Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][C:5]=1[NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8].S(OCC)(O[CH2:27][CH3:28])(=O)=O.O>CN(C=O)C>[Cl:3][C:4]1[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][C:5]=1[N:6]([CH2:27][CH3:28])[S:7]([C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1)(=[O:9])=[O:8]
Reactant: CCOS(=O)(=O)OCC
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(C#N)cc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(c1ccc(C#N)cc1Cl)S(=O)(=O)c1ccc(C)cc1
Temperature: 100 °C
Yield: 60.5 %

Procedure:
To a suspension of sodium hydride (60%, 0.07 g (1.75 mmol)) in 3.0 ml of DMF, 2′-chloro-4′-cyano-p-toluenesulfonanilide (0.50 g (1.63 mmol)) was added under cooling with ice and with stirring. To the resulting mixture, after 15 minutes' stirring under cooling with ice, diethyl sulfate (0.25 ml (1.91 mmol)) was added dropwise and the mixture heated at 100° C. for 2 hours with stirring. Then, after being left to cool to room temperature, water was added and the mixture was extracted with diethyl ether. The extract was washed with water and 1% aqueous solution of sodium hydroxide, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crystals were recrystallized from diethyl ether to give 0.33 g (61%) of the title compound as white crystals.
Reaction SMILES: [N:1]([C:4]([CH3:10])([CH3:9])[CH2:5][C:6](Cl)=[O:7])=[N+:2]=[N-:3].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.O>ClCCCl>[N:1]([C:4]([CH3:10])([CH3:9])[CH2:5][C:6]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])=[N+:2]=[N-:3]
Reactant: C1CCNC1
Reactant: CC(C)(CC(=O)Cl)N=[N+]=[N-]
Solvent: ClCCCl
Solvent: O
Product: CC(C)(CC(=O)N1CCCC1)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a stirred ice cold solution of 3-azido-3-methylbutanoyl chloride (6.00 g, 37.1 mmol) in anhydrous DCE (100 mL) was added pyrrolidine (6.19 mL, 2 equiv, 74.2 mmol) in one portion. The reaction was stirred and left at 0° C. for 1 h. Water (100 mL) was added to the reaction mixture and the contents poured into a separatory funnel. The organic layer was separated and washed with water (3×100 mL) and brine (100 mL). It was dried over anhydrous MgSO4, filtered, concentrated and dried under high vacuum to give a crude oil (6.23 g, 85.6%). This material was used without further purification. 1H NMR (CDCl3, 400 MHz): δ 1.47 (s, 6H), 1.82-1.90 (q, J=6.8, 2H), 1.92-2.00 (q, J=6.8, 2H), 2.45 (s, 2H), 3.44-3.50 (t, J=6.8, 4H). 1.43 (s, 6H), 2.11-2.15 (m, 2H), 3.09 (s, 3 H), 3.35 (s, 2H), 3.41 (dt, J=7.2, 4H). LRMS (ESI+) for C9H16N4O (196.1); Found: 197 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH3:2].[ClH:24]>C(Cl)Cl>[ClH:24].[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH3:2]
Reactant: CCOc1cc(F)ccc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Product: CCOc1cc(F)ccc1C1CCNCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.6 %

