Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[S:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1([CH3:29])[C@@H:18]([CH:19]=[C:20]2[CH2:24][CH2:23][S:22][C:21]2=[O:25])[C@H:17]1[C:26](Cl)=[O:27].N1C=CC=CC=1.Cl>C1C=CC=CC=1>[CH3:15][C:16]1([CH3:29])[C@@H:18]([CH:19]=[C:20]2[CH2:24][CH2:23][S:22][C:21]2=[O:25])[C@H:17]1[C:26]([O:14][CH2:13][C:10]1[S:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:12][CH:11]=1)=[O:27]
Reactant: OCc1cnc(Oc2ccccc2)s1
Reactant: CC1(C)[C@H](C(=O)Cl)[C@@H]1C=C1CCSC1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC1(C)[C@H](C(=O)OCc2cnc(Oc3ccccc3)s2)[C@@H]1C=C1CCSC1=O
Temperature: 20 °C
Reaction time: 24 h
Yield: 43.4 %

Procedure:
2.1 g of (2-phenoxy-5-thiazolyl)-methanol were added to a solution of 2.44 g of (1R,3S) 2,2-dimethyl-3[(dihydro-2-oxo-3-(2H)-thienylidene)-methyl]-cyclopropane-1-carboxylic acid chloride [described in French Pat. No. 70-21682] in 50 ml of benzene and 3 ml of pyridine were added thereto dropwise at 0° C. The mixture was stirred at 20° C. for 24 hours and was then poured into aqueous 2N hydrochloric acid solution. The decanted organic phase was dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with benzene. The product was crystallized from ethyl acetate to obtain 1.8 g of (2-phenoxy-5-thiazolyl)-methyl (1R,3S) 2,2-dimethyl-3-[(dihydro-2-oxo-3-(2H)-thienylidene)-methyl]-cyclopropane-1-carboxylate.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C:14]([O:16]CC3C=CC=CC=3)=[O:15])[CH:8]=2)[CH2:5][CH:4]([C:24]([NH:26][CH:27]([C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])[CH2:3]1.C(N(CC)CC)C>CO.[Pd]>[CH2:32]([O:31][C:29]([CH2:28][CH:27]([NH:26][C:24]([CH:4]1[CH2:5][N:6]([C:7]2[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)[C:2](=[O:1])[CH2:3]1)=[O:25])[C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)=[O:30])[CH3:33]
Reactant: CCOC(=O)CC(NC(=O)C1CC(=O)N(c2cccc(CC(=O)OCc3ccccc3)c2)C1)c1cccnc1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(NC(=O)C1CC(=O)N(c2cccc(CC(=O)O)c2)C1)c1cccnc1
Reaction time: 5 h

Procedure:
To a solution of ethyl 3-{(5-oxo-1-(3-{(benzyloxycarbonyl)methyl}phenyl)pyrrolidin-3-yl)carbonylamino}-3-(3-pyridyl)propanoate (2.6 g, 5.0 mmol, 1.0 eq), triethylamine (1.5 mL) in methanol (20 mL), was added 10% Pd/C (Aldrich, 0.5 g, 0.5 mmol, 0.1 eq). Hydrogenation was carried out under a pressure of 1 atm. After stirring for 5 hours, the catalyst was filtered through a pad of celite and the filtrate was concentrated with rotary evaporator. The title compound was obtained as an off-white solid. MS (ES+): 440 (M+H)+; (ES−): 438 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.Cl.[NH2:15][OH:16]>CO>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[N:15]/[OH:16])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: NO
Agent: Cl
Solvent: CO
Product: O/N=C/c1ccc(OC(F)(F)F)cc1
Temperature: 65 °C
Yield: 92.6 %

