Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][N:7](C(OC(C)(C)C)=O)[C@H:6]([C:16]2[NH:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([B:27]4[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]4)=[CH:23][CH:22]=3)=[CH:19][N:20]=2)[CH2:5]1.Cl.[CH3:37][O:38][C:39]([NH:41][C@@H:42]([CH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1)[C:43](O)=[O:44])=[O:40].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][N:7]([C:43](=[O:44])[C@@H:42]([NH:41][C:39](=[O:40])[O:38][CH3:37])[CH:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)[C@H:6]([C:16]2[NH:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([B:27]4[O:28][C:29]([CH3:34])([CH3:35])[C:30]([CH3:32])([CH3:33])[O:31]4)=[CH:23][CH:22]=3)=[CH:19][N:20]=2)[CH2:5]1
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)[nH]2)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)N[C@H](C(=O)O)C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)[nH]2)N(C(=O)[C@@H](NC(=O)OC)C2CCOCC2)C1
Temperature: 40 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To a solution of (2S,4S)-tert-butyl 4-(methoxymethyl)-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (0.50 g, 1.03 mmol) in a mixture of CH2Cl2 (10 mL) and methanol (1.0 mL) was added HCl (4M in dioxane, 6.00 mL, 24 mmol). The solution was stirred at 40° C. for 1 h, cooled to room temperature and concentrated to dryness. The crude solid was suspended in CH2CL2 (10 mL), followed by the addition of (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (0.260 g, 1.20 mmol), HATU (0.475 g, 1.25 mmol) and DIPEA (0.60 mL, 3.44 mmol). The resulting solution was stirred at room temperature for 18 h. The solution was diluted with CH2CL2 and washed with a mixture of sodium bicarbonate (aqueous, sat) and brine. The aqueous layer was back-extracted with CH2CL2. The combined organic layers were dried over Na2SO4 and concentrated to provide a crude oil. Purification by column chromatography (SiO2, 10-100% EtOAc (10% MeOH)/Hexanes) provided methyl (S)-2-((2S,4S)-4-(methoxymethyl)-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate (0.483 g, 80%). MS (ESI) m/z 583.333 [M+H]+.
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].N[C:6]1[CH:7]=[CH:8][C:9]([N+:15]([O-:17])=[O:16])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12].[CH2:18]=O.CO>C(#N)C>[CH3:18][N:2]([CH3:1])[C:6]1[CH:7]=[CH:8][C:9]([N+:15]([O-:17])=[O:16])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12]
Reactant: [BH3-]C#N
Reactant: C=O
Reactant: Nc1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CN(C)c1ccc([N+](=O)[O-])c(C(=O)O)c1
Reaction time: 16 h
Yield: 156.3 %

Procedure:
Sodium cyanoborohydride (690 mg, 10.99 mmol) was added portion wise to a mixture of 5-amino-2-nitro benzoic acid (500 mg, 2.74 mmol) and formaldehyde (40% aqueous, 2.5 mL, 83.33 mmol) in acetonitrile (10 mL) and the mixture was stirred for 16 hr. Methanol (10 mL) was added and the reaction mixture was evaporated in vacuo to afford 5-dimethylamino-2-nitro-benzoic acid (900 mg, 89%) as brownish yellow solid.
