Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=NC1CCCCC1)=NC1CCCCC1.N1(O)C2C=CC=CC=2N=N1.[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47](O)[CH2:46]2>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:10]([O:12][C@@H:47]1[CH:48]2[CH2:51][CH2:52][N:45]([CH2:50][CH2:49]2)[CH2:46]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(Cl)cc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 44.4 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)acetic acid (I46) (2.17 g, 7.58 mmol) in dry THF (70 ml), were added N,N′-methanediylidenedicyclohexanamine (1.88 g, 9.10 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (1.23 g, 9.10 mmol), and (R)-quinuclidin-3-ol (1.16 g, 9.10 mmol). The reaction was stirred at RT for 15 hours, and the solvent was evaporated. The residue was taken up with DCM, the insoluble solid was filtered off, and the organic solution was washed twice with aq. Na2CO3 and then brine, dried over Na2SO4 and evaporated. The crude was purified by flash chromatography (EtOAc/MeOH=8/2 to 85/15) to obtain (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)acetate (1.33 g; 44% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2Br)[CH:21]=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C(OCC)(=O)C.[CH3:33][N:34](C=O)C>[C-]#N.[C-]#N.[Zn+2].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:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[C:33]#[N:34])[CH:21]=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc3ccncc3cc2Br)CC1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc3ccncc3cc2C#N)CC1

Procedure:
Under argon atmosphere 35 mg (0.3 mmol) of Zn(CN)2 and 17 mg (0.05 eq) of Pd(PPh3)4 were added to a solution of 122 mg (0.3 mmol) of 4-(7-bromo-isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (13) in DMF. The reaction was heated for 5 minutes to 150° C. in a microwave reactor (CEM Discovery). After cooling to room temperature water and ethyl acetate were added. The mixture was filtered through Celite, washed with ethyl acetate and concentrated. The crude product was purified by preparative HPLC to yield 77 mg of compound 16.
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][CH2:9][C:10]([CH3:32])([CH3:31])[CH:11]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[N:19]=[CH:18]2)[CH2:12][CH:13]=[CH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].B1C2CCCC1CCC2.[OH-:42].[Na+].OO>C1COCC1.O>[C:1]([NH:5][C:6]([NH:8][CH2:9][C:10]([CH3:32])([CH3:31])[CH:11]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[N:19]=[CH:18]2)[CH2:12][CH2:13][CH2:14][OH:42])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: [OH-]
Reactant: C=CCC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(C)(C)CNC(=O)NC(C)(C)C
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)NC(=O)NCC(C)(C)C(CCCO)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of 1-tert-butyl-3-(3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethylhex-5-enyl)urea (5.0 mg, 0.01 mmol) in anhydrous THF (2 mL) at 0 C was added 9-BBN (50 μL, 0.02 mmol) under nitrogen. Allowed reaction mixture to warm to RT and stirred overnight then added 10% NaOH solution (0.2 mL) and 30% H2O2 (1 mL). and stirred for 10 min. The reaction mixture was poured into a water (4 mL), extracted with ethyl acetate (2×10 mL), dried (Na2SO4) and purified by chromatography to give 3.2 mg (50% yield) of 1-tert-butyl-3-(3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-6-hydroxy-2,2-dimethylhexyl)urea. MS found: (M+H)+=455.
Reaction SMILES: [C:1]([O:7][CH2:8]C)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH:17]([CH2:23][CH2:24][CH3:25])[C:18]([O:20][CH2:21]C)=[O:19].Cl>CN(C=O)C.O>[C:3]([CH:2]([CH:17]([CH2:23][CH2:24][CH3:25])[C:18]([O:20][CH3:21])=[O:19])[C:1]([O:7][CH3:8])=[O:6])(=[O:4])[CH3:5]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCCC(Br)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)C(C(C)=O)C(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.9 %

