Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[C:18]1[CH:19]=[C:20]([CH:23]=[O:24])[S:21][CH:22]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:18]2[CH:19]=[C:20]([CH:23]=[O:24])[S:21][CH:22]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=Cc1cc(Br)cs1
Reactant: CCCCCCOc1ccc(B(O)O)cc1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCCCOc1ccc(-c2csc(C=O)c2)cc1
Temperature: 25 °C
Yield: 52.7 %

Procedure:
A mixture of commercial available 4-(hexyloxy)phenylboronic acid (25, 5.55 g, 25.0 mmol), 4-bromothiophene-2-carbaldehyde (5.25 g, 27.5 mmol), tetrakis(triphenylphosphine)palladium(0) (0.6 g, 0.13 mmol), toluene (25 mL), ethanol (15 mL) and aqueous sodium carbonate (2 M, 25 mL) was stirred under reflux for 18 hours under a nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and the aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with saturated sodium chloride (50 mL), and dried over magnesium sulfate. After filtration and concentration, the crude material was purified by recrystallization from ethyl acetate/petroleum ether (1/2, v/v) to afford the compound 1026 (3.8 g).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH3:6][O:7][CH2:8][C:9](O)=O>O>[NH2:5][C:3]1[S:4][C:9]([CH2:8][O:7][CH3:6])=[N:1][N:2]=1
Reactant: COCC(=O)O
Reactant: NNC(N)=S
Solvent: O
Product: COCc1nnc(N)s1

Procedure:
Addition of phosphonyl chloride to a mixture of thiosemicarbazide and methoxyacetic acid at 60°-95° and working up of the product yields 5-amino-2-methoxymethyl-(1,3,4)-thiadiazole, m.p. 177°-179° (from water). When this compound is diazotised and treated with cuprous bromide 5-bromo-2-methoxymethyl-(1,3,4)-thiadiazole results and reaction of this bromo compound with zinc dust in acetic acid at room temperature yields 2-methoxymethyl-(1,3,4)-thiadiazole, m.p. 30.5°-32°.
Reaction SMILES: [F:1][C:2]1[C:25]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32][CH:31]=2)=[O:28])=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14]C2C=CC=CC=2)=[O:12])[C@H:7]([CH3:21])[CH2:6]1.CCN(CC)CC.ClC(OC)=O>CO.[Pd]>[F:1][C:2]1[C:25]([NH:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][N:33]=[C:34]([CH3:36])[CH:35]=2)=[O:28])=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH3:14])=[O:12])[C@H:7]([CH3:21])[CH2:6]1
Reactant: Cc1cc(NC(=O)Nc2cccc(CN3CCN(C(=O)OCc4ccccc4)[C@H](C)C3)c2F)ccn1
Agent: [Pd]
Agent: COC(=O)Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)N1CCN(Cc2cccc(NC(=O)Nc3ccnc(C)c3)c2F)C[C@H]1C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of (R)-benzyl 4-(2-fluoro-3-(3-(6-methylpyridin-4-yl)ureido)benzyl)-2-methylpiperazine-1-carboxylate (190 mg, 0.39 mmol, 1.0 equiv) in MeOH (20 mL) was added 10% Pd/C (approx. 100 mg). The resulting suspension was stirred and sparged with hydrogen gas using a balloon and needle. After 1 h, reaction was complete, as determined by LCMS. The mixture was filtered through a pad of Celite, and the celite pad was washed with additional methanol. The mixture was concentrated in vacuo, and the resulting residue was dissolved in dry DCM (10 mL). To this room temperature solution was added Et3N (167 uL, 1.2 mmol, 3.0 equiv), followed by the addition of methyl chloroformate (46 uL, 0.60 mmol, 1.5 equiv) by syringe. After 10 minutes the reaction mixture was quenched by the addition of methanol. The solvent was removed in vacuo, and the mixture was purified by preparative TLC (0.5% Et3N/7% MeOH/92.5% DCM) to provide (R)-methyl 4-(2-fluoro-3-(3-(2-methylpyridin-4-yl)ureido)benzyl)-2-methylpiperazine-1-carboxylate (85.9 mg, 50%). LCMS m/z (APCI)=416.3 (M+H).
Reaction SMILES: C(Cl)Cl.[CH:4]([Br:7])(Br)[Br:5].[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[CH2:23])[C:17]=1[CH3:24].[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O.C(O)C>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]2[CH2:23][C:4]2([Br:7])[Br:5])[C:17]=1[CH3:24]
Reactant: BrC(Br)Br
Reactant: C=Cc1cccc(COC2CCCCO2)c1C
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: Cc1c(COC2CCCCO2)cccc1C1CC1(Br)Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
Dihalocarbene addition: 10 ml of methylene chloride, 0.42 ml of ethanol, 0.14 g of benzyltriethylammonium chloride and 20.9 g (0.083 mole) of bromoform are added to 9.9 g (0.042 mole) of 2-methyl-3-vinylbenzyl tetrahydro-2-pyranyl ether. After the addition of 13.28 g (0.166 mole) of ice-cold 50% strength NaOH, thorough stirring is carried out for 1 hour at room temperature and for 8 hours at 50° C. The reaction mixture is poured into 300 ml of water and is extracted three times with methylene chloride. The combined extracts are dried and evaporated down. Purification by column chromatography over silica gel using toluene as the mobile phase gives 9.1 g of 3-(2',2'-dibromocyclopropyl)-2-methylbenzyl tetrahydro-2-pyranyl ether.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[C@@H:13]2[CH2:17][C@H:16]([CH2:18][OH:19])[CH:15]=[CH:14]2)=[C:6](Cl)[N:5]=1>>[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[C@@H:13]2[CH2:17][C@H:16]([CH2:18][OH:19])[CH:15]=[CH:14]2)=[C:6]([O:19][CH2:18][CH2:16][CH3:15])[N:5]=1
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Agent: [H-]
Agent: [Na+]
Product: CCCOc1nc(N)nc2c1ncn2[C@H]1C=C[C@@H](CO)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A flask was charged with sodium hydride (60% oil dispersion 158 m8, 3 mMol) which was then washed with hexanes before the addition of n-propanol (25 mL). (±)-cis-4-(2-Amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol from Example 4 (400 mg, 1.5 mmol) was added and the solution was stirred at 80° C. for 2 hours and the neutralized by the addition of 1.0 N HC1. Concentration of the solution afforded the crude product which was purified by elution from a silica gel column with 2% methanol-chloroform (350 mg, 81%). Crystallization of such a sample from ethanol-water gave an off-white powder, m.p. 97-99° C.
Reaction SMILES: [CH2:1]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:11])[CH2:2][CH3:3].Br[CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>O1CCCC1>[CH2:1]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:2][CH3:3]
Reactant: CCOC(=O)C(C)Br
Reactant: CCCc1c(O)cccc1O
Solvent: C1CCOC1
Product: CCCc1c(O)cccc1OC(C)C(=O)OCC
Temperature: 25 °C