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[N:15]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C@@H:25]([C:39]([OH:41])=O)[CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[C:30]([NH2:37])=[C:29]([Cl:38])[CH:28]=3)=[O:23])[CH2:18][CH2:17]2)[CH2:14][CH2:13][C:12]2[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=2[NH:10]1.[CH2:46]([O:48][C:49](=[O:64])[CH2:50][N:51]1[CH2:56][CH2:55][C:54]([CH3:63])([N:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:53][CH2:52]1)[CH3:47].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[O:8]=[C:9]1[N:15]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C@H:25]([CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:35])([F:34])[F:36])[C:30]([NH2:37])=[C:29]([Cl:38])[CH:28]=3)[C:39]([N:60]3[CH2:61][CH2:62][N:57]([C:54]4([CH3:63])[CH2:55][CH2:56][N:51]([CH2:50][C:49]([O:48][CH2:46][CH3:47])=[O:64])[CH2:52][CH2:53]4)[CH2:58][CH2:59]3)=[O:41])=[O:23])[CH2:20][CH2:21]2)[CH2:14][CH2:13][C:12]2[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=2[NH:10]1
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Reactant: CCOC(=O)CN1CCC(C)(N2CCNCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCC(C)(N2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.25 mL (1.18 mmol) triethylamine were added to a mixture of 250 mg (0.45 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1f), 250 mg (0.50 mmol) ethyl(4-methyl-4-piperazin-1-yl-piperidin-1-yl)-acetate (Example A7f) and 160 mg (0.50 mmol) TBTU in 2 mL DMF and the reaction mixture was stirred for 4 h at RT. It was evaporated down i. vac. and the residue was purified by HPLC; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:12](=[O:35])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([C:26]1[S:27][C:28]([C:32]([OH:34])=O)=[C:29]([CH3:31])[N:30]=1)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:43]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[N:11]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:12](=[O:35])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([C:26]1[S:27][C:28]([C:32]([NH2:43])=[O:34])=[C:29]([CH3:31])[N:30]=1)=[CH:15][CH:14]=2)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1nc(-c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccccc4)c3c2)sc1C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccccc4)c3c2)sc1C(N)=O
Yield: 86.9 %

Procedure:
A solution of 2-(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)-4-methyl-1,3-thiazole-5-carboxylic acid (0.44 g, 0.8 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.31 g, 1.6 mmol) and 1-hydroxybenzotriazole ammonium salt (0.24 g, 1.6 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crystals were recrystallized from ethyl acetate-diisopropyl ether to give tert-butyl{6-[5-(aminocarbonyl)-4-methyl-1,3-thiazol-2-yl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl}methylcarbamate (0.38 g, 86.4%) as crystals.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([O:21][CH3:22])[CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[C:15]2[CH3:20])=[O:8].[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(N(CC)CC)C>C1(C)C=CC=CC=1.ClCCl>[CH3:22][O:21][C:12]1[CH:13]=[C:14]2[C:19](=[C:10]([NH:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:32]3[CH2:33][CH2:34][N:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=4)[CH2:30][CH2:31]3)[CH:11]=1)[N:18]=[CH:17][CH:16]=[C:15]2[CH3:20]
Reactant: COc1cc(NC(=O)CCCCCBr)c2nccc(C)c2c1
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)CCCCCN2CCN(c3ccccn3)CC2)c2nccc(C)c2c1
Reaction time: 1.5 h
Yield: 84.4 %

Procedure:
A mixture of 3.3 g (0.009 mole) of 6-bromo-N-(6-methoxy-4-methyl-8-quinolinyl)hexanamide and 1.8 g (0.01 mole) of 1-(2-pyridinyl)piperazine in 10 ml of toluene was heated in an oil bath at 120° for 2.5 hr. After 1.5 hr, excess triethylamine was added slowly with stirring. After cooling, the reaction mixture was taken up in dichloromethane, washed with water, dried over anhydrous magnesium sulfate, and concentrated to dryness in vacuo. Recrystallization from 2-propanol afforded 3.4 g (85%) of the desired product, mp 120°-121°.
