Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:25][NH:26][CH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH:28]1[N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:26]([CH:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][CH:28]2[N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[CH3:25])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC1c2ccccc2CC1N1CCCC1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C(=O)Cc1ccc(Cl)c(Cl)c1)C1c2ccccc2CC1N1CCCC1
Reaction time: 1 h

Procedure:
A mixture of 2.66 g of 3,4-dichlorophenylacetic acid, 2.11 g of carbonyldiimidazole and 20 ml of tetrahydrofuran was stirred for 1 hour and then a solution of 2.16 g of the product of Step B in 5 ml of tetrahydrofuran was added slowly. The mixture was stirred for 3 hours 30 minutes and then the tetrahydrofuran was distilled off under reduced pressure. The residue was taken up in 100 ml of ether and after washing with a saturated solution of sodium bicarbonate, then with saturated salt water, drying and concentrating to dryness under reduced pressure, 4.68 g of [Trans (±)] 3,4-dichloro-N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-benzene-acetamide in the form of a base were obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7](=[O:32])[C:8]([C:27]([O:29]CC)=[O:28])=[CH:9][N:10]2[C:14]2[C:19]([F:20])=[CH:18][C:17]([F:21])=[C:16]([NH:22]C(C)(C)C)[N:15]=2)=[CH:5][C:4]=1[F:33]>O>[NH2:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7](=[O:32])[C:8]([C:27]([OH:29])=[O:28])=[CH:9][N:10]2[C:14]2[C:19]([F:20])=[CH:18][C:17]([F:21])=[C:16]([NH2:22])[N:15]=2)=[CH:5][C:4]=1[F:33]
Reactant: CCOC(=O)c1cn(-c2nc(NC(C)(C)C)c(F)cc2F)c2c(C)c(N)c(F)cc2c1=O
Agent: Cl
Solvent: O
Product: Cc1c(N)c(F)cc2c(=O)c(C(=O)O)cn(-c3nc(N)c(F)cc3F)c12
Temperature: 25 °C

Procedure:
Concentrated hydrochloric acid (2 ml) was added to ethyl 7-amino-1-(6-tert-butylamino-3,5-difluoropyridin-2-yl)-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux for 5 hours. After the reaction mixture was cooled back to room temperature, water (2 ml) was added thereto. Solids deposited were collected by filtration and washed successively with water, ethanol and diethyl ether to obtain the title compound (72 mg) as a pale yellow powder.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([S:28][CH3:29])[CH:23]=4)[N:21]=2)[N:18]=[CH:17][CH:16]=[CH:15]3)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>C1COCC1>[CH3:29][S:28][C:24]1[CH:23]=[C:22]([C:20]2[N:21]=[C:12]([N:9]3[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]3)[CH:13]=[C:14]3[C:19]=2[N:18]=[CH:17][CH:16]=[CH:15]3)[CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)C1CCN(c2cc3cccnc3c(-c3cccc(SC)c3)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CSc1cccc(-c2nc(N3CCC(C(=O)O)CC3)cc3cccnc23)c1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of 1-[8-(3-Methylsulfanyl-phenyl)-[1,7]naphthyridin-6-yl]-piperidine-4-carboxylic acid ethyl ester (134 mg, 0.33 mmol) in THF (1 ml) is added sodium hydroxide (0.33 ml of a 1M aqueous solution). The solution is stirred at room temperature for 23 hours and then partitioned between ethyl acetate and water. The aqueous extract is acidified with 7 M HCl to pH 4 and washed with ethyl acetate (3×). The combined organic layers are then concentrated to give the title compound as an amorphous solid. MS (TOF ES+) 380.1107
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])[CH:6]=[CH:7][CH:8]=1>CO>[F:19][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@H:9]2[CH2:10][NH:11][CH2:12][C@@H:13]([C:14]([O:16][CH3:17])=[O:15])[CH2:18]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1cncc(-c2cccc(C(F)(F)F)c2)c1
Solvent: CO
Product: COC(=O)[C@@H]1CNC[C@H](c2cccc(C(F)(F)F)c2)C1
Yield: 36.7 %

