Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][N:24]([S:27]([CH2:30][C:31](OCC)=O)(=[O:29])=[O:28])[CH2:23][CH2:22]3)=[CH:17][C:15]=2[N:16]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C1C[O:45][CH2:44]C1>>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:44][OH:45])(=[O:28])=[O:29])[CH2:23][CH2:22]3)=[CH:17][C:15]=2[N:16]=1
Reactant: CCOC(=O)CS(=O)(=O)N1CCC(c2ccc3oc(-c4ccc(S(C)(=O)=O)cc4F)nc3c2)CC1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CS(=O)(=O)c1ccc(-c2nc3cc(C4CCN(S(=O)(=O)CCCO)CC4)ccc3o2)c(F)c1
Reaction time: 1.5 h

Procedure:
Example 61 (0.2 g, 0.41 mmol) was dissolved in DCM and added TEA (0.33 g, 3.3 mmol). This mixture was stirred at rt for 30 mins. After 30 mins reaction mixture cooled to 0° C. and added ethyl 3-(chlorosulfonyl)propanoate (245 mg, 1.2 mmol). This reaction continued for 30 mins at rt. Work up (H2O/DCM) followed by column purification on combiflash using a gradient mixture of EtOAc and Petether (65:35) as eluent afforded ethyl 2-{4-[2-(2-fluoro-4-(methylsulfonyl)phenyl)benzo[d]oxazol-5-yl]piperidin-1-ylsulfonyl}acetate. Ethyl 2-{4-[2-(2-fluoro-4-(methylsulfonyl)phenyl)benzo[d]oxazol-5-yl]piperidin-1-ylsulfonyl}acetate (100 mg, 0.19 mmol) was dissolved in THF (5 ml) and added Lithiumaluminium hydride (14 mg, 0.37 mmol) at 0° C. This mixture was stirred at same temperature for 90 mins. After completion of the reaction, reaction mass quenched with 1N HCl (7 ml). Work up (DCM/H2O) followed by purification on combiflash using a gradient mixture of EtOAc and Petether (65:35) as eluent afforded the titled compound (120 mg) as an off-white solid. M.P.: 204-206° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.47 (t, J 8.03, 1H), 8.06 (dd, J 1.6, 10.1, 1H), 7.97 (dd, J 1.6, 8.2, 1H), 7.82-7.75 (m, 2H), 7.43 (dd, J 1.5, 8.6, 1H), 4.66 (t, J 5.3, 1H), 3.74 (d, J 12.1, 2H), 3.50 (q, J 6.1, 2H), 3.38 (s, 3H), 3.12-3.06 (m, 2H), 2.98-2.80 (m, 3H), 1.96-1.90 (m, 2H), 1.88-1.81 (m, 2H), 1.79-1.69 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.Cl[C:12]1[N:20]=[CH:19][N:18]=[C:17]2[C:13]=1[NH:14][CH:15]=[N:16]2>O>[CH2:9]([O:10][C:12]1[N:20]=[CH:19][N:18]=[C:17]2[C:13]=1[NH:14][CH:15]=[N:16]2)[C:6]1[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=1
Reactant: OCc1ccccc1
Reactant: Clc1ncnc2nc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: c1ccc(COc2ncnc3nc[nH]c23)cc1
Temperature: 100 °C

Procedure:
Sodiumhydride (60% Dispersion in mineral oil; 3.23 g; 80 mmol) was slowly added to Benzylalkohol (30 ml; 34.7 mmol). After the addition of more benzylalkohol (10 ml) and 6-chloropurine (5.36 g). The reaction mixture was heated to 100° C. for 4 hours. When the reaction mixture has reached room temperature, water (1 ml) was slowly added. 6-Benzyloxypurine was precipitated by the addition of acetic acid (4.6 ml) and diethylether (550 ml). The precipitate was separated by filtration (11.72 g). Recrystallization from ether gave (4.78 g; 65.4%). Melting point 175-177° C. (litt. 170-172° C.)[Ramazaeva N., 1989 #473] 1H-NMR (DMSO-d6): 8.53 (1H, s); 8.39 (1H, s); 7.54-7.35 (5H, m); 5.62 (2H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]#[N:12])([O-])=O.Cl[Sn]Cl>Cl>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]#[N:12]
Reactant: N#Cc1cc(F)ccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Product: N#Cc1cc(F)ccc1N

