Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=[O:3].[C:9](OC(=O)C)(=[O:11])[CH3:10]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(=O)C>[C:9]([O:3][C:2](=[CH2:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: O
Product: C=C(OC(C)=O)C(=O)OCC
Temperature: 120 °C
Reaction time: 24 h
Yield: 58.5 %

Procedure:
First, to a mixture of ethyl pyruvate (315 g, 2.7 mol) and acetic anhydride (554 g, 5.4 mol), p-toluenesulfonic acid monohydrate (8 g) was added. Then, the mixture was stirred under a nitrogen gas stream at 120° C. for 24 hours to obtain a reaction solution. Next, acetic acid generated by a reaction with excess acetic anhydride under reduced pressure (40 to 50 mmHg) was removed from the reaction solution. Thereafter, the residue was purified by reduced pressure distillation (35 to 40 mmHg, 90 to 103° C.) to obtain ethyl α-acetoxyacrylate (250 g, yield 58%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[CH:7]([CH3:11])[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].[NH2:13][CH:14]1[C:20](=[O:21])[N:19]([CH3:22])[C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=2[C:16]2[CH:27]=[CH:28][CH:29]=[CH:30][C:15]1=2.OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>C1COCC1>[C:1]([O:5][C:6](=[O:12])[CH:7]([CH3:11])[C:8]([NH:13][CH:14]1[C:20](=[O:21])[N:19]([CH3:22])[C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=2[C:16]2[CH:27]=[CH:28][CH:29]=[CH:30][C:15]1=2)=[O:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C(=O)O)C(=O)OC(C)(C)C
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled solution (0° C.) of 2-methyl-malonic acid mono-tert-butyl ester (1.01 g, 5.79 mmol) and 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one (1.15 g, 4.83 mmol) in THF (8 ml) was added hydroxybenzotriazole (652 mg, 4.83 mmol), diisopropylethylamine (624 mg, 4.83 mmol)and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (925 mg, 4.83 mmol), and the mixture was stirred overnight at r.t. The solvent was evaporated, the residue was taken up in ethyl acetate, washed with water, and dried (Na2SO4). After evaporation of the solvent, the title compound, MS: m/e=395.3 (M+H+), (920 mg, 48%) was obtained by chromatographic purification of the residue (silica gel, MeOH, CH2Cl2).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3C(=CC(Br)=[CH:9][CH:10]=3)[C:5]([CH2:31][CH2:32][CH:33]([CH3:45])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:44])[CH2:38][CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])([CH2:16][CH2:17][CH:18]([CH3:30])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:4]=2[CH:3]=1.C([Li])CCC.C(N1CCCCC1)=O.[CH2:59]1[CH2:63][O:62][CH2:61][CH2:60]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([C:11]3[CH:10]=[CH:9][C:59]([CH:63]=[O:62])=[CH:60][C:61]=3[C:5]2([CH2:31][CH2:32][CH:33]([CH3:45])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:44])[CH2:38][CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])[CH2:16][CH2:17][CH:18]([CH3:30])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:13][CH:14]=1
Reactant: C1CCOC1
Reactant: CC(C)CCCC(C)CCCC(C)CCC1(CCC(C)CCCC(C)CCCC(C)C)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: O=CN1CCCCC1
Agent: [Li]CCCC
Product: CC(C)CCCC(C)CCCC(C)CCC1(CCC(C)CCCC(C)CCCC(C)C)c2cc(Br)ccc2-c2ccc(C=O)cc21
Yield: 72 %