Procedure:
A solution of methyl 5-[3-(trifluoromethyl)phenyl]nicotinate (190.1 mg) in MeOH (30 ml) was hydrogenated (ca. 4 atm) for 2 days in a Parr low-pressure hydrogenation apparatus with a 5 wt. % Rh on Al2O3 catalyst (121.6 mg) at 90° C. Rh on Al2O3 catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was purified with silica gel column chromatography (eluent: CHCl3/MeOH=98/2˜90/10) to give methyl cis-5-[3-(trifluoromethyl)phenyl]piperidine-3-carboxylate (71.2 mg) as a pale brown oil.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-])=O)=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.B(O)(O)O.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[CH3:16][C:15]([NH:7][C:6]1[CH:1]=[CH:2][C:3]([OH:10])=[CH:4][CH:5]=1)=[O:17]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: OB(O)O
Product: CC(=O)Nc1ccc(O)cc1
Yield: 85 %

Procedure:
The following analysis compares a typical APAP product produced by the stepwise/boric acid process of this invention with high purity standards. For this example 30 lbs. of p-nitrophenol was hydrogenated at 63°-67° C. by stepwise acetylation using 10 mole percent boric acid and adding 50% acetic anhydride after completing 60% of the hydrogenation. Product yield was about 85%.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:6]=1[C:7]([OH:9])=O.[NH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>C(OCC)(=O)C>[F:20][C:2]([F:1])([F:21])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:6]=1[C:7]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[O:9]
Reactant: NCc1ccccn1
Reactant: O=C(O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Solvent: CCOC(C)=O
Product: O=C(NCc1ccccn1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Yield: 685.8 %

Procedure:
To a solution of 8.93 g (2.5 mmole) of compound (II) in 80 mL of ethyl acetate under argon, 2-(aminomethyl)pyridine (3.2 g, 3.0 mmole) were added with stirring and the mixture was refluxed for 4 hours. An additional 1 g of 2-(aminomethyl)pyridine was added and the mixture was refluxed for two more hours. The ethyl acetate was evaporated under reduced pressure and the residue was passed through a 12 cm column containing silica gel with a mixture of methylene chloride:hexane (1:1) as eluent. The column was washed with methylene chloride and the combined solutions were evaporated under reduced pressure. The residue was crystallized from CH2CI2:hexane (1:2) to give 7 g (69% yield) of 2,5-bix(2,2,2-trifluoroethoxy)-N-(2-pyridylmethyl)benzamide (V) m.p. 104-106° C., purity 99.8% (GC).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:13]([NH2:16])[CH:14]=[CH2:15]>CN(C=O)C>[CH2:13]([NH:16][C:4]1[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)[CH:14]=[CH2:15]
Reactant: C=CCN
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Solvent: CN(C)C=O
Product: C=CCNc1nc(Cl)nc2c(C)csc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
In DMF was dissolved 1.50 g (6.8 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and then 917 mg (16.1 mmol) of allylamine was added dropwise to the resulting solution under ice cooling over 5 minutes. The reaction mixture was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for one hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/8) to give 1.25 g (yield: 76.2%) of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:25]=[CH:24][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[N:26]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:25]=[CH:24][C:10]3[C:11]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)=[N:12][S:13][C:9]=3[CH:8]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C1CCNCC1
Reactant: FC(F)(F)c1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1
Product: FC(F)(F)c1ccc(-c2nsc3cc(OCCCCN4CCCCC4)ccc23)cc1

