Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[CH2:15]([Sn](CCCC)(CCCC)CCCC)[CH:16]=[CH2:17].[Cl-].[Li+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([CH2:17][CH:16]=[CH2:15])=[CH:3][C:4]=1[C:11]([F:14])([F:13])[F:12])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cc1C(F)(F)F
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
A mixture of 4-bromo-1-nitro-2-(trifluoromethyl)benzene (1.0 g, 3.7 mmol), allyl tri-n-butyltin (1.4 mL, 4.4 mmol), lithium chloride (470 mg, 11 mmol), and palladium tetrakis (210 mg, 0.18 mmol) in toluene (30 mL) was heated to reflux for 16 hours under nitrogen. TLC showed complete reaction at that point. The reaction was diluted with ethyl acetate, adsorbed onto silica gel, and purified by silica gel chromatography to afford the title product.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].O.[NH2:15][C:16]1[NH:20][N:19]=[N:18][N:17]=1>O1CCCC1.O>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:15][C:16]1[NH:20][N:19]=[N:18][N:17]=1)=[O:5]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1Cl
Reactant: Nc1nnn[nH]1
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1nnn[nH]1)c1cccc([N+](=O)[O-])c1Cl
Reaction time: 1 h

Procedure:
Similarly, a solution of 109 g of 2-chloro-3-nitrobenzoyl chloride in 100 ml of tetrahydrofuran was reacted with a mixture of 103 g of 5-aminotetrazole monohydrate in 1200 ml of hot tetrahydrofuran and 50 ml of water. A voluminous precipitate appeared and, after 1 hour, the mixture was diluted with 2 liters of water and the resulting white solid was collected and oven-dried to give 2-chloro-3-nitro-N-(1H-tetrazol-5-yl)-benzamide melting at about 279° C. with decomposition. In this case, the indicated acid chloride was obtained by the reaction of 2-chloro-3-nitrobenzoic acid with phosphorus pentachloride in cyclohexane. The acid chloride melts at about 57°-59° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([S:21][CH3:22])[C:10]([S:11]([C:14]3[C:15]([CH3:20])=[CH:16][CH:17]=[CH:18][CH:19]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:23])[CH:3]=1.[NH3:24]>CO>[CH3:23][C:4]1[CH:3]=[C:2]([NH2:24])[N:7]2[N:8]=[C:9]([S:21][CH3:22])[C:10]([S:11]([C:14]3[C:15]([CH3:20])=[CH:16][CH:17]=[CH:18][CH:19]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=1
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccccc1C
Reactant: N
Solvent: CO
Product: CSc1nn2c(N)cc(C)nc2c1S(=O)(=O)c1ccccc1C

Procedure:
In an analogous manner to that described in Example 4), from 7-chloro-5-methyl-2-methylsulphanyl-3-(toluene-2-sulphonyl)-pyrazolo[1,5-a]pyrimidine and NH3 in MeOH there was obtained 5-methyl-2-methylsulphanyl-3-(toluene-2-sulphonyl)-pyrazolo[1,5-a]-pyrimidin-7-ylamine as colorless crystals, m.p.>250°.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[S:22](Cl)(=[O:24])=[O:23]>C([O-])(O)=O.[Na+].C(OCC)C.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=1[S:22]([O:5][C:4]1[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=1)(=[O:24])=[O:23]
Reactant: Cc1cc(O)cc(O)c1
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(O)cc(OS(=O)(=O)c2cc(C(F)(F)F)ccc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and 2-chloro-5-trifluoromethylbenzenesulfonyl chloride (2.79 g, 10.0 mmol) were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 3% ethyl acetate in dichloromethane) to give the title compound as a pale yellow oil (1.50 g, 41%). 1H-NMR (300 MHz, CDCl3) δ 8.24 (d, J=1.9 Hz, 1H), 7.83 (dd, J=8.3, 2.1 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 6.57 (s, 1H), 6.55 (s, 1H), 6.46 (s, 1H), 5.07 (br s, 1H), 2.24 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH:2]=1.[Cl:18][C:19]1[C:20]2[CH:28]=C(N(C)C)N=[CH:25][C:21]=2[N:22]=[CH:23][N:24]=1>>[ClH:18].[CH3:7][N:8]([CH3:16])[N:9]1[CH:10]=[CH:25][C:21]2[N:22]=[CH:23][N:24]=[C:19]([NH:17][C:13]3[CH:12]=[C:11]4[C:16](=[CH:15][CH:14]=3)[N:8]([CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[N:9]=[CH:10]4)[C:20]=2[CH2:28]1
Reactant: Nc1ccc2c(cnn2Cc2cccnc2)c1
Reactant: CN(C)c1cc2c(Cl)ncnc2cn1
Product: CN(C)N1C=Cc2ncnc(Nc3ccc4c(cnn4Cc4cccnc4)c3)c2C1
Product: Cl