Procedure:
To a solution of ethyl acetoacetate (64 mL; 504 mmol) in dry DMF (240 mL) under a nitrogen atmosphere was added potassium carbonate (69.6 g; 504 mmol), which has been dried at 120° C. for 12 h before its use. After stirring for 15 minutes at room temperature, ethyl 2-bromovalerate (81.6 mL; 480 mmol) was slowly added under nitrogen and the mixture was vigorously stirred at room temperature for 20 h. The reaction mixture was poured in water (240 mL) and neutralized by adding HCl 2N. The product was extracted with diethyl ether (2×240 mL) and the combined organic layers were dried over magnesium sulphate and concentrated under reduced pressure. The crude yellow oil was purified by distillation under reduced pressure (160° C./6 mbar) to give 61.8 g of the title compound as a colorless liquid (HPLC purity 60%). ESI/APCI(+): 259 (M+H);
Reaction SMILES: [H-].[Na+].[CH:3]([NH:7][C:8]([CH:10]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=1)[C:11]([CH3:19])([CH3:18])[CH2:12]OS(C)(=O)=O)=[O:9])([CH2:5][CH3:6])[CH3:4]>C1COCC1.CO>[C@@H:3]([N:7]1[CH2:19][C:11]([CH3:18])([CH3:12])[C@@H:10]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23]([C:29]([F:31])([F:32])[F:30])[CH:22]=2)[C:8]1=[O:9])([CH2:5][CH3:6])[CH3:4]
Reactant: CCC(C)NC(=O)C(Oc1ccc(C#N)c(C(F)(F)F)c1)C(C)(C)COS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@H](C)N1CC(C)(C)[C@@H](Oc2ccc(C#N)c(C(F)(F)F)c2)C1=O
Temperature: 22.5 °C
Reaction time: 90 h

Procedure:
Solid NaH (60 wt % dispersion in mineral oil, 16.6 g, 416 mmol) was added portion wise over 25 min to a cold (0-5° C.) sol'n of methanesulfonic acid 3-sec-butylcarbamoyl-3-(4-cyano-3-trifluoromethylphenoxy)-2,2-dimethylpropyl ester (104 g, 208 mmol) in 400 mL dry THF under an N2 atmosphere. The reaction mixture was allowed to warm to 20-25° C. and then stirred at this temp. for 90 h. The reaction mixture was quenched by adding it to 500 mL cold (5-10° C.) sat'd aq. NH4Cl. The phases were separated and the aqueous was extracted with ethyl acetate (“EtOAc”) (2×500 mL). The pale yellow organic was conc'd under vac (40-45° C.) to an orange-yellow oil/gum (83 g). The crude product was purified by extensive silica gel (230-400 mesh) column chromatography (EtOAc/Heptane) followed by crystallization (EtOAc/Heptane). The pure desired diastereomer was isolated as a white granular solid MS+: 355. m.p. 101-102° C. Optical rotation [α]589=+180.10 (in methanol) Elemental analysis results: Obsv'd (Theor.): C, 61.03; (61.01); H, 6.02; (5.97); N, 7.88; (7.91); F, 15.98; (16.08). HPLC analysis: Chiral purity: 100%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24](O)=[O:25])=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:27][CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[NH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O.ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24]([NH:29][CH:30]4[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]4)=[O:25])=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:27][CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)O)s3)C[C@H]2OC)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)s3)C[C@H]2OC)nc1Cl
Yield: 72.6 %