Procedure:
Sodium hydride (1.08 g of a 60% oil dispersion, 27 mmoles) under an argon atmosphere was washed with 15 ml of dry hexane. The hexane supernatant was removed via syringe. Dry tetrahydrofuran (60 ml) was added to the sodium hydride and, with stirring at room temperature, the 2-propyl-1,3-dihydroxybenzene (4.08 g, 27 mmoles) was added as a 40 ml tetrahydrofuran solution. After stirring at room temperature for 25 minutes, the ethyl 2-bromopropionate (4.64 g, 26 mmoles) was added rapidly. After stirring at room temperature for 17 hours, the reaction was quenched with a saturated aqueous ammonium chloride solution and the tetrahydrofuran was removed under vacuum. The resulting aqueous mixture was extracted several times with ethyl acetate. The organic extract was dried over magnesium sulfate. Filtration and solvent removal gave an orange oil. This oil was purified by flash chromatography on silica gel eluting with 20% ethyl acetate/hexane. The desired title ester was obtained as a white solid (2.43 g, 36%).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:21][C@:8]2([O:12][C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[CH2:9]2)[CH2:7][N:6]1[C:22](=[O:37])[C@@H:23]([NH:28][C:29]([O:31][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:30])[C:24]([CH3:27])([CH3:26])[CH3:25])=[O:4].[Li+].[OH-].CO>C1COCC1>[Cl:20][C:16]1[CH:15]=[C:14]([N:10]2[CH2:9][C@@:8]3([CH2:21][C@@H:5]([C:3]([OH:4])=[O:2])[N:6]([C:22](=[O:37])[C@@H:23]([NH:28][C:29]([O:31][CH:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[O:30])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:7]3)[O:12][C:11]2=[O:13])[CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)[C@@H]1C[C@@]2(CN(c3cccc(Cl)c3)C(=O)O2)CN1C(=O)[C@@H](NC(=O)OC1CCCC1)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)[C@H](NC(=O)OC1CCCC1)C(=O)N1C[C@@]2(C[C@H]1C(=O)O)CN(c1cccc(Cl)c1)C(=O)O2
Reaction time: 8 h
Yield: 46.3 %