Procedure:
According to the method in example 7, 6-(4-Bromo-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole and Piperidine were converted to yield 6-(4-Piperidin-1-yl-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole, MS: 435 (MH+).
Reaction SMILES: [F:1][C:2]1[C:3]([O:13]C)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.B(Br)(Br)Br.[OH-].[Na+]>ClCCl>[F:1][C:2]1[C:3]([OH:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2
Reactant: COc1ccc2ccc(C)nc2c1F
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccc2ccc(O)c(F)c2n1

Procedure:
A solution of 8-fluoro-7-methoxy-2-methylquinoline (0.57 g, 2.96 mmol) was stirred in dichloromethane (5 mL) and treated with a 1M solution of BBr3 in dichloromethane (15 mL). The resulting mixture was heated at reflux for 16 hours, then poured into crushed ice and basified with a 6N NaOH solution to pH 14. The organic layer was separated and the aqueous layer was further extracted with dichloromethane. The organic layer was pH adjusted to 6 with aqueous 6N HCl and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure to afford 8-fluoro-2-methylquinolin-7-ol in quantitative yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](I)=[C:7]([O:12][CH2:13][CH3:14])[CH:6]=1)[CH3:2].[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)=[C:7]([O:12][CH2:13][CH3:14])[CH:6]=1)=[O:15])[CH3:2]
Reactant: CCOC(=O)c1ccc(I)c(OCC)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ccc(F)cc2)c(OCC)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
To a solution of 3-ethoxy-4-iodo-benzoic acid ethyl ester (0.76 g, 2.37 mmol, 1.0 equiv; [CAS RN 741699-04-7], prepared according to WO 04/072 016 A1 (Kissei Pharmaceuticals Co, Ltd.)) in anhydrous DMF (12 mL) under Ar was added 4-fluorophenyl boronic acid (0.40 g, 2.85 mmol, 1.2 equiv), K3PO4 (0.86 g, 4.04 mmol, 1.7 equiv) and tetrakis(triphenylphosphine) palladium(0) (82.3 mg, 0.071 mmol, 0.03 equiv) and the reaction mixture stirred at 80° C. for 16 h. The reaction mixture was poured on ice, extracted with ethyl acetate (2×100 mL) and the combined organic phases washed with water (2×100 mL). The organic phase was dried over MgSO4, concentrated by evaporation under reduced pressure and the crude reaction product purified with column chromatography on silica eluting with hexane/ethyl acetate (95:5) to give 0.51 g (75%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([N+:22]([O-])=O)[CH:14]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].C(N(CC)CC)C.[CH3:32][CH:33](N)[CH2:34][OH:35].C(OCC)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([NH:22][CH:33]([CH3:32])[CH2:34][OH:35])[CH:14]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:9])([F:8])[F:10]
Reactant: CC(N)CO
Reactant: Cn1nc(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)c(Cl)c1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(CO)Nc1cc(Oc2nn(C)c(C(F)(F)F)c2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 17 h
Yield: 80.8 %

Procedure:
The dinitrobenzene obtained in Step A (10.0 g, 27.3 mmol) was dissolved in dimethylformamide (40 cm3). Triethylamine (4.6 cm3, 32.7 mmol) and DL 2-aminopropanol (2.6 cm3, 32.7 mmol) were added, and the mixture stirred at room temperature for 17 hours, then at 50° C. for 4 hours. The mixture was cooled to room temperature, poured into diethyl ether (200 cm3) and washed with water (3×200 cm3). The ether layer was collected, dried (MgSO4), filtered and the solvent removed under reduced pressure to give a waxy yellow solid. Recrystallisation (ethyl acetate/hexane) gave DL-2-[5-(4-chloro-1-methyl-5-trifluoromethyl-1H-pyrazol -3-yloxy)-2-nitrophenylamino]-propane-1-ol (8.71 g) as an orange solid. m.p. 118°-120° C.
Reaction SMILES: C1COCC1.[C:6]([C:8]1[CH:9]=[C:10]([CH2:13][O:14][CH3:15])[O:11][CH:12]=1)#[CH:7].I[C:17]1[CH:42]=[CH:41][C:20]([C:21]([N:23]([CH3:40])[C@:24]([CH3:39])([C:29]([NH:31][O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)=[O:30])[C:25]([NH:27][CH3:28])=[O:26])=[O:22])=[CH:19][CH:18]=1>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.[Cu]I.C(OCC)(=O)C>[CH3:15][O:14][CH2:13][C:10]1[O:11][CH:12]=[C:8]([C:6]#[C:7][C:17]2[CH:42]=[CH:41][C:20]([C:21]([N:23]([CH3:40])[C@:24]([CH3:39])([C:29]([NH:31][O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)=[O:30])[C:25]([NH:27][CH3:28])=[O:26])=[O:22])=[CH:19][CH:18]=2)[CH:9]=1
Reactant: C#Cc1coc(COC)c1
Reactant: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2coc(COC)c2)cc1
Yield: 82.9 %

