Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=[CH:6]2.OO.[Br:19]Br>C(O)(=O)C>[Br:19][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cccc2cc(OC)ccc12
Reactant: BrBr
Agent: OO
Solvent: CC(=O)O
Product: COC(=O)c1cccc2c(Br)c(OC)ccc12
Temperature: 90 °C
Yield: 177.4 %

Procedure:
108 g (0.50 mol) of methyl 6-methoxy-1-naphthoate are dissolved in 500 ml of acetic acid, and 30 g of 35% aqueous hydrogen peroxide solution are added. 42 g (0.26 mol) of bromine are then added dropwise at 35° C. in the course of 45 minutes. The mixture is subsequently heated at 90° C. When the reaction has ended, the mixture is allowed to cool to 20° C. and is subjected to filtration with suction, and the filter cake is washed with water. Drying in vacuo at 60° C. gives 136.1 g of methyl 5-bromo-6-methoxy-1-naphthoate in the form of fine white needles.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10]([O:12][CH2:13][CH2:14]Cl)=[CH2:11].[OH-].[Na+].C(N(CC)CC)C>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:10]([O:12][CH2:13][CH2:14][O:8][C:1](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH2:11]
Reactant: C=COCCCl
Reactant: O=C(O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=COCCOC(=O)c1ccccc1
Temperature: 120 °C

Procedure:
Benzoic acid (244 g) (2 mol) was dissolved in 3,000 ml of toluene, and thereto were added 320 g of 2-chloroethyl vinyl ether, 88 g of sodium hydroxide, 25 g of tetrabutylammonium bromide, and 100 g of triethylamine. The resulting mixture was stirred with heating at 120° C. for 5 hours.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([OH:25])=[CH:22][CH:23]=3)[N:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]=2[O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:46][O:47][CH2:48][CH2:49]Br>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:49][CH2:48][O:47][CH3:46])=[CH:22][CH:23]=3)[N:18]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:17]=2[O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCBr
Reactant: Cc1ccccc1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(O)cc2n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Oc3ccccc3C)n(-c3ccccc3)c2c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
The compound of example 8 (63.0 mg, 119 μmol) was dissolved in DMF, and cesium carbonate (116 mg, 358 μmol) and 2-bromoethyl methyl ether (13.5 μl, 143 μmol) were added. The reaction mixture was stirred at 50° C. for 3 h. The cooled mixture was diluted with water and extracted with EA. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography (EA/HEP). 60.0 mg of the title compound were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([C:12]([OH:14])=O)[CH2:8][CH2:7]2.S(O)(O)(=O)=O.[CH2:20]([N:22]([CH2:30][CH3:31])[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)[CH3:21].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:30]([N:22]([CH2:20][CH3:21])[C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:12]([CH:9]2[CH2:8][CH2:7][C:6]3[C:11](=[C:2]([OH:1])[CH:3]=[CH:4][CH:5]=3)[CH2:10]2)=[O:14])=[CH:25][CH:24]=1)[CH3:31]
Reactant: CCN(CC)c1ccc(N)cc1
Reactant: O=C(O)C1CCc2cccc(O)c2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(NC(=O)C2CCc3cccc(O)c3C2)cc1
Reaction time: 8 h
Yield: 62 %

Procedure:
This phenol from Example 6A was dissolved in DMF (4.0 mL) and N,N-Diethyl-benzene-1,4-diamine sulfate (602 mg, 2.3 mmol), Et3N (707 mg, 7.0 mmol), and TBTU (738 mg, 2.3 mmol) were added at ambient temperature. The mixture was stirred overnight and purified by silica gel column chromatography to provide 8-hydroxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid (4-diethylamino-phenyl)-amide (480 mg, 62%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[S:5][C:6]=1[CH:7]([OH:10])[CH2:8][CH3:9].[H-].[Na+].[Br:23][C:24]1[CH:31]=[C:30](F)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27].O>CN(C)C=O>[Br:23][C:24]1[CH:31]=[C:30]([O:10][CH:7]([C:6]2[S:5][C:4]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=3)=[N:3][C:2]=2[CH3:1])[CH2:8][CH3:9])[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]
Reactant: N#Cc1ccc(F)cc1Br
Reactant: CCC(O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(Oc1ccc(C#N)c(Br)c1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 25 °C

