Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:24]([CH:28]=1)[C:25](Cl)=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH:39]([CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>>[CH2:44]([O:43][C:41](=[O:42])[CH2:40][N:39]([CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[C:25](=[O:26])[C:24]1[CH:28]=[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:21]=[CH:22][C:23]=1[O:29][CH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:45]
Reactant: CCOC(=O)CNCC(=O)OCC
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(OCCCc2ccccc2)c(C(=O)Cl)c1
Product: CCCCCCCCCCCCCCCCCCOc1ccc(OCCCc2ccccc2)c(C(=O)N(CC(=O)OCC)CC(=O)OCC)c1
Yield: 92 %

Procedure:
The reaction of 5-(octadecyloxy)-2-(3-phenylpropoxy)benzoic acid chloride with diethyl iminodiacetate under conditions described in Example 80 gave N-(2-ethoxy-2-oxoethyl)-N-[5-(octadecyloxy)-2-(3-phenylpropoxy)benzoyl]glycine ethyl ester (92% yield, mp 54°-55°).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH3:13])[CH:12]=2)=[CH:4][CH:3]=1.[I:14]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>ClCCl.FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH3:13])[C:12]=2[I:14])=[CH:6][CH:7]=1
Reactant: Cn1cnc(-c2ccc(Br)cc2)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cnc(-c2ccc(Br)cc2)c1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(4-bromophenyl)-1-methyl-1H-imidazole (Step 2 product, 2.8 g, 9.45 mmol) in dichloromethane (30 mL) was added N-iodosuccinimide (1.913 g, 8.50 mmol) and six drops of trifluoroacetic acid. The reaction mixture was stirred at rt for 16 h. The mixture was neutralized with aqueous sodium bicarbonate and the organics were extracted with dichloromethane. The organics were then washed with aqueous sodium thiosulfate, followed by three washes with water then dried (MgSO4). The solvent was concentrated to afford 4-(4-bromophenyl)-5-iodo-1-methyl-1H-imidazole, which was used with out further purification. LCMS: [M+1]+=363.
Reaction SMILES: BrC(C(OCC)=O)C(OCC)=O.C(N(CC)CC)C.[CH3:20][C:21]([CH3:33])([CH2:31][SH:32])[C:22]([NH:24][C@H:25]([C:28]([OH:30])=[O:29])[CH2:26][SH:27])=[O:23].Cl>C(Cl)Cl>[CH3:20][C:21]1([CH3:33])[CH2:31][S:32][S:27][CH2:26][C@@H:25]([C:28]([OH:30])=[O:29])[NH:24][C:22]1=[O:23]
Reactant: CC(C)(CS)C(=O)N[C@@H](CS)C(=O)O
Agent: CCOC(=O)C(Br)C(=O)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CSSC[C@@H](C(=O)O)NC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
To a solution of diethyl bromomalonate (10.5 g) and triethylamine (8.5 g) in methylene chloride (3.8 l), N-(2,2-dimethyl-3-mercaptopropionyl)-L-cysteine (9.5 g) dissolved in methylene chloride (0.3 l ) was added dropwise under ice-salt cooling. After the addition, the reaction mixture was stirred for 30 minutes at the same temperature and for 30 minutes at room temperature. The mixture was acidified with 6N hydrochloric acid and washed with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Separated crystals were collected by filtration to give 6.1 g (65%) of the titled compound.
Reaction SMILES: Cl[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:5]=[C:4]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([NH:28][CH3:29])=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([N:28]([CH3:29])[C:2]2[C:14]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[NH:7][C:6]=3[N:5]=[C:4]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=2)=[CH:26][CH:25]=1
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)c2c(n1)[nH]c1ccccc12
Reactant: CNc1ccc(OC)cc1
Product: COc1ccc(N(C)c2nc(NC(=O)C(C)(C)C)nc3[nH]c4ccccc4c23)cc1
Reaction time: 120 h
Yield: 37 %

