Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:6]=2/[CH:7]=[N:8]/[S@:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])[CH2:3][CH2:2]1.[CH:22]([Mg]Br)=[CH2:23]>C1COCC1.COC(C)(C)C>[CH:1]1([S:4][C:5]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:6]=2[CH:7]([NH:8][S@:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])[CH:22]=[CH2:23])[CH2:2][CH2:3]1
Reactant: C=C[Mg]Br
Reactant: CC(C)(C)[S@](=O)/N=C/c1cc([N+](=O)[O-])ccc1SC1CC1
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: C=CC(N[S@@](=O)C(C)(C)C)c1cc([N+](=O)[O-])ccc1SC1CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
To 85A (3.0 g, 9.2 mmol) in THF (30 mL) and methyl tert-butylether (50 mL) at −78° C. was added vinylmagnesium bromide (1.0 M in THF, 20 mL, 20 mmol) dropwise. The mixture was stirred at −78° C. for 1.0 h before it was quenched with sat. NH4Cl (50 mL) at −78° C. The mixture was extracted with EtOAc (3×50 mL), the organic layer was washed with brine and dried over Na2SO4. After removal of solvent, the crude was purified by silica gel column chromatography using gradient EtOAc in hexanes to give 85B (2.45 g, 78% yield). HPLC and 1H NMR indicated 85B is a mixture of two diastereoisomers in a ratio of 5:1. Major isomer: 1H NMR (400 MHz, CDCl3) δ ppm 0.70-0.81 (m, 2H) 1.17-1.24 (m, 2H) 1.26 (s, 9H) 2.17 (m, 1H) 3.53 (d, J=2.64 Hz, 1H) 5.21-5.32 (m, 3H) 5.91 (m, 1H) 7.72 (d, J=8.79 Hz, 1H) 8.09 (dd, J=8.79, 2.64 Hz, 1H) 8.26 (d, J=2.64 Hz, 1H), LC-MS 355 (M+H).
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(#N)C>[N:20]1([CH2:19][CH2:18][O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[CH:1]=[O:9])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: O=Cc1ccccc1O
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccccc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of salicylaldehyde (2 ml) in acetonitrile (20 ml) was added K2CO3 (5.71 g), followed by N-(2-choroethyl)morpholine hydrochloride (3.5 g) and then the mixture was stirred at room temperature for 2 hours, then at reflux overnight. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo to afford 2-[2-(4-morpholinyl)ethoxy]benzaldehyde, as a yellow oil.
Reaction SMILES: C([Zn][CH2:4][CH3:5])C.[CH:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCCCCC>[C:7]1([CH:6]([OH:13])[CH2:4][CH3:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1ccccc1
Reactant: CC[Zn]CC
Solvent: CCCCCC
Product: CCC(O)c1ccccc1
Reaction time: 17 h
Yield: 25 %

Procedure:
To 2.2 mL solution of diethylzinc in hexane, 0.2 mL of benzaldehyde and 2 mg of a mixture of compounds 6 and 7 was added. After 17 h, the reaction was quenched by the addition of a few drops of saturated ammonium chloride. Solvent extraction (CH2Cl2/H2O), followed by drying and evaporation of the organic solvent, and flash chromatography, resulted in the isolation of the addition product (1-phenyl-1-propanol) in 25% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21]([OH:23])=O)[N:9]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[S:55]1[C:64]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59][C:58]=2[N:57]=[CH:56]1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21]([N:61]3[CH2:62][CH2:63][C:64]4[S:55][CH:56]=[N:57][C:58]=4[CH2:59][CH2:60]3)=[O:23])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Reactant: c1nc2c(s1)CCNCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1)N1CCc2ncsc2CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 52.4 %