Procedure:
500 mg 1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propan-1-ol were dissolved in 5 ml dimethylformamide. 108 mg sodium hydride were added and the mixture stirred at room temperature. After thirty minutes commercially available 2-bromo-4-fluorobenzonitrile were added and the reaction mixture stirred at room temperature for one hour. Then 5 ml water were added and the mixture extracted three times with portions of 30 ml ethyl acetate. The combined organic layers were dried over MgSO4 and the solvent removed in vacuo. The residue was purified by reversed phase HPLC to obtain 375 mg 2-Bromo-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-benzonitrile as an oil.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:36])[C@H:6]([CH2:32][CH:33]([CH3:35])[CH3:34])[NH:7][C:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[N:11][O:10][N:9]=1)#[N:2].CS(O)(=O)=O.C([O-])(O)=O.[Na+]>C1COCC1>[C:1]([CH2:3][NH:4][C:5](=[O:36])[C@H:6]([CH2:32][CH:33]([CH3:34])[CH3:35])[NH:7][C:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)=[CH:17][CH:18]=2)=[N:11][O:10][N:9]=1)#[N:2]
Reactant: CC(C)C[C@H](Nc1nonc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(=O)NCC#N
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C[C@H](Nc1nonc1-c1ccc(N2CCNCC2)cc1)C(=O)NCC#N
Reaction time: 8 h

Procedure:
To N1-(cyanomethyl)-N2-(4-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}-1,2,5-oxadiazol-3-yl)leucinamide (170 mg, 0.33 mmol) in dry THF (1 mL) under dry nitrogen was gradually added a total of 6 equivalents of MeSO3H (120 μL, 2.0 mmol) over a period of 2 hours in portions of 2 equivalents at a time and the reaction mixture stirred overnight. Aqueous sat. NaHCO3 was added carefully and the product extracted with EtOAc (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (NH4OH/MeOH/CH2Cl2, 1/9/90) to afford N1-(cyanomethyl)-N2-[4-(4-piperazin-1-ylphenyl)-1,2,5-oxadiazol-3-yl]leucinamide.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12][C:13]3[CH:14]=[C:15]([C:19]4([C:25]#[N:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[N:3]=1.CCO.O.[NH2:31][NH2:32]>>[NH:31]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12][C:13]3[CH:14]=[C:15]([C:19]4([C:25]#[N:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[N:3]=1)[NH2:32]
Reactant: N#CC1(c2cccc(Sc3ccc4nc(Cl)ccc4c3)c2)CCOCC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: N#CC1(c2cccc(Sc3ccc4nc(NN)ccc4c3)c2)CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5h (4.4 g, 11.6 mmol) was suspended in hydrazine hydrate (11 mL) and EtOH (45 mL) and heated to 80° C. overnight. The reaction was cooled to room temperature and concentrated, and then diluted with EtOAc and water. The aqueous layer was extracted with EtOAc twice, and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was dissolved in CH2Cl2 (15 mL) and heated to dissolve as much of the material as possible. Hexanes (45 mL) was added slowly, and the mixture was stirred for 30 minutes. The precipitate was filtered, rinsed with hexanes, and dried to give the desired product, 5i.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH3:20])[CH2:15][CH2:14]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH3:20])[CH2:15][CH2:14]2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: CCN1CCC(N)CC1
Reactant: Nc1ccc(C(=O)O)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCC(NC(=O)c2ccc(N)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 22.7 %