Procedure:
The title compound was synthesized from commercially available 2-nitro-5-fluorobenzenecarbonitrile via reduction with SnCl2 in concentrated HCl as previously described in the following reference which is herein incorporated by reference in its entirety for all purposes as if fully set forth herein: Hunziker, F. et al. Eur. J. Med. Chem., Chim. Ther. 1981, 16(5), 391. GC/MS m/z: 136.1 (M+, 100%), Rt 8.87 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1>CO.[OH-].[Na+]>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([CH:11]=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)=[O:10])[CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)c1ccc(N)cc1
Reactant: COc1cccc(C=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc(C=CC(=O)c2ccc(N)cc2)c1
Yield: 56.2 %

Procedure:
A solution of p-aminoacetophenone (14.9 g, 0.11 mol) and m-anisaldehyde (10.0 g, 73 mmol) in methanol (500 ml) and 1N NaOH (260 ml) was stirred at room temperature overnight. The precipitate was collected, the filtrate was concentrated to 300 ml and the new precipitate was collected. The combined solids were recrystallized from isopropanol to give present title product as a yellow solid (10.4 g, 56%).
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[CH3:23][O:24][CH2:25][CH:26]1[NH:31][CH2:30][CH2:29][N:28]([C:32]2[N:37]=[CH:36][C:35]([C:38](OC)=[O:39])=[CH:34][N:33]=2)[CH2:27]1.Cl>C1(C)C=CC=CC=1.CO>[CH3:14][O:13][C:11]1[CH:10]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH:22][C:38]([C:35]3[CH:34]=[N:33][C:32]([N:28]4[CH2:29][CH2:30][NH:31][CH:26]([CH2:25][O:24][CH3:23])[CH2:27]4)=[N:37][CH:36]=3)=[O:39])[NH:20][N:21]=2)[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: COCC1CN(c2ncc(C(=O)OC)cn2)CCN1
Agent: C[Al](C)C
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: COCC1CN(c2ncc(C(=O)Nc3cc(CCc4cc(OC)cc(OC)c4)n[nH]3)cn2)CCN1
Temperature: 60 °C
Reaction time: 18 h
Yield: 56.9 %

Procedure:
Trimethylaluminium (2M in toluene, 1.596 mL, 3.19 mmol) was added dropwise to a solution of 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (314 mg, 1.27 mmol) and methyl 2-(3-(methoxymethyl)piperazin-1-yl)pyrimidine-5-carboxylate (338 mg, 1.27 mmol) in toluene (6.35 mL) at 25° C. The resulting mixture was stirred at 60° C. for 18 h under nitrogen. The reaction mixture was added to methanol (100 mL) and treated with HCl (2N aqueous solution, until pH was 7 or lower). The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford the crude product as a yellow dry film. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (348 mg, 57%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([Cl:14])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([Cl:15])[CH:5]=1)(=O)[NH2:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O.N1C=CC=CC=1>O>[Cl:14][C:12]1[CH:13]=[C:4]([C:1]#[N:2])[CH:5]=[C:6]([Cl:15])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1c(Cl)cc(C(N)=O)cc1Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1c(Cl)cc(C#N)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.5 %