Procedure:
A mixture of 4-(trifluoromethoxy)benzaldehyde (9.5 g, 50 mmol) and hydroxylamine hydrochloride (5.3 g, 75 mmol) in methanol (80 mL) was heated at 65° C. for 2 h. The volatiles were removed under reduced pressure and the residue was dissolved in EtOAc, and washed with H2O, brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The solid thus obtained was then recrystallized from EtOAc and petroleum ether to afford the title compound (9.5 g, 93%) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ 8.08 (s, 1H), 7.52 (d, J=7.2 Hz, 2H), 7.15 (d, J=6.8 Hz, 2H).
Reaction SMILES: [OH:1][NH:2][C:3](=[O:22])[C:4]([CH2:19][CH:20]=[CH2:21])([S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH:5]=[CH:6][CH3:7]>CO.[Pd]>[OH:1][NH:2][C:3](=[O:22])[C:4]([S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:9])=[O:10])([CH2:19][CH2:20][CH3:21])[CH2:5][CH2:6][CH3:7]
Reactant: C=CCC(C=CC)(C(=O)NO)S(=O)(=O)c1ccc(OC)cc1
Agent: [Pd]
Solvent: CO
Product: CCCC(CCC)(C(=O)NO)S(=O)(=O)c1ccc(OC)cc1

Procedure:
2-allyl-2-(4-methoxy-benzenesuifony1)-pentenoic acid hydroxyamide (326 mg, 1.0 mmol) (example 26) was dissolved in methanol (50 ml) and hydrogenated over 10% Pd/C (100 mg) at room temperature, under 49 psi pressure for 4 hours. At the end, the reaction mixture was filtered and methanol was removed. The resulting solid was crystallized from methanol. Yield: 250 mg, 75%; MS: 330 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 0.92 (t, J=4.0 Hz, 6H), 1.27-1.59 (m, 4H), 1.78-2.02 (m, 4H), 3.86 (s, 3H), 6.04 (bs, 1H), 6.97 (d, J=9Hz, 2H), 7.76 (d, J=9 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.CCN(C(C)C)C(C)C.[C:42](O)(C(F)(F)F)=[O:43]>CN(C=O)C>[F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]3[CH2:23][CH2:24][N:25]([CH:42]=[O:43])[CH2:26][CH2:27]3)=[CH:20][CH:21]=2)[CH:7]=1
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1cccc(F)c1F
Reactant: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cnc(Nc2ccc(C3CCN(C=O)CC3)cc2)cc1NCc1cccc(F)c1F

Procedure:
Compound 4-(2,3-difluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 209) (70 mg, 0.15 mmol) was stirred in 4 mL DMF with DIEA (300 μL) at 120° C. in a sealed tube for two days. The mixture was acidified with 0.5 mL TFA and subjected to reverse phase preparative HPLC to isolate the title compound (41 mg). MS found for C25H25F2N5O2 as (M+H)+ 466.4. UV: λ=259 nm. 1H NMR: (CD3OD) δ 8.15 (1H, s), 8.06 (1H, s), 7.33 (2H, dt, J=8.8; 2.0 Hz), 7.28 (1H, m), 7.16 (1H, m), 7.13-7.07 (3H, m), 5.80 (1H, s), 4.56 (2H, s), 4.48 (1H, m), 3.86 (1H, m), 3.27 (1H, m), 2.93 (1H, m), 2.82 (1H, m), 1.94 (2H, m), 1.64 (2H, m) ppm.
Reaction SMILES: [Na].[CH3:2][C:3]1([CH3:13])[C@H:8]2[CH2:9][C@@H:4]1[CH2:5][CH2:6][C@H:7]2[CH2:10][CH2:11]Cl.Cl.[CH2:15]([OH:20])[CH2:16][CH2:17][CH2:18][OH:19]>>[CH3:2][C:3]1([CH3:13])[C@H:8]2[CH2:9][C@@H:4]1[CH2:5][CH2:6][C@H:7]2[CH2:10][CH2:11][O:19][CH2:18][CH2:17][CH2:16][CH2:15][OH:20]
Reactant: CC1(C)[C@H]2CC[C@@H](CCCl)[C@@H]1C2
Reactant: OCCCCO
Agent: Cl
Agent: [Na]
Product: CC1(C)[C@H]2CC[C@@H](CCOCCCCO)[C@@H]1C2
Temperature: 130 °C