Procedure:
4-amino-3-fluorobenzoic acid (2.115 g, 13.6 mmol), 4-Amino-1-Ethyl Piperidine (Fluorochem; 1.923 g, 15 mmol), HATU (5.7 g, 15 mmol) and DIPEA (7.1 mL, 40.8 mmol) were combined in DMA (60 mL) and the resulting yellow solution stirred at room temperature for 20 minutes. The reaction was left over the weekend at room temperature, solvent evaporated and the residue dissolved in methanol (10 mL) and loaded onto an SCX-2 column (50 g) which pre-wet with MeOH (40 mL), flushed with MeOH (4×30 ml) and eluted with 7N ammonia in MeOH (4×30 mL). Product containing, ammoniacal fractions were combined to yield the title compound as a brown solid (0.819 g, 22%)
Reaction SMILES: [F:1][C:2]([F:16])([CH:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:17]12([C:27](Cl)=[O:28])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2.C(N(CC)CC)C.Cl>C(Cl)Cl>[CH2:6]([O:5][C:3]([C:2]([F:16])([F:1])[CH:8]([O:15][C:27]([C:17]12[CH2:26][CH:21]3[CH2:20][CH:19]([CH2:25][CH:23]([CH2:22]3)[CH2:24]1)[CH2:18]2)=[O:28])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4])[CH3:7]
Reactant: CCOC(=O)C(F)(F)C(O)c1ccccc1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(F)(F)C(OC(=O)C12CC3CC(CC(C3)C1)C2)c1ccccc1
Reaction time: 8 h
Yield: 97.8 %

Procedure:
Ethyl 2,2-difluoro-3-hydroxy-3-phenylpropionate acid (9 g) prepared in Synthesis Example 1-4 and 1-adamantanecarbonyl chloride (9.5 g) were dissolved in methylene chloride (60 g), and a mixed solution of triethyl amine (6 g), 4-dimethyl aminopyridine (0.5 g) and methylene chloride (20 g) was dropped into the obtained solution under ice cooling. After aging overnight, 5% by mass hydrochloric acid was added to the product and quenched, and then the reaction solution was washed with water, and concentrated. Methylisobutyl ketone was added to the concentrated solution, and was concentrated again to obtain a target compound, or 1-adamantane carboxylic acid 2-ethoxycarbonyl-2,2-difluoro-1-phenyl-ethyl ester (15 g) as a colorless oily matter (yield: 68%).
Reaction SMILES: [CH2:1]([Si]1(Cl)N(C)[C@@H](C)[C@H](C2C=CC=CC=2)O1)[CH:2]=[CH2:3].[CH:18](=[O:27])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.CCOC(C)=O>C1(C)C=CC=CC=1>[C:21]1([CH2:20][CH2:19][C@@H:18]([OH:27])[CH2:3][CH:2]=[CH2:1])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C=CC[Si]1(Cl)O[C@@H](c2ccccc2)[C@H](C)N1C
Reactant: O=CCCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CC[C@H](O)CCc1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
Enantioselective allylation of dihydrocinnamaldehyde to give (3R)-1-phenyl-hex-5-en-3-ol: To a cooled (−10° C.) solution of (4S,5S)-2-Allyl-2-chloro-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine (380 mg, 1.5 mmol) in toluene (5 mL) was added dihydrocinnamaldehyde (1.0 mmol). The reaction mixture was maintained at −10° C. for 2 h. To this cooled solution was added 1N HCl (4 mL) and EtOAc (4 mL) and the mixture was vigorously stirred for 15 min. The layers were separated and the aqueous layer was extracted with EtOAc (2×5 mL). The combined organics were dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel to give (3R)-1-phenyl-hex-5-en-3-ol in 84% yield and 88% enantiomeric excess (ee).
Reaction SMILES: P(O)([O-])([O-])=O.[K+].[K+].[Cl:8][C:9]1[CH:14]=[CH:13][C:12](B2OCCCO2)=[C:11]([F:21])[C:10]=1[O:22][CH3:23].[Cl:24][C:25]1[C:30]([Cl:31])=[C:29](Cl)[N:28]=[C:27]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.O>[Cl:24][C:25]1[C:30]([Cl:31])=[C:29]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[C:10]([O:22][CH3:23])[C:11]=2[F:21])[N:28]=[C:27]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[CH:26]=1
Reactant: COc1c(Cl)ccc(B2OCCCO2)c1F
Reactant: O=C(OCc1ccccc1)c1cc(Cl)c(Cl)c(Cl)n1
Agent: Cl[Pd]Cl
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: N#Cc1ccccc1
Solvent: O
Product: COc1c(Cl)ccc(-c2nc(C(=O)OCc3ccccc3)cc(Cl)c2Cl)c1F
Temperature: 74.5 °C