Procedure:
Prepared according to Procedure A from 1-(3-Pyridylmethyl)-1H-indazol-5-ylamine and 4-chlor-6-(N,N-dimethylamino)-pyrido[3,4-d]pyrimidine; δH [2H6]DMSO 11.50 (1H,s), 9.90(1H,s), 8.65(1H,d), 8.60(2H,m), 8.25(1H,s), 8.14(1H,s), 7.91(1H,d), 7.75 (2H,m), 7.70(1H,s), 7.50(1H,m), 5.80(2H,s), 3.20(6H,s); m/z (M+1+) 397.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH3:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[C:24]4[N:23]=[CH:22][N:21]=[CH:20][C:19]=4[NH:18][N:17]=3)=[O:15])=[CH:11][N:10]([CH:25]([CH3:29])[C:26](O)=[O:27])[N:9]=2)[CH:7]=1.Cl.[O:33]1[CH2:36][CH:35]([NH2:37])[CH2:34]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH3:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[C:24]4[N:23]=[CH:22][N:21]=[CH:20][C:19]=4[NH:18][N:17]=3)=[O:15])=[CH:11][N:10]([CH:25]([CH3:29])[C:26]([NH:37][CH:35]3[CH2:36][O:33][CH2:34]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: NC1COC1
Reactant: COc1ccc(Cl)cc1-c1nn(C(C)C(=O)O)cc1NC(=O)c1n[nH]c2cncnc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1-c1nn(C(C)C(=O)NC2COC2)cc1NC(=O)c1n[nH]c2cncnc12
Reaction time: 6 h
Yield: 52.3 %

Procedure:
A solution of 2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)propanoic acid (66.0 mg, 0.150 mmol, 1 equiv), oxetan-3-amine hydrochloride (41.0 mg, 0.374 mmol, 2.50 equiv), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)uranium hexafluorophosphate (114 mg, 0.299 mmol, 2.00 equiv), and N,N-diisopropylethylamine (522 μL, 2.99 mmol, 20.0 equiv) in N,N-dimethylformamide (1.0 mL) was heated at 50° C. After 6 h, the reaction mixture was concentrated, and the resulting residue was partitioned between saturated aqueous sodium bicarbonate (10 mL) and ethyl acetate (10 mL). The aqueous was extracted with ethyl acetate (2×5 mL). The combined organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by preparative HPLC afforded product (39 mg, 51% yield). 1H NMR (400 MHz, DMSO-d6), δ: 9.70 (s, 1H), 9.33 (m, 1H), 9.02 (d, J=6.5 Hz, 1H), 8.77 (dd, J=4.2, 1.5 Hz, 1H), 8.65 (s, 1H), 8.36 (s, 1H), 7.50 (dd, J=8.9, 2.7 Hz, 1H), 7.38 (d, J=2.6 Hz, 1H), 7.27-7.31 (m, 2H), 5.06 (q, J=7.1 Hz, 1H), 4.80 (m, 1H), 4.73 (m, 2H), 4.44 (m, 2H), 3.84 (s, 3H), 1.66 (d, J=7.1 Hz, 3H). LCMS (ESI): M+H=496.1.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([C:9]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=1)([CH2:16][CH2:17][C:18]([O:20]C)=O)[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])#[N:8].CCOC(C)=O.CCCCCCC>C1(C)C=CC=CC=1>[C:7]([C:9]1([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:10][CH:11]([C:12]([O:14][CH3:15])=[O:13])[C:18](=[O:20])[CH2:17][CH2:16]1)#[N:8]
Reactant: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)C1CC(C#N)(c2ccc(Cl)c(Cl)c2)CCC1=O
Temperature: 90 °C
Reaction time: 1 h
Yield: 121.5 %

