Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:34]=[C:33]([C:35]([NH:37][CH3:38])=[O:36])[C:32]([O:39][CH2:40][CH3:41])=[CH:31][C:3]=1[CH2:4][N:5]([CH2:13][C:14]([C:16]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]([OH:26])=[C:18]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:17]=1)=[O:15])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[C-:42]#[N:43].[Na+].C(OCC)(=O)C.O>C(#N)CC.[Cu](I)I.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>[C:42]([C:2]1[CH:34]=[C:33]([C:35]([NH:37][CH3:38])=[O:36])[C:32]([O:39][CH2:40][CH3:41])=[CH:31][C:3]=1[CH2:4][N:5]([CH2:13][C:14]([C:16]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]([OH:26])=[C:18]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:17]=1)=[O:15])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])#[N:43]
Reactant: CCOc1cc(CN(CC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C(=O)OC(C)(C)C)c(Br)cc1C(=O)NC
Reactant: [C-]#N
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1cc(CN(CC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C(=O)OC(C)(C)C)c(C#N)cc1C(=O)NC
Reaction time: 4 h
Yield: 31.8 %

Procedure:
After dissolving the tert-butyl N-{2-bromo-5-ethoxy-4-[(methylamino)carbonyl]benzyl}-N-{2-[3,5-di(tert-butyl)-4-hydroxyphenyl]-2-oxoethyl}carbamate (2.71 g) in propionitrile (11 ml), sodium cyanide (420 mg), copper iodide (163 mg) and tetrakis(triphenylphosphine)palladium (495 mg) were added under a nitrogen atmosphere and the mixture was heated to reflux for one hour. Additional copper iodide (170 mg) and tetrakis(triphenylphosphine)palladium (500 mg) were added and heating to reflux was continued for 4 hours. Ethyl acetate and water were added to the reaction mixture and the resultant mixture was filtered with celite. The filtrate was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and, after filtering off the insoluble portion, was concentrated. The residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (788 mg) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:16][OH:17])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2.I[CH3:19].[H-].[Na+]>O1CCCC1>[CH3:19][O:1][CH2:2][C:3]1([CH2:16][OH:17])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: OCC1(CO)c2ccccc2-c2ccccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1(CO)c2ccccc2-c2ccccc21
Yield: 62 %

Procedure:
Under nitrogen atmosphere and anhydrous condition, to a reactor were added in succession 80 ml of tetrahydrofuran, 22.6 g (0.1 mol) of 9,9-bis(hydroxymethyl)fluorene and 57 g (0.4 mol) of iodomethane. After the reaction mixture was admixed homogeneously by stirring, 4.6 g of 52% NaH in mineral oil (0.1 mol) was added batch-wise over 2 hours at room temperature, Upon completing the addition, the reaction mixture was stirred for further 2 hours. The unreacted iodomethane was recovered by distillation. The remainder was diluted with 100 ml of water, and extracted twice using 100 ml of diethyl ether for each time. The combined diethyl ether extract was dried over anhydrous sodium sulfate. After drying, thee ether solution was evaporated to dry to give 22.8 g of crude. The crude was purified through column chromatography to give 14.9 g of 9-methoxymethyl-9-hydroxymethyl-fluorene (yield 62%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)=[CH:32][CH:31]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:19]([C:16]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:6]2[C:5]([Cl:22])=[CH:4][N:3]=[C:2]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([CH:36]4[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]4)=[CH:32][CH:31]=3)[N:7]=2)[CH2:18][CH2:17]1)(=[O:20])[NH2:21]
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(Cl)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cc2)CC1
Temperature: 120 °C

Procedure:
A suspension of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide (A14) (100 mg, 297 μmol), Cs2CO3 (291 mg, 892 μmol) and tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (164 mg, 595 μmol) in 1,4-dioxane (2.0 mL) was sonicated for 10 min. To this Xantphos (6.88 mg, 11.9 μmol) and Pd(OAc)2 (1.33 mg, 5.95 μmol) were added and the resulting mixture heated under microwave irradiation for 20 min at 120° C. The resulting mixture was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A15 as a yellow oil (121 mg, 71%); 1H NMR (400 MHz, CDCl3) δ 8.25-8.22 (s, 1H), 7.54-7.46 (m, 3H), 7.43-7.38 (dt, J=7.4, 1.0 Hz, 1H), 7.34-7.29 (m, 2H), 7.29-7.22 (m, 1H), 7.19-7.12 (m, 2H), 5.93-5.80 (s, 1H), 5.41-5.26 (s, 1H), 4.39-4.18 (s, 2H), 3.31-3.06 (m, 4H), 2.90-2.69 (t, J=11.8 Hz, 2H), 2.69-2.54 (tt, J=12.0, 3.4 Hz, 1H), 1.88-1.68 (t, J=15.8 Hz, 4H), 1.68-1.53 (qd, J=13.0, 4.4 Hz, 2H), 1.53-1.46 (s, 9H), 1.19-1.07 (s, 2H). LCMS-A: rt 6.326 min; m/z 577 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[O:29][CH3:30])[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC=C(Cl)C=2OC)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[Cl:28][C:24]1[C:23]([O:29][CH3:30])=[C:22]([N:15]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:31])=[O:3])=[CH:8][N:9]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(Cl)c2OC)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: COc1c(Cl)cccc1NCC1CCCC1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Product: COc1c(Cl)cccc1N(CC1CCCC1)C(=O)Nc1ncc(SCC(=O)O)s1

