Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][Br:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: BrCCCCCCCCCCCCCCCCBr
Reactant: CCOC(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(-c2ccc(OCCCCCCCCCCCCCCCCBr)cc2)cc1
Yield: 70.1 %

Procedure:
An acetone solution of 90 m moles (21.8 g) of 4'-hydroxybiphenyl-4-carboxylic acid ethyl ester obtained in Example 24, 0.15 mole (57.6 g) of 1,16-dibromohexadecane, and 0.4 mole (55.3 g) of potassium carbonate was refluxed for four hours. The reaction solution was filtered. The filtrate was concentrated, and then purified by column chromatography to obtain 34.4 g of 4'-(16-bromohexadecyloxy)biphenyl-4-carboxylic acid ethyl ester. (yield: 70%)
Reaction SMILES: Cl.C[O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([OH:11])[CH2:8][NH:7]1)=O.[NH3:12]>CO>[OH:11][C@@H:9]1[CH2:8][NH:7][C@H:6]([C:4]([NH2:12])=[O:3])[CH2:10]1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1
Reactant: N
Agent: Cl
Solvent: CO
Product: NC(=O)[C@@H]1C[C@H](O)CN1
Reaction time: 4 h

Procedure:
A solution of (2S,4S)-4-hydroxy-pyrrolidine-2-carboxylic acid methyl ester hydrochloride (1 g) in a 7M solution of ammonia in methanol (10 ml) is stirred for 18 hours then evaporated and triturated with diethyl ether. The residue is dissolved in the minimum volume of hot methanol and stood at 4° C. for 4 hours. The title compound is isolated by filtration as a white solid.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[SH:11].Cl[CH:13]([C:18]([O:20][CH3:21])=[O:19])[C:14]([O:16][CH3:17])=[O:15]>C(O)C>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][CH:13]([C:18]([O:20][CH3:21])=[O:19])[C:14]([O:16][CH3:17])=[O:15]
Reactant: COc1ccccc1S
Reactant: COC(=O)C(Cl)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)C(Sc1ccccc1OC)C(=O)OC
Reaction time: 1 h

Procedure:
1 g of KOH was added to a solution of 2.2 ml of 2-methoxythiophenol in 30 ml of ethanol. The reaction mixture was treated at room temperature with a solution of dimethyl chloromalonate in 5 ml of ethanol, stirred for 1 hour and evaporated. The residue was partitioned between ether and water. The organic phase was dried, concentrated and the residue was purified over silica gel with methylene chloride. 3.6 g of dimethyl (2-methoxy-phenylsulphanyl)malonate, MS: M=270, were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]=[C:16](Br)Br)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]#[CH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CC=C(Br)Br)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 79.4 %

Procedure:
To a solution of 118 mg (0.31 mmol) of 1-(t-butoxycarbonyl)-4-(3,3-dibromoprop-2-en-1-yl)piperidine from Step A in THF (4 mL) at −78° C. was added a 2.5M solution of n-butyl lithium (0.370 mL, 0.92 mmol). After stirring at −78° C. for 45 min, the reaction mixture was quenched with sat'd ammonium chloride (4 mL) and diluted with ether (25 mL). After separating the phases, the aqueous layer was extracted with ether. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by FC (4:1 v/v hexanes/ether) to give the title compound (55 mg).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH3:14][NH:15][S:16]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22]2)(=[O:18])=[O:17].N1CCCCC1>C(O)C>[CH3:13][C:7]1[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:10][NH:9][C:8]=1[CH:11]=[C:22]1[C:21]2[C:25](=[CH:26][CH:27]=[C:19]([S:16](=[O:17])(=[O:18])[NH:15][CH3:14])[CH:20]=2)[NH:24][C:23]1=[O:28]
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]cc(CCC(=O)O)c1C)C(=O)N2
Yield: 83.8 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90.6 mg), 113 mg 5-methylaminosulfonyl-2-oxindole, and 75 μL piperidine in 2 mL of ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven to give 163 mg (83%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[NH:9][N:10]=[C:11]([CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:27].O>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1[CH:12]=[C:11]([CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[N:10]([CH2:25][C:26](=[O:27])[NH:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=2)[N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCOCCOCc1cc(C(=O)OC(C)(C)C)[nH]n1
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCCOCc1cc(C(=O)OC(C)(C)C)nn1CC(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 350 mg 5-[2-(2-Methoxy-ethoxy)-ethoxymethyl]-2H-pyrazole-3-carboxylic acid tert-butyl ester in 5 ml of DMF and 46 mg of sodium hydride (60% in mineral oil) were added at RT. After stirring for 20 min at room temperature 290 mg of 2-Bromo-N-(5-chloro-pyridin-2-yl)-acetamide were added. The reaction was stirred at room temperature for 3 h. Then 10 ml of water were added and the mixture was filtered through a chem elut® cartridge by elution with DCM. After concentration under reduced pressure the crude was subjected to the next reaction without further purification. Yield: 400 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:14][CH:15]2[CH2:19][CH2:18][O:17][CH2:16]2)=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][N:7]=[CH:6]2.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:9]1[C:10]2[C:5](=[C:4]([O:14][CH:15]3[CH2:19][CH2:18][O:17][CH2:16]3)[C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[N:7][N:8]=1
Reactant: COc1ccc2c(=O)[nH]ncc2c1OC1CCOC1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nncc2c1OC1CCOC1
Yield: 88 %

