Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][Si:8]([CH3:18])([CH3:17])[C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1.[Cl:19][C:20]1[C:21](=[O:29])[N:22]([CH2:27][CH3:28])[N:23]=[CH:24][C:25]=1[OH:26].O>CN(C)C=O>[Cl:19][C:20]1[C:21](=[O:29])[N:22]([CH2:27][CH3:28])[N:23]=[CH:24][C:25]=1[O:26][CH2:13][C:12]1[CH:15]=[CH:16][C:9]([Si:8]([CH3:18])([CH3:17])[CH3:7])=[CH:10][CH:11]=1
Reactant: C[Si](C)(C)c1ccc(CBr)cc1
Reactant: CCn1ncc(O)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1ncc(OCc2ccc([Si](C)(C)C)cc2)c(Cl)c1=O
Temperature: 25 °C
Yield: 58.7 %

Procedure:
1.8 g of anhydrous potassium carbonate and 2.1 g of p-trimethylsilylbenzylbromide were added to 1.5 g of 4-chloro-2-ethyl-5-hydroxy-3(2H)-pyridazinone dissolved in 10 ml of N,N-dimethylformamide, and the resulting mixture was heated in an oil bath of 120°-130° C. for 2 hours. After the reaction mixture was allowed to cool to room temperature, 100 ml of water was added thereto and the mixture was stirred vigorously. Precipitate was filtered, washed with water and dried to obtain 1.7 g of a crude product. The product was recrystallized from a mixed solvent of isopropyl ether and ethyl acetate to obtain the intended compound (Compound No. 4.6) having m.p. 122°-125° C. (yield: 44.8%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[C:8](=[O:24])[NH:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][C:13]([Cl:23])=[CH:12][CH:11]=3)[O:4][N:3]=1.[CH3:25][S:26]([CH2:29][CH2:30][O:31][C:32](=O)[O:33]N1C(=O)CCC1=O)(=[O:28])=[O:27]>>[CH3:25][S:26]([CH2:29][CH2:30][O:31][C:32](=[O:33])[NH:1][C:2]1[CH:6]=[C:5]([C:7]2[C:8](=[O:24])[NH:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][C:13]([Cl:23])=[CH:12][CH:11]=3)[O:4][N:3]=1)(=[O:28])=[O:27]
Reactant: Nc1cc(-c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)on1
Reactant: CS(=O)(=O)CCOC(=O)ON1C(=O)CCC1=O
Product: CS(=O)(=O)CCOC(=O)Nc1cc(-c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)on1

Procedure:
This was prepared according to Example 64 from 3-(3-amino-isoxazol-5-yl)-6-chloro-4-phenyl-1H-quinolin-2-one and carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester 2-methanesulfonyl-ethyl ester. 1H NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 10.78 (s, 1H), 7.66 (dd, 1H), 7.48 (m, 4H), 7.32 (m, 2H), 6.96 (d, 1H), 6.89 (s, 1H), 4.42 (t, 2H), 3.56 (t, 2H), 3.12 (s, 3H). Mass spectrum (ESI, m/z) calcd. for C22H18ClN3O6S 487.0, found 488.0 (M+H).
Reaction SMILES: Br[CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)=[O:4].Cl.[CH3:22][NH2:23]>>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][NH:5][C:3](=[O:4])[CH:2]([NH:23][CH3:22])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]=1)#[N:14]
Reactant: N#Cc1ccc(CNC(=O)C(Br)c2ccccc2)cc1
Reactant: CN
Agent: Cl
Product: CNC(C(=O)NCc1ccc(C#N)cc1)c1ccccc1

