1.70 g (8.9 mmol) of 3-(1-ethyl-1-methylpropyl)-6,6-dimethylfulvene in 10 ml of THF was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for 5 days. After the reaction solution was diluted with 100 ml of ether, 50 ml of water was added. The separated organic phase was washed with water and a saturated saline solution, then dried over magnesium sulfate and filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a liquid. The liquid was isolated and purified by column chromatography (silica gel, developing solvent: hexane) to obtain 1.20 g (2.56 mmol) of a white solid (yield: 37%). The analyzed values are given below.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([N+:10]([O-])=O)[CH:3]=1.[CH3:13][Si:14]([CH3:21])([CH3:20])[C:15]#[C:16][CH2:17][CH2:18][NH2:19]>>[F:1][C:2]1[CH:9]=[CH:8][C:5]2[C:4]([CH:3]=1)=[N:10][N:19]([CH2:18][CH2:17][C:16]#[C:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[CH:6]=2
Reactant: C[Si](C)(C)C#CCCN
Reactant: O=Cc1ccc(F)cc1[N+](=O)[O-]
Product: C[Si](C)(C)C#CCCn1cc2ccc(F)cc2n1
Yield: 100 %

Procedure:
The title compound was prepared in accordance with the general method of Example 149(A), from 4-fluoro-2-nitro-benzaldehyde (180 mg, 1.06 mmol) and 4-trimethylsilanyl-but-3-ynylamine (200 mg, 1.40 mmol). The crude product was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 6-fluoro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole (310 mg, 1.06 mmol).
Reaction SMILES: C([O:4][C@H:5]1[C@@H:10]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:9]([CH2:19][O:20]CC=C)[O:8][C@@H:7]([O:24][CH2:25][C@H:26]([CH2:42][O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C@@H:6]1[O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)C=C.II.O>O1CCCC1.C(Cl)(Cl)Cl.[Ir]>[CH2:59]([O:58][C@@H:6]1[C@@H:5]([OH:4])[C@@H:10]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@@H:9]([CH2:19][OH:20])[O:8][C@H:7]1[O:24][CH2:25][C@H:26]([CH2:42][O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: C=CCOC[C@H]1O[C@@H](OC[C@H](COCCCCCCCCCCCCCC)OCCCCCCCCCCCCCC)[C@H](OCc2ccccc2)[C@@H](OCC=C)[C@H]1OCc1ccccc1
Agent: [Ir]
Agent: II
Solvent: C1CCOC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCOC[C@@H](CO[C@@H]1O[C@H](CO)[C@H](OCc2ccccc2)[C@H](O)[C@H]1OCc1ccccc1)OCCCCCCCCCCCCCC
Yield: 87.4 %

Procedure:
Iridium complex (1,5-cyclooctadiene bis(methyldiphenylphosphine)iridium hexafluorophosphate, 112 mg, 0.096 mmol) was suspended in tetrahydrofuran (5 mL), and activated by stirring under H2 flow. To this solution, Compound 5 (864 mg, 0.95 mmol) dissolved in tetrahydrofuran (5 mL) was added, and the mixture was stirred at room temperature for 2 hours under argon gas flow. Then, iodine (484 mg), water (24.7 mL) and tetrahydrofuran (15 mL) were added thereto, and the mixture was further stirred at room temperature for 2 hours. The reaction mixture was diluted with chloroform, and washed successively with saturated sodium thiosulfate solution, saturated aqueous sodium hydrogencarbonate, and saturated brine. The chloroform layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:EtOAc=5:2) to obtain Compound 6 (686.6 mg, 87.1%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1C(C1N=C(C)SC=1C1C=CC(F)=CC=1)=O.[CH3:25][C:26]1[CH:27]=[CH:28][C:29]([C:35]2[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=2)=[C:30]([CH:34]=1)[C:31]([OH:33])=O>>[NH2:1][CH2:2][C@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:31]([C:30]1[CH:34]=[C:26]([CH3:25])[CH:27]=[CH:28][C:29]=1[C:35]1[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=1)=[O:33]
Reactant: Cc1nc(C(=O)N2CCC[C@@H](C)[C@@H]2CN)c(-c2ccc(F)cc2)s1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)O)c1
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@@H]2CN)c1