Procedure:
(5S,8S)-methyl-3-(3-chlorophenyl)-7-((S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl)-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylate (C3) (22 mg, 41 μmol, 1 eq.) was diluted with dry THF (0.5 mL) then 1 M LiOH (82 μL, 82 μmol, 2 eq.) and MeOH (20 μL) was added. The reaction was stirred overnight at room temp. and concentrated to give 10 mg (19 μmol) of (5S,8S)-3-(3-chlorophenyl)-7-((S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl)-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylic acid (D3). LC MS+: 522.35 at 3.14 min (10-90%, 3-5 min, Formic Acid).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([N:12]([CH2:14][C:15]1[O:19][CH:18]=[C:17]([C:20](O)=[O:21])[CH:16]=1)[CH3:13])(=[O:11])=[O:10].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:35][N:36]1[CH2:41][CH2:40][CH:39]([CH2:42][N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:38][CH2:37]1>ClCCCl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[S:9]([N:12]([CH3:13])[CH2:14][C:15]1[O:19][CH:18]=[C:17]([C:20]([N:46]2[CH2:45][CH2:44][N:43]([CH2:42][CH:39]3[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]3)[CH2:48][CH2:47]2)=[O:21])[CH:16]=1)(=[O:10])=[O:11]
Reactant: CN(Cc1cc(C(=O)O)co1)S(=O)(=O)c1c(Cl)cccc1Cl
Reactant: CN1CCC(CN2CCNCC2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: CN1CCC(CN2CCN(C(=O)c3coc(CN(C)S(=O)(=O)c4c(Cl)cccc4Cl)c3)CC2)CC1
Reaction time: 1 h

Procedure:
5-({[(2,6-dichlorophenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (465 mg, 1.3 mmol) was dissolved in DCE (40 mL) and CDI (422 mg, 2.6 mmol) was added. The reaction was stirred for 1 h. 4 mL of activated acid solution in DCE was added to a vial containing 1-[(1-methylpiperidin-4-yl)methyl]piperazine (51 mg, 0.258 mmol). The reaction was stirred at ambient temperature for 3 days, then washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and shaken with PL-MIA and Ambersep resins, then filtered. The solvent was removed in vacuo and a portion of the crude product purified using prep method B.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](Br)[C:15]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:10]([CH3:27])=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cu][C:30]#[N:31].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:30]#[N:31])[C:15]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:10]([CH3:27])=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C)n(Cc2ccccc2)c2c(OCc3ccc(F)cc3)c(Br)cnc12
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(C)n(Cc2ccccc2)c2c(OCc3ccc(F)cc3)c(C#N)cnc12
Temperature: 25 °C
Yield: 22.7 %