Procedure:
In analogy to example 81.2, (RS)-2-bromo-N-(4-cyano-benzyl)-2-phenyl-acetamide (example 81.1) was reacted with methylamine hydrochloride to give (RS)-N-(4-cyano-benzyl)-2-methylamino-2-phenyl-acetamide. Off-white amorphous solid. MS 280.1 ([M+H]+)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.[OH-].[Na+].[C:11](Cl)(=[O:15])[CH2:12][CH2:13][CH3:14]>O>[OH:8][CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:11](=[O:15])[CH2:12][CH2:13][CH3:14])[CH2:2]1
Reactant: OCC1CCCNC1
Reactant: CCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCC(=O)N1CCCC(CO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
To a solution of piperidin-3-yl-methanol (2.3 g, 20 mmol) in water (30 ml) is slowly added NaOH (1.2 g, 30 mmol). After total dissolution butyryl chloride (2.15 g, 2.11 ml, 20.2 mmol) is slowly added dropwise. The resulting mixture is allowed to stir overnight at rt. The water phase is extracted three times with dichloromethane. The combined organic phases are washed with brine and dried over Na2SO4. The solvents are evaporated in vacuo yielding the title compound (2.48 g) in 66% as a colourless oil which solidifies on standing: tR=1.52 min (LC-2), ESI-MS (pos.): m/z 208.00 [M+Na]+; 1H-NMR (CDCl3): The product is a (1:1) mixture of rotamers: δ (ppm) 0.92 (t, 3H, CH3), 1.21 (m, 0.5H), 1.33-1.52 (m, 2H), 1.57-1.84 (m, 5H), 2.26-2.32 (m, 2H, CH2C═O), 2.74 (dt, 0.5H), 2.87 (dd, 0.5H), 3.10 (dd, 1H), 3.26 (ddd, 1H), 3.39-3.45 (m, 1.5H), 3.51-3.59 (m, 1H), 3.91 (dd, 1H), 4.29 (dt, 0.5H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:13]([CH3:14])=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:15][S:16]([O:1][CH2:2][CH2:3][C:4]1[C:13]([CH3:14])=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1)(=[O:18])=[O:17]
Reactant: Cc1cc2c(cc1CCO)COC2=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: Cc1cc2c(cc1CCOS(C)(=O)=O)COC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(2-hydroxyethyl)-6-methyl-2-benzofuran-1(3H)-one (1.20 g, 6.25 mmol) and TEA (2.5 g, 25 mmol) in DCM (100 mL) was added MsCl (1.40 g, 12.5 mmol) at 0° C. The mixture was stirred at ambient temperature overnight, then was washed with water and brine. The organic layer was dried and concentrated to dryness. The collected title compound was used for the next step without any purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7])#[N:2].CO.[NH2:14][NH2:15]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:14][NH2:15])=[O:7])#[N:2]
Reactant: NN
Reactant: N#Cc1cccc(C(=O)Cl)c1
Solvent: ClCCl
Solvent: CO
Product: N#Cc1cccc(C(=O)NN)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 38.5 %

Procedure:
3-cyanobenzoyl chloride (4.8 g, 29.0 mmol) was dissolved in DCM (20 ml) and MeOH (40 ml) was added in portions at 0° C. The mixture was stirred at 0° C. for 1 h and at rt for 2 h. The solvents were evaporated and the crude methyl ester was dissolved in EtOH (50 ml) and hydrazine (24% aq., 9 ml, 45 mmol) was added. The reaction mixture was refluxed for 48 h and the solvents were evaporated (coevaporation with water). The residue was purified with prep. HPLC to give the title compound (1.8 g, 39%). 1H NMR (DMSO-d6): 9.98 (br s, 1 H), 8.21 (m, 1 H), 8.13 (m, 1 H), 7.99 (m, 1 H), 7.69 (t, 1 H), 4.61 (br s, 2 H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH3:16])([CH3:15])[C:10](=[O:14])[NH:11]2)=[CH:7][C:6]=1[N+:17]([O-])=O)(=O)[CH3:2].[H][H]>[Pt](=O)=O.C(O)(=O)C>[CH3:2][C:1]1[NH:4][C:5]2[CH:13]=[C:12]3[NH:11][C:10](=[O:14])[C:9]([CH3:16])([CH3:15])[C:8]3=[CH:7][C:6]=2[N:17]=1
Reactant: [H][H]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])C(C)(C)C(=O)N2
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: Cc1nc2cc3c(cc2[nH]1)NC(=O)C3(C)C