Reaction SMILES: [CH:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:7]([C:10](=[CH:13][CH2:14][CH2:15][CH2:16]C)[CH:11]=[O:12])[CH2:8][CH3:9]>>[CH:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:13][CH:10]([CH2:7][CH3:8])[CH:11]=[O:12].[CH2:7]([C:10](=[CH:13][CH:14]([CH3:1])[CH2:15][CH3:16])[CH:11]=[O:12])[CH2:8][CH3:9]
Reactant: CCCCC=C(C=O)CCC
Solvent: CCCCC=O
Product: CCC(C)C=O
Product: CCCC(C=O)=CC(C)CC

Procedure:
This example describes the process according to the invention for the aldol condensation of n-pentanal (n-valeraldehyde) to 2-propylheptenal (1+1 product) and the co-aldolization of n-pentanal with 2-methylbutanal to give the cross-product (1+2 product), 2-propyl-4-methylhexenal. In contrast to Example 2, the reactor used was a DN15 tube (internal diameter 17.3 mm) not of length 3 m but of length 4 m, with a total volume of 9.1 l. In this example too, about 50% of the total volume of the tubular reactor was filled with static mixers with a hydraulic diameter of 2 mm and a relative void volume of 0.80.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1([OH:37])[C:18]2[C:13](=[CH:14][C:15]([C:23](N)=[O:24])=[CH:16][C:17]=2[C:19]([F:22])([F:21])[F:20])[N:12]([CH2:26][C@H:27]2[CH2:30][C@H:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[CH2:28]2)[C:11]1=[O:36].[BrH:38].C(O)(=[O:41])C>>[BrH:38].[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1([OH:37])[C:18]2[C:13](=[CH:14][C:15]([C:23]([OH:24])=[O:41])=[CH:16][C:17]=2[C:19]([F:22])([F:21])[F:20])[N:12]([CH2:26][C@H:27]2[CH2:28][C@H:29]([N:31]([CH2:32][CH3:33])[CH2:34][CH3:35])[CH2:30]2)[C:11]1=[O:36]
Reactant: CC(=O)O
Reactant: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O)(c3ccc(Cl)cc3Cl)c3c2cc(C(N)=O)cc3C(F)(F)F)C1
Agent: Br
Agent: Cl
Product: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O)(c3ccc(Cl)cc3Cl)c3c2cc(C(=O)O)cc3C(F)(F)F)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of the compound of Example 1-4 (400.0 mg, 0.69 mmol) in acetic acid (2.5 mL) was added 47% hydrobromic acid (7.5 mL), and the mixture was stirred at 100° C. for 2 hours. The reaction solution was concentrated, and then recrystallized (methanol-diethyl ether) to give the titled compound (420.5 mg, 98%).
Reaction SMILES: [Br-].Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH2:13][N+](CC)(CC)CC)[N:6]=[CH:5][N:4]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:36]=[CH:37][CH:38]=1)[CH2:25][N:26]1[C:34]2[C:29](=[CH:30][C:31]([NH2:35])=[CH:32][CH:33]=2)[CH:28]=[N:27]1.[N:39]([C@@H:42]1[CH2:47][CH2:46][NH:45][CH2:44][C@H:43]1[OH:48])=[N+:40]=[N-:41]>CC#N>[F:21][C:22]1[CH:23]=[C:24]([CH:36]=[CH:37][CH:38]=1)[CH2:25][N:26]1[C:34]2[C:29](=[CH:30][C:31]([NH:35][C:3]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=4[CH2:13][N:45]4[CH2:46][CH2:47][C@@H:42]([N:39]=[N+:40]=[N-:41])[C@H:43]([OH:48])[CH2:44]4)[N:6]=[CH:5][N:4]=3)=[CH:32][CH:33]=2)[CH:28]=[N:27]1
Reactant: [N-]=[N+]=N[C@@H]1CCNC[C@H]1O
Reactant: CC[N+](CC)(CC)Cc1cccc2ncnc(Cl)c12
Reactant: Nc1ccc2c(cnn2Cc2cccc(F)c2)c1
Agent: [Br-]
Solvent: CC#N
Product: [N-]=[N+]=N[C@@H]1CCN(Cc2cccc3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)C[C@H]1O
Temperature: 55 °C
Yield: 45 %

Procedure:
A mixture of 14A (120 mg, 0.34 mmol) and 1-(3-fluorobenzyl)-1H-indazole-5-amine (81.0 mg, 0.34 mmol; prepared as described in US 2003/0186983 A1) in CH3CN (1.2 ml) was heated at 55° C. for 45 min. After cooled to rt, (3R,4R)-4-azidopiperidin-3-ol (475 mg, 3.34 mmol; prepared as described in U.S. patent application Ser. No. 10146 PSP) was added and the mixture was heated at 60° C. for 16 h. This mixture was diluted with CH3CN (2.4 mL), and then heated at 70° C. for 4 h and at 80° C. for 4 d. The reaction mixture was concentrated in vacuo and the residue was purified by prep HPLC. to give 19A (78 mg, 45%). It has an analytical HPLC retention time=2.43 min (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4 over 4 minutes, 4 mL/min, monitoring at 220 nm) and a LC/MS M++H=524+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]([C:11]1[N:16]=[C:15]([Cl:17])[N:14]=[C:13]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]2[CH3:28])[CH:12]=1)[CH3:10]>CN(C)C=O>[ClH:17].[CH2:9]([C:11]1[N:16]=[C:15]([N:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH3:1])[N:14]=[C:13]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]2[CH3:28])[CH:12]=1)[CH3:10]
Reactant: CNc1ccccc1
Reactant: CCc1cc(N2CCc3ccccc3C2C)nc(Cl)n1
Solvent: CN(C)C=O
Product: CCc1cc(N2CCc3ccccc3C2C)nc(N(C)c2ccccc2)n1
Product: Cl
Yield: 59.7 %

Procedure:
After N-methylaniline(0.46 ml, 4.25 mmol) was added to a mixture solution of 6-ethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloropyrimidine(0.61 g, 2.12 mmol) and dimethylformamide(5 ml), 0.50 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)=[N:5][NH:6][CH:7]=1)#[CH:2].O.FC(F)(F)C(O)=[O:21].C(OCC)C>O1CCOCC1>[N+:14]([C:10]1[CH:9]=[C:8]([C:4]2[C:3]([C:1](=[O:21])[CH3:2])=[CH:7][NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: O=C(O)C(F)(F)F
Reactant: C#Cc1c[nH]nc1-c1cccc([N+](=O)[O-])c1
Solvent: O
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(=O)c1c[nH]nc1-c1cccc([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
To a solution of 350 mg (1.6 mmol) of 4-ethynyl-3-(3-nitrophenyl)-1H-pyrazole in a mixture of 50 ml of dioxane and 0.5 ml (28 mmol) of water, 0.5 ml (6.5 mmol) of trifluoroacetic acid were added. The reaction was heated at 100° C. under stirring for 2 hours. The organic solvent was removed under reduced pressure and the residue partitioned between ethylacetate and aqueous sodium hydrogenocarbonate. The organic layer was then dried over sodium sulphate and evaporated to dryness, affording, after trituration with diethylether, 251 mg (68%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17]C(C(F)(F)F)=CC=3)[C:8]2=[O:23])[S:4][C:3]=1[C:24]([OH:26])=O.C1(CN2CCN(C3SC(C(O)=O)=C(C)C=3)C2=O)CC1.[NH2:46][CH2:47][C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1>>[CH:13]1([CH2:12][N:9]2[CH2:10][CH2:11][N:7]([C:5]3[S:4][C:3]([C:24]([NH:46][CH2:47][C:48]4[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=4)=[O:26])=[C:2]([CH3:1])[CH:6]=3)[C:8]2=[O:23])[CH2:18][CH2:17]1
Reactant: NCc1cccnc1
Reactant: Cc1cc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Agent: Cc1cc(N2CCN(CC3CC3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(CC3CC3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 59 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a colorless solid in 59% yield: mp 157-159° C.; 1H NMR (300 MHz, CDCl3) δ 8.51 (s, 1H), 8.50 (d, J=4.1 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.28-7.21 (m, 1H), 6.14 (t, J=5.6 Hz, 1H), 6.06 (s, 1H), 4.57 (d, J=5.6 Hz, 2H), 3.85-3.77 (m, 2H), 3.70-3.63 (m, 2H), 3.14 (d, J=7.1 Hz, 2H), 2.48 (s, 3H), 0.99-0.84 (m, 1H), 0.58-0.50 (m, 2H), 0.25-0.19 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 163.6, 155.8, 149.2, 148.8, 142.8, 141.8, 135.5, 134.2, 123.5, 118.6, 112.1, 48.8, 42.9, 42.1, 41.2, 16.1, 9.0, 3.4; MS (ES+) m/z 371.3 (M+1).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([N:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=2)=[O:5])[CH2:3][CH2:2]1.[CH3:15]N(C)C=O.C[I:21]>C(OCC)(=O)C>[I-:21].[CH:1]1([C:4]([C:6]2[CH:7]=[CH:8][C:9]([N+:12]([CH3:15])([CH3:14])[CH3:13])=[CH:10][CH:11]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: CI