Procedure:
2,7-Dibromo-9,9-bis(3,7,11-trimethyldodecyl)fluorene (Example 7; 21.02 g, 28.25 mmol) was reacted with n-butyllithium (1.6 M, 16.5 mL, 26.4 mmol) in THF at −78° C., and quenched with N-formyl piperidine (4.7 mL, 42.3 mmol). The crude product was chromatographed over silica gel eluting with 15 and 25% toluene-heptane to get the aldehyde product as a liquid, 13.11 g (72% Yield). Mass spec: m/z 692, 694 (M+). Anal Calcd for C44H69BrO: C, 76.16%; H, 10.02%; Br 11.51%. Found: C, 76.39%; H, 9.85%; Br, 11.49%. 1H NMR (CDCl3), δ ppm: 0.51-0.54 (m 4H), 0.67 (tt, 6H), 0.77 (tt, 6H), 0.85 (d, 12H), 0.92-1.26 (m, 30H), 1.47-1.53 (m, 2H), 1.98-2.02 (m 4H), 7.50-7.65 (m, 3H), 7.79-7.87 (m, 3H), 10.05 (s, 1H).
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][C:5]1([CH3:31])[CH2:9][CH2:8][CH:7]([CH2:10][O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]1([CH3:30])[CH3:29].[NH4+].[Cl-].[NH4+].[OH-].[CH2:36]1COCC1>>[C:25]([Si:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[O:11][CH2:10][CH:7]1[CH2:8][CH2:9][C:5]([CH3:31])([CH:4]([CH3:36])[CH:3]=[CH2:2])[C:6]1([CH3:30])[CH3:29])([CH3:28])([CH3:26])[CH3:27]
Reactant: C1CCOC1
Reactant: CC1(C=CCBr)CCC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [OH-]
Product: C=CC(C)C1(C)CCC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1(C)C
Temperature: -55 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To Me2S.CuBr (dried twice by azeotropic distillation with toluene; 5.04 g, 24.02 mmol) in dry THF (40 mL) at −78° C. was added dropwise CH3Li (1.4 M solution in Et2O; 34.30 mL, 48.04 mmol) over a period of 15 minutes. Stirring of the suspension at −50 to −60° C. for 30 minutes resulted in a color change to yellow, after which a solution of freshly fused ZnCl2 (98%; 3.49 g, 25.11 mmol) in dry THF (25 mL) was added dropwise at −50° C. to −60° C. over a period of 20 minutes. The reaction mixture was then stirred at −55° C. for 1 hour, the suspension is cooled to −78° C. and intermediate (7), (5.74 g, 11.49 mmol) in dry THF (10 mL) was added dropwise over a period of 30 minutes. The reaction mixture was stirred at −78° C. for 1 hour and then allowed to warm up to −40° C. over a period of 4 hours. After stirring at room temperature for 20 minutes, the mixture was poured into a saturated NH4Cl solution containing 10% of NH4OH (200 mL). The solution was stirred an additional 30 minutes then the aqueous layer was extracted with n-hexane/diethyl ether 95:5 (4×100 mL). The combined organic layers were dried over anhydrous MgSO4, the solvent removed under reduced pressure and the crude residue was purified over silica (n-hexane) to afford 3.96 g (79% yield) of the desired intermediate (8) as a colorless oil which was characterized as follows:
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([OH:6])=O.[NH:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26]>>[CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([N:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26])=[O:6]
Reactant: OCCNCCO
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)O
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)N(CCO)CCO
Yield: 90 %

Procedure:
The procedure of Example 1 was repeated except that 6.1 g of 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenoic acid and 2.9 ml of diethanolamine were used as starting materials. 7.0 g (yield 90%) of the title compound was obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:28])[O:10][C:11]3[C:16]([C:17]=2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[CH:15][CH:14]=[C:13]([O:26][CH3:27])[CH:12]=3)=[CH:4][CH:3]=1.[Br:29][CH:30](Br)[CH3:31].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:28])[O:10][C:11]3[C:16]([C:17]=2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:31][CH2:30][Br:29])=[CH:21][CH:20]=2)=[CH:15][CH:14]=[C:13]([O:26][CH3:27])[CH:12]=3)=[CH:6][CH:7]=1
Reactant: CC(Br)Br
Reactant: COc1ccc2c(Cc3ccc(O)cc3)c(-c3ccc(Cl)cc3)c(=O)oc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc2c(Cc3ccc(OCCBr)cc3)c(-c3ccc(Cl)cc3)c(=O)oc2c1
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A solution of 3-(4-chlorophenyl)-4-(4-hydroxybenzyl)-7-methoxychromen-2-one (21.2 g, 54 mmol), dibromoethane (50.7 g, 270 mmol), and K2CO3 (8.3 g, 60 mmol) in 200 mL of acetone was heated at reflux for 12 h. The reaction mixture was cooled to room temperature and volatiles were removed under reduced pressure. Hexanes (500 mL) was added with stirring and the resulting solid that formed was collected by filtration. The material was rinsed with hexanes (2×100 mL), collected and dried under vacuum to provide the desired product (22.5 g, 83%). 1H NMR (300 MHz, DMSO) δ 7.50 (d, 1H, J=9.1 Hz), 7.48 (d, 2H, J=8.2 Hz), 7.35 (d, 2H, J=8.2 Hz), 7.07 (d, 2H, J=8.5 Hz), 7.04 (d, 1H, J=2.6 Hz), 6.86 (dd, 1H, J=9.1, 2.6Hz), 6.82 (d, 2H, J=8.5 Hz), 4.24 (t, 2H, J=5.8 Hz), 3.98 (s, 2H), 3.84 (s, 3H), 3.76 (t, 2H, J=5.8 Hz). MS (ESI) m/z 500 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][NH:4][CH2:3]1.Br[C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:20][C:19]1[C:14]([N:4]2[CH2:5][CH2:6][CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]([OH:1])[CH2:3]2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)C1CCNCC1O
Reactant: Clc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C1CCN(c2ncccc2Cl)CC1O
Temperature: 90 °C