Procedure:
Dissolve tert-butyl 4-(2-ethoxy-4-fluoro-phenyl)piperidine-1-carboxylate (3.5 g, 10.8 mmol) in DCM (28 mL) and add HCl (4M solution in dioxanes, 27 mL, 108.2 mmol). Stir at ambient temperature for 4 hours, and then concentrate to dryness under vacuum. Triturate with diethyl ether to give a racemic mixture of the title compound as a white solid (2.4 g, 85.4%). MS (m/z): 223 (M-HCl)
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([CH2:28][C:29]([OH:31])=O)=[CH:23][C:22]=3[F:32])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CO.[CH3:45][N:46]([CH3:50])[CH2:47][CH2:48][NH2:49]>ClCCCl>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([CH2:28][C:29](=[O:31])[NH:49][CH2:48][CH2:47][N:46]([CH3:50])[CH3:45])=[CH:23][C:22]=3[F:32])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(CC(=O)O)cc3F)CC2)CC1
Reactant: CN(C)CCN
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: ClCCCl
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(CC(=O)NCCN(C)C)cc3F)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-[1-(4-carboxymethyl-2,5-difluoro-phenyl)-piperidin-4-ylidene aminooxy]-piperidine-1-carboxylic acid isopropyl ester 75b (8 mg, 0.017 mmol) was dissolved in DCE (0.5 mL) and N,N-dimethylethylenediamine (0.01 mL). HOBt (4.5 mg, 0.034 mmol) and EDC(6.5 mg, 0.034 mmol) were added and the mixture was stirred at r.t. for 16 h. MeOH was added and the mixture purified by HPLC to give 4-(1-{4-[(2-dimethylamino-ethylcarbamoyl)-methyl]-2,5-difluoro-phenyl}-piperidin-4-ylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester 75-1. LC-MS 525.9 (MH+).
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:24])=[C:13]([CH:15]=[N:16][C:17]([O:19][Si](C)(C)C)=[CH2:18])[CH:14]=1.C(OC([N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([Cl:41])[CH:39]=2)/[C:34](=[CH:42]/[C:43]2[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:44]=2[O:50][CH2:51][CH2:52][O:53]C(OC(C)(C)C)=O)/[C:33]1=[O:61])=O)(C)(C)C>CO>[Cl:41][C:38]1[CH:39]=[C:40]2[NH:32][C:33](=[O:61])[C:34]3([CH:42]([C:43]4[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:44]=4[O:50][CH2:51][CH2:52][OH:53])[CH2:19][C:17](=[O:18])[NH:16][CH:15]3[C:13]3[CH:14]=[C:9]([F:8])[CH:10]=[CH:11][C:12]=3[CH3:24])[C:35]2=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)OCCOc1ccc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCCO)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 1.1 %

Procedure:
To a toluene solution (10 mL) of 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (10.93 mmol) was added E/Z-3-[2-(2-tert-Butoxycarbonyloxy-ethoxy)-5-chloro-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1 g, 1.82 mmol). Then the reaction tube was placed into the cavity of a focused monomode microwave reactor and the contents of the flask were irradiated at 130° C. for 40 min. After the solution was cooled to room temperature, methanol was added, and then the mixture was concentrated. Then a mixture of trifluoroacetic acid and dichloromethane was added. The reaction mixture was stirred at room temperature for 10 min. The solution was concentrated and the residue was purified by Prep-HPLC to give title compound as a white solid (11 mg).
Reaction SMILES: [C:1]([C:4]1[CH:31]=[CH:30][C:7]([CH2:8][N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][N:12]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:11][C:10]2=[O:29])=[CH:6][CH:5]=1)([OH:3])=O.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.C(N(CC)CC)C>ClCCl>[N:32]1([C:1]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[CH2:13][N:12]([C:20](=[O:28])[C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)[CH2:11][C:10]3=[O:29])=[CH:30][CH:31]=2)=[O:3])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccccc32)cc1)N1CCCC1
Reaction time: 8 h

Procedure:
23 mg (0.053 mmol) of 1-(4-carboxybenzyl)-4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 5 ml of dichloromethane. 6 mg (0.079 mmol) of pyrrolidine, 13 mg (0.079 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.022 ml (0.159 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. The solvent was evaporated, and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[NH:30]1[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]1>>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5]([C:4]3[CH:27]=[CH:28][N:29]=[C:2]([N:30]4[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]4)[CH:3]=3)=[O:6])=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(Cl)c1
Reactant: OC1CCNCC1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(N2CCC(O)CC2)c1