Procedure:
The same operation as in Example (1g) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylic acid obtained in Example (14a) (30 mg, 0.07 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (16 mg, 0.08 mmol), WSC hydrochloride (44 mg, 0.23 mmol), HOBT (16 mg, 0.12 mmol), diisopropylethylamine (0.015 mL, 0.08 mmol), dichloromethane (0.75 mL) and DMA (0.75 mL), to obtain 31 mg of the title compound as a white solid (87%).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:19]1([C:25](Cl)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[NH:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH:8]([C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH3:9])=[O:6])[CH2:10][CH2:11]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(OC(=O)C1CCNCC1)C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred, ice-cooled, solution of ethyl isonipecotate (78.5 g, 0.50 mole) and triethylamine (200 ml, 1.4 mole) in CHCl3 (1000 ml), triphenylmethyl chloride (15.33 g, 0.55 mole) was added. After stirring overnight at room temperature, the reaction mixture was washed with H2O, dried (Na2SO4) and the solvent evaporated. The oily residue was crystallized from MeOH--CHCl3, yielding 108.19 (96 percent) of 4-piperidine carboxylic acid, 1-(triphenylmethyl)ethyl ester as a white solid; mp 154°-155° C.
Reaction SMILES: [OH-].[Na+].C(O)CO.N1(C([N:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([N:27]4[C:35]5[C:30](=[CH:31][C:32]([S:36]([CH2:39][CH2:40][CH3:41])(=[O:38])=[O:37])=[CH:33][CH:34]=5)[CH2:29][CH2:28]4)[CH:22]=3)[CH2:16][CH2:15]2)=O)C=CN=C1>O>[NH:14]1[CH2:15][CH2:16][CH:17]([O:20][C:21]2[N:26]=[CH:25][N:24]=[C:23]([N:27]3[C:35]4[C:30](=[CH:31][C:32]([S:36]([CH2:39][CH2:40][CH3:41])(=[O:38])=[O:37])=[CH:33][CH:34]=4)[CH2:29][CH2:28]3)[CH:22]=2)[CH2:18][CH2:19]1
Reactant: CCCS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCN(C(=O)n3ccnc3)CC2)ncn1
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: CCCS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCNCC2)ncn1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 72.5 %

Procedure:
A 2 N aqueous sodium hydroxide solution (363 mL, 0.726 mmol) was added to an ethylene glycol (3.6 mL) solution of the 1-(6-{[1-(1H-imidazol-1-ylcarbonyl)piperidin-4-yl]oxy}pyrimidin-4-yl)-5-(propylsulfonyl)indoline (180 mg, 0.363 mmol) produced in Reference Example 33, and the mixture was stirred at 100° C. for 2.5 hours. To the reaction solution, water was added, followed by extraction with ethyl acetate three times. The obtained organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as white powder (106 mg, yield: 73%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[CH:14]3)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:32]2[CH:33]=[CH:34][C:29]([CH3:28])=[CH:30][CH:31]=2)[C:15]([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[CH:14]3)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCOCC4)cc3c2)CC1
Product: Cc1ccc(-n2c(C(=O)N3CCOCC3)cc3cc(OC4CCN(C(C)C)CC4)ccc32)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from [5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-morpholin-4-yl-methanone (intermediate 2) and 4-methylbenzeneboronic acid. The title compound was obtained in 57% yield as a yellow foam. MS (m/e): 462.2 (MH+, 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9][CH3:10].C([Li])CCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C>C1COCC1>[CH3:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH3:10])=[C:2]([B:16]([OH:21])[OH:17])[CH:7]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CSc1ccc(C)cc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc(C)cc1B(O)O
Temperature: -78 °C
Reaction time: 0.03 h

