Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[C:13]1[O:17][C:16]([CH3:18])=[N:15][CH:14]=1)[C:6]([NH:8][NH2:9])=[O:7].[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28](O)=[O:29])[CH:23]=[CH:24][C:25]=1[F:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28]([NH:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:12]([C:13]3[O:17][C:16]([CH3:18])=[N:15][CH:14]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:29])[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: O=C(O)Cc1ccc(F)c(F)c1
Reactant: COc1cc(C(=O)NN)ccc1-c1cnc(C)o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NNC(=O)Cc2ccc(F)c(F)c2)ccc1-c1cnc(C)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.5 %

Procedure:
A mixture of 3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)benzohydrazide (4.10 g), 3,4-difluorophenylacetic acid (3.15 g), HATU (7.57 g) and triethylamine (2.77 mL) in DMF (77 mL) was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the resultant precipitate was collected by filtration and washed with hexane and acetone to give the title compound (4.69 g).
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C=O)C.O>[N+:13]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])([O-:15])=[O:14]
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CCCCC2)c([N+](=O)[O-])c1
Temperature: 50 °C

Procedure:
A mixture of ethyl 4-fluoro-3-nitrobenzoate (Clontech 01072, 500 mg; 2.35 mmol; 1 eq.) and piperidine (599.2 mg; 7.04 mmol; 3 eq.) in DMF (2 mL) was heated to 50° C. for 3 hours. The reaction was then allowed to return to RT and diluted with water. It was extracted with EtOAc and the organic phase was dried over sodium sulfate and concentrated in vacuo, affording ethyl 3-nitro-4-piperidin-1-ylbenzoate as a yellow oil. The residue was taken up in THF (15 mL) and lithium hydroxide (280.86 mg; 11.73 mmol; 5 eq.) was added, followed by water (15 mL). The reaction mixture was then stirred at RT for 5 hours. It was concentrated and the residue was diluted with water. The aqueous phase was washed with Et2O and acidified to pH 5 with acetic acid. It was extracted with Et2O and the organic phase was dried over magnesium sulfate and concentrated, affording the title compound as a yellow solid (562 mg, 96%). 1H NMR: (DMSO-d6, 300 MHz) δ 13.07 (s, 1H), 8.29-8.28 (d, J=2.11 Hz, 1H), 8.03-8 (dd, J=8.91 Hz, J=2.20 Hz, 1H), 7.35-7.33 (d, J=8.91 Hz, 1H), 3.15-3.13 (m, 4H), 1.64-1.60 (m, 6H). LC/MS (Method A): 252.9 (M+H)+; 250.9 (M−H)−. HPLC (Method A) Rt 3.69 min (Purity: 99.7%).
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[N:7][N:6]([C:13]2[CH:14]=[C:15]([NH:19][C:20](=[O:22])[CH3:21])[CH:16]=[CH:17][CH:18]=2)[C:5]1=[O:23])[CH:2]=[CH2:3].[CH:24]([C:27]1[CH:34]=CC(CBr)=[CH:29][CH:28]=1)([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O.O>[CH:24]([C:27]1[CH:28]=[CH:29][C:2]([CH2:1][N:4]2[C:9](=[O:10])[C:8]([O:11][CH3:12])=[N:7][N:6]([C:13]3[CH:14]=[C:15]([NH:19][C:20](=[O:22])[CH3:21])[CH:16]=[CH:17][CH:18]=3)[C:5]2=[O:23])=[CH:3][CH:34]=1)([CH3:26])[CH3:25]
Reactant: C=CCn1c(=O)c(OC)nn(-c2cccc(NC(C)=O)c2)c1=O
Reactant: CC(C)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1nn(-c2cccc(NC(C)=O)c2)c(=O)n(Cc2ccc(C(C)C)cc2)c1=O
Yield: 11.1 %