Procedure:
The title compound was prepared following the same general protocol as described for rac-trans-(2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone in Example A65 using 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoic acid. MS (ESI) 327 (M+H).
Reaction SMILES: C1([Si](C2C=CC=CC=2)(C2C=CC=CC=2)[C:8]#[C:9][C:10]2[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[Cl:18])C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:16][C:15]1[CH:14]=[C:13]([Cl:17])[CH:12]=[C:11]([Cl:18])[C:10]=1[C:9]#[CH:8]
Reactant: Clc1cc(Cl)c(C#C[Si](c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
A reaction mixture of 5 g (10.8 mmol) of triphenyl-(2,4,6-trichlorophenylethynyl)silane and 4.2 g (16.2 mmol) of tetrabutylammonium fluoride in 50 mL of absolute THF is stirred for half an hour at ambient temperature and then evaporated down. The residue is taken up in diethyl ether and water and extracted. The organic phase is dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluant: petroleum ether/toluene (9:1)). Yield: 0.46 g (20.7% of theory); Rf value: 0.6 (silica gel, petroleum ether/toluene (9:1)).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[CH3:37])[CH2:19][C:20]([C:22]3[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH3:29])[CH:23]=3)=O)=[CH:14][C:13]=2[F:38])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[NH2:40][OH:41].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[CH3:37])[CH2:19]/[C:20](=[N:40]\[OH:41])/[C:22]3[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH3:29])[CH:23]=3)=[CH:14][C:13]=2[F:38])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Oc2ccc(Cl)c(C(=O)O)c2)c(F)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Oc2ccc(Cl)c(C(=O)O)c2)c(F)c1

Procedure:
In analogy to example 151, step 3, 2-chloro-5-{4-[1-(4-chloro-2-methyl-phenyl)-3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-propyl]-2-fluoro-phenoxy}-benzoic acid was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound containing less than 10% of the corresponding Z isomer as a colourless solid, MS (ESI−): m/z=567.2 [M−H]−.
Reaction SMILES: [CH:1]([C:4]([C:24]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=1)([CH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])[C:5]#[N:6])([CH3:3])[CH3:2].C=O.[CH:38](O)=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH:1]([C:4]([C:24]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=1)([CH2:7][CH2:8][CH2:9][N:10]([CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])[CH3:38])[C:5]#[N:6])([CH3:3])[CH3:2]
Reactant: COc1cc(C(C#N)(CCCNCCCOc2ccccc2[N+](=O)[O-])C(C)C)cc(OC)c1OC
Reactant: O=CO
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1cc(C(C#N)(CCCN(C)CCCOc2ccccc2[N+](=O)[O-])C(C)C)cc(OC)c1OC
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of 2.58 g of alpha-isopropyl-alpha-[3-[N-[3-(2-nitrophenoxy)propyl]amino]propyl]-3,4,5-trimethoxyphenylacetonitrile, 4.35 ml of 37% of formalin, and 4.35 ml of 90% formic acid was stirred for 1 hour at 90° C. After cooling, to the mixture were added water and potassium carbonate to make it alkaline. The solution was extracted with chloroform and the extract was washed with water, dried, and evaporated. The residue was chromatographed on silica gel using 1% methanol-chloroform as an eluent to give 1.43 g of the desired compound as a yellow oil.
Reaction SMILES: [CH:1]1([OH:8])[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.N1C=CN=C1.[C:14]([Si:18](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:17])([CH3:16])[CH3:15]>O1CCOCC1>[Si:18]([O:7][CH:4]1[CH2:5][CH2:6][CH:1]([OH:8])[CH2:2][CH2:3]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OC1CCC(O)CC1
Agent: c1c[nH]cn1
Solvent: C1COCCO1
Product: CC(C)(C)[Si](OC1CCC(O)CC1)(c1ccccc1)c1ccccc1
Temperature: 15 °C
Yield: 54 %