Procedure:
The title compound was prepared via {2-[3-(3-chloro-2-methoxy-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(3-chloro-2-methoxy-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[S:5][C:6]=1[CH2:7][CH2:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH3:20][N:21]1[C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=[N:22]1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:20][N:21]1[C:25]([C:2]2[CH:3]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[S:5][C:6]=2[CH2:7][CH2:8][CH3:9])=[CH:24][CH:23]=[N:22]1
Reactant: CCCc1sc(C(=O)OC)cc1Br
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCc1sc(C(=O)OC)cc1-c1ccnn1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
A solution of methyl 4-bromo-5-propyl-2-thiophenecarboxylate (1.0 g, 3.80 mmol), potassium carbonate (2.63 g, 19.00 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.949 g, 4.56 mmol) [prepared according to Preparation 7] and bis(tri-t-butylphosphine)palladium(0) (0.097 g, 0.19 mmol) were combined in a sealed tube and stirred at 80° C. for 1 h. The reaction contents were then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated and purified by column chromatography (10-50% EtOAc in hexanes) affording methyl 4-(1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate (1.07 g, 3.76 mmol, 99% yield) as a yellow oil: LCMS (ES) m/e 265 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:26][CH3:27])[C:24]=1[OH:25])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:7].C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[CH3:27][O:26][C:23]1[CH:22]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:24]=1[O:25][S:36]([CH3:35])(=[O:38])=[O:37])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([CH2:13][CH2:14][O:15][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCO)(c3ccccc3)C2)cc(OC)c1O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OS(C)(=O)=O
Temperature: -5 °C
Reaction time: 18 h

Procedure:
Combine 1-(3,5-dimethoxy-4-hydroxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (0.95 g, 2.6 mmol) and triethylamine (1.0 mL, 7.7 mmol) in dichloromethane (15 mL). Cool the reaction mixture to −5° C. with an salt-ice bath. Slowly, add methanesulfonyl chloride (0.45 mL, 5.8 mmol). Warm to ambient temperature. After 18 hours, quench the reaction by the addition of ice. Separate the organic layer and extract with aqueous 1M hydrochloric acid solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain the title compound.
Reaction SMILES: CN(C)C=O.Br[CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([CH2:29][CH2:30][CH3:31])=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17]([C:25]([F:28])([F:27])[F:26])([C:21]([F:24])([F:23])[F:22])[O:16][CH2:15]2.C(=O)([O-])[O-].[K+].[K+].[O:38]1[C:42]2[CH:43]=[CH:44][C:45]([C:47]3([CH3:54])[NH:51][C:50](=[O:52])[NH:49][C:48]3=[O:53])=[CH:46][C:41]=2[O:40][CH2:39]1>O>[O:38]1[C:42]2[CH:43]=[CH:44][C:45]([C:47]3([CH3:54])[NH:51][C:50](=[O:52])[N:49]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]4[C:13]([CH2:29][CH2:30][CH3:31])=[C:14]5[C:18](=[CH:19][CH:20]=4)[C:17]([C:25]([F:28])([F:27])[F:26])([C:21]([F:24])([F:23])[F:22])[O:16][CH2:15]5)[C:48]3=[O:53])=[CH:46][C:41]=2[O:40][CH2:39]1
Reactant: CCCc1c(OCCCCBr)ccc2c1COC2(C(F)(F)F)C(F)(F)F
Reactant: CC1(c2ccc3c(c2)OCO3)NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCN2C(=O)NC(C)(c3ccc4c(c3)OCO4)C2=O)ccc2c1COC2(C(F)(F)F)C(F)(F)F
Reaction time: 8 h

