Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14](=[O:16])[CH3:15])=[CH:8][CH:7]=1)CCC.Br[C:26]1[N:27]=[C:28]([N:36]2[CH2:41][CH2:40][N:39]([CH2:42][CH3:43])[CH2:38][CH2:37]2)[C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:42]([N:39]1[CH2:38][CH2:37][N:36]([C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:35]=[C:26]([C:6]3[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][C:14](=[O:16])[CH3:15])=[CH:10][CH:11]=3)[N:27]=2)[CH2:41][CH2:40]1)[CH3:43]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(CCC(C)=O)cc1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CCN1CCN(c2nc(-c3ccc(CCC(C)=O)cc3)cc3ccccc23)CC1
Yield: 62.7 %

Procedure:
4-(4-Tributylstannylphenyl)-2-butanone (2.46 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (1.41 g) were heated under reflux in the presence of tetrakistriphenylphosphinepalladium(0) (0.22 g) in xylene in nitrogen atmosphere overnight. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted in 2N hydrochloric acid, and the resulting aqueous layer was washed with ethyl acetate, adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, and then extracted with ethyl acetate. The extract was washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (toluene/acetone system), to give 1-(4-ethylpiperazin-1-yl)-3-[4-(3-oxobutyl)phenyl]isoquinoline (1.07 g) as a pale yellow viscous oil.
Reaction SMILES: [CH3:1][NH2:2].O.F[C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15]>CN(C=O)C>[CH3:1][NH:2][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15]
Reactant: CN
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: O
Product: CNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 100 %

Procedure:
A 40% solution of methylamine in water (11 mL; 128 mmol) (or any other primary amine) was slowly added to a stirring suspension of 4-fluoro-3-nitrobenzoic acid (278, 6.1 g; 32.9 mmol) in DMF (20 mL) at room temperature. After the addition was completed the mixture was stirred at the same temperature for 60 min; concentrated in vacuo, and suspended in 5% KHSO4 (final pH=2). The suspension was stirred overnight; the precipitate was collected by filtration, washed with water, then with ether and dried to afford the title compound 279 (6.5 g; 100% yield). 1H NMR: (400.2 MHz, DMSO) δ (ppm): 12.8 (bs; 1H), 8.59 (d, J=2.0 Hz; 1H); 8.55 (q, J=5.0 Hz; 1H); 7.96 (dd, J=2.0, 9.1 Hz; 1H); 7.04 (d, J=9.1 Hz; 1H); 3.00 (d, J=5.0 Hz; 3H). MS: calc: 196.2; found: 197.1 (M+H)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][OH:28])=[O:24])[C:5]1=[O:29].C(N(C(C)C)CC)(C)C.[C:39](OC(=O)C)(=[O:41])[CH3:40].O>CN(C=O)C>[C:39]([NH:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][OH:28])=[O:24])[C:5]1=[O:29])(=[O:41])[CH3:40]
Reactant: NCCn1c(=O)c(C(=O)NCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)NCCn1c(=O)c(C(=O)NCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Temperature: 0 °C

