Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[CH2:7][C@H:8]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])(=O)=O.[CH:46]1[C:58]2[CH:57]([CH2:59][O:60][C:61]([NH:63][C@@H:64]([CH2:72][SH:73])[C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])=[O:62])[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[C:50]=2[CH:49]=[CH:48][CH:47]=1.C([O-])([O-])=O.[K+].[K+]>CCO>[CH:55]1[C:56]2[CH:57]([CH2:59][O:60][C:61](=[O:62])[NH:63][C@H:64]([C:65]([O:67][C:68]([CH3:70])([CH3:69])[CH3:71])=[O:66])[CH2:72][S:73][CH2:7][C@H:8]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:58]3[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:51]=2[CH:52]=[CH:53][CH:54]=1
Reactant: CCCCCCCCCCCCCCCCOC[C@H](COS(=O)(=O)C(F)(F)F)OCCCCCCCCCCCCCCCC
Reactant: CC(C)(C)OC(=O)[C@H](CS)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)OCCCCCCCCCCCCCCCC
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of (R)-2,3-bis(hexadecyloxy)propyl trifluoromethanesulfonate (1 eq), (R)-tert-butyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-mercaptopropanoate (8, 2 eq) and K2CO3 (1 eq) in EtOH (0.1 M) was stirred for 30 minutes at 60° C. The reaction mixture was filtered and washed with DCM. The filtrate was concentrated en vaccuo. The resulting crude was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-20% EtOAc/Hex to give (5R,9R)-tert-butyl 1-(9H-fluoren-9-yl)-9-(hexadecyloxy)-3-oxo-2,11-dioxa-7-thia-4-azaheptacosane-5-carboxylate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][N:11]([CH3:19])[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1.CC(O)=O>CCO>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:18]/[C:15]2[CH:16]=[CH:17][C:12]([N:11]([CH3:19])[CH3:10])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CN(C)c1ccc(N)cc1
Reactant: O=Cc1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: CN(C)c1ccc(/N=C/c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 73.5 %

Procedure:
To a mixture of 4-chloro-benzaldehyde (1.55 g, 11.0 mmol) and N,N-dimethyl-benzene-1,4-diamine (1.5 g, 11.0 mmol) in EtOH (15 ml) was added a catalytic amount of AcOH (0.063 ml, 1.1 mmol) at RT. The reaction mixture was heated at reflux and stirred for 14 h during which time precipitation took place. After cooling to RT, the slurry was filtered and washed with heptane. The solid was collected and dried under high vacuum to yield the title compound (2.09 g, 8.08 mmol, 73%) as a brownish solid. 1H NMR (400 MHz, CDCl3): 3.01 (s, 6H), 6.78 (m, 2H), 7.29 (m, 2H), 7.44 (m, 2H), 7.84 (m, 2H), 8.49 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH:10]=[CH:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2=[O:17])#N.C(O)=[O:19]>[Al].[Ni]>[CH:1]([C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH:10]=[CH:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2=[O:17])=[O:19]
Reactant: O=CO
Reactant: N#Cc1cc2c(=O)c3ccccc3ccn2c1
Agent: [Ni]
Agent: [Al]
Product: O=Cc1cc2c(=O)c3ccccc3ccn2c1

Procedure:
2-Cyano-11H-pyrrolo[2,1-b][3]benzazepin-11-one (222 mg.) and 222 mg. nickel-aluminum alloy in 2 ml. 75% formic acid is refluxed for 11/2 hours. The solid is filtered off and washed with ethanol. The filtrate is diluted with 50 ml. water and extracted twice with 50 ml. methylene chloride. The organic layer is washed with water, 5% sodium bicarbonate and with water; it is then dried over magnesium sulfate and evaporated to dryness. Addition of ether induces crystallization and the crystals are filtered and air-dried to yield 2-formyl-11H-pyrrolo[2,1-b][3]benzazepin-11-one.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](OC2C=CC(Cl)=C(Cl)C=2)=[C:6]([CH:9]=1)[CH:7]=[O:8].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:44]1[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=1[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: Brc1ccccn1
Reactant: O=Cc1cc(Br)ccc1Oc1ccc(Cl)c(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Fe]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=Cc1cccc(-c2ccccn2)c1
Temperature: 80 °C

