Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7]S(C)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[O:24][CH:23]=[CH:22]2.O>CN(C=O)C>[O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][O:7][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[O:24][CH:23]=[CH:22]2
Reactant: O=c1occc2cc(O)ccc12
Reactant: CS(=O)(=O)OCC1CCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1occc2cc(OC[C@H]3CCCO3)ccc12
Temperature: 80 °C
Reaction time: 7 h

Procedure:
Methanesulfonic acid tetrahydrofuran-2-ylmethyl ester (2.7 g) and cesium carbonate (12 g) were added to a solution of 6-hydroxyisochromen-1-one (2 g) in DMF (50 mL) and the mixture was stirred at 80° C. for 7 h. After addition of water, the mixture was extracted with dichloromethane, dried over magnesium sulfate and concentrated. The product with the molecular weight of 246.27 (C14H14O4) was obtained in this way; MS (ESI): 247 (M+H+). 6-[(R)-1-(Tetrahydrofuran-2-yl)methoxy]isochromen-1-one was synthesized analogously.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)#[CH:11]>C(NC(C)C)(C)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]#[C:11][C:2]2[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=2)=[CH:13][CH:14]=1
Reactant: COc1cncc(Br)c1
Reactant: C#Cc1ccc(F)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: Cc1ccccc1
Product: COc1cncc(C#Cc2ccc(F)cc2)c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 59.2 %

Procedure:
Dissolve 3-bromo-5-methoxypyridine (1.0 g, 5.35 mmol) in diisopropylamine (17 mL) and toluene (10 mL) under nitrogen. Add tetrakis(triphenylphosphine)palladium (0.200 g, 0.16 mmol). Heat at 60° C. and add 1-ethynyl-4-fluorobenzene (642 mg, 5.35 mmol) and copper (I) iodide (20 mg, 0.11 mmol). After 20 h, concentrate, and purify using silica gel chromatography, eluting with 30:70 ethyl acetate:hexanes, to give the title compound (720 mg, 60%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:24])=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[NH2:33][C:34]([C:36]1([CH3:49])[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1)=[S:35]>CN(C)C(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:35][C:34]([C:36]3([CH3:49])[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]3)=[N:33][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18]([O:19][CH2:20][CH:21]=[CH2:22])=[O:23])[C:12]=2[F:24])[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1F
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(N)=S)CC1
Agent: O=C1CCC(=O)N1Br
Solvent: CC(=O)N(C)C
Product: C=CCOC(=O)Nc1cccc(-c2nc(C3(C)CCN(C(=O)OC(C)(C)C)CC3)sc2-c2ccnc(Cl)n2)c1F
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 54 %

Procedure:
To a solution of 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (0.738 g, 2.110 mmol) in N,N-dimethylacetamide (8 mL) was added NBS (0.376 g, 2.110 mmol), and the reaction mixture was stirred for 1.5 h. 1,1-Dimethylethyl 4-(aminocarbonothioyl)-4-methyl-1-piperidinecarboxylate (0.545 g, 2.110 mmol) was added and the mixture was heated to 80° C. for 30 min. The reaction mixture was cooled, quenched with water (20 mL), and extracted with EtOAc (3×). The extract was dried over Na2SO4, filtered and concentrated. The residue was purified using column chromatography (hexane/EtOAc, 0 to 100%) to obtain the title compound (670 mg). MS (ESI): 588.2 [M+1]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:25]1([C:31]2[N:32]=[CH:33][N:34]([CH2:36][CH2:37][CH2:38][NH2:39])[CH:35]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([C:31]2[N:32]=[CH:33][N:34]([CH2:36][CH2:37][CH2:38][NH:39][C:10]([C:2]3[NH:1][C:9]4[C:4]([CH:3]=3)=[CH:5][CH:6]=[CH:7][CH:8]=4)=[O:12])[CH:35]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: NCCCn1cnc(-c2ccccc2)c1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(NCCCn1cnc(-c2ccccc2)c1)c1cc2ccccc2[nH]1