Reactant: CN(C)C=O
Reactant: CN(C)c1ccc(C(=O)C2CC2)cc1
Solvent: CCOC(C)=O
Product: C[N+](C)(C)c1ccc(C(=O)C2CC2)cc1
Product: [I-]
Reaction time: 18 h
Yield: 17.2 %

Procedure:
p-N,N-Dimethylaminophenyl cyclopropyl ketone (186.50 mg, 0.99 mmol) is added to 2 ml of dimethylformamide (DMF). Methyl iodide (0.24 g, 7.4 mmol) is added to the solution, the flask stoppered and the solution stirred for 18 hrs. Ethyl acetate is added to the flask to precipitate the product and the solution is filtered. The precipitate is washed with ethyl acetate, ether and chloroform. The precipitate is then dissolved in a minimal amount of methanol and filtered. Ether is added to the filtrate to precipitate the product. The product is filtered and washed with ether and dried. This yielded 2B as a white crystalline solid (56.25 mg, 17.2% yield); m.p. >280° C.; IR (KBr):1660 cm-1 (C=O): NMR (CD3CN) δ:1.15 (d, 4H); 2.60 (m, 1H ); 3.61 (s, 9H); 7.93 (d, 2H); 8.24 (d, 2H); mass spectrum m/e=189 (M-CH3I). Calculated for C13H18ION:C, 47.14; H, 5.49; I, 38.31, N, 4.23. Found: C, 45.60; H, 5.49; I 38.91; N, 4.50. HPLC analysis of the product show that no cyclopropyl p-fluorophenyl ketone is present in the final product.
Reaction SMILES: N1C=CC=CC=1.[O:7]([C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[CH:17]([OH:20])[CH:18]=[CH2:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:24][C:25]1([CH3:35])[CH:27]([CH:28]=[C:29]([Cl:31])[Cl:30])[CH:26]1[C:32](Cl)=[O:33]>C1C=CC=CC=1>[O:7]([C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[CH:17]([O:20][C:32]([CH:26]1[CH:27]([CH:28]=[C:29]([Cl:30])[Cl:31])[C:25]1([CH3:35])[CH3:24])=[O:33])[CH:18]=[CH2:19])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C=CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: C=CC(OC(=O)C1C(C=C(Cl)Cl)C1(C)C)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.2 g of pyridine in 10 ml of benzene is added dropwise at 5° C. to a solution of 8 g of 3-phenoxy-α-vinyl-benzyl alcohol in 30 ml of benzene, and at 10° C. is subsequently added 8 g of 2,2-dimethyl-3-(dichlorovinyl)-cyclopropanecarboxylic acid chloride. The reaction mixture is stirred for two hours at room temperature and is then allowed to stand for 12 hours. In further processing, the reaction mixture is diluted with ice water, the organic phase is extracted 3 times with 100 ml of 3% HCl solution each time and 3 times with 100 ml of 3% sodium bicarbonate solution each time; it is dried over sodium sulfate, and the benzene is distilled off. There is obtained the compound of the formula ##STR7## as colourless oil have a refractive index of nD40 =1.5710. (isomeric mixture 40% cis and 60% trans compound)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]=1[OH:12])[NH2:8])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[Cl:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28].C(OCC)(=O)C>CCOCC>[C:1]([C:5]1[CH:6]=[C:7]([NH:8][C:27](=[O:28])[CH2:26][CH2:25][CH2:24][Cl:23])[CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]=1[OH:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Reactant: O=C(Cl)CCCCl
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)CCCCl)cc(C(C)(C)C)c1O
Temperature: 3 °C
Yield: 78.2 %

Procedure:
To a stirred mixture of 65.2 g (295 mmol) of 3,5-di-tert-butyl-4-hydroxyaniline and 23.3 g (295 mmol) of pyridine in 700 ml of ether cooled to 3° C. there was slowly added 41.6 g (295 mmol) of 4-chlorobutyryl chloride. Fifteen hours later 700 ml of ethyl acetate was added and the mixture was washed successively with 500 ml of water, 500 ml of dilute sodium bicarbonate solution and again with 500 ml of water. The organic phase was dried over anhydrous magnesium sulfate and concentrated to a solid (85.3 g). This solid was triturated in hexane and filtered to yield 75.2 g of N-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-chlorobutyramide.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:12]O)CO)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CI.C1[CH2:22][O:21][CH2:20]C1.CN([CH:26]=[O:27])C>>[CH3:26][O:27][CH:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:12][CH2:20][O:21][CH3:22]
Reactant: OCC(CO)OCc1ccccc1
Reactant: CN(C)C=O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COCCC(OC)OCc1ccccc1
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of 2-benzyloxy-propane-1,3-diol (5.0 g, 27.4 mmol) in 5:1 THF-DMF (200 mL) at 0° C. was added NaH (1.5 g, 2.3 eq.) followed by methyl iodide (5.1 mL, 3.0 eq.). The resulting white slurry mixture was stirred at room temperature over weekend. The reaction mixture was quenched with sat. NH4Cl, extracted with EtOAc, dried over Na2SO4, filtered, concentrated and the product was purified by chromatography (50% EtOAc/hexanes) to give (2-methoxy-1-methoxymethyl-2-ethoxymethyl)-benzene (5.6 g, 97%).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH:15]=[CH2:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:25][C:26]1([CH3:38])[O:30][CH:29]([C:31]2[S:35][C:34]([CH:36]=[O:37])=[N:33][CH:32]=2)[CH2:28][O:27]1.C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH2:15][CH2:16][C:36]([C:34]3[S:35][C:31]([CH:29]4[CH2:28][O:27][C:26]([CH3:38])([CH3:25])[O:30]4)=[CH:32][N:33]=3)=[O:37])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CC1(C)OCC(c2cnc(C=O)s2)O1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1(C)OCC(c2cnc(C(=O)CCC(=O)C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)O1
Temperature: 25 °C
Yield: 29.5 %

Procedure:
To a solution of 4-[4-(cyclopropylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (2.00 g) in ethanol (20 mL) were added 5-(2,2-dimethyl-1,3-dioxolan-4-yl)-1,3-thiazole-2-carbaldehyde (1.50 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (170 mg) and triethylamine (345 μL), and the mixture was stirred with heating under reflux for 2 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (950 mg, yield 30%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio). MS: 562 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[I:10]N1C(=O)CCC1=O.C(OCC)(=O)C>CN(C=O)C>[NH2:1][C:2]1[C:7]([I:10])=[N:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH3:9]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc(Cl)ncc1N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)nc(I)c1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.3 %

Procedure:
5-Amino-2-chloro-4-methylpyridine (1.35 g) was dissolved in DMF (20 mL), N-iodosuccinimide (2.59 g) was added and the reaction mixture was stirred at room temperature for 12 hours. Ethyl acetate was added and the organic layer was washed 3× with water, washed with brine, dried over MgSO4 and concentrated in vacuum. The residue was purified by column chromatography (silica 60, hexane/ethyl acetate=3:1, Rf=0.30) to afford 1.38 g of the title compound of the formula