Procedure:
32 mg (3,5-bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-acetic acid was dissolved in 1.5 mL DMF. 32 mg HATU and 15 μL triethylamine were added to this solution and the mixture was stirred for 5 min. at RT. Then, 15 mg 5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine and 15 μL triethylamine in 0.5 mL DMF were added. The mixture was stirred over night at RT. The reaction solution was purified by HPLC to yield 23 mg of the desired compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:23]1([CH:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:33]1([CH:29]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:30]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[O:31])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and diphenylacetyl chloride: 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.33-7.21 (m, 13H), 6.94 (m, 2H), 4.88 (s, 1H), 3.39 (t, 2H, J=5.6 Hz), 2.93 (d, 2H, J=11.3 Hz), 2.52-2.36 (m, 4H), 1.97 (t, 2H, J=11.3 Hz), 1.83-1.58 (m, 6H), 1.24 (d, 6H, J=7.6 Hz); Anal. Calcd for C32H39N3O2+HCl+0.19CHCl3: C, 69.44; H, 7.27; N, 7.55. Found: C, 69.44; H, 7.43; N, 7.43; ESMS m/e: 498.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([SH:11])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH3:23].[OH-].[Na+]>>[NH2:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:4]([S:11][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: CCCCCBr
Reactant: Nc1cc(C(=O)O)cc(S)c1Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCSc1cc(C(=O)O)cc(N)c1Oc1ccccc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 5-amino-3-mercapto-4-phenoxybenzoic acid (5.2 g), n-pentyl bromide (5 ml), and 0.5 N sodium hydroxide is stirred at room temperature for 5 days. 5-Amino-3-n-pentylthio-4-phenxoybenzoic acid is precipitated by addition of 4 N hydrochloric acid (30 ml). After collection by filtration, recrystallisation from cyclohexane and drying, the compound is obtained with a melting point of 98°C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=2[F:17])=[C:6]([F:18])[C:5]([CH3:19])=[CH:4][CH:3]=1.C1C(=O)N([Br:27])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:27][CH2:19][C:5]1[C:6]([F:18])=[C:7]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=2[F:17])[C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Cl)c(Oc2ccc(C#N)cc2F)c1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(Oc2c(Cl)ccc(CBr)c2F)c(F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
To a solution of 4-[(6-chloro-2-fluoro-3-methylphenyl)oxy]-3-fluorobenzonitrile (2.41 g, 8.62 mmol) and NBS (1.534 g, 8.62 mmol) in carbon tetrachloride (150 ml) was added AIBN (1.415 g, 8.62 mmol) and the reaction mixture was stirred at 80° C. overnight. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-{[3-(bromomethyl)-6-chloro-2-fluorophenyl]oxy}-3-fluorobenzonitrile (1.60 g, 4.46 mmol, 52% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.08 (dd, 1H), 7.62 (d, 1H), 7.48-7.59 (m, 2H), 6.92 (t, 1H), 4.70 (s, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH:8]([O:10][C:11](=[O:13])[CH3:12])[CH2:9][C@@H:3]1[CH2:4][C:5](=[O:14])[CH2:6]2>C(O)C.[Pt](=O)=O>[OH:14][C@@H:5]1[CH2:6][CH:7]2[N:2]([CH3:1])[CH:3]([CH2:9][C@H:8]2[O:10][C:11](=[O:13])[CH3:12])[CH2:4]1
Reactant: CC(=O)OC1C[C@@H]2CC(=O)CC1N2C
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(=O)O[C@@H]1CC2C[C@H](O)CC1N2C
Reaction time: 12 h
Yield: 119.7 %