Procedure:
Analogously to Example 5, 5.00 g. (0.019 mole) 6-acetamido-5-nitro-3,3-dimethylindolin-2-one are suspended in 900 ml. glacial acetic acid and hydrogenated in the presence of 0.5 g. platinum dioxide at normal pressure and ambient temperature. After 1.4 liters of hydrogen have been taken up, the reaction mixture is filtered and the filtrate is evaporated to dryness in a vacuum. The residue is taken up in water and neutralised with a 2N aqueous ammonia solution. The precipitate obtained is filtered off with suction and recrystallised from ethyl acetate. There are obtained 2.75 g. (67% of theory) of the title compound; m.p. >300° C.
Reaction SMILES: [OH:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]3[C:19]([N:18]=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[C:16]4[C:20]([OH:22])=[O:21])=[N:11]3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[Br:23]Br>C(Cl)(Cl)Cl>[Br:23][C:3]1[CH:4]=[CH:5][C:6]2=[C:19]3[C:10](=[CH:9][CH:8]=[C:7]2[C:2]=1[OH:1])[N:11]=[C:12]1[C:17]([C:16]([C:20]([OH:22])=[O:21])=[CH:15][CH:14]=[CH:13]1)=[N:18]3
Reactant: BrBr
Reactant: O=C(O)c1cccc2nc3ccc4c(O)cccc4c3nc12
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cccc2nc3ccc4c(O)c(Br)ccc4c3nc12

Procedure:
A mixture of 4-hydroxy-benzo[a]phenazine-11-carboxylic acid (see Reference Example 1K, 102 mg) and bromine (0.04 mL) was stirred in chloroform (3 mL) at room temperature for 20 hours. The solvent was removed in vacuo and the residue was purified using flash chromatography (10% methanol in dichloromethane) to yield the title compound (24 mg) as a yellow-brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.C(O)=[O:15].O>C(OCC)(=O)C.[Al].[Ni]>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:15])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: O=CO
Reactant: N#Cc1ccc(Cl)cc1C(F)(F)F
Agent: [Ni]
Agent: [Al]
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(Cl)cc1C(F)(F)F
Temperature: 100 °C
Yield: 87 %

Procedure:
Add 4-chloro-2-trifluoromethyl-benzonitrile to formic acid (96%) (15 mL) and water (3 mL). Add nickel-aluminum alloy (1260 mg). Heat at 100° C. overnight. Dilute with ethyl acetate and filter through Celite®. Extract the filtrate with 1 N sodium hydroxide and saturated aqueous sodium chloride, dry (sodium sulfate), filter, and concentrate to give 4-chloro-2-trifluoromethylbenzaldehyde (555 mg, 87%): 1H NMR (400 MHz, MeOH-d4) δ 10.29 (m, 1H), 8.10 (d, 1H, J=8.4 Hz), 7.91 (d, 1H, J=1.6 Hz), 7.85 (dd, 1H, J=8.4, 1.6 Hz).
Reaction SMILES: CC([N:5]([C@@H:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[C:20]3=[C:21]([F:29])[CH:22]=[N:23][C:24]4[CH:25]=[CH:26][C:27](=[O:28])[N:18]([C:19]=43)[CH2:17]2)[CH2:11][C@@H:10]1[OH:30])C(=O)[O-])(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:5][C@@H:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[C:20]3=[C:21]([F:29])[CH:22]=[N:23][C:24]4[CH:25]=[CH:26][C:27](=[O:28])[N:18]([C:19]=43)[CH2:17]2)[CH2:11][C@@H:10]1[OH:30]
Reactant: CC(C)(C)N(C(=O)[O-])[C@@H]1CCN(CC2Cn3c(=O)ccc4ncc(F)c2c43)C[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CCN(CC2Cn3c(=O)ccc4ncc(F)c2c43)C[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
A solution of racemic 1,1-dimethylethyl{(3S,4R)-1-[(3-fluoro-7-oxo-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-4-yl)methyl]-3-hydroxy-4-piperidinyl}carbamate (15.57 g) in dichloromethane (170 ml) was cooled in ice-water, treated with trifluoracetic acid (137 ml), stirred 1 hour at room temperature and evaporated to dryness. After keeping under high vacuum for 1 hour, the crude material was dissolved in methanol and run through a column of Amberlyst A21 basic resin (500 ml) (Sigma-Aldrich Co.), eluting with methanol. The solution containing the product was evaporated and the residue chromatographed on silica gel, eluting with dichloromethane/methanol/0.88 ammonia (9:1:0.1) to give product (8.96 g, 76%).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([O:18][CH3:19])[CH:10]=2)[CH2:5][CH2:4]1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([N:6]2[CH2:7][CH2:8][CH:3]([N:2]([CH3:1])[CH3:20])[CH2:4][CH2:5]2)=[CH:10][C:11]=1[O:18][CH3:19]
Reactant: COc1cc(N2CCC(N(C)C)CC2)ccc1[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(N2CCC(N(C)C)CC2)ccc1N
Yield: 72 %