Procedure:
Using the general procedure described above, the reaction of 6 (180 mg, 0.59 mmol) and 4-methoxy-N-methylaniline (612 mg, 4.46 mmol) was run for 120 hours, to provide 88 mg of 11 as a brown solid in 37% yield. TLC Rf 0.57 (chloroform-methanol 15:1); mp 288.5-289.4° C.; 1H NMR (DMSO-d6) δ 1.26 (s, 9H, C(CH3)3,) 3.60 (s, 3H, OCH3), 3.69 (s, 3H, NCH3), 5.87-7.33 (m, 8H, Ar—H), 9.58 (s, 1H, 2-NH, exch), 11.88 (s, 1H, 9-NH, exch).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[Li][C:12](C)(C)[CH3:13].C(I)C>C1COCC1>[CH2:12]([C:7]1[S:6][C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[CH:8]=1)[CH3:13]
Reactant: [Li]C(C)(C)C
Reactant: Cc1ccc2sccc2c1
Solvent: CCI
Solvent: C1CCOC1
Product: CCc1cc2cc(C)ccc2s1

Procedure:
2-ethyl-5-methylbenzo[b]thiophene was prepared in the same manner as described in Example 40A. Reaction of 5-methylbenzo[b]thiophene (3.4 mmoles, 0.50 g), t-BuLi (1.7 m, 5.1 mmoles, 3.0 ml) and ethyl iodide (6.8 mmoles, 0.54 ml) in THF (10 ml) yielded 0.58 g (97%) of a light yellow liquid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([N+:26]([O-:28])=[O:27])=[C:7]([CH2:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:8]=[C:9](F)[CH:10]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>CN(C=O)C.O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([N:33]2[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]2)[CH:8]=[C:7]([CH2:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:6]=1[N+:26]([O-:28])=[O:27]
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1c(CS(=O)(=O)c2cccc3ccccc23)cc(F)cc1OCCCl
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(c2cc(CS(=O)(=O)c3cccc4ccccc34)c([N+](=O)[O-])c(OCCCl)c2)CC1
Temperature: 40 °C
Reaction time: 10 h
Yield: 850 %

