Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1(=[O:15])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.[Br:16]Br.Cl>O.C(OCC)C>[Br:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[CH2:8][CH2:7][CH2:6][C:5]2=[O:15]
Reactant: O=C1CCCc2ccccc21
Reactant: BrBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: O
Product: O=C1CCCc2c(Br)cccc21
Temperature: 80 °C

Procedure:
2.21 g of AlCl3 are placed in a round-bottomed flask, to which 0.91 ml of 3,4-dihydro-2H-naphth-1-one is added over 10 min and 0.41 ml of Br2 is added over 5 min, and the mixture is heated at 80° C. for 10 min. It is allowed to return to ambient temperature and a solution comprising 20 g of ice and 2.7 ml of concentrated hydrochloric acid is added thereto. The mixture is then diluted with water and diethyl ether. The organic phase is subsequently separated, dried and concentrated under reduced pressure. The residue is purified by reverse phase preparative chromatography. 172 mg of compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:15]2[C:23]3[C:18](=[C:19]([NH:24][S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)([CH2:13][CH3:14])[C:9]([O:11]C)=O)=[CH:4][CH:3]=1.[NH3:30]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:15]2[C:23]3[C:18](=[C:19]([NH:24][S:25]([CH2:28][CH3:29])(=[O:26])=[O:27])[CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)([CH2:13][CH3:14])[C:9]([NH2:30])=[O:11])=[CH:6][CH:7]=1
Reactant: N
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NS(=O)(=O)CC)cccc21
Solvent: CO
Product: CCC(C(N)=O)(c1ccc(Cl)cc1)n1ccc2c(NS(=O)(=O)CC)cccc21
Temperature: 25 °C
Reaction time: 10 h

Procedure:
The product from Step A above (0.43 g, 1.0 mmol) was dissolved in a 7 N solution of ammonia in methanol (25 mL). After stirring at RT for 10 h, the resulting mixture was concentrated under reduced pressure. The residue was dissolved in dioxane/water, acidified with TFA, and purified directly on RP-HPLC to give the title compound. LC/MS m/z=420.1 [M+H]+. The two enantiomers were separated by SFC chiral separation.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([OH:18])([C:14]([F:17])([F:16])[CH3:15])[C:4]=2[CH:3]=1.[CH:21]1([CH2:24]O)[CH2:23][CH2:22]1.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([O:18][CH2:24][CH:21]3[CH2:23][CH2:22]3)([C:14]([F:16])([F:17])[CH3:15])[C:4]=2[CH:3]=1
Reactant: CC(F)(F)C1(O)c2cc(Cl)ccc2Nc2ncccc21
Reactant: OCC1CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(F)(F)C1(OCC2CC2)c2cc(Cl)ccc2Nc2ncccc21
Yield: 86.1 %

Procedure:
Method KK: To a stirred suspension of 7-chloro-5-hydroxy-5-(1,1-difluoroethyl)-5,10-dihydrobenzo[b] [1,8]naphthyridine (37) (173 mg, 0.583 mmol) in cyclopropyl methanol (1.2 mL, 14.58 mmol) was added trifluoroacetic acid (446 μL, 5.83 mmol). The resulting solution was heated at reflux for 3 h 15 min. The reaction mixture was concentrated in vacuo, the residue was purified by flash chromatography (40% EtOAc-hexane) afforded 39 (176 mg, 86% yield) as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.Cl.[NH2:15][OH:16].C([O-])(O)=O.[Na+]>CO>[OH:16]/[N:15]=[C:10](\[NH2:11])/[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:1])[F:13])=[CH:8][CH:7]=1
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: N/C(Cc1ccc(C(F)(F)F)cc1)=N\O
Yield: 84.9 %