Procedure:
To a solution of the above ester (4.11 mmol, 0.811 g) in 95% ethanol (50 mL) was added platinum (IV) oxide (0.354 mmol, 0.081 g), and the reaction was pressurized to 50 psi of H2. The reaction was stirred vigorously for 12 hours. The reaction was filtered through a pad of celite and the celite was washed with portions of ethyl acetate. The solvents were removed under reduced pressure to provide acetic acid (3S,6R)-3-hydroxy-8-methyl-8-aza-bicyclo[3.2.1]oct-6-yl ester (0.98 g) which was used without further purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:28])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[NH:20][C:19]3=[O:27])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.CC(C)=O.[Cr](O)(O)(=O)=O.[OH-].[Na+]>O>[O:27]=[C:19]1[N:18]([CH:15]2[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][CH2:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:28])[CH2:13][CH2:14]2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[NH:20]1
Reactant: O=c1[nH]c2ccccc2n1C1CCN(CCCC(O)c2ccc(F)cc2)CC1
Agent: O=[Cr](=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(CCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a stirred mixture of 4 g of 1-(p-fluorophenyl)-4-[4-(2-oxo-1-benzimidazolinyl)piperidino]-1-butanol and 100 ml of acetone was added dropwise a chromic acid solution (prepared from 2 g of chromic anhydride, 5 ml of water and 2 ml of sulfuric acid) under cooling with ice. The mixture was stirred over night at room temperature, poured into 600 ml of cold water and made alkaline by addition of a 10% aqueous sodium hydroxide solution. The basic material which was separated was extracted twice with each 100 ml of chloroform and the combined extracts were washed with water and evaporated to dryness. Recrystallization of the solid residue from aqueous acetone gave γ-[4-(2-oxo-1-benzimidazolinyl)-piperidino]-p-fluorobutyrophenone, melting at 171° - 172°C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[CH:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:8]2=[N:9][CH:10]=1)=[O:4].C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[CH:49](=[O:54])[CH2:50][CH:51]([CH3:53])[CH3:52]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([CH:49]([OH:54])[CH2:50][CH:51]([CH3:53])[CH3:52])[N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: CC(C)CC=O
Reactant: COC(=O)c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cnc2c(c1)cc(C(O)CC(C)C)n2S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 36.8 %

Procedure:
To a suspension of 1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (2.0 g, 6.33 mmol) in dry tetrahydrofuran (15 mL) at −78° C. was added freshly prepared lithium diisopropylamide [prepared by adding 1.6 M n-butyllithium in n-hexane (5.3 mL, 8.55 mmol) to a 0° C. solution of diisopropylamine (1.3 mL, 9.2 mmol) in dry tetrahydrofuran (40 mL)] dropwise. The mixture was stirred at −78° C. for 5 min and then treated with isovaleraldehyde (1.4 mL, 13.3 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and then quenched with brine. The mixture was extracted with ethyl acetate (2×150 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 15% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-(1-hydroxy-3-methyl-butyl)-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester as a colorless oil (938 mg, 35%): LC/MS m/e calcd for C20H23N2O5S [M+H]+ 403.47, observed 403.3; 1H NMR (400 MHz, CDCl3) δ ppm 1.04 (d, J=6.4 Hz, 3H), 1.06 (d, J=6.4 Hz, 3H), 1.82 (m, 1H), 1.94-2.03 (m, 2H), 3.30 (br, 1H), 3.94 (s, 3H), 5.45 (m, 1H), 6.70 (s, 1H), 7.49 (m, 2H), 7.59 (m, 1H), 8.19 (m, 2H), 8.41 (d, J=2.0 Hz, 1H), 9.01 (d, J=2.0 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:13][CH:12]=3)=[CH:10][C:3]=12.Br[C:34]1[C:35]([C:41]2[CH:46]=[CH:45][C:44]([NH:47][C:48](=[O:52])[N:49]([CH3:51])[CH3:50])=[CH:43][CH:42]=2)=[N:36][N:37]([CH2:39][CH3:40])[CH:38]=1>>[CH2:39]([N:37]1[CH:38]=[C:34]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:25])=[O:26])[C:9]([C:11]4[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][N:19]5[CH2:23][CH2:22][CH2:21][CH2:20]5)=[CH:13][CH:12]=4)=[CH:10][C:3]=23)[C:35]([C:41]2[CH:46]=[CH:45][C:44]([NH:47][C:48](=[O:52])[N:49]([CH3:51])[CH3:50])=[CH:43][CH:42]=2)=[N:36]1)[CH3:40]
Reactant: O=S(=O)(c1ccccc1)n1c(-c2ccc(CCN3CCCC3)cc2)cc2c(Br)ccnc21
Reactant: CCn1cc(Br)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Product: CCn1cc(-c2ccnc3c2cc(-c2ccc(CCN4CCCC4)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Reaction time: 4.5 h