Procedure:
According to Scheme 3 Step 5: A suspension of compound 6(D) (60 mg, 0.22 mmol), 4-isopropylbenzyl bromide (41 μL, 0.24 mmol) and potassium carbonate (90 mg, 0.65 mmol) was stirred at 60° C. for 15 h in acetonitrile (2 mL). The mixture was diluted with AcOEt and water. The organic layer was washed twice with water and once with brine. The resulting organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel (Merck Flashmart prepacked column 10 g SiO2) using CH2Cl2/MeOH 98/2 as eluent to afford N-(3-(4-(4-isopropylbenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 6(E) (10 mg, 11%) as a yellow solid.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:40])[CH2:10][CH2:9][CH2:8][CH:7]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([C:19]3[C:27]4[C:22](=[N:23][CH:24]=[C:25]([Cl:28])[CH:26]=4)[N:21](S(C4C=CC(C)=CC=4)(=O)=O)[CH:20]=3)[N:13]=2)[CH:6]1[OH:39])=[O:4].C1COCC1.[Li+].[OH-]>CO>[Cl:28][C:25]1[CH:26]=[C:27]2[C:19]([C:14]3[N:13]=[C:12]([NH:11][CH:7]4[CH2:8][CH2:9][CH2:10][C:5]([CH3:40])([C:3]([OH:4])=[O:2])[CH:6]4[OH:39])[C:17]([F:18])=[CH:16][N:15]=3)=[CH:20][NH:21][C:22]2=[N:23][CH:24]=1
Reactant: COC(=O)C1(C)CCCC(Nc2nc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Cl)cc34)ncc2F)C1O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C(=O)O)CCCC(Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1O
Temperature: 25 °C

Procedure:
Racemic methyl-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-2-hydroxy-1-methyl-cyclohexanecarboxylate, 66f, (0.100 g, 0.170 mmol) was dissolved in MeOH (1 mL) and THF (1 mL) and treated with aqueous LiOH (0.24 mL of 1 M solution, 0.24 mmol) and the reaction was heated to reflux overnight. The reaction was cooled to room temperature and the resulting material directly purified by preparatory HPLC to afford 20 mg of racemic 3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-2-hydroxy-1-methyl-cyclohexanecarboxylic acid. The enantiomers of the racemic material were separated by chiral SFC purification to afford 6 mg of (1R,2R,3R)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-2-hydroxy-1-methyl-cyclohexanecarboxylic acid and 6 mg of (1S,2S,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-2-hydroxy-1-methyl-cyclohexanecarboxylic acid. LCMS: 420.36 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([NH:18][C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[N:22][C:21]=2[Cl:26])[CH:8]=[CH:9][C:10]=1[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13].CCN(CC)CC.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[Cl:26][C:21]1[N:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([NH:18][C:7]1[CH:8]=[CH:9][C:10]([C:11]([F:16])([F:17])[C:12]([F:15])([F:14])[F:13])=[C:5]([O:4][CH2:3][CH2:2][NH:1][S:36]([CH3:35])(=[O:38])=[O:37])[CH:6]=1)=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: NCCOc1cc(NC(=O)c2cccnc2Cl)ccc1C(F)(F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCOc1cc(NC(=O)c2cccnc2Cl)ccc1C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 381 mg (0.93 mmol) N-[3-(2-amino-ethoxy)-4-pentafluoroethyl-phenyl]-2-chloro-nicotinamide in 10 ml CH2Cl2 at 0° C. was added 0.389 ml Et3N and 0.072 ml (0.93 mmol) methanesulfonylchloride. After 5 min, the reaction was stirred at RT for 30 min. The reaction was diluted with CH2Cl2, washed with brine, dried over Na2SO4, filtered, concentrated, and dried under vacuum, yielding the titled compound as a white foamy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: ClCCCN1CCCCC1
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCCN2CCCCC2)CC1

Procedure:
In analogy to the procedure described in intermediate 4A, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A) and 1-(3-chloro-propyl)-piperidine gave the title compound as light yellow solid. MS: 438.1 (MH+, 2Cl).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([N+:16]([O-])=O)=[C:9]([O:14][CH3:15])[CH:10]=2)[CH2:5]1.[H][H]>C(OCC)(=O)C.[Pd].CO>[F:1][CH2:2][CH2:3][N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([NH2:16])=[C:9]([O:14][CH3:15])[CH:10]=2)[CH2:5]1
Reactant: COc1cc2c(cc1[N+](=O)[O-])CN(CCF)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N)CN(CCF)CC2
Yield: 99.6 %

Procedure:
2-(2-fluoroethyl)-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroisoquinoline (assumed 1.07 mmol from previous reaction) was dissolved in ethyl acetate (5 mL), treated with 10% palladium on carbon (50 mg, Aldrich), and then diluted with methanol (10 mL). The mixture was stirred under 60 psi of hydrogen pressure for 16 h in a Fischer-Porter apparatus. The pressure was released, the reaction vessel evacuated, and back-filled with nitrogen twice. The mixture was filtered through celite and the filtrate was concentrated to provide 2-(2-fluoroethyl)-6-(methyloxy)-1,2,3,4-tetrahydro-7-isoquinolinamine (239 mg, 100%). 1H NMR (400 MHz, CDCl3) δ ppm 2.80-2.93 (m, 6 H), 3.51 (bs, 2 H), 3.61 (s, 2 H), 3.80 (s, 3 H), 4.58-4.75 (dt, JHF=47.6, J=4.9 Hz, 2 H), 6.37 (s, 1 H), 6.50 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:12](Cl)(=[O:14])[CH3:13].C(N(CC)CC)C.O>C(Cl)Cl>[C:12]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8])(=[O:14])[CH3:13]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Cl)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.4 %