Procedure:
PdCl2(PPh3)2 (70 mg), CuI (38 mg) and TEA (1.5 mL) were added to a THF (7.0 mL) solution of 4-ethynyl-2-(methoxymethyl)furan (0.24 g) as obtained in Example 18-(3) and (2S)-2-[(4-iodobenzoyl)(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (Intermediate 15, 0.51 g), and the mixture was stirred for 5.5 hours at room temperature in a nitrogen atmosphere. Ethyl acetate (30 mL), OH type silica gel (1.9 g), cellpure (0.95 g) and activated carbon (50 mg) were added, the insolubles were filtered out, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by OH type silica gel column chromatography (gradient elution with ethyl acetate/hexane=75/25→100/0, followed by gradient elution with chloroform/acetone=100/0→70/30) to obtain (2S)-2-[(4-{[5-(methoxymethyl)furan-3-yl]ethynyl}benzoyl)(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (yellow solid) (0.43 g, 84%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Br[CH2:20][CH2:21][OH:22]>CN(C)C=O.C(OCC)(=O)C>[OH:22][CH2:21][CH2:20][O:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(O)c1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)c1cccc(OCCO)c1
Reaction time: 96 h
Yield: 31.5 %

Procedure:
3'-Hydroxyacetophenone (5.0 g, 37 mmol), potassium carbonate (6.1 g, 44 mmol), sodium iodide (0.28 g, 1.8 mmol), and 2-bromoethanol (2.6 mL, 37 mmol) were stirred in N,N-dimethylformamide (DMF) for 20 h at room temperature, then for 4 days at 70°-80° C. The reaction mixture was diluted with ethyl acetate (EtOAc) and extracted several times with water, then dried over magnesium sulfate (MgSO4), and concentrated in vacuo. Chromatography on silica gel, eluting with 30% to 50% EtOAc in hexanes, after solvent removal, gave a viscous oil (2.1 g). 1H-NMR(300 MHz, CDCl3): 7.56(d, 1H, J=8 Hz), 7.51(s, 1H), 7.39(t, 1H, J=8 Hz), 7.14(d, 1H, J=8 Hz), 4.14 (m, 2H), 3.99 (m, 2H), 2.60 (s, 3H), 2.09 (br, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].ClCCCl.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][CH:11]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH2:10][CH2:9][C:8]=2[CH:15]=1)([O-:3])=[O:2]
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc2CC1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(c1)CCC(N1CCOCC1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
To a stirred solution of 2-nitro-5,6,8,9-tetrahydrobenzocyclohepten-7-one (500 mg, 0.002 mol) in 1,2-dichloroethane (20 mL, 0.2 mol) was added morpholine (0.23 mL, 0.0027 mol) and acetic acid (0.15 mL, 0.0027 mol). Sodium triacetoxyborohydride (670 mg, 0.0032 mol) was then added to the reaction mixture and the contents stirred at room temperature overnight. The reaction mixture was cooled to 0° C., diluted with methylene chloride (20 mL), quenched with aqueous ammonium chloride (5 mL) and washed with water and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to a brown residue. The reaction mixture was purified by ISCO chromatography on silica gel (40 g column) using 10-30% ethyl acetate-hexane gradient. The major fractions corresponding to product as confirmed by LCMS were combined and concentrated in vacuo to give a light brown solid, 4-(2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-morpholine (450 mg, 70%). 1HNMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.98 (d, 1H, J=8 Hz), 7.44 (d, 1H, J=8 Hz), 3.62 (m, 4H), 3.37 (m, 1H), 3.04 (m, 4H), 2.77 (m, 4H), 2.05 (m, 2H), 1.4 (m, 2H); MS (m/e) 276 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][CH2:7][C:8]([CH3:21])([CH3:20])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-])=O)([O-])=O.[H][H]>CN(C=O)C.[Ni]>[NH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][CH2:9][C:8]([CH3:21])([CH3:20])[CH2:7][O:6][C:5]1[CH:22]=[CH:23][CH:24]=[CH:25][C:4]=1[NH2:1]
Reactant: [H][H]
Reactant: CC(C)(COc1ccccc1[N+](=O)[O-])COc1ccccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CN(C)C=O
Product: CC(C)(COc1ccccc1N)COc1ccccc1N