Procedure:
A 22-L straight wall reactor equipped with a mechanical stirrer was charged with tap water (3403 g). Dipotassium phosphate (K2HPO4; 2596 g, 14.9 mol) was then added, and the mixture was stirred until all solids dissolved while being purged with a nitrogen stream. After all the solids had dissolved, acetonitrile (8173 g) was loaded into the reactor. To a separate 30-L straight-wall jacketed reactor equipped with a bottom drain and a mechanical overhead stirrer was loaded 2-(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane (1724 g, 7.01 mol) and benzyl 4,5,6-trichloropicolinate (1630 g, 4.97 mol). The reactor was evacuated and filled with nitrogen (3×). The acetonitrile/H2O mixture containing K2HPO4 was then transferred into the 30-L reactor, and the lines were rinsed with acetonitrile (1434 g). The slurry was sparged with nitrogen for 30 min, and then triphenylphosphine (114.8 g, 0.44 mol) was added. The slurry was then sparged with nitrogen for 15 min followed by addition of bis(benzonitrile)palladium(II) chloride (83.8 g, 0.22 mol). The bright yellow slurry was sparged with nitrogen for 15 min, and then the mixture was heated to 74-75° C. After stirring at 74° C. for 3.3 h the reaction was deemed complete by HPLC analysis. At this stage the reactor cool-down temperature was set to 5° C. and immediately, cold water (4448 g, approximately 3° C.) was added to the reactor. The resulting precipitate was filtered to give a cream-white colored cake. The filter cake was washed with cold acetonitrile/H2O (3345 g, 1.4:1, 8-10° C.) to afford an off-white wet cake. The cake was dried under a stream of nitrogen to a constant weight of 2044 g. HPLC analysis using an internal standard (tetraphenylethylene) showed the product was 90.0% pure and contained 1840 g (84.0%) of the product.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].[F:45][C:46]1[CH:47]=[C:48]([CH:52]=[CH:53][CH:54]=1)[C:49](O)=[O:50]>CN(C=O)C.O>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:49](=[O:50])[C:48]2[CH:52]=[CH:53][CH:54]=[C:46]([F:45])[CH:47]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(F)c2)CC1
Reaction time: 8 h
Yield: 107.5 %

Procedure:
HOBt (290 mg, 2.14 mmol), DIEA (461 mg, 3.5 mmol), EDCI.HCl (410 mg, 2.14 mmol) followed by piperazine-1-carboxylic acid tert-butyl ester (398 mg, 2.14 mmol) were added to a stirred solution of 3-fluorobenzoic acid (250 mg, 1.78 mmol) in DMF (3 mL). The reaction mixture was stirred overnight and then diluted with cold water. The product was extracted with ethyl acetate and the organic layer was washed with brine solution, dried over Na2SO4, and concentrated under reduced pressure to afford 590 mg (92%) of 4-(3-fluoro-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[CH:4]=[C:3]1[C:12]1[CH:13]=[C:14]([N:18]2C(=O)C3C(=CC=CC=3)C2=O)[CH:15]=[N:16][CH:17]=1.NN>CCO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[CH:4]=[C:3]1[C:12]1[CH:13]=[C:14]([NH2:18])[CH:15]=[N:16][CH:17]=1
Reactant: Cc1ccc2cc(-c3cncc(N4C(=O)c5ccccc5C4=O)c3)n(C)c2c1
Agent: NN
Solvent: CCO
Product: Cc1ccc2cc(-c3cncc(N)c3)n(C)c2c1
Temperature: 25 °C