Procedure:
1-Benzyl-6-bromo-7-(4-fluorobenzyloxy)-2,3-dimethyl-1H-pyrrolo[3,2-b]pyridine hydrochloride prepared in Example 273 was neutralized with a saturated sodium carbonate solution to obtain 1-benzyl-6-bromo-7-(4-fluoro-benzyloxy)-2,3-dimethyl-1H-pyrrolo[3,2-b]pyridine (1.4 g, 3.18 mmol). A solution of 1-benzyl-6-bromo-7-(4-fluoro-benzyloxy)-2,3-dimethyl-1H-pyrrolo[3,2-b]pyridine (1.4 g, 3.18 mmol) and copper (I) cyanide (700 mg, 7.52 mmol) in anhydrous N,N-dimethylformamide (30 ml) was refluxed for 48 hours and then cooled to room temperature. Ethyl acetate was added to the reaction mixture, which was then filtered to discard insoluble solid. Water was added to the resulting solution, which was then extracted with ethyl acetate. The resulting organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/methanol=10/1, v/v) to give 278 mg of the titled compound as a white solid.
Reaction SMILES: [Cl:1]Cl.ClC(SS[C:9]([O:30][CH2:31][C:32]([F:39])([N+:36]([O-:38])=[O:37])[N+:33]([O-:35])=[O:34])([O:20][CH2:21][C:22]([N+:27]([O-:29])=[O:28])([N+:24]([O-:26])=[O:25])[F:23])[O:10][CH2:11][C:12]([N+:17]([O-:19])=[O:18])([N+:14]([O-:16])=[O:15])[F:13])(Cl)Cl>ClCCCl>[F:13][C:12]([N+:17]([O-:19])=[O:18])([N+:14]([O-:16])=[O:15])[CH2:11][O:10][C:9]([Cl:1])([O:30][CH2:31][C:32]([F:39])([N+:36]([O-:38])=[O:37])[N+:33]([O-:35])=[O:34])[O:20][CH2:21][C:22]([F:23])([N+:27]([O-:29])=[O:28])[N+:24]([O-:26])=[O:25]
Reactant: ClCl
Reactant: O=[N+]([O-])C(F)(COC(OCC(F)([N+](=O)[O-])[N+](=O)[O-])(OCC(F)([N+](=O)[O-])[N+](=O)[O-])SSC(Cl)(Cl)Cl)[N+](=O)[O-]
Solvent: ClCCCl
Product: O=[N+]([O-])C(F)(COC(Cl)(OCC(F)([N+](=O)[O-])[N+](=O)[O-])OCC(F)([N+](=O)[O-])[N+](=O)[O-])[N+](=O)[O-]
Reaction time: 8 h

Procedure:
Dry chlorine gas was passed for 2 hrs into a solution of 81.0 g (0.124 mole) of tris(2-fluoro-2,2-dinitroethoxy)methyl trichloromethyl disulfide in 300 ml of dry 1,2-dichloroethane at 60°-65° C. The solution was allowed to stand at ambient temperature overnight before the volatiles were removed with a stream of nitrogen and heating at 60°-65° C. The cooled residue was stirred with 300 ml of dry hexanes to give tris(2-fluoro-2,2-dinitroethyl)chloroorthoformate as an insoluble white solid. The hexanes solution was decanted from the solid which was washed with hexanes.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[CH2:12][CH:11]1[S:13]([NH:16][C:17]1[C:25]2[O:24][CH:23]=[N:22][C:21]=2[C:20]([F:26])=[C:19]([F:27])[C:18]=1[NH:28][C:29]1[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=1[F:36])(=[O:15])=[O:14])C1C=CC=CC=1.B(Cl)(Cl)Cl>C(Cl)Cl>[F:26][C:20]1[C:21]2[N:22]=[CH:23][O:24][C:25]=2[C:17]([NH:16][S:13]([CH:11]2[CH2:12][CH:10]2[CH2:9][OH:8])(=[O:15])=[O:14])=[C:18]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=2[F:36])[C:19]=1[F:27]
Reactant: O=S(=O)(Nc1c(Nc2ccc(I)cc2F)c(F)c(F)c2ncoc12)C1CC1COCc1ccccc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: O=S(=O)(Nc1c(Nc2ccc(I)cc2F)c(F)c(F)c2ncoc12)C1CC1CO