Procedure:
Operating analogously to example 7 starting from 6-methoxy-5-(tetrahydro-furan-3-yloxy)-2H-phthalazin-1-one (1.73 g, 6.6 mmoles) and phosphoryl chloride (6.7 ml, 73 mmoles), 1.63 g of the title product were obtained (yield: 88%).
Reaction SMILES: [CH2:1]([Si:3]([CH2:19][CH3:20])([CH2:17][CH3:18])[C:4]#[C:5][CH2:6][C@@H:7]([CH3:16])[CH2:8][O:9]C1CCCCO1)[CH3:2].Cl.[OH-].[Na+]>O1CCCC1>[CH3:16][C@H:7]([CH2:6][C:5]#[C:4][Si:3]([CH2:19][CH3:20])([CH2:1][CH3:2])[CH2:17][CH3:18])[CH2:8][OH:9]
Reactant: CC[Si](C#CC[C@@H](C)COC1CCCCO1)(CC)CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC[Si](C#CC[C@@H](C)CO)(CC)CC
Temperature: 50 °C
Reaction time: 6 h

Procedure:
A solution of triethyl-[(R)-4-methyl-5-(tetrahydro-2H-pyran-2-yloxy)pent-1-inyl]silane (3.84 g, 13 mmol) in tetrahydrofuran (50 mL) was mixed with 2 N hydrochloric acid (50 mL) and stirred for 6 h at 50° C. The reaction mixture was then adjusted to pH 7 with 2 N sodium hydroxide solution (50 mL), concentrated to low volume in a vacuum, and the aqueous phase obtained extracted with ethyl acetate (3×30 mL). The combined organic phases were dried with sodium sulphate and concentrated slightly to low volume in a vacuum. The raw product (3.33 g) was purified by flash chromatography (200 g, 20×5.7 cm) with ethyl acetate /cyclohexane (1:7).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C@@H:15]2[C@H:16]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:17][C@@:11]1([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:12]([OH:27])[CH:13]=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:34][C:35]([F:49])([F:48])[C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:39]Br.C(OCC)C>C1COCC1>[CH2:3]([N:10]1[C@@H:15]2[C@H:16]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:19])=[O:20])[CH2:17][C@@:11]1([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:12]([O:27][CH2:39][C:38]1[CH:41]=[C:42]([C:44]([F:46])([F:47])[F:45])[CH:43]=[C:36]([C:35]([F:34])([F:48])[F:49])[CH:37]=1)[CH:13]=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=S(=O)(c1ccccc1)[C@@H]1C[C@@]2(c3ccccc3)[C@@H](O)C=C[C@@H]1N2Cc1ccccc1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)[C@@H]1C[C@@]2(c3ccccc3)[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)C=C[C@@H]1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (94 mg, 60% in oil, 2.45 mmol) was added to a stirred solution of (1R*,2S*,5S*,6R*)-8-benzyl-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]oct-3-en-2-ol (Description 5b; 256 mg, 0.6 mmol) and 3,5-bis(trifluoromethyl)benzyl bromide (0.8 ml) in dry THF (3 ml) at room temperature. The reaction mixture was stirred at +50° C. for 30 minutes, then cooled to room temperature and treated with diethyl ether (70 ml). The mixture was washed twice with water, brine. The combined organic extracts were dried (Na2SO4) and concentrated. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 0-30%) to give the title compound (400 mg, quant.).