Procedure:
The compound of this Example is obtained when indole-2-carboxylic acid is reacted with 1,1'-carbonyldiimidazole and 4-phenyl-1H-imidazole-1-propanamine by the procedure of Example 33.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH:30]=O>>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:30]=[N:1][C:2]2[C:3]([C:12]=1[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]([F:11])([F:10])[F:9]
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Reactant: COc1ccccc1CC=O
Product: COc1ccccc1-c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and (2-Methoxy-phenyl)-acetaldehyde following the procedure of Example 457: MS (ESI) m/z 396; HRMS: calcd for C23H16F3NO2+H+, 396.12059; found (ESI, [M+H]+), 396.1223.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[O:3].[CH2:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.O>ClCCl>[OH:3][CH:2]([CH2:7][CH:8]=[CH:9][CH2:10][CH2:11][CH3:12])[C:1]([O:5][CH3:6])=[O:4]
Reactant: C=CCCCC
Reactant: COC(=O)C=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC=CCC(O)C(=O)OC
Temperature: 25 °C
Yield: 67 %

Procedure:
Methyl glyoxalate (8.80 g, 0.1 mol, 1.0 eq) and 1-hexene (16.80 g, 0.2 mol, 2.0 eq) are dissolved in dry dichloromethane (150 ml, freshly distilled from calcium hydride) under a nitrogen atmosphere. Stannic chloride (3.51 ml, 0.03 mol, 0.3 eq) is added dropwise with stirring and cooling at 0° C. (ice/water bath). After half an hour the reaction mixture is allowed to warm to room temperature and stirred for a further 21 hours before being neutralised with triethylamine (4.2 ml, 0.03 mol, 0.3 eq) with a further 5 minutes stirring. Water (50 ml) and dichloromethane (100 ml) are added, the organic layer is separated, washed in turn with water (50 ml) and brine (50 ml), dried over anhydrous magnesium sulphate and evaporated. The crude oil is purified by short path distillation (b p 120-130° C./0.7 mm Hg) to furnish the ester product (23) as a colourless liquid, 11.49 g (67% yield).
Reaction SMILES: [C:1]([C:3]([CH3:15])([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]CC)[CH3:4])#[N:2].N[CH2:17][CH2:18][OH:19]>C(O)CCC.O.O.C([O-])(=O)C.[Cd+2].C([O-])(=O)C>[CH3:15][C:3]([C:1]1[O:19][CH2:18][CH2:17][N:2]=1)([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:4]
Reactant: NCCO
Reactant: CCCCCCCCCCC(C)(C)C#N
Agent: CC(=O)[O-]
Agent: [Cd+2]
Solvent: O
Solvent: CCCCO
Product: CCCCCCCCC(C)(C)C1=NCCO1

Procedure:
100 mmoles of 2-cyano-2-methyldodecane is reacted with 120 mmoles of 2-aminoethanol in 50 ml of 1-butanol in presence of 2.5 mmoles of cadmium acetate dihydrate as outlined under Example 1 to give 2-(2-methyl-2-decyl)-2-oxazoline.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][O:2][C:1]2[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=2)=[CH:12][CH:11]=1
Reactant: Oc1ccc(O)cc1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Oc1ccc(OCc2ccc(F)cc2)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 40.9 %