Procedure:
Compound is formed by reacting 2-chloro-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-isonicotinamide and piperidin-4-ol under conditions described in general procedure A. 1H NMR (300 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.29 (d, 1H), 8.21 (m, 1H), 7.85 (m, 1H), 7.59 (m, 2H), 7.41 (m, 2H), 7.15 (d, 1H), 7.05 (d, 1H), 4.31 (t, 2H), 4.10 (m, 2H), 3.75 (m, 1H), 3.60 (t, 4H), 3.20 (m, 2H), 2.89 (m, 2H), 2.59 (m, 4H), 1.81 (m, 2H), 1.40 (m, 2H). MS: 477.3 (M+1).
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.Cl[C:26]1[S:27][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:29][N:30]=1>CN1CCCC1=O>[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][N:22]([C:26]3[S:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:29][N:30]=3)[CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:11][CH:12]=2)[CH2:4][CH2:3]1
Reactant: Clc1nnc(-c2ccccc2)s1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nnc(-c3ccccc3)s2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrochloride and 2-chloro-5-phenyl-[1,3,4]thiadiazole following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 16): tR=0.49 min; Mass spectrum (ESI+): m/z=472 [M+H]+.
Reaction SMILES: Br[C:2]([C:5](=[O:11])[C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)([CH3:4])[CH3:3].[N-:12]=[N+:13]=[N-:14].[Na+].O>CS(C)=O>[N:12]([C:2]([C:5](=[O:11])[C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)([CH3:4])[CH3:3])=[N+:13]=[N-:14]
Reactant: CC(C)(Br)C(=O)c1ccsc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(N=[N+]=[N-])C(=O)c1ccsc1

Procedure:
0.87 of 2-bromo-2-(3-thenoyl)propane was dissolved in 5 ml of dimethyl sulfoxide, then 0.44 g of sodium azide was added thereto and reacted at 70° C. for 1 hour. After completion of the reaction, the reaction mixture was allowed to cool and put into 200 ml of water, and then extracted with ethyl ether. The organic layer was washed with water, then dried over magnesium sulfate, followed by concentration to obtain 0.70 g of 2-azido-2-(3-thenoyl)propane. The NMR spectrum data of this product were as follows.
Reaction SMILES: Cl.[CH:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:4])[CH3:3].[CH2:32]([N:34]([CH2:38][CH3:39])[C:35](Cl)=[O:36])[CH3:33]>>[CH2:32]([N:34]([CH2:38][CH3:39])[C:35]([N:29]1[CH2:28][CH2:27][N:26]([C:24]([C:6]2[N:5]([CH:2]([CH3:3])[CH3:4])[C:13]3[C:8]([CH:7]=2)=[CH:9][C:10]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]2)=[CH:11][CH:12]=3)=[O:25])[CH2:31][CH2:30]1)=[O:36])[CH3:33]
Reactant: CCN(CC)C(=O)Cl
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCNCC2)n3C(C)C)CC1
Agent: Cl
Product: CCN(CC)C(=O)N1CCN(C(=O)c2cc3cc(OC4CCN(C(C)C)CC4)ccc3n2C(C)C)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [1-isopropyl-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone hydrochloride and N,N-diethylcarbamoyl chloride. Off-white solid. MS (m/z): 512.5 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]#[N:16].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[C:20]([CH3:26])[CH:19]=1.N1CCCCC1.[BH4-].[Na+]>C(O)C.CO>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]#[N:16])=[C:2]([NH:1][CH2:22][C:21]3[CH:24]=[CH:25][C:18]([F:17])=[CH:19][C:20]=3[CH3:26])[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: Cc1cc(F)ccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: C1CCNCC1
Product: Cc1cc(F)ccc1CNc1[nH]nc(Nc2cccc(Cl)c2)c1C#N
Temperature: 85 °C
Reaction time: 8 h

Procedure:
Dissolved 5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carbonitrile (58 mg) in 4 mL ethanol and added 0.250 mmol of 4-fluoro-2-methylbenzaldehyde followed by a single drop of piperidine. This solution was then heated to 85° C. for 17 hrs, then the ethanol was evaporated and the resulting product was scraped from the reaction vessels. The powder was then resuspended in 4 mL of MeOH and 3 eq. of sodium borohydride was added and left stirring overnight at room temperature. Then MeOH was then evaporated and the product C29 was scraped and collected. (50 mg)
Reaction SMILES: [CH2:1]=[C:2]1[C:7](=[O:8])[CH:6]2[CH2:9][CH2:10][N:3]1[CH2:4][CH2:5]2>C(O)C.[Pd]>[CH3:1][CH:2]1[CH:7]([OH:8])[CH:6]2[CH2:9][CH2:10][N:3]1[CH2:4][CH2:5]2
Reactant: C=C1C(=O)C2CCN1CC2
Agent: [Pd]
Solvent: CCO
Product: CC1C(O)C2CCN1CC2
Yield: 77.7 %