Procedure:
Under N2 in a flame-dried 25 mL round bottomed flask fitted with a magnetic stirrer was placed 200 mg (0.58 mmol) of 5-bromo-2-(3,4-dichlorophenoxy)benzaldehyde, 162 mg (0.64 mmol) of bis(pinacolato)diboron (Frontier Scientific Co.), 170 mg (1.7 mmol) of potassium acetate and 13 mg (0.018 mmol) of dichloro [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (PdCl2(dppf), Strem Chemicals) in 5 mL of anhydrous DMF. The mixture was degassed with N2 for 5 min. and then heated at 80° C. for 2.5 hr. To this was added 110 μL (1.2 mmol) of 2-bromopyridine, followed by 13 mg of PdCl2(dppf) and 0.7 mL of 2 N aqueous Na2CO3. The mixture was again heated to 80° C. under N2 for a total of 10.5 hr, then allowed to cool to room temperature overnight. The mixture was partitioned between EtOAc and H2O, the organic layer was washed with water, brine and dried over Na2CO3, then concentrated in vacuo to an oil, 359 mg. Chromatography on silica gel, eluting with a gradient system of CHCl3 (100-97% and CH3OH (0-3%) gave the title product as a light brown oil, 44 mg.
Reaction SMILES: CCN(CC)CC.[C:8](Cl)(=[O:10])[CH3:9].[CH3:12][O:13][C:14]([C:16]1[CH:26]=[C:25]([O:27][CH:28]2[CH2:31][NH:30][CH2:29]2)[C:19]2[CH2:20][C:21]([CH3:24])([CH3:23])[O:22][C:18]=2[CH:17]=1)=[O:15]>C(Cl)Cl>[CH3:12][O:13][C:14]([C:16]1[CH:26]=[C:25]([O:27][CH:28]2[CH2:29][N:30]([C:8](=[O:10])[CH3:9])[CH2:31]2)[C:19]2[CH2:20][C:21]([CH3:24])([CH3:23])[O:22][C:18]=2[CH:17]=1)=[O:15]
Reactant: COC(=O)c1cc(OC2CNC2)c2c(c1)OC(C)(C)C2
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(OC2CN(C(C)=O)C2)c2c(c1)OC(C)(C)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
Et3N (400 uL, 2.87 mmol) and acetyl chloride (70 uL, 0.99 mmol) were added to a solution of 4-(azetidin-3-yloxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (193c) (300 mg, 0.96 mmol) in CH2Cl2 (15 mL). The mixture was stirred at room temperature for 4 hr, then quenched with 1N aqueous HCl (80 mL), and extracted with CH2Cl2 (80 mL). The organic layer was dried over MgSO4 and concentrated. The residue was purified by flash column chromatograph eluting with 80% EtOAc in hexanes to give a colorless oil (239 mg, 73% yield). 1H NMR (400 MHz, CDCl3) δ 7.12 (br. s., 1 H) 6.76 (br. s., 1 H) 5.03 (br. s., 1 H) 4.55 (br. s., 1 H) 4.43 (br. s., 1 H) 4.03-4.19 (m, 2 H) 3.89 (s, 3 H) 3.00 (s, 2 H) 1.92 (s, 3 H) 1.51 (br. s., 6 H).
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([CH2:31][OH:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([OH:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:3].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.CO.O>CC(C)=O>[CH3:3][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([CH:31]=[O:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C:16](=[O:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:1]
Reactant: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 0 °C
Reaction time: 2 h
Yield: 6 %

Procedure:
In a 250 ml round-bottomed flask, equipped with a magnetic stirring bar, a 100 ml addition funnel and a septum fitted with a nitrogen inlet, was placed 1 g (2.258 mmol) betulin in 150 ml acetone. The flask was cooled with an ice-acetone bath and the suspension of betulin was treated dropwise with Jones' reagent [L. F. Fieser, M. Fieser, Reagents for Organic Synthesis, vol. 1, 1967, p. 143] over 15 minutes. The reaction mixture was stirred at 0° C. for 2 hours and then treated with methanol (25 ml) until it turned dark green. The reaction mixture was poured onto a mixture of ice and water (50 ml), then acetone and methanol were removed under reduced pressure. The aqueous residue was extracted three times with 40 ml ethyl acetate. The combined organic extracts were washed first with water (20 ml) and then with brine (15 ml), then dried (MgSO4). The solvent was evaporated under reduced pressure to give a white solid. The crude residue was purified by chromatography on silicagel 60G (ethyl acetate/petroleum ether 40-60° C., 1/9 then ¼) to yield first 59 mg (6%) betulonal as a white solid, then 880 mg (86%) betulonic acid 1 as a white solid. Betulonal (C30H46O2):
Reaction SMILES: [CH:1]1([NH:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH:23]=[N:24]OCC)[CH:21]=4)[NH:16][N:15]=3)[CH:9]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.[NH2:28][NH:29][C:30](=O)[CH2:31][N:32]([CH3:34])[CH3:33].C[O-].[Na+]>CO>[CH3:33][N:32]([CH2:31][C:30]1[N:24]=[C:23]([C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[C:10]2[CH:9]=[C:8]([C:6]([NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:7])[CH:13]=[CH:12][CH:11]=2)[NH:28][N:29]=1)[CH3:34]
Reactant: CCON=Cc1ccc2[nH]nc(-c3cccc(C(=O)NC4CCC4)c3)c2c1
Reactant: CN(C)CC(=O)NN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1n[nH]c(-c2ccc3[nH]nc(-c4cccc(C(=O)NC5CCC5)c4)c3c2)n1