Procedure:
A solution of 10 g of hydroquinone in 90 ml of acetonitrile was treated with 8.58 g of 4-fluorobenzylbromide and 15.7 g of potassium carbonate. The mixture was heated to 90° C. and stirred during 18 h. For the working-up, the reaction mixture was cooled to room temperature and treated with cold water. The solid material that has formed was filtered, washed twice with cold water and dried. For purification and separation from the bis-ether, the crude material was chromatographed on silica gel using a 4:1 mixture of heptane and ethyl acetate as the eluent. There were obtained 4.05 g (27% of theory) of 4-(4-fluoro-benzyloxy)-phenol as a white solid; MS: m/e=218 (M)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])(=[S:3])[NH2:2].Cl[CH:14]([C:20]([CH3:22])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].O>O1CCOCC1>[C:7]([C:6]1[CH:5]=[C:4]([C:1]2[S:3][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:20]([CH3:22])[N:2]=2)[CH:12]=[CH:11][CH:10]=1)([OH:9])=[O:8]
Reactant: NC(=S)c1cccc(C(=O)O)c1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(-c2cccc(C(=O)O)c2)nc1C
Temperature: 90 °C
Yield: 63.5 %

Procedure:
720 mg of 3-Thiocarbamoylbenzoic acid was suspended in 10 ml of dioxane, 720 mg of ethyl 2-chloroacetoacetate was added thereto, and the mixture was heated at 90° C. for 18 hours. After the reaction mixture was cooled, the resulting crystal was collected from the suspension by filtration and recrystallized from 20 ml of ethanol and a small amount of water to give 735 mg of ethyl 2-(3-carboxyphenyl)-4-methyl-5-thiazolecarboxylate (yield: 63%). 290 mg of the crystal was dissolved in 5 ml of 1N sodium hydroxide, and the mixture was heated at 60° C. for one hour. After the completion of the reaction, the reaction mixture was neutralized with 1N hydrochloric acid. The resulting crystal was collected by filtration and recrystallized from a 80% aqueous ethanol solution to give 258 mg of 2-(3-carboxyphenyl)-4-methyl-5-thiazolecarboxylic acid (yield: 83%).
Reaction SMILES: [C:1]([CH:3]1[CH:7]([CH2:8][CH2:9][C:10]2[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:23])#[N:2].[CH:24](N(CC)C(C)C)(C)C.C[Si](C=[N+]=[N-])(C)C.C(O)(=O)C>CO.C(#N)C.CCCCCC>[C:1]([C:3]1[CH:7]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])=[CH:21][CH:22]=2)[CH2:6][CH2:5][C:4]=1[O:23][CH3:24])#[N:2]
Reactant: CC(C)(C)OC(=O)c1ccc(CCC2CCC(=O)C2C#N)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCCCCC
Solvent: CC#N
Product: COC1=C(C#N)C(CCc2ccc(C(=O)OC(C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
t-Butyl 4-[2-(2-cyano-1-cyclopentanon-3-yl)ethyl]benzoate (0.43 g, 1.37 mmol) prepared in the Preparative Example 105 and N,N-diisopropylethylamine (0.21 g, 1.64 mmol) were dissolved in a methanol/acetonitrile (1:5) mixture, followed by the addition of 3.2 g of a 10% by weight solution of trimethylsilyldiazomethane in hexane. The obtained mixture was stirred at room temperature for 2 hours, followed by the addition of a small amount of acetic acid. The mixture this obtained was stirred and distilled to remove the solvent. The residue was dissolved in diethyl ether, washed with diluted hydrochloric acid, dilute alkali ind an aqueous solution of common salt, dehydrated and concentrated to dryness. The residue was purified by silica gel column chromatography to give the objective compound. yield: 0.23 g
Reaction SMILES: [CH3:1][C@@:2]1([C:12](O)=[O:13])[CH2:6][CH2:5][C@H:4]([C:7](O)=[O:8])[C:3]1([CH3:11])[CH3:10].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1>C1COCC1>[CH3:1][C@@:2]1([CH2:12][OH:13])[CH2:6][CH2:5][C@H:4]([CH2:7][OH:8])[C:3]1([CH3:10])[CH3:11]
Reactant: CC1(C)[C@@H](C(=O)O)CC[C@@]1(C)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)[C@@H](CO)CC[C@@]1(C)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
A solution of (1R,3S)-1,2,2-trimethylcyclopentane-1,3-dicarboxylic acid (26.25 g, 131 mmol) in THF (400 mL) was cooled in an ice bath (10° C.) and to this was added 1M LiAlH4/THF (328 mL, 328 mmol), dropwise over 1 h. The ice bath was removed and the white slurry was stirred for 5 h at room temperature and 17 h at reflux. After cooling to room temperature, the mixture was diluted with Et2O (500 mL), cooled in an ice bath and carefully quenched with water (12.2 mL), 15% NaOH (12.2 mL) and water (36.7 mL). After stirring for 30 min at room temperature, the white slurry was filtered through a pad of CELITE®, then dried (Na2SO4), filtered and concentrated to give ((1R,3S)-1,2,2-trimethylcyclopentane-1,3-diyl)dimethanol (21.665 g, 126 mmol, 96% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ: 3.73 (1 H, dd, J=10.2, 5.3 Hz), 3.58 (1 H, d, J=10.7 Hz), 3.51 (1 H, dd, J=10.1, 8.5 Hz), 3.46 (1 H, d, J=10.7 Hz), 2.04-2.12 (1 H, m), 1.89-1.99 (1 H, m), 1.55-1.64 (1 H, m), 1.31-1.41 (2 H, m), 1.22 (2 H, brs), 1.02 (3 H, s), 1.01 (3 H, s), 0.78 (3 H, s).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[CH3:26][C:27]1[C:31]([CH3:32])=[C:30]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[O:29][N:28]=1.NC1ON=C(C)C=1C>>[CH3:26][C:27]1[C:31]([CH3:32])=[C:30]([NH:33][C:34]([N:2]2[CH2:7][CH2:6][C:5](=[CH:8][C:9]3[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=4)[CH:10]=3)[CH2:4][CH2:3]2)=[O:35])[O:29][N:28]=1
Reactant: Cc1noc(NC(=O)Oc2ccccc2)c1C
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Agent: Cc1noc(N)c1C
Agent: Cl
Product: Cc1noc(NC(=O)N2CCC(=Cc3cccc(Oc4ccc(C(F)(F)F)cn4)c3)CC2)c1C