Procedure:
(2-Bromo-4-methylphenyl)(methyl)sulfane (700 mg, 3.20 mmol) was dissolved in THF (5.0 mL) and cooled to −78° C. To the cooled solution was added n-butyl lithium (2.2 mL, 3.60 mmol) dropwise. The reaction was stirred for 2 min at −78° C. then the triisopropyl borate (0.82 mL, 3.56 mmol) was added dropwise and the reaction mixture was allowed to warm to 0° C. over a period of approximately 90 min. The reaction was quenched by addition of 1N HCl solution and was stirred for 5 min. The mixture was then extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (1×30 mL), brine (1×30 mL) and dried over MgSO4. The crude product was then triturated with EtOAc and hexanes to give 5-methyl-2-(methylthio)phenylboronic acid. The mother liquor was purified by column chromatography (silica gel, 0 to 30% EtOAc:hexanes) to give more desired product. Mass Spectrum (ESI) m/e=183.1 (M+1).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][OH:10].[F:11][CH2:12][CH2:13][N:14]1[C:19]2[CH:20]=[CH:21][C:22]([O:24][C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=3)[C:28]#[N:29])=[CH:23][C:18]=2[S:17](=[O:34])(=[O:33])[N:16]=[CH:15]1>CS(C)=O>[F:11][CH2:12][CH2:13][N:14]1[C:19]2[CH:20]=[CH:21][C:22]([O:24][C:25]3[CH:26]=[C:27]([C:28](=[N:9][OH:10])[NH2:29])[CH:30]=[CH:31][CH:32]=3)=[CH:23][C:18]=2[S:17](=[O:33])(=[O:34])[N:16]=[CH:15]1
Reactant: NO
Reactant: N#Cc1cccc(Oc2ccc3c(c2)S(=O)(=O)N=CN3CCF)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: NC(=NO)c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=CN3CCF)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
770 μL (5.52 mmol) of triethylamine are added to a solution of hydroxylamine hydrochloride (384 mg, 5.52 mmol) in 1.8 ml of DMSO, and the suspension is stirred for 20 minutes at ambient temperature. The precipitate is filtered off and the filtrate is concentrated in vacuo. To the resulting filtrate there are added 225 mg (0.921 mmol) of the compound of Step A above and the solution is stirred at 75° C. for 4 hours. The reaction mixture is cooled to ambient temperature and the reaction mixture is precipitated from water. A white, non-filterable, gummy paste is obtained which is separated from the aqueous phase by simple decanting. The gum is triturated in ethanol until crystallisation occurs. The solid is filtered off to yield the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].Br[CH2:12][CH2:13][Cl:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:12][CH2:13][Cl:14])([O-:3])=[O:2]
Reactant: ClCCBr
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1OCCCl
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A suspension of 2-nitrophenol (50.0 g, 0.36 mol), 1-bromo-2-chloroethane (45 mL, 0.54 mol), and K2CO3 (100.0 g, 0.72 mol) in DMF (200 mL) was stirred at 90° C. for 2 h, cooled to room temperature, poured into ice-water, filtered, washed with H2O and dried to give Compound 7, 70.3 g (96%) as a yellow solid.
Reaction SMILES: COC1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C(OC)=CC=1.[CH3:21][O:22][C:23]1[C:36]2[C:35](=[O:37])[C:34]3[C:29](=[C:30]([O:40]C)[CH:31]=[CH:32][C:33]=3[O:38]C)[C:28](=[O:42])[C:27]=2[C:26]([O:43][CH3:44])=[CH:25][CH:24]=1>>[CH3:44][O:43][C:26]1[C:27]2[C:28](=[O:42])[C:29]3[C:30](=[O:40])[CH:31]=[CH:32][C:33](=[O:38])[C:34]=3[C:35](=[O:37])[C:36]=2[C:23]([O:22][CH3:21])=[CH:24][CH:25]=1
Reactant: COc1ccc(OC)c2c1C(=O)c1c(OC)ccc(OC)c1C2=O
Agent: COc1ccc(OC)c2c1C(=O)c1ccccc1C2=O
Product: COc1ccc(OC)c2c(=O)c3c(=O)ccc(=O)c=3c(=O)c12

Procedure:
In accordance with the above procedure, but where in place of 1,4-dimethoxyanthraquinone there is utilized 1,4,5,8-tetramethoxyanthraquinone, there is obtained the corresponding 1,4-dimethoxy-5,8,9,10-anthradiquinone as a purple solid, m.p. 277-278; NMR: δ 3.96 (s, 6H), 6.89 (s, 2H), 7.37 (s, 2H); IR: 5.93, 6.10, 6.41 microns.
Reaction SMILES: [ClH:1].Cl.[NH2:3][N:4]1[CH:8]=[N:7][N:6]=[C:5]1[NH:9][NH2:10].[C:11]1([CH3:19])[C:12]([CH:17]=O)=[CH:13][CH:14]=[CH:15][CH:16]=1>C(O)C>[ClH:1].[NH2:3][N:4]1[CH:8]=[N:7][N:6]=[C:5]1[NH:9][N:10]=[CH:19][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: Cc1ccccc1C=O
Reactant: NNc1nncn1N
Agent: Cl
Solvent: CCO
Product: Cc1ccccc1C=NNc1nncn1N