Procedure:
Into a 1000-mL 3-necked round-bottom flask was placed cyclohexane-1,4-diol (20 g, 172.18 mmol, 1.00 equiv), 1,4-dioxane (500 mL) and 1H-imidazole (17.58 g, 258.24 mmol, 1.50 equiv). This was followed by the addition of a solution of tert-butyl(chloro)diphenylsilane (49.69 g, 180.78 mmol, 1.05 equiv) in dioxane (100 mL) dropwise with stirring at 15° C. The resulting solution was stirred for 15 h at 15-20° C. The solids were filtered out. The filtrate was diluted with 200 mL of water. The resulting solution was extracted with 3×200 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:1-1:60-1:50-1:30-1:20). Purification afforded 32.98 g (54%) of 4-[(tert-butyldiphenylsilyl)oxy]cyclohexan-1-ol (74.1) as a white semi-solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:10][O-:11].[Na+].CO>CO>[CH3:10][O:11][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cnccc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccncc1C#N
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To a solution of compound (20)(2.77 g, 20.0 mmol) in methanol (5 ml) was added a 28% sodium methylate-methanol solution (5.0 g, 24.0 mmol) at room temperature and the mixture was stirred for one hr. The solvent was concentrated and the obtained residue was partitioned between ethyl acetate and iced-brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from a small amount of isopropyl ether to give the title compound (2.3 g, 86%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH2:18][CH2:19][CH2:20][N:21]([N:30]2[CH:34]=[N:33][N:32]=[CH:31]2)[C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].C1COCC1.C(O)C>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH2:18][CH2:19][CH2:20][N:21]([N:30]2[CH:31]=[N:32][N:33]=[CH:34]2)[C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: N#Cc1ccc(N(CCCS(=O)(=O)c2ccc(OCc3ccccc3)cc2)n2cnnc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1ccc(N(CCCS(=O)(=O)c2ccc(O)cc2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Palladium on charcoal (50 mg, 10% Pd) was added to a solution of 4-{[3-(4-Benzyloxy-benzenesulfonyl)-propyl]-[1,2,4]triazol-4-yl-amino}-benzonitrile (CAB02168, 118 mg, 0.25 mmol) in THF (10 mL) and ethanol (10 mL). The mixture was stirred under hydrogen atmosphere (balloon) for 18 h at room temperature. The reaction mixture was filtered through celite and the clear colourless filtrate was concentrated under reduced pressure. The residue was crystallised from acetone/water. Yield: 68 mg (71%) colourless crystals. 1H-NMR (400 MHz, d6-DMSO) δ=1.68-1.76 (m, 2H), 3.38 (t, J=7.6 Hz, 2H), 3.92 (t, J=7.2 Hz, 2H), 6.57 (d, J=9.0 Hz, 2H), 6.95 (d, J=9.0 Hz, 2H), 7.68 (d, J=9.0 Hz, 2H), 7.73 (d, J=9.0 Hz, 2H), 8.97 (s, 2H), 10.64 (s, 1H, —OH). LRMS (FAB+): 384.0 (100, [M+H]+). HRMS (FAB+): 384.11248 C18H18N5O3S requires 384.11304.
Reaction SMILES: [C:1]([C:3]1([CH2:9][C:10]([O-:12])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].[Na+].C(C1(CC([O-])=O)CCCCC1)#N.[K+]>>[C:1]([C:3]1([CH2:9][C:10]([OH:12])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(CC(=O)[O-])CCCCC1
Agent: [K+]
Agent: [Na+]
Product: N#CC1(CC(=O)O)CCCCC1

Procedure:
sodium 1-cyanocyclohexaneacetate; and potassium 1-cyanocyclohexaneacetate.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([S:8][CH2:9][C:10]([NH2:12])=[O:11])=[O:7].[C:13](OC(=O)C)(=[O:15])[CH3:14].C(Cl)(=O)C>>[C:13]([NH:12][C:10](=[O:11])[CH2:9][S:8][C:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:7])(=[O:15])[CH3:14]
Reactant: NC(=O)CSC(=O)c1ccco1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)Cl
Product: CC(=O)NC(=O)CSC(=O)c1ccco1
Temperature: 0 °C

Procedure:
A reaction mixture comprising 2.8 g. of the product of Step A above, 30 ml. of acetic anhydride and 2 ml. of acetyl chloride, was heated on a steambath for 6 hours. The reaction mixture was then cooled and poured into ice water, giving a gummy solid after about 15 minutes. The product was filtered and air dried to yield 1.1 g. This was recrystallized from toluene to yield 0.65 g., m.p. 103°-105° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:6]([NH:16][C:17](=O)[CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:5]=1.Cl>O1CCOCC1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:17]([CH2:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[N:16][C:6]=2[CH:5]=1)=[O:25]
Reactant: CCC(CC)Nc1ccc(C(=O)OC)cc1NC(=O)CC1CCCC1
Agent: Cl
Solvent: C1COCCO1
Product: CCC(CC)n1c(CC2CCCC2)nc2cc(C(=O)OC)ccc21
Temperature: 140 °C
Yield: 968.4 %

Procedure:
2.93 g of 3-(2-Cyclopentyl-acetylamino)-4-(1-ethyl-propylamino)-benzoic acid methyl ester were dissolved in 7.5 ml of dry dioxane and 7.5 ml of 4M hydrochloric acid in dioxane were added. The reaction was heated in a microwave reactor to 140° C. for 30 min. The reaction mixture was concentrated, the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulphate and concentrated to yield 26.9 g (97%) of 2-Cyclopentylmethyl-1-(1-ethyl-propyl)-1H-benzoimidazole-5-carboxylic acid methyl ester as a brown solid which was used in the next step without further purification.