Procedure:
Compound 1L was prepared from 2-(benzyloxymethyl)-N-(4,5-difluoro-6-(2-fluoro-4-iodophenylamino)benzo[d]oxazol-7-yl)cyclopropane-1-sulfonamide (150 mg, 0.238 mmol) in DCM (10 mL) was reacted with 1.0M solution of BCl3 in DCM (0.9 mL, 0.952 mmol) to afford the crude product. The reaction mixture was quenched with methanol (0.5 mL) and partitioned between water and ethyl acetate. The organic layer was washed with water, brine solution, dried over anhydrous Na2SO4 and concentrated. Purification by column chromatography on silica gel (60-100% ethyl acetate in hexane) afforded 65 mg of the product (54% yield). H1NMR (CDCl3, 300 MHz): δ 7.7-7.6 (bs, 1H), 7.4-7.3 (m, 1H), 7.3-7.2 (m, 1H), 6.6 (s, 1H), 6.2 (s, 1H), 6.2-6.0 (m, 1H), 3.1-3.0 (t, 1H), 4.2-4.0 (m, 2H), 2.6-2.5 (m, 1H), 1.5-1.4 (m, 1H), 1.0-0.9 (m, 2H). LCMS: 100%, m/z=539.6 (M+H). HPLC: 83.1%
Reaction SMILES: [NH2:1][C:2]1[C:13]2=[C:14]3[N:9]([CH:10]([CH3:15])[CH2:11][CH2:12]2)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6](=[O:19])[C:5]3=[CH:4][C:3]=1[Cl:20].[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([NH:1][C:2]1[C:13]2=[C:14]3[N:9]([CH:10]([CH3:15])[CH2:11][CH2:12]2)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6](=[O:19])[C:5]3=[CH:4][C:3]=1[Cl:20])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CC1CCc2c(N)c(Cl)cc3c(=O)c(C(=O)O)cn1c23
Product: CC(=O)Nc1c(Cl)cc2c(=O)c(C(=O)O)cn3c2c1CCC3C

Procedure:
Using the method of Example 49, 8-amino-9-chloro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid is reacted with acetic anhydride to provide 8-acetamido-9-chloro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, m.p. 234°-236° C.
Reaction SMILES: [CH2:1]([CH:4]([S:8]([CH2:11][C@@H:12]([C:14]([OH:16])=[O:15])[NH2:13])(=[O:10])=[O:9])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[C:17](NC(=O)CCC(N)=O)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].CN1CCOCC1>C(Cl)Cl>[CH2:20]([O:19][C:17]([NH:13][C@H:12]([C:14]([OH:16])=[O:15])[CH2:11][S:8]([CH:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])(=[O:9])=[O:10])=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NC(=O)CCC(=O)NC(=O)OCc1ccccc1
Reactant: CCCC(CCC)S(=O)(=O)C[C@H](N)C(=O)O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCC(CCC)S(=O)(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 4 h

Procedure:
3-[(1-Propylbutyl)sulfonyl]alanine (LXXXIII, 7.8 g, 27 mmole) and N-CBZ succinamide (7.4 g, 30 mmole) are mixed in methylene chloride (100 ml). The reaction is cooled to 0°, and NMM (6.9 g) is added dropwise. The reaction is allowed to warm to 20–25° and stirred for 4 hours at which point HPLC analysis indicated complete reaction. The reaction mixtue is concentrated under reduced pressure and partitioned between ethyl acetate and hydrochloric acid (1 N). The organic phase is washed with water, saline, dried over sodium sulfate, and concentrated under reduced pressure to give N-[(benzyloxy)carbonyl]-3-[(1-propylbutyl)sulfonyl]alanine (LXXXIV) that is used without further purification, M+H=386.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([C:19](O)=[O:20])[CH:18]=1)[NH:15][CH:14]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:32][CH2:31][O:30][C:29]3=[O:33])[CH:23]=1)[CH2:13][C:12]2([CH3:35])[CH3:34].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([C:19]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:20])[CH:18]=1)[NH:15][CH:14]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:32][CH2:31][O:30][C:29]3=[O:33])[CH:23]=1)[CH2:13][C:12]2([CH3:35])[CH3:34]
Reactant: CC1(C)CC(c2cccc(N3CCOC3=O)c2)Nc2c(C(=O)O)cc(Cl)cc21
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(c2cccc(N3CCOC3=O)c2)Nc2c(C(=O)NS(C)(=O)=O)cc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.7 %