Procedure:
A mixture of methyl 4-carbamoyl-2,6-dichlorobenzoate (57 g, 230 mmol), trifluoroacetic anhydride (46 mL) and pyridine (46 mL) in dixoane (400 mL) was stirred at room temperature for 24 hours, diluted with water (300 mL) and extracted with ethyl acetate (3×300 mL). The combined organic extracts were washed with brine (200 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with petroleum-diethyl ether (10:1) to give methyl 2,6-dichloro-4-cyanobenzoate (32 g, yield: 61%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 3.91 (s, 3H), 7.95 (s, 2H). LCMS (ESI) m/z: 230.1 [M+H+].
Reaction SMILES: Cl.[CH2:2]([N:5]([CH2:37][CH2:38][CH3:39])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:33]C(O)=O)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([CH2:27][C:28]2[NH:29][CH:30]=[CH:31][N:32]=2)[CH2:20][C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[CH:14][CH:13]=1)[CH2:3][CH3:4].OCCN1C(=O)CCC1=O.[CH3:50][N:51]([CH:53]=[O:54])[CH3:52]>>[CH2:37]([N:5]([CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][N:19]([CH2:27][C:28]2[NH:29][CH:30]=[CH:31][N:32]=2)[CH2:20][C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[CH:16][CH:17]=1)[CH2:33][C:53]([N:51]([CH3:52])[CH3:50])=[O:54])[CH2:38][CH3:39]
Reactant: CCCN(CCC)CCCCN(CC(=O)O)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Reactant: CN(C)C=O
Agent: Cl
Agent: O=C1CCC(=O)N1CCO
Product: CCCN(CCC)CCCCN(CC(=O)N(C)C)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1

Procedure:
The hydrochloride (190 mg) of the compound obtained in Example 65-1 was dissolved in DMF (5.0 ml) and added with N-(2-hydroxyethyl)-succinimide (57.8 mg) and the whole was refluxed under heating for 4 hours. After completion of the reaction, the solvent was distilled off. The resultant was dissolved in chloroform and added with a saturated aqueous sodium hydrogen carbonate solution and the whole was stirred for a while. The solution was subjected to extraction with chloroform and washed with a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining a hydrochloride (82.5 mg) of the subject compound as a pale-yellow solid.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9](/[CH:12]=[CH:13]/[CH2:14][CH2:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].CC(C)=[O:26].OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[CH2:1]([C@H:6]1[CH2:7][CH2:8][C@H:9](/[CH:12]=[CH:13]/[CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:26])=[O:21])=[CH:22][CH:23]=2)[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](/C=C/CCc2ccc(C=O)cc2)CC1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCC[C@H]1CC[C@H](/C=C/CCc2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4 g of 4-[4E-(trans-4-pentylcyclohexyl)-3-butenyl]benzaldehyde (prepared according to Example 5) in 100 ml of acetone was treated dropwise with 10 ml of Jones' reagent. The mixture was stirred at room temperature for 1 hour and then poured into 100 ml of water. The precipitate which thereby resulted was filtered off, washed portionwise with water and dried in a vacuum. The crude product was recrystallized from ethanol and gave 2.5 g of pure 4-[4E-(trans-4-pentylcyclohexyl)-3-butenyl]benzoic acid.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[NH2:12][C:13]1[CH:14]=[C:15]([NH:20][C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:16]=[CH:17][C:18]=1[CH3:19]>>[F:29][C:28]([F:30])([F:31])[C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([NH:20][C:15]1[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([NH:12][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([CH2:2][Cl:1])[CH:4]=2)[CH:14]=1)=[O:32]
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N
Reactant: O=C(Cl)c1cccc(CCl)c1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1NC(=O)c1cccc(CCl)c1
Yield: 94 %

Procedure:
Using an analogous procedure to that described in Example 37, 3-chloromethylbenzoyl chloride was reacted with N-(3-amino-4-methylphenyl)-3-trifluoromethylbenzamide to give the title compound in 94% yield; NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 4.85 (s, 2H), 7.25 (d, 1H), 7.6 (m, 3H), 7.8 (m, 2H), 7.95 (d, 2H), 8.05 (s, 1H), 8.16 (m, 2H), 9.96 (s, 1), 10.44 (s, 1H); Mass Spectrum: M−H− 445.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:10][C:11]1[CH:21]=[CH:20][C:14]([CH:15]=[CH:16][C:17]([OH:19])=O)=[CH:13][CH:12]=1)(=[O:9])[CH3:8].[NH2:22][C:23]1[CH:35]=[C:34]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=[CH:32][C:24]=1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[C:7]([O:10][C:11]1[CH:12]=[CH:13][C:14](/[CH:15]=[CH:16]/[C:17]([NH:22][C:23]2[CH:35]=[C:34]([O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:33]=[CH:32][C:24]=2[C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])=[O:19])=[CH:20][CH:21]=1)(=[O:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Reactant: CC(=O)Oc1ccc(C=CC(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(/C=C/C(=O)Nc2cc(Oc3ccccc3)ccc2C(=O)OC(C)(C)C)cc1
Reaction time: 1 h