Procedure:
To a 12-L, three-neck flask equipped with a temperature probe, reflux condenser, addition funnel and overhead stirrer was charged with potassium tert-butoxide (266 g, 2.3 mol) and toluene (1 L). A solution of dimethyl 4-cyano-4-(3,4-dichlorophenyl)-heptanedioate (402 g, crude, 386 g theoretical, 1.07 mol) in toluene (3 L) was added through an addition funnel. The reaction mixture was heated to 90° C. and stirred for 1 h. The progress of the reaction was monitored by TLC (4:6 EtOAc/Heptane; stained using Hanessian solution). After 1 h, the reaction mixture was cooled to 15° C. and quenched slowly with 2 M HCl (2.3 L). The phases were separated and the aqueous phase was extracted with MTBE (1 L). The combined organic phases were washed with brine (2×1 L), dried over MgSO4, filtered and concentrated under reduced pressure at 40-45° C. to yield the title compound (424 g, >100%) as a yellow solid. The crude was taken into next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CN(C)C.Cl[C:20]([O:22][CH2:23][C:24]#[CH:25])=[O:21].C(Cl)Cl.[OH2:29]>C(Cl)Cl>[CH2:23]([O:22][C:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:20]([O:22][CH2:23][C:24]#[CH:25])=[O:29])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)=[O:21])[C:24]#[CH:25]
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: C#CCOC(=O)Cl
Reactant: O
Agent: CN(C)C
Solvent: ClCCl
Product: C#CCOC(=O)Oc1ccc(-c2ccc(OC(=O)OCC#C)cc2)cc1
Yield: 93.6 %

Procedure:
A flask equipped with a stirrer, thermometer, nitrogen gas tube and reflux condenser was charged with 18.6 g of 4,4'-dihydroxybiphenyl and 23.0 g of trimethylamine in 50.0 g of methylene chloride. To the flask was added 26.0 g of propargyl chloroformate dropwise over one hour and the mixture was allowed to react for 6 hours at 30° C. After the reaction, the reaction mixture was treated with methylene chloride-water mixture and the organic phase was separated followed by drying over magnesium sulfate overnight. After filtering, the filtrate was evaporated in a rotary evaporator. The resulting crystals were recrystallized to give the title compound at a yield of 93.6% of theory.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[NH:10][C:11]1([C:14](=O)/[N:15]=[CH:16]/[N:17](C)C)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[NH2:24]N.CCOC(C)=O.O>CC(O)=O>[CH2:1]([O:8][C:9](=[O:21])[NH:10][C:11]1([C:14]2[NH:15][CH:16]=[N:17][N:24]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)/C=N/C(=O)C1(NC(=O)OCc2ccccc2)CC1
Reactant: NN
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC1(c2nnc[nH]2)CC1)OCc1ccccc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 68.4 %

Procedure:
To a solution of (1-{[1-dimethylamino-meth-(E)-ylidene]-carbamoyl}-cyclopropyl)-carbamic acid benzyl ester (1.11 g, 3.83 mmol) in AcOH (6 ml) was added hydrazine dihydrochloride (803 mg, 7.65 mmol). The reaction mixture was stirred at 90° C. for 1.5 h. The reaction mixture was poured into EtOAc/water. The organic phase was separated, washed with water, sat. NaHCO3, brine, dried over anhydrous Na2SO4, filtered, concentrated and dried under high vacuum to afford 677 mg of [1-(4H-[1,2,4]triazol-3-yl)-cyclopropyl]-carbamic acid benzyl ester as a off-white solid, m/z 259.6 [M+1]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12].[O:17]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C.CCOCC>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([O:13][CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[C:24]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:25]=1)=[O:12]
Reactant: CC(C)C(C(=O)O)c1cc2ccccc2s1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: CC(C)C(C(=O)OCc1cccc(Oc2ccccc2)c1)c1cc2ccccc2s1
Reaction time: 8 h