Procedure:
12.2 g elemental sodium were dissolved in portions spread over 12 hours in 320 ml 1,4-butanediol at a temperature of 90° C. Then 80 g 2-((1S,2S,5S)-6,6dimethylbicyclo[3,1,1]hept-2-yl)-ethyl chloride were added in drops to this solution, and the reaction mixture was heated to 130° C. for 15 hours. In order to work up the reaction mixture it was cooled to room temperature, then 300 ml of a 5% aqueous hydrochloric acid solution were added, and the mixture was extracted with ether. After evaporation of the ether extract, 95.2 g crude 4-[2-((1S,2S,5S)-6,6dimethylbicyclo[3,1,1]hept-2-yl)-ethoxy]-butanol were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].Cl[CH2:22][CH2:23][N:24]([CH2:34][CH2:35]Cl)[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1>>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:35][CH2:34][N:24]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH2:23][CH2:22]1)=[O:20])[CH3:2]
Reactant: CC#CCOc1ccc(S(=O)(=O)CC(=O)OCC)cc1
Reactant: COc1ccc(CN(CCCl)CCCl)cc1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(OC)cc3)CC2)cc1

Procedure:
4-(4-but-2-ynyloxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in Example 1. Starting from (4-but-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (2 g, 6.73 mmol) and bis-(2-chloro-ethyl)-(4-methoxy-benzyl)-amine (2.61 g, 8.75 mmol) and following the procedure as outlined in Example 1 (Step 6) 2.5 g of the product was isolated. Yield 2.5 g (77%); yellow oil; MS: 486 (M+H)+
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3](=[O:17])[C@@H:4]([NH:9]C(=O)OC(C)(C)C)[C:5]([CH3:8])([CH3:7])[CH3:6].Cl.CCN(CC)CC.[F:27][C:28]([F:43])([F:42])[C:29]1[CH:30]=[C:31]([N:39]=[C:40]=[S:41])[CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1>O1CCOCC1>[F:36][C:35]([F:37])([F:38])[C:33]1[CH:32]=[C:31]([NH:39][C:40](=[S:41])[NH:9][C@@H:4]([C:5]([CH3:8])([CH3:7])[CH3:6])[C:3]([N:2]([CH3:18])[CH3:1])=[O:17])[CH:30]=[C:29]([C:28]([F:42])([F:27])[F:43])[CH:34]=1
Reactant: FC(F)(F)c1cc(N=C=S)cc(C(F)(F)F)c1
Reactant: CN(C)C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(C)C(=O)[C@@H](NC(=S)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
A 50-mL round-bottomed flask was charged with (S)-tert-butyl 1-(dimethylamino)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (6c) (860 mg, 2.0 mmol, 1.0 equiv) and 4N HCl in dioxane (5.0 mL). The reaction mixture was stirred at room temperature for 2 h, then concentrated under reduced pressure and maintained at ˜1 torr for 1 h. The resulting white, foamy solid was dissolved in CH2Cl2 (10 mL). Et3N (562 μL, 4.0 mmol, 2.0 equiv) and 3,5-bis(trifluoromethyl)phenylisothiocyanate (596 mg, 2.2 mmol, 1.1 equiv) were added sequentially via syringe. The flask was capped with a plastic stopper, and the reaction mixture was stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to purification by flash column chromatography on silica gel (gradient elution, 3:1 hexanes/Et2O→1:1 hexanes/Et2O) to provide the product (4a) as a white solid (613 mg, 1.43 mmol, 71% yield over two steps). [α]D25=−32.8° (c 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ 9.06 (1H, s), 7.90 (2H, s), 7.77 (1H, d, J=9 Hz), 7.56 (1H, s), 5.68 (1H, d, J=9 Hz), 3.35 (3H, s), 2.97 (3H, s), 1.12 (9H, s). 13C {1H}NMR (100 MHz, CDCl3): δ 181.8, 174.0, 140.3, 131.7 (q, JC-F=33 Hz), 123.7 (m), 123.3 (q, JC-F=272 Hz), 118.1 (m), 60.9, 39.1, 36.2, 36.0, 27.2. IR (cm−1): 3322 (br m), 2972 (m), 1611 (m), 1532 (s), 1474 (m), 1385 (m), 1274 (s), 1174 (m), 1126 (s), 963 (m), 883 (m), 848 (w), 700 (m), 680 (m). LRMS (ESI): 452.1 (60%) [M+Na]+.
Reaction SMILES: [Mg].Br[CH2:3][CH3:4].[Cl:5][C:6]1[N:11]=[C:10]([Cl:12])[C:9]([F:13])=[CH:8][N:7]=1.II>O1CCCC1.C(COC)OC.C(N(CC)CC)C>[Cl:5][C:6]1[N:11]=[C:10]([Cl:12])[C:9]([F:13])=[C:8]([CH2:3][CH3:4])[N:7]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CCBr
Agent: II
Agent: [Mg]
Solvent: COCCOC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1nc(Cl)nc(Cl)c1F
Temperature: 15 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a stirred mixture of magnesium turnings (12.1 kg) in tetrahydrofuran (161 L) was added a solution of bromoethane (54.3 kg) in tetrahydrofuran (53 L) maintaining the reaction temperature below 50° C. during the addition. The solution of the Grignard reagent was cooled to 0° C. and a solution of the compound of part (i) (56 kg) in dimethoxyethane (170 L) added, maintaining the reaction temperature below 15° C. during the addition. The reaction was stirred for 1 hour at 15° C. and cooled to 0° C. A solution of triethylamine (34 kg) in tetrahydrofuran (70 L) was added, maintaining the reaction temperature at about 5° C., followed by a solution of iodine (85 kg) in tetrahydrofuran (256 L), maintaining the reaction temperature below 15° C. The reaction was then quenched with water (840 L), maintaining the reaction temperature below 25° C. The pH was adjusted to 1 using 5N aqueous hydrochloric acid solution (50 L) and the mixture extracted with toluene (1×490 L followed by 1×210 L). The combined organic layers were washed with 2% w/w aqueous sodium metabisulphite solution (700 L) then water (700 L) added and the remaining tetrahydrofuran removed by distillation under reduced pressure. The mixture was cooled, the organic layer separated, washed with water (425 L) and then concentrated under reduced pressure to provide the product as an oil (50 kg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O.Cl.C1COCC1>O1CCOCC1>[ClH:28].[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:17]2[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=2)[CH2:14][N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(Oc3ccc(Cl)cc3)c2)CC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Clc1ccc(Oc2cccc(CN3CCNCC3)c2)cc1
Reaction time: 3 h
Yield: 211.7 %