Procedure:
A mixture of 1-[3-(2-chloroethoxy)-5-fluoro-2-nitrophenylmethanesulfonyl]-naphthalene (0.42 g, 0.1 mmoles) and N-methylpiperazine (0.168 g, 1.1 mmoles) in DMF was stirred under nitrogen at 40° C. for 10 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The extracts were combined, washed sequentially with water and brine, dried over Na2SO4, and concentrated under vacuum to afford the title compound (0.45 g, 0.85 mmoles), identified by HNMR and mass spectral analysis.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1.C=O.[C:31](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH2:24][CH2:25][N:26]([CH3:31])[CH2:27][CH2:28]3)=[CH:21][CH:22]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(N2CCNCC2)cc1
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CN1CCN(c2ccc(-c3oc(-c4c(F)cccc4F)nc3C(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
To a stirred suspension of 2-(2,6-difluorophenyl)-5-(4-(piperazin-1-yl)phenyl)oxazole-4-carboxamide (0.025 g, 0.065 mmol) in DCE (2 mL) under an N2 atmosphere at room temperature was added formaldehyde 37% solution (10 uL, 0.12 mmol) followed by sodium triacetoxyborohydride (0.066 g, 0.31 mmol) and the resulting mixture stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM and washed with saturated sodium bicarbonate solution. The aqueous phase was extracted with DCM and the combined organic phases dried over MgSO4 and the solvent removed in vacuo to afford 2-(2,6-difluorophenyl)-5-(4-(4-methylpiperazin-1-yl)phenyl)oxazole-4-carboxamide (0.019 g, 0.048 mmol, 72%) as a white solid. 1H NMR (CDCl3) 2.36 (3H, s), 2.57 (4H, t), 3.34 (4H, t), 5.49 (1H, br. s), 6.97 (2H, d), 7.07 (2H, t), 7.19 (1H, br. s), 7.45 (1H, m), 8.31 (2H, d). LCMS (2) Rt: 2.75 min; m/z (ES+) 399.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)=[CH:20][CH:19]=4)[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>ClCCl>[N:27]1([CH2:26][CH2:25][O:24][C:21]2[CH:22]=[CH:23][C:18]([NH:17][C:15]3[N:16]=[C:12]4[CH:11]=[CH:10][CH:9]=[C:8]([C:5]5[CH:6]=[CH:7][C:2]([NH:1][C:39](=[O:46])[C:40]6[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=6)=[CH:3][CH:4]=5)[N:13]4[N:14]=3)=[CH:19][CH:20]=2)[CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred suspension of [5-(4-amino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (0.05 g, 0.121 mmol) and triethylamine (19 μl, 0.133 mmol) in dichloromethane (1 ml) was added benzoyl chloride (17 μl, 0.133 mmol). The mixture was stirred for 18 hours at room temperature, then filtered through a plug of silica, washed with methanol and the filtrates combined and concentrated in vacuo. The product was purified by preparatory LCMS to provide the desired product. RT: 2.77 min, MI: 519, Method: 2; 1H NMR (DMSO, 300 MHz): 8.62 (s, 1H), 8.07 (2H, d), 7.97 (2H, d), 7.92 (d, 2H) 7.54-7.41 (m, 5H), 7.01 (1H, d), 6.85 (d, 2H), 4.31 (t, 2H), 3.37 (t, 2H), 3.26 (s, 4H), 3.12 (s, 1H), 2.99 (s, 1H), 2.02 (s, 4H).
Reaction SMILES: C(O[C@H:5]1[CH2:9][N:8](C(OC(C)(C)C)=O)[C@@H:7]([CH2:17][OH:18])[CH2:6]1)C=C.[CH:19]([C@@H:22]([CH2:26][CH:27]=C)[C:23]([OH:25])=O)([CH3:21])[CH3:20].[Li+].[OH-:30].OO>C1COCC1.O>[CH:19]([C@H:22]1[CH2:26][CH2:27][N:8]([C@@H:7]([CH2:6][CH2:5][C:9]2[CH:17]=[CH:7][CH:6]=[CH:5][CH:9]=2)[C:17]([OH:18])=[O:30])[C:23]1=[O:25])([CH3:20])[CH3:21]
Reactant: [OH-]
Reactant: C=CC[C@@H](C(=O)O)C(C)C
Reactant: C=CCO[C@@H]1C[C@H](CO)N(C(=O)OC(C)(C)C)C1
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@H]1CCN([C@@H](CCc2ccccc2)C(=O)O)C1=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Step D (3): (R)-2-isopropylpent-4-enoic acid. To a solution of the compound of step D (2) (1.08 g, 3.59 mmol) in THF (14.4 mL) was added water (3.59 mL), and the mixture cooled to 0° C. A solution of LiOH (172.5 mg, 7.20 mmol) and 30% H2O2 (3.26 mL) in water (11.2 mL) was added, and the combined mixture stirred for 10 minutes at 0° C. The ice bath was removed, and the reaction was allowed to continue for 1 h at rt. A solution of sodium sulfite (3.63 g) was added, and the reaction stirred for 10 min. Saturated sodium carbonate solution was added, and the reaction was extracted with methylene chloride. The aqueous layer was acidified to pH 1 with 6 N HCl, and extracted 3 times with diethyl ether. The combined ether layers were washed with brine, and dried over MgSO4. The extract was filtered, and concentrated in vacuo to afford the desired product.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][CH2:30]Cl.[NH:32]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[N:32]1([CH2:33][CH2:34][CH2:35][CH2:36][N:20]2[C:19]([O:23][CH3:24])=[N:18][C:17]3[C:21]2=[N:22][C:14]([O:13][C@@H:9]([CH3:8])[CH2:10][CH2:11][CH3:12])=[N:15][C:16]=3[NH2:25])[CH2:38][CH2:37][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C1CCCNCC1
Reactant: CCC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: ClCCCCBr
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCN3CCCCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 36 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate, 1-bromo-4-chlorobutane, and hexahydro-1H-azepine but with three sequential MDAPs using Method B followed by Method A (×2).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:31])[CH2:7][CH:8]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)[CH:9](C(OCC)=O)[C:10]=1[OH:11])(=[O:4])[CH2:2][CH3:3].[OH-].[Na+].Cl>C(O)C.O>[C:1]([C:5]1[C:6](=[O:31])[CH2:7][CH:8]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:19][CH:18]=2)[CH2:9][C:10]=1[OH:11])(=[O:4])[CH2:2][CH3:3]
Reactant: CCOC(=O)C1C(O)=C(C(=O)CC)C(=O)CC1c1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC(=O)C1=C(O)CC(c2ccc(OCc3ccccc3)cc2)CC1=O
Temperature: 70 °C