Procedure:
A mixture of 2-(2-benzothienyl)-3-methylbutanoic acid (1 g, 4.3 mmol), 3-phenoxybenzyl bromide (1.1 g, 4.3 mmol) and K2CO3 (8.6 mmol) in 25 ml of THF/HMPA (1:1) is stirred overnight. The reaction is worked up by diluting with ether, washing with water, drying over Na2SO4, and solvent removed to yield 3-phenoxybenzyl 2-(2benzothienyl)-3-methylbutanoate which can be further purified by preparing thin layer chromatography eluting with 5 percent ether/hexane.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14]C)=[O:12])[C:6]([O:8][CH2:9]C)=[O:7])(=[O:3])[CH3:2].[H-].[Na+].[CH2:18]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[C:31](=[CH2:35])[C:30](=[O:36])[CH2:29]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].CCOCC>C1COCC1.O>[CH3:14][O:13][C:11](=[O:12])[C:5]([NH:4][C:1](=[O:3])[CH3:2])([CH2:35][CH:31]1[C:32]2[C:28](=[CH:27][C:26]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:34][CH:33]=2)[CH2:29][C:30]1=[O:36])[C:6]([O:8][CH3:9])=[O:7]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: C=C1C(=O)Cc2cc(CCCCCCCC)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc2c(c1)CC(=O)C2CC(NC(C)=O)(C(=O)OC)C(=O)OC

Procedure:
Diethyl acetamidomalonate (4.55 g, 21.0 mmol) is dissolved in THF (40 mL). Sodium hydride (0.600 g, 25.0 mmol) is added. The reaction is brought to reflux for 2.0 hours. The residue (compound 16) from Example 12, dissolved in THF (40 mL) is added. The reaction is maintained at reflux for an additional 4 hours, cooled, and poured into a separatory funnel containing ether (100 mL) and water (75 mL). The ether layer is separated and the aqueous layer is re-extracted with ether (100 mL). The combined organic layers are dried over MgSO4 and the solvent removed in vacuo. The residue is chromatographed over silica gel yielding 17 (FIG. 7).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[C:5]([CH2:11][CH3:12])[CH:4]=1)[CH3:2].CO[CH2:15][Cl:16].C(O)(=O)C>O>[CH2:11]([C:5]1[CH:6]=[C:7]([CH2:9][CH3:10])[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[CH2:15][Cl:16])[CH3:12]
Reactant: COCCl
Reactant: CCc1cc(CC)cc(CC)c1
Solvent: O
Solvent: CC(=O)O
Product: CCc1cc(CC)c(CCl)c(CC)c1
Temperature: 120 °C
Reaction time: 7 h
Yield: 64.6 %

Procedure:
A mixture of 81.1 g of 1,3,5-triethylbenzene, 60.4 g of chloromethyl methyl ether and 6.0 g of acetic acid was stirred in a sealed tube at 120° C. for 7 hours. The reaction mixture was poured into 500 ml of water and extracted with hexane. The organic layer was washed with an aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was distilled under reduced pressure to obtain 68.07 g of 2,4,6-triethylbenzyl chloride. Boiling point: 88 to 98° C. (0.18 kPa).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[Br:12][C:13]1[C:18]([O:19][CH2:20][CH3:21])=[CH:17][C:16]([OH:22])=[C:15]([CH2:23][CH3:24])[CH:14]=1>C(Cl)Cl>[Br:12][C:13]1[C:18]([O:19][CH2:20][CH3:21])=[CH:17][C:16]([O:22][C:1](=[O:3])[CH3:2])=[C:15]([CH2:23][CH3:24])[CH:14]=1
Reactant: CCOc1cc(O)c(CC)cc1Br
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(OC(C)=O)c(CC)cc1Br
Reaction time: 0.75 h
Yield: 53.4 %