Procedure:
A solution of 4-[3-(4-chloro-phenoxy)-benzyl]-piperazine-1-carboxylic acid tert-butyl ester (29.6 g, 73.5 mmol) in 4:1 dioxane:H2O (100 mL) was treated with 4 M HCl in dioxane (60 mL). After 3 h, THF (200 mL) was added and the resulting white precipitate was filtered and dried under vacuum to give 1-[3-(4-chloro-phenoxy)-benzyl]-piperazine hydrochloride (26.4 g, 95%). MS (ESI+): calcd for C17H19ClN2O m/z 302.12, found 303.1 (M+H)+.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[C:19]4[C:14](=[CH:15][C:16]5[O:22][CH2:21][O:20][C:17]=5[CH:18]=4)[NH:13][C:12](=O)[N:11]=3)=[CH:4][C:3]=2[O:2]1.P(Cl)(Cl)([Cl:26])=O.[OH-].[Na+]>CN(C=O)C>[Cl:26][C:12]1[N:11]=[C:10]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)[C:19]2[C:14](=[CH:15][C:16]3[O:22][CH2:21][O:20][C:17]=3[CH:18]=2)[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2[nH]1)OCO3
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Clc1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2n1)OCO3
Temperature: 25 °C
Yield: 111.1 %

Procedure:
4-(3,4-Methylenedioxyphenyl)-6,7-methylenedioxyquinazolin-2(1H)-one (1 g, 3.23 mmol) was treated with DMF (one drop) and phosphorous oxychloride (7 mL, 75 mmol) and the suspension was heated to reflux for 4 h. Upon cooling to rt, the reaction mixture was poured into ice and the pH was adjusted to ˜8 with 3N NaOH solution. The precipitate was vacuum filtered and dried to give the title compound as a brown granular solid (1.18 g). 1H NMR (DMSO-d6) 6.16 (s, 2H), 6.32 (s,2H), 6.85-7.41 (m, 5H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].[SH:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:27]([CH:22]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:21][O:20][C:18](=[O:19])[CH2:17][CH2:16][S:15][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6])[CH3:28]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CCCCC(CC)COC(=O)CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCC(CC)COC(=O)CCSc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Reaction time: 16 h
Yield: 82.7 %