Procedure:
Following the procedure in Example 1, Step 6, 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (150 mg, 0.40 mmol, from Example 1, Step 5) and phenyl 3,4-dimethylisoxazol-5-ylcarbamate (94 mg, 0.40 mmol, prepared according to the procedure described in Synthesis, 1997, 1189-1194 from 5-amino-3,4-dimethylisoxazole) were used to provide the title compound (187 mg). MS (APCI 10V) AP+ 473.3, AP− 471.2; 1H NMR (400 MHz, CD3OD) δ ppm 1.83 (s, 3H) 2.18 (s, 3H) 2.41-2.49 (m, 2H) 2.53-2.62 (m, 2H) 3.49-3.57 (m, 2H) 3.58-3.66 (m, 2H) 6.46 (s, 1H) 6.97-7.05 (m, 2H) 7.10-7.20 (m, 2H) 7.40 (tt, J=7.64, 0.76 Hz, 1H) 8.08 (dd, J=8.65, 2.51 Hz, 1H) 8.33-8.51 (m, J=2.31, 1.33, 0.88, 0.74 Hz, 1H).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH:6]1[CH2:8][CH2:7]1)[OH:5].O.[NH2:11][NH2:12]>CO>[CH:6]1([CH:4]([OH:5])[C:3]([NH:11][NH2:12])=[O:2])[CH2:8][CH2:7]1
Reactant: NN
Reactant: COC(=O)C(O)C1CC1
Solvent: CO
Solvent: O
Product: NNC(=O)C(O)C1CC1
Yield: 69 %