Procedure:
To a N,N-Dimethylformamide (2 mL) solution of 5-(4-bromobutoxy)-4-propyl-1,1-bis(trifluoromethyl)-1,3-dihydroisobenzofuran (25 mg, 0.0557 mmol), potassium carbonate mg, 0.111 mmol) and 5-(benzo[d][1,3]dioxol-5-yl)-5-methylimidazolidine-2,4-dione (CAS: 308122-40-9:DE335993) (19.6 mg, 0.0835 mmol) were added and the mixture was stirred overnight. The reaction solution was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by thin-layer silica-gel column chromatography (hexane:ethyl acetate=2:1) and of the title compound (30.7 mg, 92%) was obtained as colorless oil.
Reaction SMILES: [C:1]1(=[O:11])[C:5]2([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][C:3](=[O:10])[O:2]1.[CH3:12][CH2:13][OH:14]>>[CH2:13]([O:14][C:3](=[O:10])[CH2:4][C:5]1([C:1]([OH:11])=[O:2])[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:12]
Reactant: O=C1CC2(CCCC2)C(=O)O1
Reactant: CCO
Product: CCOC(=O)CC1(C(=O)O)CCCC1
Temperature: 70 °C
Reaction time: 22 h

Procedure:
A solution of 2-oxaspiro[4.4]nonane-1,3-dione (522 mg, 3.39 mmol) in anhydrous EtOH (15 ml) was allowed to stir at 70° C. for 22 hours under nitrogen. The reaction mixture was concentrated to give a crude 1-(2-ethoxy-2-oxoethyl)cyclopentanecarboxylic acid (compound A, 672 mg). The product (86% purity) was used for next step without further purification; 1H NMR (400 MHz, CDCl3) δ ppm 1.24 (t, J=7.2 Hz, 3H) 1.57-1.81 (m, 6H) 2.19-2.25 (m, 2H) 2.69 (s, 2H) 4.12 (q, J=7.2 Hz, 3H) 11.65 (br s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3](C(O)=O)=[N:4][C:5]([CH2:8][CH3:9])=[N:6][CH:7]=1>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([CH2:8][CH3:9])=[N:6][CH:7]=1
Reactant: CCc1ncc(Br)c(C(=O)O)n1
Solvent: Cc1ccccc1C
Product: CCc1ncc(Br)cn1
Yield: 37.4 %

Procedure:
A mixture of 5-Bromo-2-ethylpyrimidine-4-carboxylic acid (5.6 g, 24.3 mmol) in xylene (50 mL) was refluxed for 2 h. After cooling, the mixture was applied directly to a silica column, which was eluted with petroleum ether, then ethyl acetate in petroleum ether (5%) to give compound 0601-121 (1.7 g, 38%) as a yellow liquid. 1H NMR (400 MHz, DMSO-d6): 1.26 (t, J=7.6 Hz, 3H), 2.87 (q, J=7.6 Hz, 2H), 8.90 (s, 2H).
Reaction SMILES: [CH:1]1([NH:6][CH2:7][C:8]([OH:16])([CH2:14][CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C(#N)C>[CH2:17]([N:6]([CH2:7][C:8]([OH:16])([CH2:14][CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(O)(CC)CNC1CCCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C(O)(CC)CN(Cc1ccccc1)C1CCCC1
Temperature: 80 °C
Yield: 75.7 %

Procedure:
To ethyl 2-((cyclopentylamino)methyl)-2-hydroxybutanoate (2.7 g, 12 mmol) in 50 ml of acetonitrile at room temperature, was added benzyl bromide (2.1 ml, 18 mmol) dropwise, followed by K2CO3 (5 g, 35 mmol). The reaction mixture was heated at 80° C. for 18 h. It was then diluted to EtOAc, washed by brine and water. Organic extract dried and concentrated to a residue, which was purified on silica gel column chromatographically (Hex/EtOAc=100:1 to 4:1) to give 2.9 g product (77%). [M+H] calc'd for C19H29NO3, 320. found 320.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][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.[CH3:22][O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[CH:26]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:22][O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:17](=[O:18])[CH2:16][O:15][C:14]2[CH:13]=[CH:12][C:11]([C:1]34[CH2:10][CH:5]5[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]5)[CH2:8]3)[CH2:2]4)=[CH:21][CH:20]=2)[CH:26]=1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: COC(=O)c1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
To a solution of the (4-adamantan-1-yl-phenoxy)-acetic acid (140 mg, 0.5 mmol) and 3-aminobenzoic acid methyl ester (110 mg, 0.75 mmol) in DMF (5.0 mL) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC) (144.0 mg, 0.75 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (101 mg, 0.75 mmol), and N,N-diisopropylethylamine (DIPEA) (0.13 mL, 0.75 mmol). The reaction mixture was stirred at room temperature overnight, and then partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. Purification by silica gel column chromatography (n-Hexane:Ethyl acetate:MeOH=15:3:1) gave 3-[2-(4-Adamant-1-yl-phenoxy)-acetylamino]-benzoic acid methyl ester as a white solid (160 mg, 76% yield).
Reaction SMILES: CN(C)S([N:6]1[CH:10]=[C:9]([CH:11]([O:19][CH3:20])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=[C:7]1[Si](C(C)(C)C)(C)C)(=O)=O.Cl.[OH-].[Na+]>C(O)C.O>[CH3:20][O:19][CH:11]([C:9]1[N:8]=[CH:7][NH:6][CH:10]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(Cc1ccccc1)c1cn(S(=O)(=O)N(C)C)c([Si](C)(C)C(C)(C)C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COC(Cc1ccccc1)c1c[nH]cn1
Temperature: 25 °C
Yield: 75.8 %