Procedure:
The 2-methylenequinuclidin-3-one (3.50 g) in ethanol (30 mL) was reduced over 10% Pd/C (50 wt %) under a H2 atmosphere. When judged complete by TLC (˜3 days), the catalyst was filtered off and the filter cake washed with ethyl acetate. The solvent was removed in vacuo to afford the desired product (2.80 g, 80%) was obtained and used without further purficiation. 1H NMR (400 MHz, CDCl3) 3.37-3.31 (m, 1H), 3.21-3.13 (m, 2H), 3.09-3.00 (m, 1H), 2.97-2.89 (m, 1H), 2.46-2.43 (m, 1H), 2.05-1.91 (m, 4H), 1.34 (d, J=7.6 Hz, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:35]([O:37]C)=[O:36])=[CH:10][CH:11]=[C:12]([CH2:14][N:15]2[C:19](=[O:20])[N:18]([CH2:21][C@H:22]([OH:27])[C:23]([F:26])([F:25])[F:24])[C:17]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[N:16]2)[CH:13]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:35]([OH:37])=[O:36])=[CH:10][CH:11]=[C:12]([CH2:14][N:15]2[C:19](=[O:20])[N:18]([CH2:21][C@H:22]([OH:27])[C:23]([F:24])([F:25])[F:26])[C:17]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)=[N:16]2)[CH:13]=1
Reactant: COC(=O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)cc1-c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)cc1-c1ccccc1Cl

Procedure:
Analogously to the preparation of Example 141, 218 mg (0.39 mmol) of the compound from Example 140 were reacted with 2 N aqueous sodium hydroxide solution. This gave 220 mg (quant.) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:34]#[C:35][C:36]([CH3:45])([CH3:44])[CH2:37][CH2:38][O:39][Si](C)(C)C)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][CH:23]([O:26][Si](C(C)(C)C)(C)C)[CH2:22][CH2:21]1)[C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[O:46]1[CH2:51][CH2:50][C:49](=O)[CH2:48][CH2:47]1.C([SiH](CC)CC)C.C([O-])(O)=O.[Na+]>[N+](C)([O-])=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:34]#[C:35][C:36]([CH3:45])([CH3:44])[CH2:37][CH2:38][O:39][CH:49]2[CH2:50][CH2:51][O:46][CH2:47][CH2:48]2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([CH:13]1[CH2:14][CH2:15][CH:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12])=[O:4]
Reactant: O=C1CCOCC1
Reactant: COC(=O)c1sc(C#CC(C)(C)CCO[Si](C)(C)C)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C[N+](=O)[O-]
Product: COC(=O)c1sc(C#CC(C)(C)CCOC2CCOCC2)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.8 %