Procedure:
A suspension of [4-(trifluoromethyl)phenyl]acetonitrile (1.0 g, 5.4 mmoles), hydroxylamine hydrochloride (0.41 g, 5.9 mmoles) and NaHCO3 (0.50 g, 5.9 mmoles) in MeOH (15 ml) was refluxed for 4 hours. The reaction mixture was then concentrated to remove the solvent methanol. The residue was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na2SO4 and concentrated to afford the desired product (1.0 g, 84.9%) as white solid. LCMS calculated for C9H10F3N2O (M+H): 219.1. Found: 219.1.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]([CH3:12])=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C([O-])=O.[NH4+]>[C].[Pd].C(O)C>[CH3:12][C:4]1[NH:3][CH:2]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=1
Reactant: CCOC(=O)c1cc(C)[nH]c1Cl
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1c[nH]c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10% palladium carbon (anhydrous) (2.5 g) was suspended with ethanol (500 mL) under argon gas atmosphere. Ethyl 2-chloro-5-methyl-1H-pyrrole-3-carboxylate (50 g; see, Tetrahedron Letters, Vol. 35, No. 33, 5989-5992 (1994)) and ammonium formate (51 g) were added to the reaction mixture at room temperature, and it was stirred at room temperature for 8 hours. The reaction mixture was subjected to filtration with Celite (trade name), the filtrate was concentrated under reduced pressure. Water and ethyl acetate were added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed by water and a saturated aqueous solution of sodium chloride, and concentrated under reduced pressure after drying with anhydrous magnesium sulfate, to thereby obtain a title compound (40 g) having the following physical properties.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[C:18][CH2:19][OH:20])[CH:5]=[CH:6][C:7]=1[OH:8].N1C2C(=CC=CC=2)C=CC=1>C(O)C.[Pd]>[OH:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][OH:20])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: OCC#CCCCCCCC#Cc1ccc(O)c(O)c1
Agent: [Pd]
Solvent: CCO
Solvent: c1ccc2ncccc2c1
Product: OC/C=C\CCCCCC/C=C\c1ccc(O)c(O)c1
Yield: 75.2 %

Procedure:
A solution of 0.545 g of the product obtained in Example 7 in 20 ml of absolute ethanol containing 0.1 ml of freshly distilled quinoline was hydrogenated at room temperature and normal pressure using as catalyst 0.136 g of palladium on calcium carbonate (5% Pd; poisoned with lead "Lindlar-catalyst"). After consumption of the theoretical amount of hydrogen, the catalyst was filtered off and the filtrate evaporated in a vacuum. The residue was purified by HPLC with methanol/water (6:4) to yield 0.416 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([NH:7][C:8]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][NH:13]2)=[O:6])[CH3:2].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:21])[C:5](=[O:6])[N:7]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][NH:13]2)[CH3:2]
Reactant: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])ccc2c1CCCN2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(=O)N(Cc1ccccc1)c1c([N+](=O)[O-])ccc2c1CCCN2
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
A mixture of the product from Example 87 (0.58 g, 2 mmol), benzylbromide (0.41 g, 2.4 mmol) and cesium carbonate (0.78 g, 2.4 mmol) in 10 mL of acetonitrile was stirred at room temperature for 2 hours. The triethylamine hydrobromide was removed by filtration and the filtrate evaporated. The residue was purified by silica gel chromatography (2:1 heptane:ethyl acetate as eluant) to give the title compound as a yellow solid (0.7 g, 91% yield).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[C:7](F)([F:9])=[O:8]>>[C:2]([CH2:3][O:4][C:7]([F:9])=[O:8])([F:6])([F:5])[F:1]
Reactant: O=C(F)F
Reactant: OCC(F)(F)F
Product: O=C(F)OCC(F)(F)F