Procedure:
To a solution of 5-amino-2-chloro-benzoic acid (0.50 g, 2.9 mmol) in DCM (15 mL) was added acetyl chloride (0.30 mL, 4.2 mmol) followed by triethylamine (1.2 mL, 8.6 mmol). The mixture was stirred at RT for 2 h and poured into water. The mixture was extracted with ethyl acetate and the combined organic layers washed with water, brine, dried over Na2SO4 and filtered. The filtrate was concentrated and afforded the title compound (0.17 g, 27%) as a brown solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12].[CH:17](O[Na])=[O:18]>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:17]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])=[O:18]
Reactant: O=CO[Na]
Reactant: CON(C)C(=O)c1n[nH]c2ccc(I)cc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)c1n[nH]c2ccc(C=O)cc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 15.6 %

Procedure:
A mixture of 5-iodo-N-methoxy-N-methyl-1H-indazole-3-carboxamide (5 g, 15.1 mmol), HCOONa (1.85 g, 30.2 mmol), and PdCl2(PPh3)2 (320 mg, 0.453 mmol) in DMF (20 mL) was put under vacuum, and charged with CO. This process was repeated three times, and the mixture was kept at 110° C. for 6 hr. After cooling to rt, the reaction mixture was diluted with brine and extracted with EtOAc. The organic phases were combined, washed with brine, dried, and concentrated. The crude product was purified by column chromatography to afford 5-formyl-N-methoxy-N-methyl-1H-indazole-3-carboxamide (550 mg, 15.6%) as a white solid.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][CH3:3].C1(C)C=CC=CC=1.[O-2].[O-2].[O-2].[O-2].[O-2].[V+5:17].[V+5]>O>[O-:4][CH2:1][CH2:2][CH3:3].[V+5:17].[O-:4][CH2:1][CH2:2][CH3:3].[O-:4][CH2:1][CH2:2][CH3:3].[O-:4][CH2:1][CH2:2][CH3:3].[O-:4][CH2:1][CH2:2][CH3:3]
Reactant: CCCO
Agent: [V+5]
Agent: [O-2]
Solvent: Cc1ccccc1
Solvent: O
Product: CCC[O-]
Temperature: 90 °C

Procedure:
60 ml of n-propanol and 60 ml of toluene were added to 18.2 g of vanadium pentoxide. The mixture was heated to 90° C., and formed water was azeotropically removed to obtain vanadium propoxide. Here, about 60% of vanadium pentoxide was converted to vanadium propoxide. To such the reaction solution, 70 ml of isobutanol was added, and 7.2 ml of water was further added for hydrolysis, whereby a gel-like precipitate formed. Then, 200 ml of butanol and 32.8 g of 100% phosphoric acid were added thereto. The temperature was raised with stirring, and refluxing was continued to obtain a blue solid. After conducting the refluxing for 10 hours, the mixture was cooled and subjected to filtration to obtain a catalyst precursor C. The catalyst precursor C had a size and shape as shown in FIG. 8.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:11][CH3:12])[C:3]1=[O:13].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[CH3:1][C:2]1([CH3:14])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:11][CH3:12])[CH:3]1[OH:13]
Reactant: COc1cccc2c1CC(C)(C)C2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1cccc2c1CC(C)(C)C2O
Reaction time: 8 h