Procedure:
A mixture of 54 g (0.13 mol) of 2-propionyl-3-hydroxy-5-(4-benzyloxyphenyl)-4-(carboethoxy)cyclohex-2-en-1-one and 30 g (0.37 mol) of 50 percent sodium hydroxide in 450 mL of 95 percent ethanol and 100 mL of water was stirred mechanically and heated at about 70° C. for 16 hours. The resulting clear yellow solution was cooled to about 60° C. and treated with 50 mL of concentrated HCl. The product precipitated from the solution and was isolated by filtration. Recrystallization from absolute ethanol gave the above named product as a beige crystalline solid in a yield of 24 g (54 percent of theoretical). The product melted at 114°-115° C.; 1H NMR (CDCl3): δ 1.17 (t, 3H, --CH3), 2.60-3.48 (m, 7H, ring protons and --CH2CH3), 5.05 (s, 2H, ArCH 2O--), 6.83-7.55 (m, 9H, ArH's), 18.1 (s, 1H, enol, H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=O)[CH3:13].[CH2:25]([O:27][C:28](=[O:33])/[CH:29]=[C:30](\[NH2:32])/[CH3:31])[CH3:26]>C(O)C>[CH2:25]([O:27][C:28]([C:29]1[CH:5]([C:4]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([F:1])[CH:3]=2)[C:16]([C:15]([O:14][CH2:12][CH3:13])=[O:24])=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:32][C:30]=1[CH3:31])=[O:33])[CH3:26]
Reactant: COc1ccc(C=O)cc1F
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: CCOC(=O)/C=C(/C)N
Solvent: CCO
Product: CCOC(=O)C1=C(C(=O)OCC)C(c2ccc(OC)c(F)c2)C(C(=O)OCC)=C(C)N1

Procedure:
After heating a solution of 17 g of 3-fluoro-4-methoxybenzaldehyde, 20.9 g of oxalacetic acid diethyl ester and 14.3 g of β-aminocrotonic acid ethyl ester in 80 ccs of ethanol under reflux, the mixture is evaporated in vacuo and the reaction product is obtained as a light yellow oil.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].Br[C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[O:25][CH3:26]>>[NH2:15][C:7]1[C:6]([C:4]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[O:25][CH3:26])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: COc1ccc(Cl)cc1Br
Product: CCSc1ncc(C(=O)c2cc(Cl)ccc2OC)c(N)n1

Procedure:
The same procedure as described in Example 47 was used, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide, Example 1, and 2-bromo4-chloroanisole (Aldrich), to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(5-chloro-2-methoxy-phenyl)-methanone as a white solid. MS (M+H)+, 324.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[C:8](=[O:13])[CH2:9][C@@H:10]([OH:12])[CH:11]=1)=[O:5])[CH3:2].N1C=CN=C1.[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20].[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=CC=2)[CH:30]=[CH:29][C:28]=1O.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.ClCCl>[CH:2]1[C:36]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:1]=1[O:3][C:4]([CH2:6][C:7]1[C:8](=[O:13])[CH2:9][C@@H:10]([O:12][Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:26])[CH3:25])[CH:11]=1)=[O:5]
Reactant: CCOC(=O)CC1=C[C@H](O)CC1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2ccccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1C=C(CC(=O)Oc2ccc3ccccc3c2)C(=O)C1
Temperature: 0 °C
Reaction time: 15 h
Yield: 48.4 %