Procedure:
To a stirred suspension of 2-(tert-butyl-dimethyl-silanyl)-4-(1-methoxy-2-phenyl-ethyl)-imidazole-1-sulfonic acid dimethylamide (105 mg) at r.t. in ethanol (3 ml) under an argon atmosphere was added 2 N HCl (3 ml). The mixture was heated to reflux for 3 hours. The mixture was cooled to r.t. and concentrated to leave a light yellow solid which was taken up in H2O and brought to pH 12 by the addition of 4 N NaOH. The product was extracted with CH2Cl2/MeOH 4:1. The combined organics were dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 9:1) to give 4-(1-methoxy-2-phenyl-ethyl)-1H-imidazole (38 mg) as white solid. MS (ISP): 203.4 ([M+H]+)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][N:14]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=4)[CH2:13]3)[C:9]2=[O:28])=[C:4]([CH3:29])[CH:3]=1.O1CCOCC1.CN[C@H]1CCCC[C@@H]1NC.[C:46]([NH2:49])(=[O:48])[CH3:47].C(=O)([O-])[O-].[K+].[K+]>[Cu]I>[CH3:29][C:4]1[CH:3]=[C:2]([NH:49][C:46](=[O:48])[CH3:47])[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][CH2:15][N:14]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=3)[CH2:13]2)[C:9]1=[O:28]
Reactant: Cc1cc(Br)ccc1N1CCC2(CCCN(c3ccc(C(F)(F)F)cn3)C2)C1=O
Reactant: CC(N)=O
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(N2CCC3(CCCN(c4ccc(C(F)(F)F)cn4)C3)C2=O)c(C)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-bromo-2-methylphenyl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one (38.1 mg, 0.0000814 mol), in 1,4-dioxane (0.5 mL, 0.006 mol) was added (1S,2S)—N,N′-dimethylcyclohexane-1,2-diamine (2.3 mg, 0.000016 mol), copper(I) iodide (1.6 mg, 0.0000081 mol), acetamide (9.6 mg, 0.00016 mol), and potassium carbonate (23.6 mg, 0.000171 mol) and the mixture was stirred at 100° C. overnight. The product was purified by prep-HPLC. LC-MS: 447.2 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH:9]=O)=[CH:2]1.[C:14]([CH2:16]C(O)=O)#[N:15].C([O-])(=O)C.[NH4+].N1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)/[CH:9]=[CH:16]/[C:14]#[N:15])=[CH:2]1
Reactant: N#CCC(=O)O
Reactant: O=Cc1cccc(-c2ccsc2)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1C
Product: N#C/C=C/c1cccc(-c2ccsc2)c1
Yield: 35.6 %