Procedure:
As described for example 112a, (rac.)-2-cyclopropyl-2-hydroxy-acetic acid methyl ester (Newall, Christopher Earle; Foxton, Michael Walter; Hartley, Charles David; Looker, Brian Edgar. Cephalosporin antibiotics. Eur. Pat. Appl. (1985), 57 pp) in methanol was reacted with hydrazine hydrate (1.0 equivalent) at rt for 76 h. All volatiles were evaporated and the residue was triturated with hexane to afford the title compound as a white solid (yield: 69%). MS: m/e=112.2 [M−H2O]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:35]=[CH:34][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:16]3[N:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][C:17]=3OS(C(F)(F)F)(=O)=O)[CH:12]=[CH:13][C:14]=2[Cl:15])=[CH:5][CH:4]=1.[CH3:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCOCC.CCOC(C)=O.O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:16]3[N:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][C:17]=3[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[CH3:36])[CH:12]=[CH:13][C:14]=2[Cl:15])=[CH:34][CH:35]=1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(-c2ccc(Cl)c(OCc3ccc(OC)cc3)c2)n1
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2C)c(-c2ccc(Cl)c(OCc3ccc(OC)cc3)c2)n1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A solution of 2.6 g (4.88 mmol) of methyl 6-[3-[(4-methoxybenzyl)oxy]-4-chlorophenyl]-5-{[(trifluoromethyl)sulfonyl]oxy}pyridine-2-carboxylate (Example 1.4) and 880 mg (6.48 mmol) of 2-methylphenylboronic acid in 20 mL of anhydrous DMF is stirred for 15 minutes while sparging with argon, followed by addition of 1.27 g (6 mmol) of anhydrous K3PO4 and 0.58 g (0.5 mmol) of Pd(PPh3)4, and the reaction mixture is stirred for 18 hours at 90° C. under argon. The reaction medium is then poured at room temperature into 120 ml of a 1/1/2 ether/EtOAc/water mixture. After extracting, the aqueous phase is re-extracted with 10 mL of EtOAc, the organic phases are combined and washed with 4×30 mL of water, dried over Na2SO4 and then concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluting with a heptane/EtOAc gradient of from 0 to 20% EtOAc. After concentrating under reduced pressure, 1.8 g of methyl 6-[3-[(4-methoxybenzyl)]oxy-4-chlorophenyl]-5-(2-methylphenyl)pyridine-2-carboxylate are obtained in the form of an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([CH:11]([CH2:16][N+:17]([O-:19])=[O:18])[CH2:12][CH:13]([CH3:15])[CH3:14])C(OCC)=O)[CH3:2].O.[Na+].[Cl-].C(OC)(C)(C)C>CS(C)=O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:11]([CH2:16][N+:17]([O-:19])=[O:18])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)C(CC(C)C)C[N+](=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CC(CC(C)C)C[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 94.8 %