Procedure:
A solution of 2,2-dimethyl-4-methoxyindanone (13.7 g) in anhydrous diethyl ether (575 ml) is added dropwise to a stirred suspension of LAH (2.87 g) in anhydrous diethyl ether (575 ml) and the mixture is refluxed under nitrogen for two hours. The reaction mixture is quenched with H2O, 15% aq. NaOH and H2O, stirred overnight, filtered and the filtrate evaporated in vacuo affording the desired compound as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C:10]([N:12]1[C@@H:19]([C:20]#[CH:21])[CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:28]1CCOCC1.C(OC(Cl)=O)C(C)C.N.O1CCOCC1.OS([O-])(=O)=O.[K+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C:10]([N:12]1[C@@H:19]([C:20]#[CH:21])[CH2:18][CH2:17][C@H:13]1[C:14]([NH2:28])=[O:16])=[O:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN1CCOCC1
Reactant: C#C[C@H]1CC[C@@H](C(=O)O)N1C(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCCC1
Agent: CC(C)COC(=O)Cl
Agent: N
Agent: O=S(=O)([O-])O
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: O
Product: C#C[C@H]1CC[C@@H](C(N)=O)N1C(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCCC1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (5R)-1-{(2S)-2-((tert-butoxycarbonyl)amino)-2-cyclopentylethanoyl}-5-ethynyl-L-proline (1.28 g, 3.38 mmol) in THF (25 mL) at −15° C. under nitrogen, was added 4-methylmorpholine (0.44 mL, 4.05 mmol), and isobutylchloroformate (0.5 mL, 3.72 mmol) over 2 minutes. The reaction mixture was stirred at −15° C. under nitrogen for 30 minutes, and a solution of 0.5 M NH3 in dioxane (34 mL, 16.90 mmol) was added. The reaction mixture diluted with water, the pH adjusted to 4 by the addition of 4% KHSO4 and extracted with ethyl acetate (3×). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by flash column chromatography (5% MeOH/CH2Cl2) to provide the titled compound. MS (CI) m/e 364 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:21][C:22]1([CH3:25])[CH2:24][O:23]1>C(Cl)Cl>[CH3:21][C:22]([OH:23])([CH3:25])[CH2:24][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 120 °C

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (500 mg, 2.57 mmol), Cs2CO3 (840 mg, 2.57 mmol) and 2,2-dimethyloxirane (2 mL) was heated in a sealed vial at 120° C. for 3 minutes with stirring in a Smith Synthesizer microwave oven (at 300 W), then allowed to cool and diluted with CH2Cl2. The resulting suspension was filtered, and the filtrate was concentrated to give the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=O)[CH2:11][CH3:12])=O.[NH3:14].CO>>[CH2:11]([C:10]1[N:14]=[CH:1][C:3]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:9]=1)[CH3:12]
Reactant: N
Reactant: CCC(=O)Nc1ccccc1C=O
Solvent: CO
Product: CCc1ncc2ccccc2n1
Temperature: 80 °C
Yield: 100 %

Procedure:
A mixture of the title compound from Step A (1.4 g, 7.9 mmol) and 2M ammonia in methanol (40 ml, 80 mmol) was heated at 80° C. in a flask stoppered with a septa and vented with a 21 gauge needle, overnight. The mixture was cooled and evaporated to afford the title compound 1.39 g (100%). 1H NMR (CDCl3): 1.50 (t, J 7.6 Hz, 3H), 3.19 (q, J 7.6 Hz, 2H), 7.60 (d, J 7.4 Hz, 1H), 7.90 (m, 2H), 7.99 (d, J 8.5 Hz, 1H), 9.37 (d, J 8.5 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH:5]=O.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:15][C:16]([OH:18])=[O:17])[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11]
Reactant: O=Cc1ccc(C(F)(F)F)c(F)c1
Reactant: O=C(O)CC(=O)O
Product: O=C(O)C=Cc1ccc(C(F)(F)F)c(F)c1

Procedure:
According to the previously described general procedure (GP1), Knoevenagel condensation (75° C.; 3h20) between 3-fluoro-4-trifluoromethyl-benzaldehyde (9.000 g; 46.848 mmol) and malonic acid (9.262 g; 89.012 mmol) gave the product 3-(3-fluoro-4-trifluoromethyl-phenyl)-acrylic acid as a colorless solid (9.520 g; 87%). LC-MS: tR=0.90 min; [M+H]+: no ionisation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:21][CH2:22][O:23]C2CCCCO2)[CH2:10][N:11]([CH3:20])[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[OH-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:21][CH2:22][OH:23])[CH2:10][N:11]([CH3:20])[C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(CC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(CC(CCO)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To a solution of N-[2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butyl]-N-methylbenzamide (10.5 g) in tetrahydrofuran (100 mL) was added 6N hydrochloric acid (50 mL), and the resulting solution was allowed to stir overnight. The mixture was neutralized with 10N sodium hydroxide, diluted with water, and extracted with dichloromethane. The organic layer was dried and evaporated. The resulting yellow solid was suspended in ether and filtered to give the alcohol as a white solid (8.4 g); MS: m/z=352(M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10](I)=[C:9](OC)[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1>C(NCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH:10]=[C:9]([N:7]([CH2:8][CH3:9])[CH2:6][CH3:5])[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1
Reactant: COc1c(I)c(=O)c2ccc(Cl)cc2[nH]c1=O
Solvent: CCNCC
Product: CCN(CC)c1cc(=O)c2ccc(Cl)cc2[nH]c1=O
Temperature: 60 °C