Procedure:
To a solution of nickel (II) chloride hexahydrate (0.58 g, 2.5 mmol) and N,N-dimethyl-1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinamine (1.37 g, 4.90 mmol) in MeOH (25 mL) cooled to 0° C. was added NaBH4 (280 mg, 7.4 mmol) slowly to avoid foaming. When TLC indicated the consumption of starting material, the solution was concentrated to a purple residue. The purple residue was taken up in EtOAc and filtered through a pad of celite. The yellow filtrate was concentrated onto silica gel and purified by flash column chromatography to give the title compound of step B (0.88 g, 74%). 1H NMR (400 MHz, DMSO-d6) δ 6.48-6.45 (m, 2H), 6.26 (dd, J=8.2 and 2.2 Hz, 1H), 4.17 (br s, 2H), 3.70 (s, 3H), 3.38 (d, J=12.4 Hz, 2H), 2.49-2.43 (m under DMSO peak, 2H), 2.16 (s, 6H), 2.11-2.04 (m, 1H), 1.78 (d, J=12.4 Hz, 2H), 1.50-1.40 (m, 2H).
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[C:12]([NH:15][C:16]1[N:20]([C:21]2[C:26]([F:27])=[CH:25][C:24]([C:28]([F:31])([F:30])[F:29])=[CH:23][C:22]=2[Cl:32])[N:19]=[CH:18][CH:17]=1)(=[O:14])[CH3:13]>C(O)(=O)C>[C:12]([NH:15][C:16]1[N:20]([C:21]2[C:26]([F:27])=[CH:25][C:24]([C:28]([F:30])([F:31])[F:29])=[CH:23][C:22]=2[Cl:32])[N:19]=[CH:18][C:17]=1[N+:8]([O-:11])=[O:9])(=[O:14])[CH3:13]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccnn1-c1c(F)cc(C(F)(F)F)cc1Cl
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1c([N+](=O)[O-])cnn1-c1c(F)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 85 %