Procedure:
Ethyl 3-hydroxy-4-piperidinecarboxylate, 2-bromo-3-chloropyridine (700 mg, 3.6 mmol), and potassium carbonate (1.0 g, 7.2 mmol) were and heated at 90° C. for 2 days. Standard work-up gave the title compound.
Reaction SMILES: [Se](=O)=[O:2].[CH3:4][C:5]([O:14][C:15](=[O:17])[CH3:16])([C:7]1[C:8]([CH3:13])=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:6]>O.O1CCOCC1>[CH:13]([C:8]1[C:7]([C:5]([O:14][C:15](=[O:17])[CH3:16])([CH3:4])[CH3:6])=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:2]
Reactant: CC(=O)OC(C)(C)c1cccnc1C
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)OC(C)(C)c1cccnc1C=O
Temperature: 100 °C
Reaction time: 60 h
Yield: 46.2 %

Procedure:
Selenium dioxide (1.44 g, 13.0 mmol) was added to a solution of acetic acid 1-methyl-1-(2-methyl-pyridin-3-yl)-ethyl ester (1.25 g, 6.48 mmol) dissolved in a mixture of water (2.5 mL) and 1,4-dioxane (25 mL). The resulting mixture was stirred at 100° C. for 60 hours. The solvent was removed under reduced pressure and the brown oil was quenched with saturated NaHCO3 (30 mL) and extracted with CH2Cl2 (5×50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to afford a brown oil. Purification via column chromatography on silica gel (hexanes:EtOAc, 1:1, v/v) afforded acetic acid 1-(2-formyl-pyridin-3-yl)-1-methyl-ethyl ester as a yellow oil (0.62 g, 46%). 1H NMR (CDCl3) δ 1.91 (s, 6H), 2.03 (s, 3H), 7.48 (dd, 1H, J=9.0, 6.0 Hz), 7.83 (dd, 1H, J=9.0, 3.0 Hz), 8.69 (dd, 1H, J=6.0, 3.0 Hz), 10.49 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([CH:23]=O)=[CH:22][C:16]=3[N:15]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl.[NH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].[Na]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([CH2:23][NH:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:22][C:16]=3[N:15]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCCCCCCOc1ccc(Cc2nc3cc(C=O)ccc3[nH]2)cc1
Agent: Cl
Agent: [Na]
Solvent: ClCCl
Product: CCCCCCCOc1ccc(Cc2nc3cc(CNCC(=O)OC(C)(C)C)ccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a stirred solution of 2-(4-(heptyloxy)benzyl)-1H-benzo[d]imidazole-5-carbaldehyde INT-47 (571 mg, 1.63 mmol) in DCM (6 mL) was added tert-butyl 2-aminoacetate hydrochloride (328 mg, 1.96 mmol). After 1 h, sodium triacetoxyhydroborate (691 mg, 3.26 mmol) was added. After stirring at room temperature for 18 h, the reaction mixture was quenched with NaHCO3 (10 mL), stirred for 10 min and split through a hydrophobic frit and evaporated. The crude product was purified by column chromatography (MeOH/EA) to give 228 mg (30%) of tert-butyl 2-(((2-(4-(heptyloxy)benzyl)-1H-benzo[d]imidazol-5-yl)methyl)amino)acetate INT-48 as a pale yellow oil. LCMS-ESI (m/z) calculated for C28H39N3O3: 465; found 466 [M+H]+, tR=1.17 min (Method 3).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[N:10]1[C@H:16]([CH3:17])[CH2:15][C:14]2[CH:18]=[C:19]3[O:24][CH2:23][O:22][C:20]3=[CH:21][C:13]=2[C:12]([C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=2)=[N:11]1.C([O-])=O.[K+]>C(O)C.O.[Pd]>[N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:1][C:2]=1[N:10]1[C@H:16]([CH3:17])[CH2:15][C:14]2[CH:18]=[C:19]3[O:24][CH2:23][O:22][C:20]3=[CH:21][C:13]=2[C:12]([C:25]2[CH:26]=[CH:27][C:28]([NH2:31])=[CH:29][CH:30]=2)=[N:11]1