Procedure:
1.0 g of 3-(3-thienyl)benzaldehyde, 0.5 g of cyanoacetic acid, 15 mg of ammonium acetate and 1 ml of s pyridine were dissolved in 1.5 ml of xylene, and the mixture was refluxed for 5.5 hours. The solvent was evaporated, and the residue was dissolved in a mixture of ethyl ether and water, then the resulting solution was acidified with diluted hydrochloric acid. The organic layer separated was worked up in a customary manner, and the product purified by medium-pressure liquid chromatography [silica gel column, hexane/ethyl acetate=7/1→5/1] to give 0.4 g of (E)-3-(3-thienyl)cinnamonitrile as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[F:12][C:8]1[CH:9]=[C:10]([F:11])[C:2]2[NH:1][C:14](=[O:16])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1c(F)cc(F)cc1C(=O)O
Solvent: C1CCOC1
Product: O=c1[nH]c2c(F)cc(F)cc2c(=O)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
2-Amino-3,5-difluoro-benzoic acid (2.44 g, 0.0141 mol) was dissolved in Tetrahydrofuran (100 mL). Triphosgene (4.18 g, 0.0141 mol) was dissolved in Tetrahydrofuran (10 mL) and added. The resulting solution was stirred for 4 h at rt. The reaction mixture was concentrated, and the resulting residue was sonicated in H20. The peach ppt was filtered, taken up in acetone, and was concentrated under reduced pressure. It was then azeotroped in toluene to give 6,8-Difluoro-1H-3,1-benzoxazine-2,4-dione as tan solids (2.64 g, 94%). 1H-NMR (DMSO): 12.00 (s, 1H), 7.85 (m, 1H), 7.60 (m, 1H); 19F-NMR (DMSO): −116, −125.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[C:14]([CH3:22])[CH:15]=[N:16][C:17]=3[O:19][CH2:20][CH3:21])[NH:12][C:11]([CH3:23])=[C:10]2[C:24](O)=[O:25])=[C:5]([O:27][CH3:28])[CH:4]=1)#[N:2].C(N1C=CN=C1)([N:31]1C=CN=C1)=O.N>C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[C:14]([CH3:22])[CH:15]=[N:16][C:17]=3[O:19][CH2:20][CH3:21])[NH:12][C:11]([CH3:23])=[C:10]2[C:24]([NH2:31])=[O:25])=[C:5]([O:27][CH3:28])[CH:4]=1)#[N:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOc1ncc(C)c2c1C(c1ccc(C#N)cc1OC)C(C(=O)O)=C(C)N2
Agent: N
Solvent: CCOC(C)=O
Product: CCOc1ncc(C)c2c1C(c1ccc(C#N)cc1OC)C(C(N)=O)=C(C)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.46 g (3.84 mmol) of the compound from Example 30A are introduced into 50 ml of ethyl acetate and, after addition of 777 mg (4.79 mmol) of 1,1′-carbonyldiimidazole, stirred at room temperature overnight. A TLC check (silica gel; mobile phase: ethyl acetate) shows complete conversion. The volatile components are removed in a rotary evaporator, and the residue is taken up in 20 ml of DMF. Then 10.74 ml of ammonia (28% by weight solution in water, 76.8 mmol) are added, and the reaction mixture is heated at 100° C. for 30 min. The solvent is distilled out under reduced pressure, and the residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). The residue after concentration of the product fractions is dissolved in 40 ml of dichloromethane/methanol (1:1 v/v) and mixed with 100 ml of ethyl acetate. The solvent is concentrated to a volume of about 20 ml, whereupon the product crystallizes. The precipitate is filtered off and washed with a little diethyl ether. Drying at 40° C. in a vacuum drying oven results in 1.40 g (96% of theory) of the title compound.
Reaction SMILES: [OH-].[Li+].C([O:5][P:6]([CH2:15][C@@H:16]([OH:33])[CH2:17][NH:18][C@H:19]([C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=1)[CH3:20])([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7])C>O>[CH3:32][O:31][C:23]1[CH:22]=[C:21]([C@@H:19]([NH:18][CH2:17][C@H:16]([OH:33])[CH2:15][P:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:5])[OH:7])[CH3:20])[CH:26]=[C:25]([O:27][CH3:28])[C:24]=1[O:29][CH3:30]
Reactant: CCOP(=O)(Cc1ccccc1)C[C@@H](O)CN[C@@H](C)c1cc(OC)c(OC)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: COc1cc([C@H](C)NC[C@H](O)CP(=O)(O)Cc2ccccc2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
10 ml of water and 0.24 g of lithium hydroxide are added to a solution of 2.05 g of 3-{N-[1(S)-(3,4,5-trimethoxyphenyl)ethyl]amino}-2(S)-hydroxy-propyl(benzyl)-phosphinic acid ethyl ester in 4 ml of water and the mixture is heated at reflux overnight. The then clear solution is cooled to room temperature, adjusted to pH 7 with phsophoric acid and concentrated to dryness by evaporation under reduced pressure. The evaporation residue is made into a slurry in hot methanol and filtered. After concentration of the filtrate by evaporation there remains a foam which, after crystallisation from isopropanol, yields 3-{N-[1(S)-(3,4,5-trimethoxyphenyl)ethyl]amino}-2(S)-hydroxypropyl-(benzyl)-phosphinic acid having a melting point of 204°-206°, [α]20D =-35.2°±1.2° (c=0.812 in methanol).