Procedure:
2 ml (0.021 mol) of acetic anhydride and 0.9 ml (0.02 mol) of 98% strength nitric acid are successively added to 6 g (0.019 mol) of 5-acetamido-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-pyrazole in 15 ml of glacial acetic acid at room temperature, and the mixture is stirred at room temperature for 15 hours. For working-up, the reaction mixture is added dropwise to 200 ml of ice-water, and the precipitate formed is filtered off, washed with water and dried in vacuo at 50° C. 5.8 g (85% of theory) of 5-acetamido-4-nitro-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-pyrazole of melting point 129°-130° C. are obtained.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[C:27]([CH2:29][NH:30][CH3:31])[C:26]([O:32]COCC[Si](C)(C)C)=[C:25]([O:41][CH3:42])[CH:24]=2)[N:20]=[N:19][C:18]=1[O:43]C)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[OH:32][C:26]1[C:27]([CH2:29][NH:30][CH3:31])=[CH:28][C:23]([C:21]2[CH:22]=[C:17]([C:9]3[NH:8][C:16]4[C:11]([CH:10]=3)=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:18](=[O:43])[NH:19][N:20]=2)=[CH:24][C:25]=1[O:41][CH3:42]
Reactant: CNCc1cc(-c2cc(-c3cc4ccccc4n3C(=O)OC(C)(C)C)c(OC)nn2)cc(OC)c1OCOCC[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1cc(-c2cc(-c3cc4ccccc4[nH]3)c(=O)[nH]n2)cc(OC)c1O
Temperature: 85 °C

Procedure:
118 mg of 2-{3-Methoxy-6-[3-methoxy-5-methylaminomethyl-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-pyridazin-4-yl}-indole-1-carboxylic acid tert-butyl ester is dissolved in 5 ml of dichloromethane and 5 ml of trifluoroacetic acid and the solution is stirred for 4 h at RT. The solvents are removed under reduced pressure. The residue is dissolved in 26 ml of acetonitrile and 117 mg of potassium iodide and 76 mg of chlorotrimethylsilane are added. The reaction is heated to 85° C. for 3 h. The reaction is quenched by the addition of a drop of water, the solvent is removed under reduced pressure and the product is purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). Yield 13 mg. LC-MS (ES+) 377 (M+H)+.
Reaction SMILES: C1(O[C:8](=[O:25])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([B:16]3[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]3)=[CH:12][CH:11]=2)C=CC=CC=1.[F:26][CH:27]([F:30])[CH2:28][NH2:29]>>[F:26][CH:27]([F:30])[CH2:28][NH:29][C:8]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([B:16]2[O:17][C:18]([CH3:24])([CH3:23])[C:19]([CH3:21])([CH3:22])[O:20]2)=[CH:14][CH:15]=1)=[O:25]
Reactant: NCC(F)F
Reactant: CC1(C)OB(c2ccc(NC(=O)Oc3ccccc3)cc2)OC1(C)C
Product: CC1(C)OB(c2ccc(NC(=O)NCC(F)F)cc2)OC1(C)C
Yield: 48 %

Procedure:
Method as described for intermediate 13 using phenyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (intermediate 17) and 2,2-difluoroethylamine to afford a pink oil (505 mg, 48%).
Reaction SMILES: C([NH:8][C:9]1([CH:13]([CH3:16])[CH2:14][OH:15])[CH2:12][CH2:11][CH2:10]1)C1C=CC=CC=1>CCO.[Pd]>[NH2:8][C:9]1([CH:13]([CH3:16])[CH2:14][OH:15])[CH2:12][CH2:11][CH2:10]1
Reactant: CC(CO)C1(NCc2ccccc2)CCC1
Agent: [Pd]
Solvent: CCO
Product: CC(CO)C1(N)CCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.7 %

Procedure:
10% Pd—C (700 mg) was added to a solution of 2-[1-(benzylamino)cyclobutyl]propanol (6.81 g, 31.1 mmol) in EtOH (150 mL) and the mixture was stirred under H2 gas 5 kgf/cm2 at room temperature for 6 hours. The mixture was filtered, and the filtrate was concentrated in vacuo. Distillation of the residue gave the title compound as a colorless oil (2.96 g, 74%). 1H-NMR (400 MHz, CDCl3) δ1.03 (3H, d, J=7.3 Hz), 1.63-1.74 (3H, m), 1.78-1.94 (2H, m), 2.10-2.28 (2H, m), 3.50 (1H, dd, J=11.0 and 4.3 Hz), 3.91 (1H, dd, J=11.0 and 3.1 Hz).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=O)[CH3:17])=[CH:12][CH:11]=2)[N:3]=[CH:2]1.Cl.[NH2:20][OH:21].[OH-].[Na+].C(O)C>O>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[N:20][OH:21])[CH3:17])=[CH:12][CH:11]=2)[N:3]=[CH:2]1
Reactant: NO
Reactant: CC(=O)c1ccc(OCCCc2c[nH]cn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=NO)c1ccc(OCCCc2c[nH]cn2)cc1