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxyethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.019 g, 0.047 mmol) and diisopropyl ethylamine (0.075 mL, 0.43 mmol) in DMF (1 mL) under nitrogen was treated with acetic anhydride (0.004 mL, 0.042 mmol) at ambient temperature. The reaction was warmed slightly to solubilize then reacted at ambient temperature for 10 min. Water was added (2 mL) and the reaction was cooled to 0° C. and concentrated in vacuo. The resulting residue was treated with 1 N NaHSO4 and filtered then triturated with Et2O and dried in air to provide the title compound as an off-white solid: 1H NMR (300 MHz, DMSO-D6) δ ppm 1.7 (s, 3 H), 3.3 (dd, J=3.1, 1.3 Hz, 2 H), 3.4 (m, 2 H), 3.6 (m, 2 H), 4.1 (s, 2 H), 4.3 (m, 2 H), 4.9 (t, J=4.8 Hz, 1 H), 7.1 (t, J=8.8 Hz, 2 H), 7.4 (m, 2 H), 8.0 (m, 1 H), 8.2 (s, 1 H), 8.5 (s, 1 H), 10.4 (d, J=6.2 Hz, 1 H), 17.2 (s, 1 H); ES+ MS: 443 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][NH:13][CH3:14])=[CH:5]2.[O:15]=[C:16]1[NH:25][C:24]2[N:23]=[CH:22][C:21](/[CH:26]=[CH:27]/[C:28]([OH:30])=O)=[CH:20][C:19]=2[CH2:18][CH2:17]1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][N:13]([CH3:14])[C:28](=[O:30])/[CH:27]=[CH:26]/[C:21]1[CH:22]=[N:23][C:24]3[NH:25][C:16](=[O:15])[CH2:17][CH2:18][C:19]=3[CH:20]=1)=[CH:5]2
Reactant: CNCc1cc2cc(F)ccc2n1C
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1cc2cc(F)ccc2n1C)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To a solution of (5-fluoro-1-methyl-1H-indol-2-yl)-N-methylmethanamine (70 mg, 0.36 mmol) in DMF (5 mL) were added in sequential order (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid (72 mg, 0.33 mmol), 1-hydroxybenzotriazole (49 mg, 0.36 mmol), diisopropylethylamine (191 uL, 1.1 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (72 mg, 0.36 mmol). The mixture was stirred at room temperature overnight, cooled in an ice bath and water added with rapid stirring. The product precipitated and was filtered, triturated with ether and dried to yield title compound as a pale brown solid (97 mg, 76%): 1H NMR (300 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.40 (s, 1H), 8.08-8.18 (m, 1H), 7.91-8.08 (m, 1H), 7.52-7.68 (m, 1H), 7.37-7.52 (m, 1H), 7.13-7.36 (m, 2H), 6.42 (s, 1H), 4.86-5.06 (rotamers, 2s, 2H), 3.71 (s, 3H), 3.14 (m, 2H), 2.81-2.97 (m, 2H), 2.75 (s, 3H); MS (ESI) m/e 393 (C22H21FN4O2+H)+.
Reaction SMILES: C(Cl)CCl.[Cl:5][C:6]1[CH:28]=[CH:27][C:9]([O:10][CH2:11][CH2:12][CH2:13][S:14]([CH2:17][C:18]2([C:24](O)=[O:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)(=[O:16])=[O:15])=[CH:8][CH:7]=1.[Si]([NH:36][OH:37])(C(C)(C)C)(C)C>ClCCl>[OH:37][NH:36][C:24]([C:18]1([CH2:17][S:14]([CH2:13][CH2:12][CH2:11][O:10][C:9]2[CH:27]=[CH:28][C:6]([Cl:5])=[CH:7][CH:8]=2)(=[O:16])=[O:15])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:25]
Reactant: CC(C)(C)[Si](C)(C)NO
Reactant: O=C(O)C1(CS(=O)(=O)CCCOc2ccc(Cl)cc2)CCOCC1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(NO)C1(CS(=O)(=O)CCCOc2ccc(Cl)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.5 %

Procedure:
EDC (40 mg) was added to a solution of Example 13 (75 mg) in dichloromethane (20 ml), followed by tert-butyldimethylsilylhydroxylamine (32 mg) and N,N-dimethylaminopyridine (2 mg), and the resulting clear solution was stirred at room temperature for 3 h. The mixture was then washed with water, saturated bicarbonate and brine, dried over MgSO4 and evaporated. The residue was dissolved in a minimum amount of fresh dichloromethane and 1M aqueous hydrochloric acid in ether (2 ml) was added. The solution was stirred for 10 min, then evaporated and the residue purified by chromatography on silica, eluting with ethyl acetate, to give the title compound (30 mg) as a colourless glass.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([I:1])[CH:3]=1
Reactant: CO
Reactant: Cc1ccc(C(=O)O)cc1I
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)c(I)c1
Temperature: 70 °C