Procedure:
Following the procedure described for Intermediate 32 using 4-bromo-1-(phenylsulfonyl)-2-{4-[2-(1-pyrrolidinyl)ethyl]phenyl}-1H-pyrrolo[2,3-b]pyridine and then following the procedure described for Intermediate 100 using N′-[4-(4-bromo-1-ethyl-1H-pyrazol-3-yl)phenyl]-N,N-dimethylurea and stirring for 4.5 hours provided the title compound. ESMS [M+H]+: 688.6.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:53])[NH:19][CH2:20][C:21]([N:23]2[CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[CH:26]([S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[CH:39]=3)(=[O:37])=[O:36])[CH2:25][CH:24]2[C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[O:22])[CH:14]=[CH:15][CH:16]=1)=[O:10])C1C=CC=CC=1>[Pd].C(O)C>[C:49]([O:48][C:46]([CH:24]1[CH2:25][CH:26]([S:35]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[CH:39]=2)(=[O:37])=[O:36])[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[N:23]1[C:21](=[O:22])[CH2:20][NH:19][C:18](=[O:53])[NH:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[C:9]([OH:10])=[O:8])=[O:47])([CH3:52])([CH3:50])[CH3:51]
Reactant: COc1cccc(S(=O)(=O)C2CC(C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc3cccc(C(=O)OCc4ccccc4)c3)C2c2ccccc2F)c1
Agent: [Pd]
Solvent: CCO
Product: COc1cccc(S(=O)(=O)C2CC(C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc3cccc(C(=O)O)c3)C2c2ccccc2F)c1
Yield: 75.1 %

Procedure:
A The process is performed as described in Example 2A, but starting with 5.3 g of tert-butyl (2RS,4SR,5RS)-1-{2-[3-(3-benzyloxycarbonylphenyl)ureido]acetyl}-5-(2-fluorophenyl)-4-(3-methoxyphenyl)sulphonyl-2-pyrrolidinecarboxylate, 0.4 g of 10% palladium-on-charcoal and 100 cm3 of ethanol under a hydrogen atmosphere (130 kPa). After treatment, 3.5 g of (2RS,4SR,5RS)-3-(3-{2-[2-tert-butoxycarbonyl-5-(2-fluorophenyl)-4-(3-methoxyphenyl)sulphonyl-1-pyrrolidinyl]-2-oxoethyl}ureido)benzoic acid are obtained [Rf=0.3; eluent: methylene chloride/methanol (90/10); 1H NMR spectrum (250 MHz, (CD3)2SO with addition of a few drops of CD3COOD, at a temperature of 393 K, δ in ppm): 1.54 (s, 9H: C(CH3)3); from 2.40 to 2.60 and 2.82 (2 mts, 1H each: CH2 at 3); 3.68 and 3.98 (broad d and d respectively, J=17 Hz, 1H each: COCH2N); 3.88 (s, 3H: OCH3); 4.11 (mt, 1H: H4); 4.67 (t, J=8 Hz, 1H: H2); 5.72 (d, J=3 Hz, 1H: H5); from 7.00 to 7.65 (mt, 10H: aromatic H); 7.80 (broad t, J=8 Hz, 1H: H of the aromatic at 5 (H6)); 8.00 (mt, 1H: aromatic H (H2: ortho to the COOH))].
Reaction SMILES: C(O)(=O)C=C.[CH2:6]([OH:10])[CH2:7][CH2:8][CH3:9].[CH2:11]([O:15][C:16](=[O:19])[CH:17]=[CH2:18])[CH2:12][CH2:13][CH3:14]>O>[CH2:11]([O:15][C:16](=[O:19])[CH:17]=[CH2:18])[CH2:12][CH2:13][CH3:14].[CH2:6]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCO
Agent: C=CC(=O)O
Agent: C=CC(=O)OCCCC
Solvent: O
Product: CCCCOCCCC