Procedure:
8-Chloro-4-iodo-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.4 g) was treated with diethylamine (20 mL). The mixture was sealed in a pressure vessel and heated to 60° C. for 17 hours. The reaction mixture was concentrated to a brown solid which was recrystallized from hot ethyl acetate. The solid was filtered, washed and air dried to give the title compound as a yellow solid; NMR: 5.70 (s,1); MS: m/z=279(M+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[CH:4]=[O:5].[CH2:11](O)[CH2:12][CH2:13][OH:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[CH:4]1[O:14][CH2:13][CH2:12][CH2:11][O:5]1
Reactant: OCCCO
Reactant: O=Cc1c(F)cccc1I
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Fc1cccc(I)c1C1OCCCO1
Yield: 98.7 %

Procedure:
2-Fluoro-6-iodo-benzaldehyde (3.0 g, 12 mmol), 1,3-propanediol (1.3 ml, 18 mmol), and para-toluenesulfonic acid (342 mg, 1.8 mmol) is heated at reflux in toluene (60 ml) using a Dean-Stark apparatus for 2 hours. The organic layer is washed with brine and dried over MgSO4 and evaporated to afford the desired compound (3.65 g).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].C(O[C:14]([CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)=[O:15])C.[CH2:29]([O:36][N:37]=[CH2:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[NH4+].[Cl-]>O1CCCC1>[CH2:22]([N:19]1[CH2:18][CH2:17][C:16]2([C:14](=[O:15])[N:37]([O:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:38]2)[CH2:21][CH2:20]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Reactant: C=NOCc1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Product: O=C1N(OCc2ccccc2)CC12CCN(Cc1ccccc1)CC2
Reaction time: 1 h

Procedure:
Lithium hexamethyldisilazane (180 mL, 0.18 mol, 1 M in tetrahydrofuran) under nitrogen was cooled to not more than 5° C. with a ice bath. A solution of 1-benzyl-piperidine-4-carboxylic acid ethyl ester from Example 7B (40.0 g, 0.16 mol) in tetrahydrofuran (450 mL) was added at such a rate as to keep the internal temperature at not more than 5° C., and the mixture was stirred at not more than 5° C. for 1 hour. A solution of formaldehyde O-benzyl-oxime from Example 7A (20.0 g, 0.15 mol) in tetrahydrofuran (200 mL) was added, and the reaction mixture stirred at not more than 5° C. for 1 hour. A saturated aqueous solution of NH4Cl (300 mL) was added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (500 mL). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (300 g) eluting with hexane/ethyl acetate (4:1 to 1:1) to afford the titled compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.54-1.63 (m, 2 H) 1.91 (ddd, J=13.17, 9.47, 3.70 Hz, 2 H) 2.03-2.17 (m, 2 H) 2.68-2.77 (m, 2 H) 3.03 (s, 2 H) 3.45 (s, 2 H) 4.93 (s, 2 H) 7.19-7.42 (m, 10 H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]=1[NH2:19])(C)(C)C.CC1(C)O[C:26]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[C:31]#[N:32])=[CH:25][C:24](=[O:36])O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:36]=[C:24]1[CH2:25][C:26]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[C:31]#[N:32])=[N:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[CH:10][C:9]=2[NH:19]1
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccc(-c4cccs4)cc3NC(=O)C2)c1

Procedure:
Prepared from (2-amino-4-thiophen-2-yl-phenyl)-carbamic acid tert.-butyl ester (Example G18) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (108 mg).
Reaction SMILES: [CH2:1]([CH:3]1[C:8]2([C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]([CH3:15])[CH:6]=[CH:5][CH2:4]1)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH2:1]([CH:3]1[C:8]2([CH:13]([OH:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]([CH3:15])[CH:6]=[CH:5][CH2:4]1)[CH3:2]
Reactant: CCC1CC=CC(C)C12CCCCC2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCC1CC=CC(C)C12CCCCC2O
Yield: 92 %

Procedure:
11-Ethyl-7-methylspiro[5,5]undec-8-en-1-one was reduced with LiAlH4 according to the general procedure (example 2, procedure 3) to give the title compound in 92% yield, as a 4:1 mixture of isomers. The crude product was purified by bulb-to-bulb distillation (B.p.=102° C./0.03 mbar).