Procedure:
To a solution of 3-iodo-4-methyl-benzoic acid (10.0 g, 38.2 mmol) in methanol (70 ml) is added concentrated sulfuric acid (0.5 ml). The reaction mixture is heated at 70° C. for 48 hours, cooled to room ambient temperature and then concentrated. After that, ethyl acetate (100 ml) and aqueous NaHCO3 (saturated, 100 ml) solution are added to the residue. The organic layer is separated and washed again with aqueous NaHCO3 (saturated, 100 ml) solution. The organic layer is separated, dried over anhydrous Na2SO4 and concentrated to yield 3-iodo-4-methyl-benzoic acid methyl ester 1. It is used without further purification in the next step. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1 H), 7.87 (d, 1 H, J=8.4 Hz), 7.48 (d, 1 H, J=8.4 Hz), 3.85 (s, 3 H), 3.35 (s, 3 H); LC-MS m/z: 277.0 (M+1).
Reaction SMILES: [CH2:1]1[C:6]2([C:16](=O)[NH:15][C:14](=O)[C:8]3([CH2:13]CCC[CH2:9]3)[NH:7]2)[CH2:5]CCC1.CC1(C)C(=O)NC(=O)C(C)(C)N1>>[CH3:5][C:6]1([CH3:1])[CH2:16][NH:15][CH2:14][C:8]([CH3:13])([CH3:9])[NH:7]1
Reactant: O=C1NC(=O)C2(CCCCC2)NC12CCCCC2
Agent: CC1(C)NC(C)(C)C(=O)NC1=O
Product: CC1(C)CNCC(C)(C)N1

Procedure:
By following the above procedure, and substituting for 7,15-diazadispiro[5,1,5,3]hexadecane14,16-dione an equivalent amount of 2,2,6,6-tetramethyl-3,5-diketopiperazine, there is obtained 2,2,6,6-tetramethylpiperazine.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([F:34])([F:33])[C:7]([F:32])([F:31])[C:8]([F:30])([F:29])[C:9]([F:28])([F:27])[C:10]([F:26])([F:25])[C:11]([F:24])([F:23])[C:12]([F:22])([F:21])[C:13]([F:20])([F:19])[CH2:14][CH2:15][CH2:16][CH2:17]Br.[OH:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([C:48]#[N:49])=[CH:44][CH:43]=2)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([F:34])([F:33])[C:7]([F:31])([F:32])[C:8]([F:30])([F:29])[C:9]([F:27])([F:28])[C:10]([F:25])([F:26])[C:11]([F:23])([F:24])[C:12]([F:22])([F:21])[C:13]([F:19])([F:20])[CH2:14][CH2:15][CH2:16][CH2:17][O:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]2[CH:47]=[CH:46][C:45]([C:48]#[N:49])=[CH:44][CH:43]=2)=[CH:40][CH:41]=1
Reactant: FC(F)(CCCCBr)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCBr
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(-c2ccc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCBr)cc2)cc1

Procedure:
A solution of 1,16-dibromo-5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12-hexadecafluorohexadecane (20.16 g), 4'-hydroxy-4-cyanobiphenyl (2.05 g), potassium carbonate (2.07 g) and acetone (30 mL) is refluxed for 8 hrs. The acetone is removed under reduced pressure and the residue diluted with water and extracted with ethyl ether. The extracts are washed with water and brine, dried (MgSO4), concentrated, and purified by chromatography to give 4'-(16-bromo-5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12-hexadecafluorohexadecyloxy)-4-cyanobiphenyl.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:12][C:11]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:31])([F:30])[F:29])[OH:27])=[N:10]1.[OH:36][C:37]([CH3:42])([CH3:41])[C:38](O)=[O:39].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:38](=[O:39])[C:37]([OH:36])([CH3:42])[CH3:41])[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[CH2:12][C:11]([C:26]([C:28]([F:31])([F:30])[F:29])([C:32]([F:33])([F:35])[F:34])[OH:27])=[N:10]1
Reactant: CC(C)(O)C(=O)O
Reactant: OC(C1=NN(c2ccccc2Cl)C(c2ccc(N3CCNCC3)cc2)C1)(C(F)(F)F)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(O)C(=O)N1CCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 28.1 %