Procedure:
5 g (27.1 mmol, 98% e.e.) of (R)-2-ethoxycarbonylmethyl-4-hydroxy-2-cyclopenten-1-one was dissolved in ethyl acetate and the solution was placed in a nitrogen-purged flask. Imidazole (2.77 g, 40.7 mmol) was added. The solution was cooled to 0° C. and tert-butyldimethylchlorosilane (5.3 g, 35 mmol) was added in portions. The reaction mixture was allowed to warm to room temperature, and stirred for 15 hours. After filtration, the filtrate was washed with a saturated sodium bicarbonate solution and a brine solution, respectively, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue and 1 g of Candida antartica lipase were suspended in 100 ml of phosphate buffer (10 mM, pH 6.5-7.5) and stirred at room temperature. The pH of the solution was maintained by 1N sodium hydroxide solution and finally adjusted to 7.0 upon completion of the reaction and the Lipase was removed by filtration. The reaction mixture was extracted with 50 ml of toluene twice. The pH of the aqueous layer was further adjusted to 6.0 using a saturated sodium hydrogensulfate solution. The aqueous layer was extracted twice again using 100 ml of ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue and 2-naphthol (5.0 g, 34.7 mmol) was dissolved in dichloromethane (50 ml), and 0.2 g 4-(dimethylamine)pyridine were added together to a 30 ml dichloromethane solution containing 1,3-dicyclohexylcarbodiimide (7.5 g, 36 mmol). The reaction mixture was stirred at room temperatures for about 4 hours. The precipitate was filtered off. The filtrate was washed with a saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and evaporated under vacuum. The residue was purified by flash chromatography on silica gel to give the titled compound as white solid (5.2 g, 48%).
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:21]3[CH2:27][CH:26]4[N:28]([C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[CH:23]([CH2:24][CH2:25]4)[CH2:22]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[C:13]([F:20])[CH:12]=3)=[O:5])[CH3:2].C(N(CC)C(C1C=CC2C(=C3CC4N(C(=O)C(F)(F)F)C(CC4)C3)C3C(OC=2C=1)=C(OC)C=CC=3)=[O:41])C.C(N(CC)C(C1C=CC2C(=C3CC4NC(CC4)C3)C3C(OC=2C=1)=C(Br)C=CC=3)=O)C>>[CH2:35]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:21]3[CH2:27][CH:26]4[NH:28][CH:23]([CH2:24][CH2:25]4)[CH2:22]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[C:13]([F:20])[CH:12]=3)=[O:5])[CH3:36].[C:29]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:41]
Reactant: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccc(F)cc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F
Reactant: CCN(CC)C(=O)c1ccc2c(c1)Oc1c(OC)cccc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F
Agent: CCN(CC)C(=O)c1ccc2c(c1)Oc1c(Br)cccc1C2=C1CC2CCC(C1)N2
Product: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccc(F)cc1C2=C1CC2CCC(C1)N2
Product: O=C(O)C(F)(F)F

Procedure:
Using an adaptation of the method described in Procedure 17, substituting 7-fluoro-9-[8-(2,2,2-trifluoro-acetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-xanthene-3-carboxylic acid diethylamide, 5e for 5-methoxy-9-[8-(2,2,2-trifluoro-acetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-xanthene-3-carboxylic acid diethylamide, 5d, the title compound 9-(8-aza-bicyclo[3.2.1]oct-3-ylidene)-7-fluoro-9H-xanthene-3-carboxylic acid diethylamide, 6e was obtained as TFA salt after reverse phase HPLC purification (eluent gradient: CH3CN in H2O containing 0.1% TFA). MS m/z (MH+) 407.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:11])[C:9]=1[OH:10])[CH:5]=[O:6].O[C:13]1[CH:20]=CC(C=O)=C[CH:14]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:11])[C:9]=1[O:10][CH2:14][CH2:13][CH3:20])[CH:5]=[O:6]
Reactant: O=Cc1cc(Cl)c(O)c(Cl)c1
Reactant: O=Cc1ccc(O)cc1
Product: CCCOc1c(Cl)cc(C=O)cc1Cl
Yield: 94 %