Procedure:
2.0 mL of methylene chloride, 3.9 μL of N,N-dimethylformamide and 0.094 mL of oxalyl chloride were added to 206 mg of 4-acetoxycinnamic acid at room temperature sequentially and stirred at the same temperature for 1 hour. The reaction mixture was added to a mixed solution of 86 mg of tert-butyl 2-amino-4-phenoxybenzoate, 3.0 mL of methylene chloride and 0.67 mL of triethylamine and stirred at room temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane; ethyl acetate=4:1] to obtain tert-butyl 2-((E)-3-(4-acetoxyphenyl)acrylamido)-4-phenoxybenzoate.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:15](=[C:16]3[C:21]=1[CH:20]=[CH:19][CH:18]=[CH:17]3)[CH:14]=[CH:13][C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=1)[CH3:2].C1C2C=CC3C(=CC([CH:40]=[O:41])=C4C=3C=CC=C4)C=2C=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:6](=[C:7]3[C:12](=[C:13]([CH:40]=[O:41])[CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH:5]=1)[CH3:2]
Reactant: O=Cc1cc2c3ccccc3ccc2c2ccccc12
Reactant: CCOc1cc2c3ccccc3ccc2c2ccccc12
Solvent: ClCCl
Product: CCOc1cc2c3ccccc3c(C=O)cc2c2ccccc12
Yield: 64 %

Procedure:
6-Ethoxychrysene (Cambridge Chemical, Inc., 48 g, 0.176 mol) was formylated according to the procedure outlined in 1A, except that CH2Cl2 (1 L) was used as the reaction solvent. After isolation, the crude material was chromatographed on a plug of SiO2 (500 g) using CH2Cl2 as the eluting solvent to give (after removal of solvent and drying) 33.7 g (64%) of 12-ethoxychrysene-6-carbaldehyde mp 173.5°-176°, (C, H).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH3:5].[Mg].Cl[SiH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([O:28][CH:29]([F:31])[F:30])=[C:23]([F:32])[CH:22]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1>C1COCC1>[CH2:1]([Si@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[C:23]([F:32])[C:24]([O:28][CH:29]([F:31])[F:30])=[C:25]([F:27])[CH:26]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCBr
Reactant: Fc1cc(-c2ccc(C3CC[SiH](Cl)CC3)cc2)cc(F)c1OC(F)F
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC[Si@H]1CC[C@H](c2ccc(-c3cc(F)c(OC(F)F)c(F)c3)cc2)CC1