Procedure:
To a suspension of methanesulfonamide (665 mg, 7 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (280 mg, 7 mmol). The resulting mixture was stirred at 25° C. for 1 h to afford Solution A64. A solution of 6-chloro-4,4-dimethyl-2-[3-(2-oxo-oxazolidin-3-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (400 mg, 1 mmol) and 1,1′-carbonyldiimidazole (325 mg, 2 mmol) in N,N-dimethylformamide (2 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B64. Solution B64 was added to Solution A64 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-{6-chloro-4,4-dimethyl-2-[3-(2-oxo-oxazolidin-3-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carbonyl}-methanesulfonamide (37 mg, 7%) as a white solid: MS (ESI) M+1=478.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]=[CH:15][C:16]([O:18][C:19]3[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=3)=[O:17])[CH:5]=[CH:4][C:3]1=2.C1COCC1.CCCCCC.[BH4-].[Na+]>O>[CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH:14]=[CH:15][C:16]([O:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:23][OH:24])=[CH:25][CH:26]=3)=[O:17])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C=CC(=O)Oc3ccc(C=O)cc3)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC1(C)CCC(C)(C)c2cc(C=CC(=O)Oc3ccc(CO)cc3)ccc21
Reaction time: 3 h

Procedure:
3.1 g (8.5 mmol) of 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acryloyloxy]benzaldehyde and 50 ml of a mixture of THF and methanol (50/50) are introduced into a round-bottomed flask. 163 mg (4.25 mmol) of sodium borohydride is added portionwise and the mixture is stirred at [lacuna] temperature for three hours. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate, filtered and evaporated. The solid obtained is recrystallized from a mixture of diisopropyl ether and hexane. After filtration and drying, 1.6 g (53%) of 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acryloyloxy]benzenemethanol, with a melting point of 140-50° C., are collected.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)#[CH:18]>>[Cl:25][C:21]1[CH:20]=[C:19]([C:17]#[C:18][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH:24]=[CH:23][CH:22]=1
Reactant: C#Cc1cccc(Cl)c1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: O=c1[nH]c2nccc(C#Cc3cccc(Cl)c3)c2c2ccccc12
Yield: 72.4 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 160 using Compound 83 (100 mg, 0.43 mmol) and 1-ethynyl-3-chloro-benzene (88 mg, 0.65 mmol) to provide 165 (103 mg, 72% yield) as a white solid. LC-MS (M+H=331, obsd.=331).
Reaction SMILES: [N:1]1([CH:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][O:9][C:8]3[CH:17]=[CH:18][C:19]([C:21]([O:23]C)=[O:22])=[CH:20][C:7]2=3)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[K+].Cl>CO.O1CCCC1>[N:1]1([CH:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][O:9][C:8]3[CH:17]=[CH:18][C:19]([C:21]([OH:23])=[O:22])=[CH:20][C:7]2=3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)c1ccc2c(c1)C(n1ccnc1)c1ccccc1CO2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)C(n1ccnc1)c1ccccc1CO2
Temperature: 70 °C

Procedure:
Dissolve 3.1 gm of the ester of Step A in a mixture of 60 ml of methanol and 60 ml of tetrahydrofuran. Add 60 ml of 5% aqueous potassium hydroxide and heat the mixture at 70° C. under a nitrogen atmosphere for 5 hours. Pour the mixture onto ice and acidify to pH 5 with concentrated hydrochloric acid. Separate the solids by filtration. Wash with cold water and dry at 60° C. under vacuum for 2 hours to obtain the title product (m.p. 244°-255° C. dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([F:35])=[C:13]([CH:20](C(OC(C)(C)C)=O)[C:21]([O:23]C(C)(C)C)=[O:22])[CH:14]=[CH:15][C:16]=2[N+:17]([O-:19])=[O:18])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([F:35])=[C:13]([CH2:20][C:21]([OH:23])=[O:22])[CH:14]=[CH:15][C:16]=2[N+:17]([O-:19])=[O:18])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])c(Oc2cc(Cl)cc(C#N)c2)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2c([N+](=O)[O-])ccc(CC(=O)O)c2F)c1
Temperature: 25 °C

Procedure:
The crude bis(1,1-dimethylethyl) {3-[(3-chloro-5-cyanophenyl)oxy]-2-fluoro-4-nitrophenyl}propanedioate was dissolved in CH2Cl2 (25 mL) and TFA (25 mL) and heated to reflux for 2 h. The reaction mixture was cooled to RT and evaporated. Water (50 mL) and EtOAc (50 mL) were added, the layers were separated and the aqueous layer extracted with EtOAc (3×50 mL). The organic extracts were combined, dried over Na2SO4, filtered and evaporated to give the title compound as an oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.03 (d, 1H), 7.81 (s, 1H), 7.50-7.62 (m, 3H), 3.84 (s, 2H). MS: m/z 349.1 (M−1).