Procedure:
236faE (CAS Reg. No. 20193-67-3) has been prepared by reaction of 2,2,2-trifluoroethanol with carbonyl fluoride to give the intermediate, CF3CH2OCOF, which was in turn reacted with sulfur tetrafluoride at 150°-200° C. to give the product as disclosed by Eisemann in U.S. Pat. No. 3,394,878.
Reaction SMILES: [OH:1][C@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@:8]3([OH:24])[CH2:9][CH2:10][C@@H:11]2[C:12](=O)[CH3:13])[CH2:3]1.C(=O)(O)O.[NH2:29][NH:30][C:31]([NH2:33])=[NH:32].Cl>O1CCOCC1.O>[NH:30](/[N:29]=[C:12](/[C@@H:11]1[C@:15]2([CH3:23])[C@@:8]([OH:24])([C@H:7]3[C@H:18]([CH2:17][CH2:16]2)[C@:19]2([CH3:22])[C@@H:4]([CH2:3][C@@H:2]([OH:1])[CH2:21][CH2:20]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1)\[CH3:13])[C:31]([NH2:33])=[NH:32]
Reactant: CC(=O)[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: N=C(N)NN
Agent: Cl
Agent: O=C(O)O
Solvent: O
Solvent: C1COCCO1
Product: C/C(=N\NC(=N)N)[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 72 h
Yield: 34.3 %

Procedure:
A mixture of 1.00 g of 3β,14β-dihydroxy-5β-pregnane-20-one (Templeton J. F. et al., J. Chem. Soc., Perkin Trans. 1, 1991, 823), 1.20 g of aminoguanidine hydrogencarbonate in 40 ml of dioxane and 10 ml of water acidified at pH 2.5 with 0.01M hydrochloric acid was stirred at room temperature for 3 days. The precipitate was collected by filtration and purified by flash-chromatography (SiO2) using chloroform/methanol/28% ammonium hydroxide 78/20/2; the fractions containing the title compound were collected and evaporated to dryness. The crude product was ground with ethanol to give 0.40 g of the title compound (I-bk) as a white solid.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:33][O:34][CH2:35][CH2:36][N:37]=[N+]=[N-])[C:10]([NH:12][CH:13]2[C:31](=[O:32])[N:15]3[C:16]([C:28]([OH:30])=[O:29])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH3:27])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]>[C].[Pd].C(O)(=O)C>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:33][O:34][CH2:35][CH2:36][NH2:37])[C:10]([NH:12][CH:13]2[C:31](=[O:32])[N:15]3[C:16]([C:28]([OH:30])=[O:29])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH3:27])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCN=[N+]=[N-])c3csc(NC=O)n3)[C@H]2SC1
Agent: [Pd]
Solvent: CC(=O)O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCN)c3csc(NC=O)n3)[C@H]2SC1
Reaction time: 13 h
Yield: 52.3 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-(2-azidoethoxyimino)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 0.70 g.), 10% palladium carbon (0.85 g.) and acetic acid (10 ml.) was subjected to catalytic reduction under ordinary pressure at room temperature for 13 hours. The resultant mixture was filtered, and the filtrate was concentrated in vacuo. The residue was stirred in diisopropyl ether (30 ml.) and methanol (10 ml.) for an hour. The precipitates were collected by filtration, washed with diisopropyl ether and dried to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-aminoethoxyimino)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 0.35 g.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:20])=[C:4]([CH:14]2[CH2:18][O:17][C:16](=[O:19])[NH:15]2)[C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:8](O)[CH3:9])[CH:7]=1.CN(C)C=O.S(Cl)([Cl:28])=O>ClCCl>[Cl:1][C:2]1[C:3]([F:20])=[C:4]([CH:14]2[CH2:18][O:17][C:16](=[O:19])[NH:15]2)[C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH2:8][CH2:9][Cl:28])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: CCOc1c(C(C)O)cc(Cl)c(F)c1C1COC(=O)N1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1c(CCCl)cc(Cl)c(F)c1C1COC(=O)N1

Procedure:
4-[3-chloro-6-ethoxy-2-fluoro-5-(1-hydroxyethyl)phenyl]-1,3-oxazolidin-2-one (150 mg, 0.49 mmol) (from Step 10) was stirred in dichloromethane (4 mL) with N,N-dimethylformamide (96 μL) and thionyl chloride (110 μL, 1.5 mmol) was added. The mixture was evaporated. Water was added and the mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to give the desired compound, 159 mg, 100%.
Reaction SMILES: C1COCC1.C([O:9][C:10]12[CH2:14][C:12]([NH:15][C:16](=[O:18])[CH3:17])([CH2:13]1)[CH2:11]2)(=O)C.[OH-].[Na+]>CO>[OH:9][C:10]12[CH2:14][C:12]([NH:15][C:16](=[O:18])[CH3:17])([CH2:13]1)[CH2:11]2
Reactant: CC(=O)NC12CC(OC(C)=O)(C1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)NC12CC(O)(C1)C2