Procedure:
3.0 g (20 mmol) of n-pentyl bromide was dripped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 7.8 g (20 mmol) of 4'-(4-chloro-4-silacyclohexyl)-3,5-difluoro-4-difluoromethoxybiphenyl to obtain 4'-(trans-4-n-pentyl-4-silacyclohexyl)-3,5-difluoro-4-difluoromethoxybiphenyl. The silacyclohexane rings of this product were a mixture of trans and cis isomers. They were separated by means of chromatography to obtain 6.6 g of the trans isomer (yield 82%).
Reaction SMILES: CON(C)[C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:17][O:18][CH3:19])=[O:5].[CH3:21][Mg]Br.C1(C)C=CC=CC=1.C1COCC1>C1COCC1>[CH3:19][O:18][CH2:17][C:7]1[N:8]=[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[S:10][C:6]=1[C:4](=[O:5])[CH3:21]
Reactant: C[Mg]Br
Reactant: COCc1nc(-c2ccccc2)sc1C(=O)N(C)OC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COCc1nc(-c2ccccc2)sc1C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of the above-prepared 4-methoxymethyl-2-phenyl-thiazole-5-carboxylic acid methoxy-methyl amide (6.706 g, 22.9 mmole, 1.0 eq) in dry THF (25 ml) at 0° C. was added dropwise a solution of 1.4M methylmagnesium bromide in (3:1)toluene-THF (32.7 ml, 45.8 mmole, 2.0 eq). The resulting tan suspension was stirred under nitrogen at room temperature for 30 minutes, then quenched by the addition of saturated ammonium chloride and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a brown oil. Silica gel chromatography using a gradient elution of (9:1) to (4:1) hexanes-ethyl acetate provided the title compound (6.033 g, 81%) as a yellow crystalline solid. 1H NMR (CDCl3): δ 2.7 (s, 3H), 3.5 (s, 3H), 4.9 (s, 2H) 7.4-7.5 (m, 3H), 8.0 (m, 2H).
Reaction SMILES: Cl.[O:2]1[C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:27]1([C:33]2[S:34][CH:35]=[C:36]([C:38](O)=[O:39])[N:37]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[C:27]1([C:33]2[S:34][CH:35]=[C:36]([C:38]([N:5]3[CH2:6][C:7]4([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]4)[O:2][CH2:3][CH2:4]3)=[O:39])[N:37]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)c1csc(-c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCCO2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(C(=O)c1csc(-c3ccccc3)n1)CCO2
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A solution of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (0.60 g) in DMF (11 mL) was treated with triethylamine (1.1 mL), followed by 2-phenyl-1,3-thiazole-4-carboxylic acid (0.421 g) and then O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.09 g). The resulting mixture was stirred at RT for 7 h. DMF was removed in vacuo. The residue was taken up in EtOAc (50 mL) and washed with saturated sodium bicarbonate solution (2×30 mL), water (30 mL) and brine (30 mL), dried over sodium sulphate, filtered and evaporated in vacuo. The brown oil was purified by silica gel chromatography eluting with 0-10% MeOH in DCM to give the subtitled compound as a brown solid. Yield 0.857 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][OH:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>ClCCl.[O-2].[O-2].[Mn+4]>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]=[O:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(CO)nc3N21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(C=O)nc3N21
Yield: 80.5 %

Procedure:
To a solution of 2.00 g (4R,9aR)-6-Hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 20 ml dichloromethane was added 6.00 g manganese dioxide in 3 portions of 2.00 g in intervals of 1 h at room temperature while stirring. The reaction mixture was stirred for 2 more hours at room temperature. The solids were removed by filtration over dicalite and the mother liquor was evaporated and the residue was purified by chromatography on silica gel with heptane:ethyl acetate=1:1 to yield 1.600 g of the title compound as slightly yellow crystals (MS: 316.0 (M+H+))
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8][C:9]([O:11]CC)=O)=[O:7].[NH2:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[CH:18]2>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:7])[CH2:8][C:9]([NH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[CH:18]2)=[O:11]
Reactant: CCOC(=O)CC(=O)c1ccco1
Reactant: Nc1ccc2[nH]ncc2c1
Product: O=C(CC(=O)c1ccco1)Nc1ccc2[nH]ncc2c1
Temperature: 180 °C