Procedure:
Acetyl chloride (0.91 mL, 12.8 mmol) followed by triethylamine (1.8 mL, 12.8 mmol) were added to a stirred solution of 4-bromo-5-ethoxy-2-ethyl-phenol (2.6 g, 10.7 mmol) dissolved in CH2Cl2 (20 mL). The reaction was stirred for 45 mins and then partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine dried over Na2SO4 and concentrated. Purification by flash column chromatography (0% to 20% EtOAc in hexanes) gave the product as a clear oil (1.64 g, 53%). 1H NMR (400 MHz, CDCl3): δ 1.16 (t, J=7.6 Hz, 3 H), 1.45 (t, J=7.1 Hz, 3 H), 2.31 (s, 3 H), 2.45 (q, J=7.6 Hz, 2 H), 4.05 (q, J=7.1 Hz, 2 H), 6.58 (s, 1 H), 7.41 (s, 1 H).
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].[CH:13]1([CH2:16][N:17]([CH2:39][CH2:40][CH3:41])[C:18]([C:20]2[N:24]3[CH2:25][CH2:26][N:27]([C:28]4[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=4[CH3:36])[C:23]3=[N:22][C:21]=2[CH2:37]C)=O)[CH2:15][CH2:14]1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH:13]1([CH2:16][N:17]([CH2:18][C:20]2[N:24]3[CH2:25][CH2:26][N:27]([C:28]4[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=4[CH3:36])[C:23]3=[N:22][C:21]=2[CH3:37])[CH2:39][CH2:40][CH3:41])[CH2:15][CH2:14]1
Reactant: CCCN(CC1CC1)C(=O)c1c(CC)nc2n1CCN2c1c(C)cc(C)cc1C
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCN(Cc1c(C)nc2n1CCN2c1c(C)cc(C)cc1C)CC1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
A solution of Red-al (3.3 M in toluene, 0.70 mL, 2.33 mmol) was added dropwise to a solution of 2-ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-α]imidazole-3-carboxylic acid cyclopropylmethyl-propyl-amide (0.177 g, 0.46 mmol) in toluene (3 mL) at 0° C. After stirring at room temperature for 24 h, the reaction mixture was cooled to 0° C. and 1 N sodium hydroxide (10 mL) was added dropwise. The above mixture was extracted with dichloromethane (40 mL), and the organic extracts were washed with water and dried over anhydrous sodium sulfate. Solvents were removed in vacuo to afford the title compound as a light yellow oil which solidified upon cooling (109 mg, 65% yield). The purity of the product was determined to be 91% by LC/MS. 1H NMR (CDCl3, 300 MHz) δ 6.85 (s, 2H), 4.09-3.96 (m, 4H), 3.45 (s, 2H), 2.44 (t, J=7.1 Hz, 2H), 2.29 (d, J=6.5 Hz, 2H), 2.23 (s, 3H), 2.19 (s, 6H), 2.04 (s, 3H), 1.46 (quintet, J=7.3 Hz, 2H), 1.28-1.25 (m, 1H), 0.87 (t, J=7.2 Hz, 3H), 0.49-0.46 (m, 2H), 0.09-0.06 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 155.4, 137.1, 136.9, 136.0, 135.0, 129.7, 117.7, 58.5, 55.5, 53.8, 48.0, 42.4, 20.9, 20.3, 18.2, 13.3, 12.0, 8.9, 4.0. Mass spec.: 367.24 (MH+).
Reaction SMILES: C([C:6]1[C:7](=[O:18])[NH:8][C:9]2[CH2:10][CH2:11][CH:12]([CH3:17])[CH2:13][C:14]=2[C:15]=1[OH:16])(OCC)=O.Cl>CC(O)=O>[OH:16][C:15]1[C:14]2[CH2:13][CH:12]([CH3:17])[CH2:11][CH2:10][C:9]=2[NH:8][C:7](=[O:18])[CH:6]=1
Reactant: CCOC(=O)c1c(O)c2c([nH]c1=O)CCC(C)C2
Agent: Cl
Solvent: CC(=O)O
Product: CC1CCc2[nH]c(=O)cc(O)c2C1