Procedure:
The conditions were the same as those described in Example 1, but acrylic acid and n-butanol were used in the molar ratio of 1:1. The reactor was supplied with 297 g/h of a mixture consisting of 138 g of acrylic acid, 142 g of n-butanol and 17 g of butylacrylate. An identical quantity of reaction product consisting of 173 g of butylacrylate, 46 g of acrylic acid, 50 g of butanol, 22 g of water and 6 g of residue was discharged. 66.7% of the acrylic acid underwent conversion. 154 g/h of pure butylacrylate free from dibutylether was obtained. This corresponded to a yield of 94.1%, based on the acrylic acid converted. The catalyst performance was 933 g of butylacrylate per kg of catalyst per hour.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:14][CH3:15])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].N1C=CC=CC=1>ClCCl>[CH3:15][O:14][C:3]1[C:2]([NH:1][C:17](=[O:18])[O:19][CH2:20][CH3:21])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:12][CH3:13])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Cl
Reactant: COc1ccc2nc(OC)c(N)nc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 96.1 %

Procedure:
3-Amino-2,6-dimethoxyquinoxaline (616 mg, 3.00 mmol) and ethyl chloroformate (391 mg, 3.60 mmol) were dissolved in dichloromethane (50 ml) at room temperature and thereto pyridine (285 mg, 3.60 mmol) was added. The resulting mixture was stirred at room temperature for 10 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (3:1) mixture and concentration gave 799 mg of the titled compound (yield, 96%).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:15])[CH2:4][CH2:5][C:6]([CH3:14])([CH3:13])[C:7]=1[C:8](=[O:12])[CH2:9][CH:10]=[CH2:11].C(OCC)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[CH3:1][C:2]1[C:3](=[O:15])[CH2:4][CH2:5][C:6]([CH3:14])([CH3:13])[C:7]=1[C:8](=[O:12])[CH:9]=[CH:10][CH3:11]
Reactant: C=CCC(=O)C1=C(C)C(=O)CCC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC=CC(=O)C1=C(C)C(=O)CCC1(C)C
Yield: 100.2 %

Procedure:
153 g (0.74 mole) of 2,4,4-trimethyl-3-(but-3-en-1-on-1-yl)-cyclohex-2-en-1-one (Ib) were stirred under reflux together with 135 ml of ethyl acetate and 3 g of p-toluenesulfonic acid for 2 hours. When the solution had cooled, 1,000 ml of ether were added to it, the mixture was washed with water and with saturated sodium bicarbonate solution and dried with sodium sulfate, and the solvent was distilled off under about 20 mbar. 153 g of 2,4,4-trimethyl-3-(but-2-en-1-on-1-yl)-cyclohex-2-en-1-one (Ia) were obtained, the yield being quantitative, and the product being only slightly impure according to thin-layer chromatography. Recristallization from 500 ml of cyclohexane gave 132 g (yield: 86.8% of theory) of a product which was pure according to thin-layer chromatography; evaporating down the mother liquor gave a further 21 g (yield: 13.2% of theory) of a somewhat impure product.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10](=O)[NH:9][C:7]=2[N:8]=1.O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:10]1[CH:11]=[CH:12][C:6]2[CH:5]=[N:4][C:3]([S:2][CH3:1])=[N:8][C:7]=2[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1ncc2ccc(=O)[nH]c2n1
Product: CSc1ncc2ccc(Cl)nc2n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 13 %