Procedure:
To a solution of 14.0 g (0.075 mole) of 4-amino-3-hydrazino-1, 2,4-triazole dihydrochloride in 200 ml of 75 percent ethanol was added 9.0 g (0.075 mole) of o-tolualdehyde. The mixture was stirred and heated at reflux for 1.5 hour. The solution was cooled and the precipitate formed collected by filtration and washed with ether. Yield: 18.4 g, m.p. 230°-232° (D). After recrystallization from aqueous ethanolisopropyl ether the product melts at 233°-234° (D).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:3]1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:21]([CH:24]=1)[C:22]#[N:23].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:22]([C:21]1[CH:24]=[C:17]([NH:16][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:5]=2)=[O:9])[CH:18]=[CH:19][C:20]=1[O:25][CH2:26][C:27]([CH3:29])([CH3:28])[CH3:30])#[N:23]
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Reactant: Cn1nc(-c2ccccc2)cc1C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1nc(-c2ccccc2)cc1C(=O)Nc1ccc(OCC(C)(C)C)c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.7 %

Procedure:
1-Methyl-3-phenylpyrazole-5-carboxylic acid (0.8 g), 5-amino-2-neopentyloxybenzonitrile (0.8 g), triethylamine (1.2 g) and diethyl cyanophosphate (1.0 g) were added to dimethylformamide (10 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from hydrous methanol to give the title compound (0.3 g), melting point: 223–224° C.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([CH2:11][P:12](=[O:17])([O:15]C)[O:13]C)(O)=[O:9].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH:1]1([NH:7][C:8]([CH2:11][P:12](=[O:13])([OH:17])[OH:15])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COP(=O)(CC(=O)O)OC
Reactant: NC1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CP(=O)(O)O)NC1CCCCC1
Yield: 57 %

Procedure:
Cyclohexyl amine (0.045 mole) and dimethyl (carboxymethyl)phosphonate (0.04 mole) were dissolved in 100 ml. of methylene chloride. As the solution was stirred, dicyclohexylcarbodiimide (0.045 mole) was added portionwise. The solution was stirred overnight and the mixture filtered. The filtrate was concentrated to a solid and the solid recrystallized from an appropriate solvent such as methanol. m.p. 180°-3° C.; yield 57%.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[C:17]([S:19]([C:22]1[CH2:26][C:25]([CH3:28])([CH3:27])[O:24][N:23]=1)(=[O:21])=[O:20])=[CH2:18]>CS(C)=O>[F:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[C:11]=1[C:17]1([S:19]([C:22]2[CH2:26][C:25]([CH3:28])([CH3:27])[O:24][N:23]=2)(=[O:20])=[O:21])[CH2:2][CH2:18]1
Reactant: C[S+](C)(C)=O
Reactant: C=C(c1c(F)cccc1F)S(=O)(=O)C1=NOC(C)(C)C1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C)CC(S(=O)(=O)C2(c3c(F)cccc3F)CC2)=NO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
Trimethylsulfoxonium iodide (0.28 g, 1.25 mmol) was added to a suspension of sodium hydride (60% by weight in paraffin oil) (0.052 g, 1.3 mmol) in DMSO (4 ml). The mixture was stirred for 30 minutes at room temperature. A solution of 3-[1-(2,6-difluoro-phenyl)-ethenesulfonyl]-5,5-dimethyl-4,5-dihydroisoxazole (prepared according to Example P12) (80% purity) (0.3 g, 0.8 mmol) in DMSO (2 ml) was added dropwise. The mixture was stirred at room temperature for 1 hour. The reaction was quenched by addition of saturated aqueous ammonium chloride solution and the mixture was extracted several times with diethyl ether. The combined organic phases were dried over magnesium sulfate and concentrated. Purification by chromatography on silica gel (eluent: ethyl acetate/hexane) gave the product (Compound No. 1.01 in Table 27) (70 mg, 28% yield).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([O:20]C)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[OH-].[Li+]>O1CCCC1>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.7 %

Procedure:
To a solution of 100 mg (0.345 mmol) of (2S,5R)-methyl 6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate in tetrahydrofuran (3 mL) was added water (3 mL), followed by cooling to 0° C., and 15.2 mg (0.362 mmol) of lithium hydroxide monohydrate was added, followed by stifling at the same temperature for 15 minutes. The reaction mixture was washed with ethyl acetate, and the aqueous layer was made acidic with saturated aqueous sodium dihydrogen phosphate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and subsequently the solvent was concentrated under reduced pressure to afford 93.1 mg of the title compound as a colorless foamy solid (yield 98%). Instrumental data were consistent with those of Example 9.