Procedure:
The title compound was prepared according to the procedure of Example 367 C using N-cyclobutyl(3-[5-(ethoxyiminomethyl)(1H-indazol-3-yl)]phenyl)carboxamide.2HCl (460 mg, 1.06 mmol), N-amino-2-(dimethylamino)acetamide (372 mg, 3.17 mmol) and sodium methoxide (608 μL of a 25% w/w in methanol) in anhydrous methanol (7.0 mL) with a reaction time of 44 h. Purification of the residue by flash chromatography on silica gel with 50% methanol in ethyl acetate gave the desired product as a pale yellow solid. The residue was dissolved in a minimum amount of anhydrous methanol and excess 1.0 N HCl in anhydrous ethyl ether was added dropwise to precipitate the desired product as the bis-hydrochloride salt. The product was collected and dried under vacuum to afford the title compound (27 mg, 5% yield) as a light yellow powder. 1H NMR (DMSO-d6) δ 10.6 (br s, 1H), 8.89 (d, 1H), 8.84 (s, 1H), 8.4 (s, 1H), 8.17 (d, 1H), 8.12 (d, 1H), 7.91 (d, 1H), 7.76 (d, 1H), 7.63 (t, 1H), 4.5–4.4 (m, 1H), 4.44 (s, 2H), 2.83 (s, 6H), 2.23–2.0 (m, 4H), 1.72–1.62 (m, 2H); ES-MS (m/z) 416 [M+H]+ (HCl salt not detected).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:28])[CH2:4][NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=2)[N:9]=[C:8]([N:17]2[CH2:23][CH2:22][CH2:21][C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[CH2:18]2)[CH:7]=1.[CH2:29]1C2C=CC=CC=2CCC[NH:30]1.NCC(O)CN.C(N)CN.NCC(O)CNC1C2C(=CC=CC=2)N=C(N2CCCC3C=CC=CC=3C2)C=1>>[NH2:30][C:29]1[O:28][CH:3]([CH2:4][NH:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=3)[N:9]=[C:8]([N:17]3[CH2:23][CH2:22][CH2:21][C:20]4[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=4[CH2:18]3)[CH:7]=2)[CH2:2][N:1]=1
Reactant: NCC(O)CNc1cc(N2CCCc3ccccc3C2)nc2ccc(Cl)cc12
Reactant: c1ccc2c(c1)CCCNC2
Agent: NCC(O)CN
Agent: NCC(O)CNc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Solvent: NCCN
Product: NC1=NCC(CNc2cc(N3CCCc4ccccc4C3)nc3ccc(Cl)cc23)O1

Procedure:
The title compound was prepared in analogy to Example 9-1 by using 1-amino-3-{6-chloro-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]amino}propan-2-ol [It was prepared in Scheme 1 by using 2,3,4,5-tetrahydro-1H-2-benzazepine (commercial available) and 1,3-diamino-propan-2-ol (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine and ethane-1,2-diamine respectively.] instead of 1-amino-3-{[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]amino}propan-2-ol. MS obsd. (ESI+) [(M+H)+] 422. 1H NMR (400 MHz, CD3OD) δ ppm 8.17 (s, 1 H), 7.82 (d, J=8.8 Hz, 1 H), 7.69 (m, 1 H), 7.52 (s, 1 H), 7.22 (m, 3 H), 6.15 (s, 1 H), 5.42 (m, 1 H), 4.99 (s, 2 H), 4.11 (m, 3 H), 3.94 (d, J=5.6 Hz, 2 H), 3.77 (dd, J=9.6, 6.8 Hz, 1 H), 3.09 (m, 2 H), 2.00 (d, J=5.6 Hz, 2 H).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C@@H:11]([O:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:6]=1[O:20][CH3:21])=O.[NH2:22][C:23]([NH2:25])=[S:24]>C(O)C>[CH3:21][O:20][C:6]1[C:7]([C@@H:11]([O:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[N:22]=[C:23]([NH2:25])[S:24][CH:2]=1
Reactant: NC(N)=S
Reactant: CCCCCC[C@H](OC)c1cccc(C(=O)CCl)c1OC
Solvent: CCO
Product: CCCCCC[C@H](OC)c1cccc(-c2csc(N)n2)c1OC
Temperature: 100 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
(S)-2-chloro-1-(2-methyloxy-3-(1-methyloxyheptyl)phenyl)ethanone (11) obtained in the third step was dissolved in ethanol (30 ml,), thiourea (1.4 g) was added, and the mixture was stirred at 100° C. for 3 hours. Extraction with toluene and purification by silica gel chromatography afforded (S)-4-(2-methyloxy-3-(1-methyloxyheptyl)phenyl)thiazole-2-amine (12, 4.22 g, yield 32%).
Reaction SMILES: [CH2:1]([N:8]1[C:17]([C:18]([OH:20])=O)=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:27])[CH:14]=2)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][NH:30][CH3:31].C1COCC1>>[CH3:29][N:30]([CH3:31])[C:18]([C:17]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9](=[O:28])[C:10]2[C:15]([C:16]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:14][C:13]([Br:27])=[CH:12][CH:11]=2)=[O:20]
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1