Procedure:
To a THF (2 mL) solution of 3-acetamidobicyclo[1.1.1]pentan-1-yl acetate (3) (1 mmol) is added methanol (0.7 mL) followed by a aqueous solution of NaOH (1.4 M, 0.7 mL, 1 eq.) at r.t. The mixture is stirred and monitored by TLC. After complete consumption of the starting material, saturated ammonium chloride is added and the mixture is stirred for 5 min. The volatiles are removed under vacuum and the resultant mixture is extracted with EtOAc (3×). The organic layers are combined, dried (magnesium sulfate), filtered, and concentrated. The crude residue is subjected to flash chromatography (silica gel, EtOAc/hexanes) to give compound 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@H:4]([NH:13][C:14](=[O:23])[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[NH2:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[CH:25]1([C:31]2[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH3:1][O:2][C:3](=[O:24])[C@@H:4]([NH:13][C:14](=[O:23])[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[NH2:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:28]2[CH:27]=[CH:26][C:25]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:30][CH:29]=2)=[CH:8][CH:7]=1
Reactant: OB(O)c1ccc(C2CCCCC2)cc1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc(Cl)ccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C3CCCCC3)cc2)cc1)NC(=O)c1cc(Cl)ccc1N
Temperature: 80 °C

Procedure:
(2S)-(2-Amino-5-chloro-benzoylamino)-3-(4′-cyclohexyl-biphenyl-4-yl)propionic acid methyl ester compound was prepared following General Procedure D using (S)-2-(2-amino-5-chloro-benzoylamino)-3-(4-bromo-phenyl)-propionic acid methyl ester (1.803 g, 4.38 mmol), 4-cyclohexyl-benzene boronic acid (1.61 g, 98%, 7.88 mmol), palladium tetrakis-triphenylphosphine (0.462 g, 0.4 mmol), and aqueous Na2CO3 (2.0 N, 16 mL, 32 mmol) in DME (32 mL). The mixture was heated at 80° C. for 14 h. Purification by flash chromatography (ethyl acetate/hexanes 1:3, 1:2) gave product as a red solid (2.01 g, 4.09 mmol, 93% yield).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2([NH:13][C:14]([C:16]3[C:17]4[CH:24]=[N:23][N:22]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)[C:18]=4[CH:19]=[N:20][CH:21]=3)=[O:15])[CH2:12][CH2:11]2)[CH:5]=1.[NH3:33].CO>>[C:3]([C:4]1[CH:5]=[C:6]([C:10]2([NH:13][C:14]([C:16]3[C:17]4[CH:24]=[N:23][N:22]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)[C:18]=4[CH:19]=[N:20][CH:21]=3)=[O:15])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)(=[O:2])[NH2:33]
Reactant: N
Reactant: COC(=O)c1cccc(C2(NC(=O)c3cncc4c3cnn4-c3ccc(F)cc3)CC2)c1
Solvent: CO
Product: NC(=O)c1cccc(C2(NC(=O)c3cncc4c3cnn4-c3ccc(F)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 78 h

Procedure:
A solution of 3-(1-{[1-(4-fluoro-phenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-cyclopropyl)-benzoic acid methyl ester (70.0 mg, 0.163 mmol) in a 7M solution of ammonia in methanol (1.00 mL, 7.00 mmol) is stirred at 120° C. in a sealed pressure tube. After 78 hours, the reaction vessel is cooled to room temperature, vented and opened. The reaction mixture is concentrated in vacuo, and the resulting residue is purified by silica gel chromatography eluting with a gradient of 0-10% methanol in methylene chloride to afford the title compound a solid.
Reaction SMILES: [ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Br[CH2:30][CH2:31][CH:32]1[O:36][CH2:35][CH2:34][O:33]1>>[ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH2:30][CH2:31][CH:32]4[O:36][CH2:35][CH2:34][O:33]4)[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Reactant: BrCCC1OCCO1
Agent: Cl
Product: O=C1N(CCC2OCCO2)CN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2