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][C@@H:51]([C:53]([F:56])([F:55])[F:54])[CH2:52][N:44]2[C:43]1=[O:57]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9](=[O:10])[NH:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][C@@H:51]([C:53]([F:55])([F:54])[F:56])[CH2:52][N:44]2[C:43]1=[O:57])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: N[C@H]1CCS[C@H]2CC[C@@H](C(F)(F)F)CN2C1=O
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCS[C@H]4CC[C@@H](C(F)(F)F)CN4C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-oxo-6-((4S,8R,10aS)-5-oxo-8-(trifluoromethyl)octahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylamino)hexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (15 mg, 0.026 mmol) and Intermediate 61 (8.5 mg, 0.032 mmol) to give a white solid (16 mg, 73% yield). Anal. Calcd. for C41H51F3N4O6S2 m/z 816.4. found: 817.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.43 (d, J=7.0 Hz, 1H), 7.36 (d, J=7.0 Hz, 1H), 7.30-7.06 (m, 10H), 5.33 (t, J=4.5 Hz, 1H), 5.26 (t, 1H), 5.12-5.06 (m, 1H), 5.00 (qd, J=10.2, 3.2 Hz, 2H), 4.47 (dd, J=13.4, 4.5 Hz, 1H), 3.68 (s, 3H), 3.17-3.03 (m, 2H), 2.89 (dd, J=15.3, 10.4 Hz, 2H), 2.84-2.70 (m, 5H), 2.55 (ddd, J=14.5, 5.9, 2.9 Hz, 1H), 2.49-2.38 (m, 3H), 2.38-2.24 (m, 1H), 2.16-1.99 (m, 4H), 1.99-1.86 (m, 1H), 1.83-1.45 (m, 11H), 1.22 (td, J=11.0, 8.0 Hz, 1H).
Reaction SMILES: [SH:1][CH:2]1[N:5]([C:6](=[C:20]([OH:23])[CH2:21]Br)[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C:4](=[O:24])[CH:3]1[NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1C=CC=CC=1>[OH:23][C:20]1[CH2:21][S:1][C@@H:2]2[CH:3]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:4](=[O:24])[N:5]2[C:6]=1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:8]
Reactant: O=C(COc1ccccc1)NC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(O)CBr)C1S
Solvent: c1ccccc1
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of p-nitrobenzyl α-[4-mercapto-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)acetate (106 mg) in benzene (5 ml) is added silica gel F-254 (500 mg) distributed by E. Merck Ag., and the mixture is shaken at room temperature for 1 hour. The insoluble material is removed by filtration, and washed several times with chloroform. The filtrate and washed solution are combined and evaporated under reduced pressure to give p-nitrobenzyl 3-hydroxy-7-phenoxyacetamido-3-cephem-4-carboxylate (60 mg). Yield: 66.3%. m.p. 95.5°-99.5° C. IR: νmaxCHCl3 3400, 1785, 1685, 1605. NMR: δCDCl3 2.03s2H, 4.60s2H, 5.07+5.37ABq(4)2H, 5.37d(4)1H, 5.68dd(9;4)1H, 6.83-8.32m9H.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:20][CH3:21]>C(#N)C>[CH2:20]([N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH2:4][CH2:3]1)[CH3:21]
Reactant: OCCCCC1CCNCC1
Reactant: CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCC(CCCCO)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.9 %