Procedure:
1.2 mmol of (4-(3-(1H-imidazol-4-yl)propyloxy)phenyl)ethanone (Example 78), 2.4 mmol of hydroxylamine hydrochloride and 4.8 mmol of NaOH are heated under reflux in 10 ml of water and 10 ml of ethanol for 7 hours. The mixture is concentrated under reduced pressure and alkalized with saturated K2CO3 solution, and the crude product is filtered off and washed with water. The product is crystallized as hydrogen maleate from diethyl ether and ethanol.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([N:12]3[CH2:16][C@H:15]([C:17]([NH2:19])=[O:18])[O:14][C:13]3=[O:20])=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=[O:21].[CH3:22]N>CO>[CH3:22][NH:19][C:17]([C@@H:15]1[O:14][C:13](=[O:20])[N:12]([C:10]2[CH:9]=[CH:8][C:7]3[N:2]([CH3:1])[C:3](=[O:21])[CH2:4][O:5][C:6]=3[CH:11]=2)[CH2:16]1)=[O:18]
Reactant: CN1C(=O)COc2cc(N3C[C@H](C(N)=O)OC3=O)ccc21
Reactant: CN
Solvent: CO
Product: CNC(=O)[C@H]1CN(c2ccc3c(c2)OCC(=O)N3C)C(=O)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.1 %

Procedure:
To a stirred suspension of (5R)-3-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-7-yl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester (EXAMPLE 59, Step 3, 200 mg, 0.65 mmol) in MeOH (5 mL) is added MeNH2 (5 mL, 10 mmol, 2 M solution in MeOH). The resulting solution is stirred for 3 h at room temperature at which time the resulting white precipitate is filtered, washed with additional MeOH (5 mL), and dried under high vacuum to give the title compound (153 mg, 77%); 1H NMR (300 MHz, DMSO) δ 8.56 (br t, 1H), 7.50 (d, 1H), 7.41–7.33 (m, 2H), 5.23 (dd, 1H), 4.85 (s, 2H), 4.45 (dd, 1H), 4.15 (dd, 1H), 3.45 (s, 3H), 2.84 (d, 2H); MS for C14H15N3O5 m/z 306.5 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2[CH:14]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[O:16][C:10]=2[CH2:9]1)C1C=CC=CC=1>CO.[C].[Pd]>[O:16]1[C:10]2[CH2:9][NH:8][CH2:13][CH2:12][C:11]=2[CH:14]=[C:15]1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1cc2c(o1)CN(Cc1ccccc1)CC2
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc2c(o1)CNCC2

Procedure:
A solution of 0.285 g (1.050 mmol) of methyl 6-benzyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridine-2-carboxylate in 30 ml of methanol was hydrogenated at room temperature at atmospheric pressure over 0.2 g of 10% palladium-carbon (50% wet) overnight. After the catalyst was filtered off, the filtrate was evaporated under reduced pressure to yield the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16](=O)[CH3:17])=[CH:11][C:10]=1[CH3:19])([CH3:7])[CH3:6])[CH3:2].ClCC1[C:24]([CH:39]2[CH2:41][CH2:40]2)=[N:25][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)=[N:27][CH:28]=1>>[CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[C:24]([CH:39]3[CH2:40][CH2:41]3)=[N:25][C:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)=[N:27][CH:28]=2)=[CH:11][C:10]=1[CH3:19])([CH3:7])[CH3:6])[CH3:2]
Reactant: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(SC(C)=O)cc1C
Product: CCOC(=O)C(C)(C)Oc1ccc(SCc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1C