Procedure:
The title compound, white solid, m. p. 205° C. and MS: m/e=470.6 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and 2-(2-bromoethyl)-1,3-dioxolane.
Reaction SMILES: [C:1]12([C:11]3[CH:23]=[CH:22][C:14]([O:15][CH2:16][C:17]([O:19]CC)=[O:18])=[C:13]([CH3:24])[CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O.[OH-].[Li+].Cl>O.C1COCC1>[C:1]12([C:11]3[CH:23]=[CH:22][C:14]([O:15][CH2:16][C:17]([OH:19])=[O:18])=[C:13]([CH3:24])[CH:12]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CCOC(=O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
To a solution of ethyl 2-(4-(adamantan-1-yl)-2-methylphenoxy)acetate (1.1 g, 3.50 mmol) in H2O/THF (1 mL/1.20 mL) was added lithium hydroxide monohydrate (0.29 g, 7.00 mmol), and stirred at room temperature overnight. The reaction mixture was adjusted to acidic solution with 1 N aqueous HCl and extracted with dichloromethane. The organic layer was washed with H2O and brine, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by silica gel column chromatography to give 2-(4-(adamantan-1-yl)-2-methylphenoxy)acetic acid as a white solid (0.54 g, 96.7% yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:12])=[CH:5][C:6]=1[C:7](OCC)=[O:8].[CH:13]([NH2:15])=O>>[CH3:12][C:4]1[S:3][C:2]2[N:1]=[CH:13][N:15]=[C:7]([OH:8])[C:6]=2[CH:5]=1
Reactant: CCOC(=O)c1cc(C)sc1N
Reactant: NC=O
Product: Cc1cc2c(O)ncnc2s1
Temperature: 25 °C
Yield: 25 %

Procedure:
Into a 25-mL round-bottom flask placed ethyl 2-amino-5-methylthiophene-3-carboxylate (500 mg, 2.70 mmol, 1.00 equiv) in 10 mL of formamide was stirred for 8 h at 180° C. in an oil bath. After completion of the reaction, the reaction mixture was cooled down to room temperature and then quenched with water/ice, extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (2:1) to provide the resulted 6-methylthieno[2,3-d]pyrimidin-4-ol (114 mg, 25%) as a yellow solid. MS (ES, m/z): 167 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][CH:8]([NH:13][C:14]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1C(OCC1C=CC=CC=1)=O)=[O:15])[CH:9]([OH:12])[CH2:10][F:11])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:32])[CH2:7][CH:8]([NH:13][C:14]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][NH:17]1)=[O:15])[CH:9]([OH:12])[CH2:10][F:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(NC(=O)C1CCCCN1C(=O)OCc1ccccc1)C(O)CF
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC(NC(=O)C1CCCCN1)C(O)CF
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred solution of [3S/R,4S/R,(2S)]-5-fluoro-4-hydroxy-3-[1-(benzyloxycarbonyl)-2-piperidinecarboxamido]-pentanoic acid tert-butyl ester (7.37 g, 16.29 mmol) in ethyl acetate (150 ml) was treated with 10% Pd/C (830 mg). The reaction mixture was then thoroughly degassed and placed under a hydrogen balloon. The resulting mixture was stirred at room temperature for 3 hrs after which it was filtered through celite and concentrated to the sub-title compound as a colorless gum (5.17 g, 100%): 1H NMR (400 MHz, CDCl3) δ 1.16-2.00 (15H, m), 2.51-2.78 (3H, m), 2.99-3.09 (1H, m), 3.18-3.28 (1H, m), 3.93-4.56 (4H, m), 7.39-7.58 (1H, m); 19F (376 MHz, CDCl3) δ −229.34 (t), −229.42 (t), −229.87 (t), 230.02 (t).
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)#[N:6].[CH2:15]([NH2:19])[CH:16]([CH3:18])[CH3:17].C(O)(=O)C>CO>[CH2:15]([NH:19][CH2:11][C:10]1[CH:13]=[CH:14][C:7]([C:5]#[N:6])=[CH:8][CH:9]=1)[CH:16]([CH3:18])[CH3:17]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC(C)CN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)CNCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
Under a nitrogen atmosphere add sodium cyanoborohydride (5.77 g, 91.6 mmol) to 4-cyanobenzaldehyde (3 g, 22.9 mmol), iso-butylamine (3.34 g, 45.8 mmol) and acetic acid (1.37 g, 22.9 mmol) in methanol (30 mL) at 0° C. Warm the mixture to room temperature and stir overnight. Add water (40 mL), saturated aqueous K2CO3 (30 mL) and extract with DCM. Wash the combined organic extracts with water and brine. Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify the residue by chromatography on silica gel (500 g) eluting with 9:1 DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) to obtain the desired intermediate (3.63 g, 84%). MS (APCI+) m/z: 189 (M+H)+.
Reaction SMILES: [O-]CC.[Na+].[Na].[OH:6][C:7]1[CH:8]=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[C:11]([CH3:13])[CH:12]=1.[C:17]1([CH2:23][CH2:24]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[N+:14]([C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][C:11]=1[CH3:13])([O-:16])=[O:15]
Reactant: BrCCc1ccccc1
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: Cc1cc(OCCc2ccccc2)ccc1[N+](=O)[O-]