Procedure:
A suspension of 2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (297 mg, 1.54 mmol) in POCl3 (6 mL) was stirred under argon at 80° C. for 16 hours. The solution was cooled, and the resulting precipitate was filtered and washed with EtOAc to afford the title compound (43 mg, 13%). The filtrate was diluted with EtOAc, washed with NaHCO3 and dried with Na2SO4. After removal of the solvent, a second crop was obtained (154 mg, 48%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=2[O:8][N:7]=1)=[O:5])[CH3:2].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O.CCOC(C)=O.O>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][C:9]=2[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1noc2cc(O)ccc12
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1noc2cc(OCc3ccccc3)ccc12
Temperature: 56 °C
Reaction time: 5 h

Procedure:
To a solution of 0.98 g (4.73 mMol) 6-hydroxy-benzo[d]isoxazole-3-carboxylic acid ethyl ester [preparation see: J. Am. Chem. Soc. 97 (1974), 7305] in 100 ml acetone, 545 μl (4.73 mMol) benzylchloride, 3.08 g (9.46 mMol) Cs2CO3 und 10 mg NaI are added. Then the mixture is stirred for 2 h at rt and 5 h at 56° C. The reaction mixture is diluted with EtOAc and water, the aq. phase separated off and extracted with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated after addition of 10 g SiO2. The resulting powder is put on top of a chromatography column (SiO2) and the title compound eluated with hexan/EtOAc 9:1→8:2→7:3: MS: [M+1]+=298; TLC(hexane/EtOAc 3:1): Rf=0.54.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][N:6](C(OCC2C=CC=CC=2)=O)[CH2:5][CH:4]([CH3:18])[N:3]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CO.[Pd]>[C:22]([O:21][C:19]([N:3]1[CH:4]([CH3:18])[CH2:5][NH:6][CH2:7][CH:2]1[CH3:1])=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC1CN(C(=O)OCc2ccccc2)CC(C)N1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC1CNCC(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
A solution of 4-benzyl 1-tert-butyl 2,6-dimethylpiperazine-1,4-dicarboxylate (4.8 g, 0.0144mol) in methanol (25 mL) was added 480 mg of 10% Pd/C and stirred at room temperature under H2 overnight. The resulting mixture was filtered and concentrated to give the title product (2.8 g, 97%) as colorless oil. LC-MS (ESI) m/z: 215 (M+1)+. 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.25 (d, J=6.8 Hz, 3H), 1.46 (s, 9H), 1.64 (s, 1H), 2.78-2.87 (m, 4H), 3.99-4.05 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=O)[N:10]=2)=[CH:5][CH:4]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[NH:59]1[CH2:62][CH2:61][CH2:60]1.C(N(C(C)C)CC)(C)C>CO.C(Cl)Cl>[N:59]1([CH2:21][C:20]2[CH:23]=[C:16]([C:11]3[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([N:8]([CH2:7][C:6]4[CH:42]=[CH:43][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH2:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=4)[N:10]=3)[C:17]([NH:24][C:25]3[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)=[N:18][CH:19]=2)[CH2:62][CH2:61][CH2:60]1
Reactant: C1CNC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCC4)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
5-(4-(Bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (228 mg, 0.395 mmol) and sodium triacetoxyborohydride (125 mg, 0.592 mmol) were added to a solution of azetidine hydrochloride (Aldrich, St. Louis, Mo.) (48.0 mg, 0.513 mmol) in methanol (2 mL), DCM (2 mL) and diisopropylethylamine (103 μL, 0.592 mmol). The reaction mixture was stirred at ambient temperature for 2 h. More sodium triacetoxyborohydride was added and the mixture was allowed to stir at ambient temperature for 30 min. The reaction mixture was concentrated and diluted with 150 mL of DCM, added to a separatory funnel, partitioned with water, washed 2 times with 50 mL of sodium bicarbonate (saturated, aqueous), separated, diluted with a small amount of methanol to make the solution clear, dried over sodium sulfate, and concentrated to give 4-(5-(azetidin-1-ylmethyl)-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (150 mg, 61.4% yield). m/z (ESI, +ve ion) 619.2 (M+H)+.