Procedure:
10.0 g (34 mmol) of 2-(3-methyl-1-nitromethyl-butyl)-malonic acid diethyl ester (XII, R1=ethyl) were dissolved in 140 mL of DMSO. Water (10.4 mL) and solid NaCl (14.6 g) were added and the mixture was heated for 6 hours at 150° C. After complete conversion, the reaction mixture was cooled to 25° C. and 150 mL of methyl tert-butyl ether were added. 100 mL of water were added slowly. The heterogeneous mixture was stirred for 5 minutes prior to layer separation. The aqueous layer was washed once with 75 mL of methyl tert-butyl ether. The organic layers were combined and washed once with 50 mL of water. The combined organic layers were dried and the volatiles were removed under reduced pressure to give 7.0 g of 5-methyl-3-nitromethyl-hexanoic acid ethyl ester (VIII, R1=ethyl; 93% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[C:27]([F:29])[CH:28]=1)#[N:22]>>[CH3:20][C:2]1([CH3:1])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:25]3[CH:24]=[C:23]([CH:28]=[C:27]([F:29])[CH:26]=3)[C:21]#[N:22])[CH:9]=2)[C:4](=[O:19])[CH2:3]1
Reactant: N#Cc1cc(F)cc(B(O)O)c1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: CC1(C)CC(=O)c2ccc(-c3cc(F)cc(C#N)c3)cc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 3-cyano-5-fluorophenyl boronic acid according to the procedure described in example 21. MS (ES) m/z 280.1; HRMS: calcd for C18H14FNO+H+, 280.11322; found (ESI, [M+H]+), 280.1129.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH2:33]1[C:35]2([CH2:40][NH:39][CH2:38][CH2:37][N:36]2C(OC(C)(C)C)=O)[CH2:34]1>>[NH:26]1[C:22]([C:21]2[C:2]([N:39]3[CH2:40][C:35]4([CH2:33][CH2:34]4)[NH:36][CH2:37][CH2:38]3)=[N:3][CH:4]=[C:5]([CH:20]=2)[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:18])([F:19])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:23][CH:24]=[N:25]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC12CC2
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCNC3(CC3)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 33 using 6-chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 32.1) and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate to afford an amorphous white powder. HPLC (Condition 4) tR=4.17 min, UPLC-MS (Condition 3) tR=0.78 min, m/z=459.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.46-0.85 (m, 4H) 3.04 (br. s, 2H) 3.16-3.37 (m, 5H) 6.67 (br. s, 1H) 7.34 (d, J=8.60 Hz, 2H) 7.86 (d, J=9.38 Hz, 3H) 8.34 (br. s, 1H) 8.75 (s, 1H) 10.43 (s, 1H) 12.96-13.19 (m, 1H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1.I[CH3:14]>>[Br:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH3:14])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: Brc1ccc2c(c1)CNCC2
Reactant: CI
Agent: Cl
Product: CN1CCc2ccc(Br)cc2C1

Procedure:
Following the procedure described for Intermediate 3 using 7-bromo-1,2,3,4-tetrahydroisoquinoline hydrochloride and iodomethane provided the title compound. ESMS [M+H]+: 226.0.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH2:20][CH:21]=[CH2:22])[C:17]([OH:19])=[O:18])=[CH:12][CH:11]=1)=O)(C)(C)C.Cl.[CH3:24]O>C(OCC)C>[CH3:24][O:19][C:17](=[O:18])[CH:16]([C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH2:8])=[CH:11][CH:12]=1)[CH2:20][CH:21]=[CH2:22]
Reactant: CO
Reactant: C=CCC(C(=O)O)c1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCOCC
Product: C=CCC(C(=O)OC)c1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.9 %

Procedure:
To a stirred solution of commercially available (Astatech) 2-[4-(tert-butoxycarbonylamino-methyl)-phenyl]-pent-4-enoic acid (2.00 g, 6.55 mmol) in methanol (30 cm3) under an atmosphere of dry nitrogen at ambient temperature was added 2M HCl in diethyl ether. The solution was stirred at ambient temperature for 20 hours and the filtrate volatile fractions removed in vacuo to afford the title compound as a white solid (1.67 g, 99.9%) with a positive ion ESI (M+H)+219.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[C:4]([O:20][CH3:21])[CH:3]=1.[CH3:22][S:23]([C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[C:29](O)=[O:30])(=[O:25])=[O:24]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH2:15][C:16]([F:18])([F:17])[F:19])[C:29](=[O:30])[C:28]2[CH:32]=[C:33]([C:35]([F:38])([F:36])[F:37])[CH:34]=[C:26]([S:23]([CH3:22])(=[O:25])=[O:24])[CH:27]=2)=[C:4]([O:20][CH3:21])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: COc1cc(F)ccc1-c1ccncc1NCC(F)(F)F
Product: COc1cc(F)ccc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-(2,2,2-trifluoro-ethyl)-amine (example 133, intermediate a) and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 114, intermediate a) after a reaction time of 72 hours. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of CH2Cl2: EtOAc (100:0 to 85:15). Light yellow foam (43%). MS (ESI): m/z=551.087 [M+H]+.