Procedure:
To 1-(2-chloro-phenyl)-5-[4-(piperazin-1-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Step 1 of Example 312, were added 2-hydroxyisobutyric acid (7.0 mg, 0.07 mmol), dichloromethane (1.0 mL), HOBT (15.0 mg, 0.11 mmol), EDAC (21.0 mg, 0.11 mmol), and triethylamine (23.0 uL, 0.17 mmol). The reaction mixture was stirred at room temperature for 12 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1) to give 10.0 mg of the titled compound as a pale yellow liquid.
Reaction SMILES: [OH:1][C:2]([CH3:11])([CH3:10])[CH2:3][C@H:4]1[CH2:8][O:7]C(=O)[NH:5]1.[OH-].[Ba+2].[OH-].C(O)C.C(=O)=O>O>[NH2:5][C@@H:4]([CH2:3][C:2]([CH3:11])([OH:1])[CH3:10])[CH2:8][OH:7]
Reactant: CC(C)(O)C[C@H]1COC(=O)N1
Agent: O=C=O
Agent: [Ba+2]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(O)C[C@H](N)CO
Reaction time: 8 h
Yield: 83.7 %

Procedure:
A mixture of (4S)-4-(2-hydroxy-2-methylpropyl)-1,3-oxazolidin-2-one (1.0 g, 6.28 mmol), barium hydroxide (3.2 g, 18.8 mmol), ethanol (50 mL) and water (50 mL) was heated to reflux for 4 hours. See Gauthier et al., 2008, Bioorg. Med. Chem. Lett., 18:923-928. After cooling, dry ice (5.5 g, 125.6 mmol) was added and the mixture was stirred vigorously overnight. The suspension was then filtered over CELITE®, rinsing with ethanol. The filtrate was diluted with toluene and evaporated to dryness, yielding crude (S)-2-amino-4-methylpentane-1,4-diol (0.7 g) which was used without further purification in the next step.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[CH2:13][C:12](=O)[CH2:11][CH2:10]2)(=[O:3])[CH3:2].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C(O)(=O)C.C([BH3-])#N.[Na+]>C1C=CC=CC=1.CN(C=O)C.CC1C=CC(S(O)(=O)=O)=CC=1>[C:1]([NH:4][C:5]1[C:14]2[CH2:13][CH:12]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1CC(=O)CC2
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc2c1CC(N1CCCC1)CC2
Reaction time: 16 h
Yield: 69.7 %

Procedure:
A mixture of 8-acetamido-2-tetralone (0.4 g, 2 mmol), pyrrolidine (0.28 g, 4 mmol) and tosic acid (10 mg) in benzene:DMF (5:1, 12 mL) was heated at reflux with a Dean-Stark trap for 4 h. The solvent was evaporated and the residue dissolved in 1:1 MeOH:THF (10 mL). Acetic acid (1 mL) and sodium cyanoborohydride (0.25 g, 4 mmol) were added, and the reaction stirred for 16 h. The solvent was evaporated and the residue taken up in water:methylene chloride. The aqueous layer was basified with 12.5% NaOH, and back extracted. The combined organic phase was dried over sodium sulfate, filtered and evaporated. The residue solidified upon standing, and was crystallized from tolune:hexane to give the product (0.36 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:15]4([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)[CH2:14][NH:13][CH2:12][C:11]3=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:15]4([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)[CH2:14][NH:13][CH2:12][CH2:11]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C1CNCC2(CCCCC2)N1c1ccc2[nH]ncc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1cc2[nH]ncc2cc1N1CCNCC12CCCCC2
Temperature: 80 °C
Yield: 72.8 %