Procedure:
3-[[4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexyl]-(4-methyl-cyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-5-trimethylsilanyloxy-pent-1-ynyl)-thiophene-2-carboxylic acid methyl ester (230 mg, 0.34 mmol) was added to a solution of tetrahydro-pyran-4-one (29 mg, 0.29 mmol) and FeCl3 (2.8 mg, 0.017 mmol) in nitromethane (5.0 mL) at 0° C. Triethylsilane (0.054 mL, 0.34 mmol) was added and the reaction warmed to room temperature and stirred for 2 h. Sat. NaHCO3 was added and the reaction extracted with dichloromethane. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated to give the crude product. Purification by HPLC with CH3CN (0.1% TFA)/H2O (0.1% TFA) provided 5-[3,3-dimethyl-5-(tetrahydro-pyran-4-yloxy)-pent-1-ynyl]-3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (8 mg, 4%) as solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].I[C:15]1[CH:24]=[CH:23][C:18]2[N:19]=[C:20]([CH3:22])[S:21][C:17]=2[CH:16]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:22][C:20]1[S:21][C:17]2[CH:16]=[C:15]([N:10]3[CH2:11][CH2:12][N:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:9]3=[O:13])[CH:24]=[CH:23][C:18]=2[N:19]=1
Reactant: Cc1nc2ccc(I)cc2s1
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1nc2ccc(N3CCN(c4cnccc4C)C3=O)cc2s1
Yield: 63.3 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 100 mg, 0.5643 mmol) was reacted with 6-iodo-2-methyl-benzothiazole (154 mg, 0.5598 mmol), 1,4-dioxane (20 mL), copper iodide (10.7 mg, 0.056 mmol), trans-1,2-diamino cyclohexane (19.4 mg, 0.169 mmol) and potassium phosphate (300 mg, 1.413 mmol) to afford the crude product. Purification by column chromatography on silica gel (5% MeOH in CHCl3) afforded 115 mg of the product (62.8% yield).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH:12]([N:15]([CH:26]([CH3:28])[CH3:27])[CH2:16][CH2:17][CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)O)([CH3:14])[CH3:13]>CS(O)(=O)=O>[CH:26]([N:15]([CH:12]([CH3:14])[CH3:13])[CH2:16][CH2:17][CH:18]([C:11]1[CH:10]=[C:5]([CH:4]=[CH:3][C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([CH3:28])[CH3:27]
Reactant: CC(C)N(CCC(O)c1ccccc1)C(C)C
Reactant: COC(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)O
Product: COC(=O)c1ccc(O)c(C(CCN(C(C)C)C(C)C)c2ccccc2)c1
Temperature: 52.5 °C
Yield: 92 %

Procedure:
Methyl 4-hydroxy-benzoate (52.0 g, 340 mmol) is suspended in methanesulfonic acid (90 ml) in a round-bottom flask under inert atmosphere and the mixture is heated at a temperature of 50-55° C. 3-Diisopropylamino-1-phenyl-propan-1-ol (20.0 g, 85.0 mmol) is slowly added in about 2 hours and the mixture is reacted while hot for 5-6 hours. The mixture is cooled at room temperature and slowly poured in ice/water (200 g) under strong stirring. The product is extracted with dichloromethane (200 ml) and the organic phase is washed with a 10% sodium hydroxide solution (2×100 ml), then with an ammonium chloride aqueous solution until neutral pH. 28.9 g of a product are obtained in 92% yield.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@H:4]([C@@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=[O:14])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(N(CC)CC)C.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[C:27]([NH:1][CH2:2][CH2:3][C@@H:4]([C@@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=[O:14])[C:5]([O:7][C:8]([CH3:10])([CH3:11])[CH3:9])=[O:6])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)C[C@@H](C(=O)O)[C@H](CCN)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)O)[C@H](CCNC(=O)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
A solution of 1.0 g of 2(R)-[3-amino-1(S)-(tert-butoxycarbonyl)propyl]-4-methylvaleric acid in 20 ml of dichloromethane was cooled to 5° C. under nitrogen and treated with 1.3 ml of triethylamine and a solution of 0.54 g of benzoyl chloride in 10 ml of dichloromethane. The mixture was stirred overnight at room temperature and then the solvent was evaporated. The residue was dissolved in ethyl acetate and washed with 2M aqueous hydrogen chloride and water. Drying over anhydrous magnesium sulfate, filtration and evaporation of the solvent gave a pale yellow oil which was purified by flash column chromatography on silica gel, using ethyl acetate/hexane (3:1), to give 0.78 g of 2(R)-[3-benzamido-1(S)-(tert-butoxycarbonyl)propyl]-4-methylvaleric acid in the form of a colorless oil.
Reaction SMILES: ClC1C=CC(NC=C(C2ON=C(C)C=2)C(NC2C=CC(F)=CC=2)=O)=CC=1.C([O:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][CH:37]=[C:38]([C:49]2[O:53][N:52]=[C:51]([CH3:54])[CH:50]=2)[C:39]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)=[O:40])=[CH:32][CH:31]=1)C.ClC1C=CC(NC(=O)C(=CNC2C=CC=C(F)C=2)C2ON=C(C)C=2)=CC=1>>[F:48][C:45]1[CH:46]=[CH:47][C:42]([NH:41][C:39](=[O:40])[C:38](=[CH:37][NH:36][C:33]2[CH:32]=[CH:31][C:30]([OH:29])=[CH:35][CH:34]=2)[C:49]2[O:53][N:52]=[C:51]([CH3:54])[CH:50]=2)=[CH:43][CH:44]=1
Reactant: CCOc1ccc(NC=C(C(=O)Nc2ccc(F)cc2)c2cc(C)no2)cc1
Agent: Cc1cc(C(=CNc2ccc(Cl)cc2)C(=O)Nc2ccc(F)cc2)on1
Agent: Cc1cc(C(=CNc2cccc(F)c2)C(=O)Nc2ccc(Cl)cc2)on1
Product: Cc1cc(C(=CNc2ccc(O)cc2)C(=O)Nc2ccc(F)cc2)on1
Yield: 40 %