Procedure:
343 g 1,3-bis-(2-nitrophenoxy)-2,2-dimethyl-propane were hydrogenated at 60° C./50 bar in 1800 ml DMF in the presence of 53 g Raney nickel. After the uptake of hydrogen had stopped, the catalyst was filtered off and the solvent was removed in vacuo.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].N1C=CC=CC=1C1C=CC=CN=1.C([Li])CCC.[Cl:24][C:25]1[CH:32]=[CH:31][C:28](CCl)=[CH:27][N:26]=1.Cl>C1COCC1.CCCCCC>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([C:4](=[O:6])[CH2:3][C:1]#[N:2])=[CH:27][N:26]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: N#CCC(=O)O
Agent: Cl
Agent: [Li]CCCC
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#CCC(=O)c1ccc(Cl)nc1
Reaction time: 1 h

Procedure:
3-(2-Chloropyridin-5-yl)-3-oxopropionitrile was prepared by treating a solution of cyanoacetic acid (9.10 g, 53.5 mmol) and 2,2′-bipyridyl (5 mg) in dry THF (500 ml), cooled to −70° under a nitrogen atmosphere, dropwise with n-butyllithium (85.6 ml, 214 mmol of a 2.5M solution in hexane). The reaction was allowed to warm to 0° over a period of 1 h and then recooled to −70°, at which point a solution of 6-chloronicotinyl chloride (9.42 g, 53.5 mmol) in THF (75 ml) was added to the resulting red slurry. The reaction was stirred at −70° for a further 1 h upon complete addition, and then allowed to reach 0° where upon 2M hydrochloric acid (250 ml) was added. The reaction was extracted with chloroform (2×400 ml) and the combined organic phases were then washed with saturated aqueous NaHCO3 (1×250 ml) and saturated brine (1×250 ml), dried (MgSO4) and concentrated under reduced pressure. The resulting solid was triturated with diethyl ether/n-hexane (1:5) to give the desired material (4.20 g) as a pale yellow powder m.p. 122-123°.
Reaction SMILES: [N+]([O-])(OCCCCC)=O.N[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[N:16][C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:14]2[OH:26].[S:27]1[CH:31]=[CH:30][CH:29]=[CH:28]1>>[OH:26][C:14]1[C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:28]3[S:27][CH:31]=[CH:30][CH:29]=3)[CH:12]=2)[N:17]=[N:16][C:15]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: c1ccsc1
Reactant: CCOC(=O)c1nnc2ccc(N)cc2c1O
Agent: CCCCCO[N+](=O)[O-]
Product: CCOC(=O)c1nnc2ccc(-c3cccs3)cc2c1O