Reactant: C[C@@H]1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1c1nc2ccccc2[nH]1)OCO3
Agent: [Pd]
Agent: O=C[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C[C@@H]1Cc2cc3c(cc2C(c2ccc(N)cc2)=NN1c1nc2ccccc2[nH]1)OCO3
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a solution of the product of Example 22 (669 mg, 1.52 mmol) in 20 mL of absolute ethanol under a N2 blanket was added 10% Pd/C (335 mg) followed by a solution of potassium formate (461 mg, 5.48 mmol) in 0.5 mL of water. After 1 h, the reaction mixture was filtered through a pad of celite and concentrated by rotary evaporation. The solid residue was partioned between ethyl acetate and water and the organic layer was washed with brine and dried over Na2SO4. Solvent was removed by rotary evaporation and the residue was purified by silica gel chromatography (40% hexanes in ethyl acetate) to afford 478 mg (76.5%) of the title compound. MS (FD+)=411. IR: 1623, 1543, 1486 cm-1. 1H NMR (CDCl3, 300 MHz) δ 1.29 (d, 3, J=7); 2.82 (dd, 1, J=10, 14); 3.02 (dd, 1, J=4, 14); 3.96 (s, 2); 5.46 (m, 1); 6.00 (d, 2, J=8); 6.71 (m, 4); 7.08 (m, 2); 7.30 (s, 1); 7.52 (m, 3); 9.00 (s, 1).
Reaction SMILES: [C:1]([C:4]1[CH:20]=[CH:19][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([N+:16]([O-])=O)[CH:13]=[CH:14][CH:15]=2)=[CH:6][C:5]=1[OH:21])(=[O:3])[CH3:2]>C(O)C.[Fe]>[C:1]([C:4]1[CH:20]=[CH:19][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[NH2:16])=[CH:6][C:5]=1[OH:21])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(OCc2cccc([N+](=O)[O-])c2)cc1O
Agent: [Fe]
Solvent: CCO
Product: CC(=O)c1ccc(OCc2cccc(N)c2)cc1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 81 %

Procedure:
A mixture of 3-[(4-acetyl-3-hydroxyphenoxy)methyl]nitrobenzene (10.2 g) and iron powder (10.4 g) in ethanol (150 ml, saturated with anhydrous HCl) is stirred at room temperature for 15 hours. After removal of excess iron and concentration in vacuo, the residue is partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic phase is filtered through a Florisil column with the aid of dichloromethane. Concentration gives 7.4 g of product (81% yield) m.p. 153°-154° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10](=[O:15])[CH2:9]2)=[CH:4][C:3]=1[C:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[K+].[C:47]([C:49]1[N:50]=[C:51]([C:62]([O-])=[O:63])[N:52]([CH2:54][O:55][CH2:56][CH2:57][Si:58]([CH3:61])([CH3:60])[CH3:59])[CH:53]=1)#[N:48].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:16]1([C:3]2[CH:4]=[C:5]([CH:8]3[CH2:9][C:10](=[O:15])[NH:11][C:12](=[O:14])[CH2:13]3)[CH:6]=[CH:7][C:2]=2[NH:1][C:62]([C:51]2[N:52]([CH2:54][O:55][CH2:56][CH2:57][Si:58]([CH3:61])([CH3:60])[CH3:59])[CH:53]=[C:49]([C:47]#[N:48])[N:50]=2)=[O:63])[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: Nc1ccc(C2CC(=O)NC(=O)C2)cc1C1=CCCCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CC(=O)NC(=O)C2)cc1C1=CCCCC1
Yield: 50.6 %