Procedure:
Yield 40%. α-[[(4-Chlorophenyl)amino]methylene]-N-(4-fluorophenyl)-3-methyl-5-isoxazoleacetamide: Yield 44%, 1H NMR (400 MHz, CDCl3) δ 11.50 (d, 1H), 8.28 (s, 1H), 7.70 (d, 1H), 7.50 (d, 2H), 7.30 (d, 4H), 7.00 (d, 2H), 6.01, 6.20 (s, 1H), 2.30, 2.35 (s, 3H); TOF MS ES+ m/z 372, 374 (MH+); 394, 396 (M+Na+); α-[[(4-Ethoxyphenyl)amino]methylene]-N-(4-fluorophenyl)-3-methyl-5-isoxazoleacetamide: Yield 47%; 1H NMR (400 MHz, CDCl3) δ 11.40 (d, 1H, J=12.3 Hz), 8.26 (br s, 1H), 7.67 (d, 1H, J=12.9 Hz), 7.48 (d, 2H, J=9.1 Hz), 7.04 (d, 2H, J=8.9 Hz), 7.01 (d, 2H, J=8.9 Hz), 6.98 (d, 2H, J=8.9 Hz), 5.95 (s, 1H), 4.00 (q, 2H, J=6.9 Hz), 2.31 (s, 3H), 1.40 (t, 2H, J=6.9 Hz); N-(4-Chlorophenyl)-α-[(3-fluorophenylamino)methylene]-3-methyl-5-isoxazole-acetamide; Isolated in 44% yield. 1H NMR (400 MHz, CDCl3) δ 11.50 (d, 1H), 8.30, 8.15 (d, 1H), 7.70 (d, 1H), 7.50 (d, 2H), 7.30 (dd, 3H), 6.80 (m, 3H), 6.22, 6.02 (s, 1H), 2.35, 2.30 (s, 3H). TOF MS ES+ m/z 372, 374 (M+H+) 394, 396 (M+Na+).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([O:11][Si](C)(C)C)[CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[Li+].[OH-].Cl>CO.O>[CH3:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cc(O[Si](C)(C)C)ccc1C(=O)[O-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(O)ccc1C(=O)O
Temperature: 0 °C

Procedure:
A 100 mL round bottom flask equipped with magnetic stir bar was charged with 5.7 g methyl. 2-methyl-4-trimethylsilyloxybenzoate and 2.0 g LiOH in 40 mL methanol and 10 mL water. After 2 hours at reflux the reaction was poured into 10 mL concentrated HCl and then 100 g ice. Extraction with ethyl acetate followed by concentration in vacuo gave a crude solid (70:30) product:starting material. Flash Chromatography using 50-50 ethyl acetate/hexanes as an eluent gave 1.15 g 2-methyl-4-hydroxybenzoic acid, m/e=193(M+H).