Procedure:
Amyl nitrate (1 ml.) was added to a stirred suspension of ethyl 6-amino-4-hydroxycinnolin-3-yl carboxylate (1 g.) in thiophen (100 ml.). The suspension was stirred and heated under reflux for 2 hours. The suspension was filtered whilst hot and the filtrate was evaporated, giving a brown crystalline residue. The solid was applied to a silica column (100 g. of Kieselgel 60) and eluted with a 10% v/v mixture of dry ethanol and chloroform. The appropriate fractions were evaporated, and the residue was crystallised from 1:1 v/v aqueous ethanol to give ethyl 4-hydroxy-6-thienylcinnolin-3-yl carboxylate, m.p. 258°-260° C.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[CH:27]=[C:26]([CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[N:25]([CH3:34])[N:24]=1)=[O:4].[OH-].[Li+]>>[CH3:34][N:25]1[C:26]([CH:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)=[CH:27][C:23]([N:6]2[CH2:7][C@H:8]([S:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:21])([F:22])[F:20])(=[O:12])=[O:11])[CH2:9][C@H:5]2[C:3]([OH:4])=[O:2])=[N:24]1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C2CCOCC2)n(C)n1
Agent: [Li+]
Agent: [OH-]
Product: Cn1nc(N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@H]2C(=O)O)cc1C1CCOCC1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-1-[1-methyl-5-(tetrahydro-pyran-4-yl)-1H-pyrazol-3-yl]-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as yellow oil which was used in the next step without further purification. MS (ESI): m/z=488.3 [M+H]+.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:38])[C@H:7]([CH3:37])[CH2:8][C@H:9]([OH:36])[C@@H:10]([NH:28]C(OC(C)(C)C)=O)[CH2:11][C@@H:12]([CH:25]([CH3:27])[CH3:26])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[C:16]([OH:24])[CH:15]=1)[CH2:2][CH2:3][CH3:4].[ClH:39]>O1CCOCC1>[ClH:39].[CH2:1]([NH:5][C:6](=[O:38])[C@H:7]([CH3:37])[CH2:8][C@H:9]([OH:36])[C@@H:10]([NH2:28])[CH2:11][C@@H:12]([CH:25]([CH3:26])[CH3:27])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:22])([CH3:23])[CH3:21])=[C:16]([OH:24])[CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)c(O)c1)C(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H](N)C[C@H](Cc1ccc(C(C)(C)C)c(O)c1)C(C)C

Procedure:
30 mg of N-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-tert-butyl-phenyl)-octanoic acid (N-butyl)amide are treated with 0.6 ml of 4N hydrochloric acid in dioxane analogously to Example 1 and the product is purified by means of FC (15 g of silica gel, dichloromethane/methanol=9:1). The title compound is obtained: Rf (dichloromethane/methanol=9:1)=0.17; Rt (I)=28.54 minutes; FAB-MS (M+H)+ =435.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][NH:5][C:6]=1[CH3:7].C([O-])([O-])=O.[K+].[K+].[CH3:15][S:16][CH2:17]Cl>CC(C)=O.C(Cl)Cl>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][N:5]([CH2:15][S:16][CH3:17])[C:6]=1[CH3:7]
Reactant: CSCCl
Reactant: Cc1n[nH]c(C)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CSCn1nc(C)c(Br)c1C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 4-bromo-3,5-dimethyl-1H-pyrazole (2.10 g, 14.3 mmol) in acetone (20 mL) was added K2CO3 (2.37 g, 17.1 mmol) followed by chloromethyl methyl sulfide (1.3 mL, 5.7 mmol). The light yellow suspension was stirred at room temperature for 96 hr. At this time the reaction was thick with white precipitate. The reaction mixture was stripped off volatiles, diluted with methylene chloride and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a light yellow oil which was used without further purification.