Procedure:
To stirring solution of 4-(4-piperidinyl)-1-butanol hydrochloride (4.51 g, 23.28 mmol) and potassium carbonate (8.04 g, 58.2 mmol) in dry acetonitrile (60 ml) was added iodoethane (2.070 ml, 25.6 mmol). The reaction mixture was allowed to stir at room temperature for 4 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between water (20 ml) and ethyl acetate (30 ml). The aqueous was re-extracted with ethyl acetate (1×30 ml) then dichloromethane (1×30 ml), the organic layers dried by passage through a hydrophobic frit), combined and concentrated in vacuo to give the title compound as a yellow gum (2.41 g).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10]2)=[O:7])=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21].S(=O)(=O)(O)O>C(OCC)(=O)C>[F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH:9]2[CH2:10][C:11]3[C:16](=[CH:15][CH:14]=[C:13]([N+:20]([O-:22])=[O:21])[CH:12]=3)[CH2:17]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(NC1Cc2ccccc2C1)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: O=C(NC1Cc2ccc([N+](=O)[O-])cc2C1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 5.0 g (19.6 mmol) 4-fluoro-N-(indan-2-yl)-benzamide was given, at 5-10° C., a nitrating mixture of 10 ml conc. nitric acid and 12 ml conc. sulfuric acid, followed by stirring over 3 h at room temperature. The mixture was worked up by pouring onto an ice/water mixture, extraction with ethyl acetate, washing of the organic phase with a solution of sodium hydrogen carbonate, drying and evaporating to dryness. The thus-obtained residue was crystallized form ethyl acetate/heptane. yield: 3.2 g (54%), mp.: 167° C.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16](O)=[O:17])=[CH:13][CH:14]=3)[CH:9]([CH2:19][CH2:20][C:21](=[O:34])[N:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH2:32][CH2:31][CH2:30][C:29]4=[O:33])[CH2:24][CH2:23]3)[C:8]=2[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:41][N:42]([CH3:47])[S:43]([NH2:46])(=[O:45])=[O:44].Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.CC(N(C)C)=O>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([NH:46][S:43]([N:42]([CH3:47])[CH3:41])(=[O:45])=[O:44])=[O:17])=[CH:13][CH:14]=3)[CH:9]([CH2:19][CH2:20][C:21](=[O:34])[N:22]3[CH2:23][CH2:24][CH:25]([N:28]4[CH2:32][CH2:31][CH2:30][C:29]4=[O:33])[CH2:26][CH2:27]3)[C:8]=2[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc2c(c1)C(CCC(=O)N1CCC(N3CCCC3=O)CC1)C(c1ccccc1)=C2C1CCCCC1
Reactant: CN(C)S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CN(C)S(=O)(=O)NC(=O)c1ccc2c(c1)C(CCC(=O)N1CCC(N3CCCC3=O)CC1)C(c1ccccc1)=C2C1CCCCC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1-cyclohexyl-3-(3-oxo-3-(4-(2-oxopyrrolidin-1-yl)piperidin-1-yl)propyl)-2-phenyl-3H-indene-5-carboxylic acid, (46 mg, 0.083 mmol), N,N-dimethylsulfamide (51 mg, 0.42 mmol) and DMAP (51 mg, 0.42 mmol) in dimethylacetamide (1 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (64 mg, 0.33 mmol). The reaction solution was stirred in a sealed tube under nitrogen at 50° C. overnight and purified by reverse phase prep-HPLC to yield 1-cyclohexyl-N-[(dimethylamino)sulfonyl]3-(3-oxo-3-(4-(2-oxopyrrolidin-1-yl)piperidin-1-yl)propyl)-2-phenyl-3H-indene-5-carboxamide as an off-white solid. 1H NMR (500 MHz, CDCl3) δ 8.91 (br s, 1H), 8.09 (s, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.57-7.41 (m, 5H), 6.86 (s, 1H), 5.10 (br s, 1H), 4.41 (br s, 1H), 4.05-3.50 (m, 7H), 3.07 (s, 6H), 2.81 (m, 1H), 2.44 (m, 2H), 2.05-1.38 (m, 16H). LCMS: m/e 658 (M+H)+, ret time 2.43 min, column 3, 2 minute gradient. The next set of experimental procedures constitute a the start of a new section which stand alone:
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]([CH3:33])=[CH:31][CH:32]=2)=[CH:24][CH:23]=1>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[O:29][C:30]([CH3:33])=[CH:31][CH:32]=4)=[CH:24][CH:23]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2ccc(C)o2)cc1
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4ccc(C)o4)cc3)o2)cc(OC)c1Br
Yield: 47 %