Procedure:
Refluxing a suspension of 3-carboethoxy-4-hydroxy-6-methyl-5,6,7,8-tetrahydrocarbostyril (20 g; 0.08 mole) with 2N hydrochloric acid (300 ml) over 48 hrs. afforded the decarboethoxylated product isolated as in Example 1 m.p. (AcOH) >365° C.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH:7]([NH:20][C:21]([C:23]1[CH:24]=[C:25]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[CH:26]=[CH:27][CH:28]=1)=[O:22])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](O)=[N:16][OH:17])=[C:11]([F:19])[CH:10]=1)(C)(C)C.C(OC(=O)[CH:43]([NH:54][C:55]([C:57]1C=C(C2C=CC(C)=CC=2)C=CC=1)=[O:56])[CH2:44][C:45]1[CH:50]=[CH:49]C(C#N)=C(F)[CH:46]=1)(C)(C)C.Cl.[NH2:72]O.C([O-])(O)=O.[Na+]>C(O)C>[F:19][C:11]1[CH:10]=[C:9]([CH2:8][CH:7]([NH:20][C:21]([C:23]2[CH:24]=[C:25]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)[CH:26]=[CH:27][CH:28]=2)=[O:22])[C:6]([OH:5])=[O:36])[CH:14]=[CH:13][C:12]=1[C:15]1[N:72]=[C:57]([C:55]([N:54]2[CH2:43][CH2:44][CH:45]([CH3:46])[CH2:50][CH2:49]2)=[O:56])[O:17][N:16]=1
Reactant: Cc1ccc(-c2cccc(C(=O)NC(Cc3ccc(C#N)c(F)c3)C(=O)OC(C)(C)C)c2)cc1
Reactant: Cc1ccc(-c2cccc(C(=O)NC(Cc3ccc(C(O)=NO)c(F)c3)C(=O)OC(C)(C)C)c2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(-c2cccc(C(=O)NC(Cc3ccc(-c4noc(C(=O)N5CCC(C)CC5)n4)c(F)c3)C(=O)O)c2)cc1
Yield: 93 %

Procedure:
3-[3-Fluoro-4-(hydroxy-hydroxyimino-methyl)-phenyl]-2-[(4′-methyl-biphenyl-3-carbonyl)-amino]-propionic acid tert-butyl ester. A mixture of 3-(4-cyano-3-fluoro-phenyl)-2-[(4′-methyl-biphenyl-3-carbonyl)-amino]-propionic acid tert-butyl ester (10 g, 0.02 mol), hydroxylamine hydrochloride salt (7 g, 0.1 mol), and NaHCO3 (10 g, 0.12 mol) in ethanol (150 mL) was refluxed overnight. TLC showed the reaction was completed. The mixture were filtered and concentrated to give the title compound (10 g, 93% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([F:18])=[C:12]([I:17])[CH:13]=2)[N:8]([C@H:19]([CH2:23][OH:24])[CH:20]([CH3:22])[CH3:21])[CH:7]=1)=[O:5])[CH3:2].N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([F:18])=[C:12]([I:17])[CH:13]=2)[N:8]([C@H:19]([CH2:23][O:24][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH:20]([CH3:21])[CH3:22])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)c1cn([C@H](CO)C(C)C)c2cc(F)c(I)cc2c1=O
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn([C@H](CO[Si](C)(C)C(C)(C)C)C(C)C)c2cc(F)c(I)cc2c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
The compound (150 g, 335 mmol) obtained in Step 3 was dissolved in dimethylformamide (500 ml), imidazole (30 g, 0.436 mmol) and tert-butyldimethylsilyl chloride (56 g, 369 mmol) were added, and the mixture was stirred at room temperature for 1.5 hr. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous ammonium chloride solution and saturated brine, and dried over sodium sulfate. The organic layer was filtered and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:3 to 1:2) to give 1-((S)-1-tert-butyldimethylsilyloxymethyl-2-methylpropyl)-7-fluoro-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (173 g, yield 92%) as a colorless amorphous form.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2([C:36]#[N:37])[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:28][C@H:27]([CH2:29][NH:30][C:31](=O)[CH3:32])[O:26][C:25]4=[O:34])=[CH:20][C:19]=3[F:35])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:47])=CC=1>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2([C:36]#[N:37])[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:28][C@H:27]([CH2:29][NH:30][C:31](=[S:47])[CH3:32])[O:26][C:25]4=[O:34])=[CH:20][C:19]=3[F:35])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)c1ccc(NC2(C#N)CCN(c3ccc(N4C[C@H](CNC(C)=O)OC4=O)cc3F)CC2)cc1
Product: COC(=O)c1ccc(NC2(C#N)CCN(c3ccc(N4C[C@H](CNC(C)=S)OC4=O)cc3F)CC2)cc1
Yield: 61 %

Procedure:
By using procedure as described in Example 82 and by reacting (S)-N-{3-[4-(4-(4-methoxycarbonylphenylamino)-4-cyanopiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide and Lawesson's reagent the compound was obtained in 61% yield.