Procedure:
Ethyl 2-(fur-2-oyl)acetate (3 mL) was mixed with 5-aminoindazole (0.50 g) and heated in a SmithSynthesizer to 180° C. for 300 seconds. The crude mixture was then purified by silica gel chromatography to yield the title compound as a light purple solid. 1H NMR (keto tautomer) (400 MHz, DMSO-D6) δ ppm 12.99 (s, 1H), 10.22 (s, 1H), 8.11 (s, 1H), 8.05 (s, 1H), 8.02 (s, 1H), 7.58 (d, 1H), 7.49 (d, 1H), 7.40 (dd, 1H), 6.77 (dd, 1H), 3.96 (s, 2H). MS m/z 270 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][C:16]1[C:21]([CH:22]=O)=[CH:20][CH:19]=[CH:18][N:17]=1.Cl.[F:25][C:26]1([F:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)CC)C.C(O)(=O)C.C([BH3-])#N>ClC(Cl)C>[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][C:16]1[C:21]([CH2:22][N:29]2[CH2:30][CH2:31][C:26]([F:32])([F:25])[CH2:27][CH2:28]2)=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: FC1(F)CCNCC1
Reactant: O=Cc1cccnc1Oc1ccc2c(nnn2CC2CC2)c1Br
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: FC1(F)CCN(Cc2cccnc2Oc2ccc3c(nnn3CC3CC3)c2Br)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 2-{[4-bromo-1-(cyclopropylmethyl)-1H-benzotriazol-5-yl]oxy}pyridine-3-carbaldehyde (13, 20 mg, 0.05 mmol, 1 equiv.) and 4,4-difluoropiperidine hydrochloride (13 mg, 0.08 mmol, 1.5 equiv) in dichloroethane (1 mL) was treated with triethylamine (14 uL, 0.10 mmol, 2 equiv) and stirred for 5 min. The mixture was treated with acetic acid (14 uL, 0.25 mmol, 5 equiv) and resin-bound MP-cyanoborohydride (50 mg, 2.08 mmol/g, 2 equiv.) and was irradiated at 110° C. in a microwave reactor for 20 min. The mixture was cooled to ambient temperature and partitioned between sodium bicarbonate (saturated aqueous, 50 mL) and ethyl acetate (3×30 mL). The combined organic layers were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography (100:0 to 30:70; hexanes:ethyl acetate) to afford 4-bromo-1-(cyclopropylmethyl)-5-({3-[(4,4-difluoropiperidin-1-yl)methyl]pyridin-2-yl}oxy)-1H-benzotriazole (194) as a white powder, 1H NMR (400 MHz, CDCl3) δ 7.98 (dd, 1H, J=4.9, 2.0 Hz), 7.85 (br d, 1H, J=7.4 Hz), 7.56 (d, 1H, J=8.8 Hz), 7.36 (d, 1H, J=8.8 Hz), 7.04 (dd, 1H, J=7.5, 4.9 Hz), 4.52 (d, 2H, J=7.1 Hz), 3.85 (s, 2H), 2.73 (ap t, 4H, J=5.3 Hz), 2.11-2.01 (m, 4H), 1.47-1.37 (m, 1H), 0.71-0.67 (m, 2H), 0.54-0.50 (m, 2H) ppm. High resolution mass spectrometry (ES+) m/z=478.1062, [(M+H)+ calculated for C21H23BrF2N5O: 478.1049].
Reaction SMILES: C(O)(=O)C1C=C[N:5]=CC=1.C(OC(=O)C[CH2:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([C:25](=[NH:28])[NH:26][OH:27])=[CH:20][C:19]=1CC)(C)(C)C>>[CH2:18]([C:19]1[CH:20]=[C:21]([CH:22]=[C:23]([CH3:24])[N:5]=1)[C:25]([NH:26][OH:27])=[NH:28])[CH3:17]
Reactant: CCc1cc(C(=N)NO)cc(C)c1CCC(=O)OC(C)(C)C
Reactant: O=C(O)c1ccncc1
Product: CCc1cc(C(=N)NO)cc(C)n1

Procedure:
The title compound is prepared from isonicotinic acid 4 in analogy to steps e) to g) of the preparation of 3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenyl]-propionic acid tert-butyl ester; LC-MS: tR=0.23 min; [M+1]+=180.07; 1H NMR (d6-dmso): δ 1.22 (t, J=7.0 Hz, 3H), 2.44 (s, 3 H), 2.70 (q, J=7.8 Hz, 2H), 5.89 (s, 2 H), 7.31 (s, 2 H), 9.88 (s, 1 H).