Procedure:
2-(4-Bromo-3,5-dimethoxyphenyl)furan was coupled with N,2-dimethoxy-N-methyl-2-(4-(5-methylfuran-2-yl)phenyl)acetamide following the method used for the final coupling step of Example 12. Purification by chromatography (30-60% EtOAc-hexanes) provided 1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methylfuran-2-yl)phenyl)ethanone as a pale orange colored solid (0.172 g, 47% yield). MS: m/z 511.0 [M+H]+.
Reaction SMILES: [C:1]([N:4]([CH3:32])[CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:15]=2)[C:10]([OH:25])=[C:9]([C:26](OCC)=[O:27])[C:8]1=[O:31])(=[O:3])[CH3:2].[NH2:33][C@H:34]([CH3:37])[CH2:35][OH:36]>>[C:1]([N:4]([CH3:32])[CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:15]=2)[C:10]([OH:25])=[C:9]([C:26]([NH:33][C@H:34]([CH3:37])[CH2:35][OH:36])=[O:27])[C:8]1=[O:31])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN(C)C(C)=O)c1=O
Reactant: C[C@@H](N)CO
Product: CC(=O)N(C)CCn1c(=O)c(C(=O)N[C@H](C)CO)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 1-{2-[acetyl(methyl)amino]ethyl}-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (2R)-2-amino-1-propanol using methods similar to Example 574: step 2 to provide an off-white solid: 1H NMR (400 MHz, DMSO-d6@90° C.) δ ppm 1.23 (d, J=6.72 Hz, 3 H), 1.85 (s, 3 H), 2.80 (s, 1 H), 2.95 (s, 2 H), 3.50-3.55 (m, 4 H), 4.05-4.14 (m, 1 H), 4.18 (d, J=0.82 Hz, 2 H), 4.35 (s, 2 H), 4.70 (t, J=5.56 Hz, 1 H), 7.09-7.15 (m, 2 H), 7.36-7.42 (m, 2 H), 8.08 (s, 1 H), 8.55 (s, 1 H), 10.06-10.42 (m, 1 H), 17.06-17.18 (m, 1 H); ES− MS: 471 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([OH:13])[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[C:26]([O:30][CH3:31])(=[O:29])[CH:27]=[CH2:28]>C(Cl)(Cl)Cl>[OH:12][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:28][CH2:27][C:26]([O:30][CH3:31])=[O:29])=[O:13]
Reactant: C=CC(=O)OC
Reactant: OP(O)CCCCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCP(=O)(O)CCCCc1ccccc1
Yield: 88.6 %

Procedure:
To a solution of 4-phenylbutyl phosphonous acid (1 g, 0.005 mole) in chloroform (40 ml) was added triethylamine (1.55 ml, 0.0111 mole), trimethyl silylchloride (1.41 ml, 0.0111 mole) and methyl acrylate (0.50 ml, 0.0055 mole). The reaction mixture was stirred at reflux for 18 hours. CHCl3 was removed in vacuo. The residue was diluted with ether and extracted with 5% aqueous NaHCO3 solution. Aqueous layers were acidified with concentrated HCl and extracted with ether. Organic layers were extracted with brine and dried over Na2SO4. Solvent was removed in vacuo to give 1.26 g of an oil. T-60 1H NMR appeared to characterize product from Michael addition.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:31]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[N:32]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:24]([O:23][CH2:22][C:19]1([CH3:21])[S:18][CH2:17][CH2:16][N:15]2[C:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:33]5[NH:32][N:31]=[CH:35][CH:34]=5)=[CH:3][CH:4]=4)[CH2:10][CH2:9]3)=[N:12][N:13]=[C:14]2[CH2:20]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Br)cc4)CC3)n2CCS1
Reactant: CC1(C)OB(c2cc[nH]n2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ccn[nH]5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 100.9 %

Procedure:
A solution of the compound (300 mg, 0.59 mmol) obtained in Example 16-4), 1H-pyrazole-3-boronic acid pinacol ester (126 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (68 mg, 0.06 mmol), and potassium carbonate (163 mg, 1.18 mmol) in 1,2-dimethoxyethane (3 mL) and water (1.5 mL) was stirred at 120° C. for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature, water (3 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate:methanol=70:30) to obtain the title compound (295 mg, quant.) in an orange oily form.