Procedure:
A flask is charged with 2-[5-(1,6-dimethyl-1H-indol-2-yl)-pyridin-3-yl]-isoindole-1,3-dione (1.10 g, 2.096 mmol) and EtOH (30 mL). Hydrazine (1.316 mL, 41.9 mmol) is added and the reaction mixture is refluxed for 1 hour. The reaction mixture is cooled to room temperature, filtered and the precipitate is washed thoroughly with ethyl acetate. The filtrate is concentrated in vacuo. The crude is taken up 1M HCl solution and then extracted with EtOAc. The aqueous layer is separated, basified to pH 14 using 4M aqueous NaOH and extracted with DCM thrice. The organic layer is dried over Na2SO4 and concentrated in vacuo to afford 5-(1,6-dimethyl-1H-indol-2-yl)-pyridin-3-ylamine. MS (ESI) m/z 238.4 (M+H)+
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]12[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12]C(=O)O[C:8]2=[O:9]>C1(C)C=CC=CC=1>[NH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=1[C:8]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:9]
Reactant: C1CCNCC1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: Cc1ccccc1
Product: Nc1ccccc1C(=O)N1CCCCC1
Reaction time: 0.33 h

Procedure:
Piperidine (1.63 liter) was added over a period of 30 minutes to a slurry of 2.5 kg isatoic anhydride in 12.5 liters of toluene. The reaction mixture was stirred for 20 minutes and extracted four times with 5 liters of 1.2N hydrochloric acid. The extracts were made basic and the product extracted with 12.5 liters of isopropyl acetate. The organic layer was washed with water and saturated sodium chloride solution and then concentrated to a thick slurry with a volume of 4 liters. The solid product was collected, washed with cold isopropyl acetate and dried overnight in vacuo to give 2.22 kg of 1-(2-aminobenzoyl)piperidine. Concentration of the filtrate afforded a second crop of 0.23 kg.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][CH2:10][CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH:3]1[NH2:12].[C:14]([N:16]=[CH:17]OCC)#[N:15]>C(O)C>[C:14]([N:16]=[CH:17][NH:12][CH:3]1[CH:4]2[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:10][CH2:11][C:2]1([CH3:13])[CH3:1])#[N:15]
Reactant: CC1(C)CCC2CCCCC2C1N
Reactant: CCOC=NC#N
Solvent: CCO
Product: CC1(C)CCC2CCCCC2C1NC=NC#N
Reaction time: 2 h
Yield: 54.1 %

Procedure:
To a stirred and heated (<40° C.) solution of 96 parts of decahydro-2,2-dimethyl-1-naphthalenamine in 400 parts of ethanol were added dropwise 48 parts of ethyl N-cyanomethanimidate. Upon complete addition, stirring was continued for 2 hours. The precipitated product was filtered off (and set aside) and the filtrate was evaporated. The residue was treated with 2,2'-oxybispropane. The precipitated product was filtered off and combined with the product, which was set aside (see above). Both were crystallized from acetonitrile. The product was filtered off and dried, yielding 67 parts (54.1%) of N'-cyano-N-(decahydro-2,2-dimethyl-1-naphthalenyl)methanimidamide; mp. 227.6° C. (intermediate 7).
Reaction SMILES: OC(C(F)(F)F)=O.[CH2:8]1[C:11]2([CH2:15][CH2:14][CH2:13][NH:12]2)[CH2:10][O:9]1.[F:16][CH:17]([F:46])[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:28][C:27]([C:29]([N:31]3[CH2:34][CH:33]([O:35][C:36]4[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][C:37]=4[O:44][CH3:45])[CH2:32]3)=[O:30])=[N:26][N:25]=2)=[CH:20][CH:19]=1.C(N(CC)CC)C.[Na].C([O-])(O)=O.[Na+]>ClCCl>[CH2:10]1[C:11]2([CH2:15][CH2:14][CH2:13][N:12]2[CH2:40][C:39]2[CH:42]=[CH:43][C:36]([O:35][CH:33]3[CH2:34][N:31]([C:29]([C:27]4[O:28][C:24]([C:21]5[CH:20]=[CH:19][C:18]([CH:17]([F:46])[F:16])=[CH:23][CH:22]=5)=[N:25][N:26]=4)=[O:30])[CH2:32]3)=[C:37]([O:44][CH3:45])[CH:38]=2)[CH2:8][O:9]1
Reactant: COc1cc(C=O)ccc1OC1CN(C(=O)c2nnc(-c3ccc(C(F)F)cc3)o2)C1
Reactant: C1CNC2(C1)COC2
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(CN2CCCC23COC3)ccc1OC1CN(C(=O)c2nnc(-c3ccc(C(F)F)cc3)o2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
2-Oxa-5-azaspiro[3.4]octane TFA salt (0.1.1 g, ca. 70%, 0.34 mmol) and 4-(1-(5-(4-(difluoromethyl)phenyl)-1,3,4-oxadiazole-2-carbonyl)azetidin-3-yloxy)-3-methoxybenzaldehyde (0.146 g, 0.34 mmol) were mixed in dichloromethane (2 ml). Triethylamine (0.1 ml, 0.72 mmol) was added, followed by sodium triacetoxyhydroborate (0.144 g, 0.68 mmol). The mixture was stirred at ambient temperature overnight (16 h). LC-MS showed some remaining starting material and an additional amount of sodium triacetoxyhydroborate (0.113 g) was added. Stirring continued for 6 h. The reaction mixture was then diluted with dichloromethane (10 ml) and shaken with NaHCO3 (sat. 3 ml). The two phases were separated by the use of a phase separator. Evaporation of the organic phase afforded a residue, which was purified by preparative reverse-phase HPLC at pH 10 to give 0.112 g (62%) of the desired product as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:31][CH2:32][CH2:33][OH:34].C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[OH:34][CH2:33][CH2:32][NH:31][C:14]([C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:18][CH:17]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: NCCO
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)NCCO)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.2 %