Procedure:
A solution of 73.5 mg (0.259 mmol) of 4-(4-amino-3-cyclohex-1-enyl-phenyl)-piperidine-2,6-dione (as prepared in the previous step) in CH2Cl2 (20 mL) was treated with 64.4 mg (0.388 mmol) of PyBroP, 86.8 mg (0.284 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in this Example, step (d)), and 135 μL (0.775 mmol) of DIEA at RT for 2 h. The mixture was diluted with CH2Cl2 (50 mL) and washed with saturated aqueous NaHCO3 (2×30 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to afford 70.0 mg (51%) of the title compound as an off-white solid: Mass spectrum (ESI, m/z): Calcd. for C28H35N5O4Si, 534.3 (M+H). found 534.2.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCC1CCN(Cc2ccccc2)CC1)c1ccc(F)cc1
Reactant: C1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(CCC1CCN(Cc2ccccc2)CC1)c1ccc(N2CCCC2)cc1
Temperature: 150 °C

Procedure:
A mixture consisting of 0.5 g of 1-benzyl-4-[2-(4-fluorobenzoyl)ethyl]piperidine and 2 ml of pyrrolidine was heated at 150° C. for 24 hours and the reaction mixture was subjected to distribution between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried and the solvent was distilled off. The residue was recrystallized from ethyl acetate to give 0.7 g of colorless crystals melting at 144°-145° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].C(=O)([O-])[O-].[K+].[K+].[Cl:16][CH2:17][CH2:18]Cl>CN(C)C=O>[Cl:16][CH2:17][CH2:18][N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]1=[O:7]
Reactant: ClCCCl
Reactant: CC1(C)NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)NC(=O)N(CCCl)C1=O

Procedure:
A mixture of 1,664 g of 5,5-dimethyl-hydantoin (13.0 mols), 897 g of anhydrous potassium carbonate (6.5 mols), 5,148 g of 1,2-dichloroethane (52 mols) and 1,458 ml of dimethylformamide is reacted for 18 hours and 20 minutes at 90°C to 100°C internal temperature (external temperature 155°C), whilst constantly removing the resulting water of reaction by azeotropic circulatory distillation. Water of reaction eliminated: 110 g (94.0% of theory). Thereafter the reaction mixture, whilst still hot, is separated by filtration from the potassium chloride produced, the filtrate is concentrated on a rotary evaporator at 100°C under a waterpump vacuum and the residue is dried to constant weight at 100°C and 10-1 mm Hg.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7]([O:23][CH3:24])=[C:8]([C:12]([CH2:15][S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]([OH:11])=[O:10])=[CH:2]1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7]([O:23][CH3:24])=[C:8]([C:12]([CH2:15][S:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:14]=2)[C:9]([O:11][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:10])=[CH:2]1
Reactant: COc1c(-c2ccoc2)ccc(CSc2ccccc2)c1C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1c(-c2ccoc2)ccc(CSc2ccccc2)c1C(=O)OCc1ccccc1
Yield: 91.5 %