Procedure:
The present compound was synthesized by a method similar to that in Example 249 and using 2-benzyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (250 mg) and dimethylamine THF solution. Colorless crystals (180 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]([C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1)[CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH3:2].[C:24]([O:28][C:29](=[O:42])[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:37][C:38](=[O:41])[CH:39]=[CH2:40])([CH3:27])([CH3:26])[CH3:25].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[NH4+].[Cl-]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([C:16]1[CH:21]=[CH:20][C:19]([CH:40]=[CH:39][C:38](=[O:41])[NH:37][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[NH:30][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:42])=[CH:18][CH:17]=1)[CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH3:2]
Reactant: CCOC(=O)C(CCO[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1
Reactant: C=CC(=O)Nc1ccccc1NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CCO[Si](C)(C)C(C)(C)C)c1ccc(C=CC(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-(4-Bromo-phenyl)-4-(tert-butyl-dimethyl-silanyloxy)-butyric acid ethyl ester (4.5 g, 11.22 mmol), (2-acryloylamino-phenyl)-carbamic acid tert-butyl ester (3.1 g, 11.78 mmol), Pd2(dba)3 (839 mg, 0.92 mmol), tri-o-tolylphosphine (546 mg, 1.79 mmol) and triethylamine (4.53 g, 44.88 mmol) in DMF (50 mL) was stirred at 110 degrees Celsius under N2 for 4 hours. After cooling to room temperature, the mixture was poured into a saturated aqueous solution of NH4Cl, and extracted with ethyl acetate (200 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated in vacuo, and purified by flash column chromatography to obtain a pale yellow solid. (2.63 g, 42%). MS: calc'd 583 (MH+), exp 583 (MH+).
Reaction SMILES: [F:1][C:2]([F:10])([CH2:6][C:7]([OH:9])=[O:8])[C:3]([OH:5])=[O:4].[CH:11]1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[CH3:11][O:4][C:3](=[O:5])[C:2]([F:10])([F:1])[CH2:6][C:7]([OH:9])=[O:8]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)CC(F)(F)C(=O)O
Solvent: C1CCOC1
Product: COC(=O)C(F)(F)CC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
Commercially available 2,2-difluorosuccinic acid (8.0 g, 51.9 mmol) was dissolved in THF and cooled on ice before addition of 1,3-dicyclohexylcarbodiimide (11.8 g, 57.2 mmol). The mixture was stirred at room temperature for 3 hours, cooled and filtered. The filtrate was concentrated in vacuo. The residue was stirred with methanol (50 ml) for 3 hours at room temperature and then solvents were removed in vacuo to afford the crude ester as an oil (8.4 g). The oil was purified by column chromatography on silica gel column and elution with a 0-100% ethyl acetate/toluene gradient to afford 2,2-difluorosuccinic acid 1-methyl ester as a colorless oil (6.8 g).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:38]3[CH:39]=[CH:40][C:35]([C:34]([F:45])([F:44])[F:33])=[CH:36][CH:37]=3)[C:18]([C:23]([N:25]3[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccc(C(F)(F)F)cc1)N1CCN(C2CCCC2)CC1
Yield: 51 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), 4-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white foam (51%).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.[Br:29][C:30]1[C:31]([O:38][CH3:39])=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O>C1COCC1>[Br:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:32](/[CH:33]=[CH:2]/[O:3][CH3:4])[C:31]=1[O:38][CH3:39]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1c(Br)cccc1C=O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CO/C=C/c1cccc(Br)c1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84.3 %