Procedure:
To a sodium ethoxide solution prepared from 15 g (0.652 Mol) of sodium and 500 ml of anhydrous ethanol were added, successively, 100 g (0.653 Mol) of 5-hydroxy-2-nitrotoluene and 90 ml (121.95 g=0.659 Mol) of 2-phenylethylbromide and the mixture was refluxed for 5 hours. A further 50 ml (0.366 Mol) of 2-phenylethylbromide were added and again the mixture was refluxed for 10 hours. The solvent was distilled off in vacuo, the residue was taken up in ether and extracted several times with dilute sodium hydroxide solution. The ethereal phase was evaporated down, the residue was stirred thoroughly with 400 ml of petroleum ether 35/60. The resulting crystals were suction filtered and washed with petroleum ether. Yield: 95.2 g (57% of theory) of slightly yellowish crystals, Mp. 70-72° C. IR (CH2Cl2): 1340, 1515 (NO2) cm-1
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.Br[CH2:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[C:23]#[N:24]>>[CH3:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:19][C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=2)[C:23]#[N:24])[C:4]=1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: Cc1c(-c2cccnc2)[nH]c2ccccc12
Agent: Cl
Product: Cc1c(-c2cccnc2)n(Cc2cccc(C#N)c2)c2ccccc12

Procedure:
3-Methyl-2-pyridin-3-yl-1H-indole hydrochloride (Example 1) and 3-bromomethyl-benzonitrile are processed according to the method described in Example 25 to give 3-(3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile. 1H NMR (400 MHz, MeOD) δ ppm 2.33 (s, 3H), 5.41 (s, 2H), 7.08 (d, J=8.1 Hz, 1H), 7.16 (s, 1H), 7.20 (t, J=7.2 Hz, 1H), 7.27 (ddd, J=7.6, 1.0 Hz, 1H), 7.37 (d, J=5.8 Hz, 1H), 7.38-7.42 (m, 1H), 7.54-7.57 (m, 1H), 7.57 (s, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.85 (dt, J=7.8, 1.9 Hz, 1H), 8.50 (d, J=2.0 Hz, 1H), 8.60 (dd, J=4.8, 1.5 Hz, 1H). HRMS (ESI) m/z 324.1491 [(M+H)+ Calcd for C22H18N3: 324.1501].