Procedure:
2.06 g (8.21 mmol) of 4-[(tert-butoxycarbonylamino)methyl]benzoic acid suspended in 40 mL of methylene chloride was mixed with 1.63 g (10.1 mmol) of 1,1′-carbonyldiimidazole at room temperature and stirred at room temperature for 1.5 hours. The reaction solution was further stirred with 1.8 mL (30 mmol) of 2-aminoethanol overnight, and after addition of 40 mL of saturated aqueous sodium hydrogen carbonate, 20 mL of water and 200 mL of methylene chloride, was allowed to separate. The organic layer was washed with 80 mL of 1 M hydrochloric acid, with 40 mL of saturated aqueous sodium hydrogen carbonate and with 20 mL of saturated aqueous sodium chloride twice, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the desired product (2.30 g, yield 95%).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17](C)(C)O[SiH2]C(C)(C)C)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:26]1[C:27](=[O:41])[N:28](COCC[Si](C)(C)C)[CH:29]=[C:30]([NH2:32])[CH:31]=1)=O)(C)(C)C.[C:42]1([C@@H:48]([N:50]2[CH:54]=[C:53]([C:55](Cl)=[O:56])[CH:52]=[N:51]2)[CH3:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[O:41]=[C:27]1[NH:28][CH:29]=[C:30]([NH:32][C:55]([C:53]2[CH:52]=[N:51][N:50]([C@H:48]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH3:49])[CH:54]=2)=[O:56])[CH:31]=[C:26]1[C:9]1[NH:8][C:16]2[C:11]([CH:10]=1)=[CH:12][C:13]([CH2:17][N:28]1[CH2:29][CH2:30][CH2:31][CH2:26][CH2:27]1)=[CH:14][CH:15]=2
Reactant: C[C@@H](c1ccccc1)n1cc(C(=O)Cl)cn1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(N)cn(COCC[Si](C)(C)C)c2=O)cc2cc(C(C)(C)O[SiH2]C(C)(C)C)ccc21
Product: C[C@@H](c1ccccc1)n1cc(C(=O)Nc2c[nH]c(=O)c(-c3cc4cc(CN5CCCCC5)ccc4[nH]3)c2)cn1

Procedure:
The title compound was prepared by the route outlined in Scheme 8, following the same experimental procedures as for Example 37, reacting intermediate (8d), 2-[5-Amino-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-(tert-butyl-dimethyl-silanyloxymethyl)-indole-1-carboxylic acid tert-butyl with intermediate (6h), 1-((S)-1-Phenyl-ethyl)-1H-pyrazole-4-carbonyl chloride in the coupling step as described for Example 160.