Procedure:
To a stirred solution of 1-(1H-indazol-5-yl)-1,4-diaza-spiro[5.5]undecan-2-one (0.250 g, 0.880 mmol) in THF (30 mL) at ambient temperature and under nitrogen was added LiAlH4 (2.64 mL of a 1.0 M solution in THF, 2.64 mmol) dropwise over 1 minute, then the reaction mixture was warmed to 80° C. After 3 hours the reaction mixture was cooled to room temperature and quenched by the addition of sodium sulfate decahydrate (1 g). The reaction mixture was diluted with DCM and filtered. The filter cake was washed with DCM:MeOH:NH4OH (90:9:1, 3×20 mL) then the combined filtrates were concentrated in vacuo to a solid residue (0.250 g). Purification by chromatography (silica, 5 to 10% of a 9:1 MeOH:NH4OH solution in DCM) gave 1-(1H-indazol-5-yl)-1,4-diaza-spiro[5.5]undecane (0.173 g, 0.641 mmol, 73%) as a pale yellow foam; 1H NMR (300 MHz, MeOD) δ 7.99 (d, J=0.9 Hz, 1H), 7.55-7.49 (m, 1H), 7.41 (d, J=8.9 Hz, 1H), 7.22 (dd, J =8.9, 1.9 Hz, 1H), 3.25-3.14 (m, 2H), 3.01-2.91 (m, 4H), 2.06-1.95 (br. d, J=11.5Hz, 2H), 1.62-1.18 (m, 7H), 0.91-0.70 (m, 1H).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7](F)[C:6]=1[S:16][CH3:17].O>O1CCCC1>[Cl:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:2][CH3:1])[C:6]=1[S:16][CH3:17]
Reactant: C[O-]
Reactant: COC(=O)c1ccc(Cl)c(SC)c1F
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(Cl)c(SC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
Sodium methoxide (5.6 g) was added to a solution of methyl 4-chloro-2-fluoro-3-(methylsulphenyl)benzoate (85% pure, 19.2 g) in dry tetrahydrofuran and the mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with ether, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give methyl 4-chloro-2-methoxy-3-(methylsulphenyl)benzoate (17.1 g) as a yellow oil NMR (CDCl3) 2.5(s,3H), 3.95(s,3H), 4.0(s,3H), 7.25(d,1H), 7.65(d, 1H) contaminated with 15% methyl 4-chloro-3-(chloromethylsulphenyl)-2-methoxybenzoate (determined by the ratio of NMR signals).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C(N(CC)CC)C.[N+:22]([C:25]1[CH:26]=[C:27]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:28]=[CH:29][CH:30]=1)([O-:24])=[O:23]>CN(C=O)C>[CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:34]2[CH2:35][CH2:36][N:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([N+:22]([O-:24])=[O:23])[CH:26]=3)[CH2:32][CH2:33]2)=[O:10])[N:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1
Reactant: O=[N+]([O-])c1cccc(N2CCNCC2)c1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCN(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.1 %