Procedure:
In analogy to the procedure described in example 142D], 2-(4-acetylsulfanyl-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 142C]) was reacted with 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F]) to give the title compound as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH:11]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH:15]=[CH:14][CH2:13][CH2:12]1>>[CH:11]1([C:18]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[O:19])[CH2:17][CH2:16][CH:15]=[CH:14][CH2:13][CH2:12]1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)C1CCC=CCC1
Product: O=C(O)c1ccc(NC(=O)C2CCC=CCC2)cc1

Procedure:
4-(4-Cycloheptene-1-carbonylamino)-benzoic acid was prepared as described in Example 3 from 4.45 g (0.0324 mol) of p-aminobenzoic acid and 5.7 g (0.0359 mol) of 4-cycloheptene-1-carboxylic acid chloride.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([OH:26])=O)[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:59][NH:60][CH2:61][C:62]1[CH:74]=[CH:73][C:65]([CH2:66][N:67]2[CH2:71][CH2:70][CH:69]([OH:72])[CH2:68]2)=[CH:64][CH:63]=1>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([N:60]([CH2:61][C:62]3[CH:74]=[CH:73][C:65]([CH2:66][N:67]4[CH2:71][CH2:70][CH:69]([OH:72])[CH2:68]4)=[CH:64][CH:63]=3)[CH3:59])=[O:26])[CH:20]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)O)co2)C2CC2)c(C)c1
Reactant: CNCc1ccc(CN2CCC(O)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)N(C)Cc3ccc(CN4CCC(O)C4)cc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)furan-3-carboxylic acid (40 mg, 0.105 mmol), EDCI (28 mg, 0.158 mmol), HOBt (21 mg, 0.16 mmol), DIPEA (0.036 mL, 0.21 mmol), 1-{4-[(methylamino)methyl]benzyl}pyrrolidin-3-ol dihydrochloride (34 mg, 0.13 mmol) and DCM (10 mL).
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br.O>C1COCC1>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:13][CH2:12][CH2:11][CH2:10][CH2:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCCCCc1ccccc1
Reactant: BrCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: BrCCCCCCOCCCCc1ccccc1
Yield: 48 %

Procedure:
NaH (46% dispersion in oil; 6.5 g) was added portionwise to a solution of 4-phenyl-1-butanol (15.0 g) and 1,6-dibromohexane (48.8 g) in THF (200 ml) under nitrogen. The resulting suspension was refluxed for 27 h and treated with H2O (80 ml). The mixture was extracted with ER (2×200 ml) and the dried extract was evaporated to leave an orange oil. The oil was purified on a column of silica (800 ml) [A] to give a yellow oil which on distillation gave the title compound as a colourless oil (15.0 g) b.p. 90°-95°/0.1 mmHg.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].N1C=CC=CC=1.[C:16](Cl)(=[O:21])[O:17][CH:18]([Cl:20])[CH3:19]>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][O:8][CH3:9])[C:16](=[O:21])[O:17][CH:18]([Cl:20])[CH3:19]
Reactant: COCCNCCOC
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCCN(CCOC)C(=O)OC(C)Cl
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a cooled solution of bis(2-methoxyethyl)amine (1.94 g, 14.5 mmol, Aldrich) and pyridine (1.26 g, 1.29 mL, 15.9 mmol) in methylene chloride (18 mL) at −78° C., was added slowly 1-chloroethyl carbonochloridate (1.98 g, 1.5 mL, 13.8 mmol, Aldrich) over ˜15 min. The reaction mixture was allowed to stir at −78° C. for 3 h, giving a white precipitate. This cold reaction mixture was filtered to remove the solid and the filtrate was concentrated to dryness, giving the crude 1-chloroethyl bis(2-methoxyethyl)carbamate used for the next step without further purification.