Procedure:
A solution of 3-(furan-3-yl)-2-methoxy-6-(phenylthiomethyl)benzoic acid (Intermediate 223, 0.83 g), benzyl bromide (0.46 g) and potassium carbonate (0.55 g) in THF (15 ml) was heated to 60° C. for 8 hours. After cooling, the mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-10% to give benzyl 3-(furan-3-yl)-2-methoxy-6-(phenylthiomethyl)-benzoate (0.96 g) as a white solid.
Reaction SMILES: C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[N:30]1[CH:35]=[C:34]([C:36]([NH:38][C:39]2([C:42]([OH:44])=O)[CH2:41][CH2:40]2)=[O:37])[CH:33]=[N:32][CH:31]=1.[F:45][CH:46]([F:64])[O:47][C:48]1[CH:63]=[CH:62][C:51]([O:52][C:53]2[CH:58]=[CH:57][C:56]([CH:59]([NH2:61])[CH3:60])=[CH:55][CH:54]=2)=[CH:50][CH:49]=1>CN(C=O)C>[F:45][CH:46]([F:64])[O:47][C:48]1[CH:63]=[CH:62][C:51]([O:52][C:53]2[CH:58]=[CH:57][C:56]([CH:59]([NH:61][C:42]([C:39]3([NH:38][C:36]([C:34]4[CH:33]=[N:32][CH:31]=[N:30][CH:35]=4)=[O:37])[CH2:40][CH2:41]3)=[O:44])[CH3:60])=[CH:55][CH:54]=2)=[CH:50][CH:49]=1
Reactant: CC(N)c1ccc(Oc2ccc(OC(F)F)cc2)cc1
Reactant: O=C(NC1(C(=O)O)CC1)c1cncnc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(NC(=O)C1(NC(=O)c2cncnc2)CC1)c1ccc(Oc2ccc(OC(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
376 μL (2.70 mmol) of triethylamine and 0.52 g (1.62 mmol) of TBTU were added to a solution of 0.28 g (1.35 mmol) of 1-[(pyrimidin-5-carbonyl)-amino]-cyclo-propanecarboxylic acid (from 1b) in 5 mL DMF and the mixture was stirred for 5 min at RT. Then 0.42 g (1.50 mmol) of 1-[4-(4-difluoromethoxy-phenoxy)-phenyl]-ethylamine was added and the mixture was stirred for 30 min at ambient temperature. The reaction mixture was purified by chromatography (reversed phase). The acetonitrile was distilled off, the aqueous phase was made basic with ammonia and extracted with dichloromethane. The organic phase was dried and evaporated down.
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]([NH2:19])[CH2:11][CH2:10]1.[CH3:20][N:21]([CH3:25])[C:22](Cl)=[O:23]>ClCCl>[CH3:20][N:21]([CH3:25])[C:22]([NH:19][CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](=[O:8])[CH2:10][CH2:11]1)=[O:23]
Reactant: NC1CCC(=O)c2ccccc21
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)NC1CCC(=O)c2ccccc21
Temperature: 25 °C

Procedure:
In 25 ml of dichloromethane containing 2.8 ml of triethyl amine, 2,32 g of 1,2,3,4-tetrahydro-4-oxo-1-naphthylamine are added followed by 2.16 g of dimethylcarbamoyl chloride. The mixture is heated at reflux for 3 hours, cooled to room temperature, washed successively with 50 ml of H2O, 50 ml of 3N NaOH, 50 ml of 3N HCl and 50 ml of H2O. The organic phase is dried over magnesium sulfate and evaporated to dryness. The residue is recrystallized from toluene to give the title compound, melting point 157° C to 162° C.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C([Si]([C:29]#[C:30][C:31]1[CH:32]=[C:33]([C:37]2([C:40]([NH2:42])=[O:41])[CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1)(C(C)C)C(C)C)(C)C>C1COCC1.O.CCOC(C)=O>[C:30]([C:31]1[CH:32]=[C:33]([C:37]2([C:40]([NH2:42])=[O:41])[CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1)#[CH:29]
Reactant: CC(C)[Si](C#Cc1cccc(C2(C(N)=O)CC2)c1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cccc(C2(C(N)=O)CC2)c1
Reaction time: 0.25 h

Procedure:
A 1.0 M TBAF solution in THF (10.5 mL, 10.5 mmol) was added to a solution of 1-(3-((triisopropylsilyl)ethynyl)phenyl)cyclopropanecarboxamide A59 (1.20 g, 3.50 mmol) in THF (50 mL) and stirred for 15 minutes. The mixture was diluted with water (200 mL) and EtOAc (200 mL) before the organic fraction was separated and washed with 0.5 M citric acid solution (200 mL), water (200 mL), brine (50 mL) and dried (Na2SO4). The volatiles were removed in vacuo and the resulting solid was suspended in cyclohexane (50 mL) and sonicated for 10 minutes. The solid was collected by filtration and dried to give the title compound A60 as a tan solid (386 mg, 59%). LCMS-A: rt 5.635 min; m/z 186.2 [M+H]+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[CH2:9](B(O)O)[CH2:10][CH:11]=[CH2:12]>>[CH2:12]([C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH:10]=[CH2:9]
Reactant: O=Cc1ccc(Br)s1
Reactant: C=CCCB(O)O
Product: C=CCCc1ccc(C=O)s1
Yield: 54.7 %

Procedure:
The compound was synthesized as in Example 3.1 using 5-bromo-2-formylthiophene (191 mg, 1.0 mmol) in place of 5-bromo-2-formylfuran and 3-butenylboronic acid (150 mg, 1.5 mmol) in place of hexylboronic acid to give 5-(3-butenyl)-2-formylthiophene (91 mg, 55%). Used without further characterization.