Procedure:
Methyl 3-fluoro-4-nitrobenzoate (8.72 g, 43.8 mmol) was added to a suspension of 2-ethylhexyl 3-sulfanylpropanoate (10.5 g, 48.2 mmol) and potassium carbonate (9.08 g, 65.7 mmol) in DMF (50 mL) at room temperature, and the mixture was stirred for 16 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water, 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 7:3) to give the title compound (14.4 g, yield 83%).
Reaction SMILES: [C:1]([Si:5]([CH3:26])([CH3:25])[O:6][CH:7]([CH2:21][N:22]([CH3:24])[CH3:23])[CH2:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]C)=[O:18])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([Si:5]([CH3:25])([CH3:26])[O:6][C:7]([CH2:21][N:22]([CH3:24])[CH3:23])=[CH:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:13][CH:14]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)/C=C/c1ccc(CC(CN(C)C)O[Si](C)(C)C(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)CC(=Cc1ccc(/C=C/C(=O)O)cc1)O[Si](C)(C)C(C)(C)C
Yield: 54.5 %

Procedure:
This product was prepared by refluxing for four hours (E)-3-[4-(2-(tertbutyldimethylsilanyloxy)-3-dimethylaminopropanyl)phenyl]acrylic acid, methyl ester (0.8 g, 2.03 mmol) and NaOH (1N) (4 mL, 2 equiv.) in 10 mL of MeOH. Evaporation of the solvent in vacuo and treatment with 5 mL of HCl (1 N) gave the title compound (0.4 g, 60%) as a beige solid solid.
Reaction SMILES: C[O:2][C:3](=[O:39])[C@@H:4]([NH:31][S:32]([CH2:35][CH2:36][CH2:37][CH3:38])(=[O:34])=[O:33])[CH2:5][NH:6][C:7]([C:9]1[O:13][N:12]=[C:11]([O:14][CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH:10]=1)=[O:8].O[Li].O.O.OS([O-])(=O)=O.[Na+]>C1COCC1>[C:24]([N:21]1[CH2:20][CH2:19][CH:18]([CH2:17][CH2:16][CH2:15][O:14][C:11]2[CH:10]=[C:9]([C:7]([NH:6][CH2:5][C@H:4]([NH:31][S:32]([CH2:35][CH2:36][CH2:37][CH3:38])(=[O:34])=[O:33])[C:3]([OH:39])=[O:2])=[O:8])[O:13][N:12]=2)[CH2:23][CH2:22]1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: CCCCS(=O)(=O)N[C@@H](CNC(=O)c1cc(OCCCC2CCN(C(=O)OC(C)(C)C)CC2)no1)C(=O)OC
Agent: O=S(=O)([O-])O
Agent: [Li]O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCS(=O)(=O)N[C@@H](CNC(=O)c1cc(OCCCC2CCN(C(=O)OC(C)(C)C)CC2)no1)C(=O)O

Procedure:
A solution of 3-8 (1.86 mg, 0.32 mmol), LiOH.H2O (67 mg, 1.6 mmol), H2O (2 mL), and THF (8 mL) was stirred at ambient temperature for 1.0 h. The solution was acidified with 1M NaHSO4 followed by evaporation of THF. The residue was partitioned between EtOAc and brine. The EtOAc layer was then dried (MgSO4) and concentrated to give 3-9 as a pale yellow solid. Rf 0.40 (silica, 9/.0.5/0.5 CH2Cl2 :CH3OH:HOAc).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.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.[Br:46][C:47]1[CH:48]=[C:49]2[C:53](=[CH:54][CH:55]=1)[NH:52][CH2:51][CH2:50]2>CN(C)C=O>[Br:46][C:47]1[CH:48]=[C:49]2[C:53](=[CH:54][CH:55]=1)[N:52]([C:10](=[O:12])[CH2:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[F:1])[CH2:51][CH2:50]2
Reactant: O=C(O)Cc1cc(F)ccc1F
Reactant: Brc1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1cc(F)ccc1F)N1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
To a mixture of (2,5-difluorophenyl)acetic acid (0.869 g, 5.05 mmol) and HATU (2.112 g, 5.55 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added Hunig's base (0.882 mL, 5.05 mmol), and the resulting mixture was stirred for 15 minutes at room temperature. 5-bromo-2,3-dihydro-1H-indole (1 g, 5.05 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The mixture was poured onto water, and the resulting aqueous mixture was filtered to afford 5-bromo-1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indole (1.6 g) as a tan solid.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[CH:5][CH:4]=1.[Cl:12][CH2:13][Si:14]([CH3:17])([CH3:16])Cl.Cl>O1CCCC1>[Cl:12][CH2:13][Si:14]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[CH:5][CH:4]=1)([CH3:17])[CH3:16]
Reactant: CCOc1ccc(Br)cc1
Reactant: C[Si](C)(Cl)CCl
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOc1ccc([Si](C)(C)CCl)cc1
Temperature: -78 °C
Yield: 23.1 %