Procedure:
In a dried three-necked flask, to a solution of [(methyloxy)methyl](triphenyl) phosphonium chloride (3.59 g, 10.46 mmol) in THF (20 mL) was added BuLi (3.91 mL, 9.77 mmol) dropwise at −78° C. After addition, the reaction mixture was stirred at room temperature for 20 min. Then the reaction mixture was cooled to −78° C. A solution of 3-bromo-2-(methyloxy)benzaldehyde (D99) (1.5 g, 6.98 mmol) in THF (5 mL) to the reaction mixture dropwise. After addition, the reaction mixture was stirred at −78° C. for 2 hour and then warmed to room temperature. The mixture was stirred at room temperature overnight. Then the reaction was quenched with water. The organic phase was separated. The aqueous phase was extracted with EA (10 mL). The combined organic solution was dried over anhydrous sodium sulphate. After filtration, and concentration, the residue was purified by column chromatography (EA/Hexane: 0 to 30%) to give 1-bromo-2-(methyloxy)-3-[(E)-2-(methyloxy)ethenyl]benzene (D100) (1.43 g). MS (ES): C10H11BrO2 requires 241.9. found 243.0 (M+H+).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:23])[CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:24]1[C:31](=[O:32])[CH2:30][C:28](=[O:29])[NH:27][C:25]1=[O:26]>>[O:23]=[C:14]([C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)[CH2:15][CH:16]([CH:30]1[C:28](=[O:29])[NH:27][C:25](=[O:26])[NH:24][C:31]1=[O:32])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(C=Cc1ccccc1)c1ccc(Oc2ccccc2)cc1
Reactant: O=C1CC(=O)NC(=O)N1
Product: O=C1NC(=O)C(C(CC(=O)c2ccc(Oc3ccccc3)cc2)c2ccccc2)C(=O)N1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 1-(4-phenoxyphenyl)-3-phenylprop-2-en-1-one and barbituric acid, 5-(3-oxo-3-(4-phenoxyphenyl)-1-phenylpropyl)pyrimidine-2,4,6(1H,3H,5H)-trione was obtained as yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.S([O-])([O-])(=O)=O.[Na+].[Na+].O.[C:19]1(C)[CH:24]=CC(S(O)(=O)=O)=C[CH:20]=1.C(OC=CC)C>C(Cl)(Cl)Cl.O>[Br:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:19]([CH3:24])[CH:20]=[N:1]2)=[CH:6][CH:7]=1
Reactant: Nc1cc(Br)ccc1C=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CC=COCC
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cnc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
A 1 L round bottom flask fitted with a stirbar, a Dean-Stark trap for solvents heavier than water, and a condenser was charged with 2-amino-4-bromobenzaldehyde (20 g, 100 mmol), sodium sulfate (71.0 g, 500 mmol), and p-toluenesulfonic acid monohydrate (4.75 g, 25.00 mmol). The solids were taken up in anhydrous chloroform (498 mL) and the suspension treated with 1-ethoxyprop-1-ene (14.39 mL, 130 mmol). The mixture was then heated to reflux with stirring overnight. The reaction mixture was cooled to room temperature and transferred to a 2 L separatory funnel. The solution was extracted twice with 200 mL saturated aq sodium bicarbonate and once with 200 mL water. The organic layer was isolated and the aqueous layers were combined and re-extracted twice with an additional 100 mL dichloromethane. The organics were then pooled, dried over sodium sulfate, filtered, and concentrated to a residue. The residue was purified by flash chromatography (0.2-1.9% methanol:dichloromethane). Fractions containing the desired material were pooled and concentrated to afford the title compound as a bright orange solid (5.603 g, 25.2 mmol, 25% yield). MS(ES)+ m/e 221.8 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CCOCC>C(Cl)(Cl)(Cl)Cl>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][Cl:14])=[N:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc(-c2ccccc2)cn1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: ClCc1ccc(-c2ccccc2)cn1

Procedure:
To a solution of 5-phenyl-2-picoline (6.2 g) in CCl4 (250 mL) were added N-chlorosuccinimide (5.85 g) and benzoylperoxide (100 mg). The reaction was then heated to reflux and irradiated with a 225 watt lamp for 5 hours. After cooling, Et2O was added, the solid filtered and the filtrate was evaporated to dryness. The crude residue was chromatographed on silica gel (hexane/EtOAc 9:1) to give the pure title product.