Procedure:
When 3,5-dichloro-4-hydroxybenzaldehyde was substituted for 4-hydroxy-benzaldehyde in Example 50, Step A the similar procedure afforded the title compound in 94% yield, as pale oil. 1H-NMR (CDCl3) 1.1 (tr, 3H, J=7.41 Hz); 1.82-1.93 (m, 2H); 4.04 (tr, 2H, J=6.54 Hz); 7.8 (s 2H); 9.84 (s, 1H).
Reaction SMILES: [Na].C(O[CH:7]=[CH:8][C:9](=O)[C:10]([F:16])([F:15])[C:11]([Cl:14])([F:13])[F:12])CCC.[C:18]([NH2:24])(=[O:23])[CH2:19][C:20]([NH2:22])=[O:21]>CO>[Cl:14][C:11]([F:12])([F:13])[C:10]([C:9]1[NH:22][C:20](=[O:21])[C:19]([C:18]([NH2:24])=[O:23])=[CH:7][CH:8]=1)([F:15])[F:16]
Reactant: CCCCOC=CC(=O)C(F)(F)C(F)(F)Cl
Reactant: NC(=O)CC(N)=O
Agent: [Na]
Solvent: CO
Product: NC(=O)c1ccc(C(F)(F)C(F)(F)Cl)[nH]c1=O

Procedure:
0.53 g (22.8 mmol) of sodium were dissolved in 50 ml of methanol, 5.0 g (19.0 mmol) of 1-butoxy-5-chloro-4,4,5,5-tetrafluoropent-1-en-3-one and 2.0 g (19.0 mmol) of malonamide were then added and the mixture was heated under reflux for 6 h. The mixture was concentrated, and 1N hydrochloric acid was then added. The resulting precipitate was filtered off with suction and dried. This gave 3.8 g (73% of theory) of a brownish powder.
Reaction SMILES: Cl[C:2]1([C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[C:12]([CH3:17])=[N:13][O:14][C:15]=3[CH3:16])[CH:9]=2)[NH:4][C:3]1=[O:18].CCN(C(C)C)C(C)C.[NH2:33][CH2:34][CH2:35][OH:36]>C(Cl)Cl.O>[CH3:17][C:12]1[C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][C:3](=[O:18])[C:2]3([NH:33][CH2:34][CH2:35][OH:36])[C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)=[C:15]([CH3:16])[O:14][N:13]=1
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(Cl)(c1ccsc1)C(=O)N2
Reactant: NCCO
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(C)c1-c1ccc2c(c1)C(NCCO)(c1ccsc1)C(=O)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
110 mg (0.33 mmol) Of 3-chloro-5-(3,5-dimethylisoxazol-4-yl)-3-(thiophen-3-yl)indolin-2-one and 220 mg (1.65 mmol) of DIPEA were dissolved in 25 ml of CH2Cl2. After the addition of 55 mg (0.65 mmol) of 2-aminoethanol, the reaction solution was stirred for 16 h at room temperature. Subsequently, the solution was diluted with water. The aqueous phase was extracted with CH2Cl2 (2×20 mL). The combined organic phases were washed with aqueous NaHCO3 and with water, dried and concentrated in vacuo. The resulting residue was purified by chromatography (eluent: CH2Cl2/MeOH=20/1) to give product (85 mg, 69.8%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ H 7.48-7.50m, 1H), 7.20-731 (m, 3H), 6.97 (d, J=8.0 Hz, 1H), 4.47 (t, J=5.6 Hz, 1H), 3.20-3.38 (m, 4H), 3.17 (d, J=5.3 Hz, 2H), 2.37 (s, 3H), 2.20 (s, 3H). MS (ESI) m/e [M+1]+ 370.