Procedure:
To a mixture of 5.1 g (0.21 mole) of powdered magnesium metal in 100 mL of dry tetrahydrofuran was added dropwise 40 g (0.20 mole) of ethyl 4-bromophenyl ether. Upon completion of addition this mixture was heated at reflux for one hour. In a second flask was placed 28.5 g (0.199 mole) of (chloromethyl)dimethylchlorosilane in 100 mL of tetrahydrofuran, and this flask was cooled to -78° C. The contents of the first flask were added dropwise to the second flask. The temperature of the reaction mixture was maintained at -78° C. for one hour after addition was complete, and it was then poured into 200 mL of 10% hydrochloric acid. The organic phase was washed once with 10% hydrochloric acid. The aqueous phase was extracted with diethyl ether, and these extracts were combined with the organic phase. After being dried, filtered, and having the solvent evaporated under reduced pressure, the residue was vacuum distilled, yielding 10.5 g of (chloromethyl)(4-ethoxyphenyl)dimethylsilane, b.p. 99-110 ° C./0.12 mm of Hg. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:11]([C:14]3[CH:19]=[C:18]([Cl:20])[C:17](=[O:21])[N:16]([CH3:22])[CH:15]=3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH2:30]([O:32][C:33](=[O:52])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=1)[CH3:31].BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[CH2:30]([O:32][C:33](=[O:52])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([C:2]2[N:6]([CH:7]([CH3:8])[CH3:9])[C:5]3[CH:10]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)[N:11]([C:14]4[CH:19]=[C:18]([Cl:20])[C:17](=[O:21])[N:16]([CH3:22])[CH:15]=4)[C:12](=[O:13])[C:4]=3[CH:3]=2)[CH:36]=1)[CH3:31]
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)cc1)N(c1cc(Cl)c(=O)n(C)c1)C2=O
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: CCOC(=O)Cc1ccc(OC)c(-c2cc3c(n2C(C)C)C(c2ccc(Cl)cc2)N(c2cc(Cl)c(=O)n(C)c2)C3=O)c1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 2-bromo-5-(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate E) and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (Intermediate AQ) were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The title compound (partially hydrolyzed to the acid) was obtained as a yellow foam. tR: 6.78 min (HPLC 2); ESI-MS: tR=1.12 min, [M+H]+ 594/596 (LC-MS 1).
Reaction SMILES: CO[C:3](=[O:13])[CH2:4][NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[CH2:16].CC([O-])(C)C.[K+]>C1COCC1>[CH2:19]([O:18][C:14]([CH:15]1[C:3](=[O:13])[CH2:4][N:5]([C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])[CH2:16]1)=[O:17])[CH3:20]
Reactant: COC(=O)CNC(=O)OC(C)(C)C
Reactant: C=CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of BOC glycine methyl ester (J. Med. Chem. 2001, 44, 8, 1192-1201) (19.2 g, 101.5 mmol) in THF at 0° C. was added dropwise ethyl acrylate (11 mL, 101.5 mmol) over 10 minutes. The solution was stirred for 20 minutes, then KOtBu (111.65 mL, 111.65 mmol) was added over 45 minutes. The solution was allowed to warm to 25° C. overnight. The resulting solution concentrated in vacuo and portioned between ethyl acetate and water containing 5 mL of acetic acid. The ethyl acetate layer was removed and aqueous layer extracted with 2×200 mL of ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford an oil. MS (DCI/NH4) m/z=258 (M+H)+, 275 (M+NH4)+.