Procedure:
To a solution of (5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (1.1 g, 5.28 mmol) in DMF (10 mL) is added triethylamine (1.47 mL, 10.57 mmol), followed by 1-hydroxy-7-benzotriazole (0.755 g, 5.55 mmol) and 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (1.06 g, 5.55 mmol). After stirring 15 min at RT, 1-(3-nitro-phenyl)-piperazine (1.09 g, 5.28 mmol) is added to the reaction mixture. After stirring overnight at RT, solvent is evaporated and the resulting yellow oil is dissolved in ethylacetate (20 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL), and brine (50 mL). The organic layer is dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude mixture is purified by column chromatography on silica gel (cyclohexane/ethylacetate 0-80%) to give 2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(3-nitro-phenyl)-piperazin-1-yl]-ethanone (1.24 g, 59%). 1H-NMR (400 MHz, MeOD): δ=2.31 (s, 3H), 3.31-3.40 (m, 2H), 3.41-3.49 (m, 2H), 3.77-3.85 (m, 4H), 5.25 (s, 2H), 6.43 (s, 1H), 7.38-7.42 (m, 1H), 7.44-7.51 (m, 1H), 7.69-7.72 (m, 1H), 7.80-7.81 (s, 1H). MS: m/z=398 (M+1).
Reaction SMILES: C=O.[CH2:3]([N:10]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]1=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[CH2:18]([NH:25][CH2:26][C:27](O)=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C1(C)C=CC=CC=1>[CH2:3]([N:10]1[C:14](=[O:15])[CH:27]2[CH:12]([CH2:13][N:25]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:26]2)[C:11]1=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Reactant: O=C(O)CNCc1ccccc1
Agent: C=O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C2CN(Cc3ccccc3)CC2C(=O)N1Cc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of paraformaldehyde (3.37 g), N-benzylmaleimide (2.80 g) and N-benzylglycine hydrochloride (3.02 g) in toluene (100 mL) was heated to reflux with azeotropic removal of water for 16 hours. The mixture was cooled to room temperature, filtered and concentrated in vacuo. The residue was purified by flash chromatography (20% EtOAc/hexane) to afford the title compound 1 as a low melting white solid (3.60 g, 75%). LCMS: Rf: 2.616 min, M+H+: 321.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.Br[C:12](=[CH:18][CH2:19][CH2:20][CH3:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(CC)CC)C.CCCCCC>ClCCl.CN(C)C=O>[CH2:19]([C:18]1[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)=[N:2][O:1][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:20][CH3:21]
Reactant: O/N=C(\Cl)c1ccccn1
Reactant: CCCC=C(Br)C(=O)OCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCc1c(-c2ccccn2)noc1C(=O)OCC
Temperature: 25 °C

Procedure:
To a light orange, homogeneous mixture of (Z)—N-hydroxypicolinimidoyl chloride (0.637 g, 4.07 mmol) and ethyl 2-bromohex-2-enoate (0.900 g, 4.07 mmol) in dichloromethane (17 mL) and N,N-dimethylformamide (1 mL) at room temperature was added triethylamine (1.70 mL, 12.2 mmol) slowly over 5 min. The homogeneous reaction mixture was stirred at room temperature over the weekend. The solvent was removed under reduced pressure, and the residue was diluted with ether (100 mL), washed with water (3×75 mL), washed with a saturated aqueous solution of lithium chloride (1×75 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by trituration with hexane, with sonication, afforded a reddish solid and the hexane filtrate containing the desired product and remaining ethyl 2-bromohex-2-enoate. Concentration under reduced pressure followed by purification by flash silica gel chromatography using a mixture of ethyl acetate and hexane (0:100-0.5:99.5-1:99) afforded ethyl 4-propyl-3-(pyridin-2-yl)isoxazole-5-carboxylate (0.015 g, 0.058 mmol, 1.5% yield) as a white solid. The compound was had an HPLC ret. time=2.61 min.—Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=261.0. 1H NMR (500 MHz, CDCl3) δ ppm 0.92 (t, J=7.42 Hz, 3H), 1.45 (t, J=7.15 Hz, 3H), 1.55-1.64 (m, 2H), 3.11-3.17 (m, 2H), 4.47 (q, J=7.15 Hz, 2H), 7.37 (dd, J=7.70, 4.95 Hz, 1H), 7.81 (td, J=7.70, 2.20 Hz, 1H), 7.98 (d, J=7.70 Hz, 1H), and 8.72 (d, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][C:9](=[O:21])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[F:20])[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].[O:24]([CH2:31][CH2:32]O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:21])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:32][CH2:31][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:15][C:14]=2[F:20])[O:11][CH3:12])=[CH:22][CH:23]=1)#[N:2]
Reactant: OCCOc1ccccc1
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(O)cc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(OCCOc2ccccc2)cc1F

Procedure:
In analogy to example 22.1, (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-4-hydroxy-phenyl)-2-methoxy-acetamide (example 70.4) was reacted with 2-phenoxyethanol, diethyl azodicarboxylate and triphenyl-phosphine in THF to give (RS)-N-(4-cyano-benzyl)-2-[2-fluoro-4-(2-phenoxy-ethoxy)-phenyl]-2-methoxy-acetamide. Colorless oil. MS 435.3 ([M+H]+)