Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:6]([N+]([O-])=O)=[N:7][CH:8]=[CH:9][CH:10]=1.CC1(C)[O:19][CH2:18][CH:17]([CH2:20][OH:21])[O:16]1>CN(C)P(=O)(N(C)C)N(C)C>[CH3:3][O:4][C:5]1[C:6]([O:19][CH2:18][CH:17]([OH:16])[CH2:20][OH:21])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: COc1cccnc1[N+](=O)[O-]
Reactant: CC1(C)OCC(CO)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1cccnc1OCC(O)CO
Reaction time: 15 h

Procedure:
26.5 g of sodium hydride are added in the course of one hour to a mixture of 161 g of 3-methoxy-2-nitropyridine and 144 g of 2,2-dimethyl-5-hydroxymethyl-1,3-dioxolane in 1,000 ml of hexamethylphosphoric acid triamide, with stirring; by means of cooling, the temperature is kept at 0°-10° during the addition. The reaction mixture is then stirred for a further 5 hours with ice-cooling and then for 15 hours at room temperature. The reaction mixture is poured onto ice and extracted with diethyl ether. The organic extract is washed with a concentrated aqueous solution of sodium chloride, dried and evaporated. The residue is dissolved in 1,000 ml of ethanol, 100 ml of 2 N hydrochloric acid are added and the mixture is left to stand for 8 hours. After evaporating off the solvent, the residue is rendered alkaline with a concentrated solution of sodium hydroxide in water and extracted with ethyl acetate. Evaporating off the solvent yields a crude product from which crystalline 3-(3-methoxy-2-pyridyloxy)-1,2-propanediol with a melting point of 62°-65° is obtained on the addition of diethyl ether.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[ClH:7].[C:8]([C:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[N:24]=[CH:23][CH:22]=[CH:21]3)[CH:12]=1)(O)=[O:9]>ClCCl>[ClH:4].[Cl:7][C:8]([C:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[N:24]=[CH:23][CH:22]=[CH:21]3)[CH:12]=1)=[O:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccn(-c2cccc3cccnc23)c1
Agent: Cl
Solvent: ClCCl
Product: O=C(Cl)c1ccn(-c2cccc3cccnc23)c1
Temperature: 22 °C
Reaction time: 15 h
Yield: 86.9 %

Procedure:
0.45 mL (5.16 mmol) of oxalyl chloride is added to a solution, cooled to a temperature in the region of 5° C., of 0.45 g (1.64 mmol) of 3-carboxy-1-(quinol-8-yl)-1H-pyrrole hydrochloride in 20 mL of dichloromethane under an argon atmosphere. After stirring at a temperature in the region of 22° C. for 15 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), then it is placed under an argon atmosphere and 20 mL of dichloromethane and 0.45 mL (5.16 mmol) of oxalyl chloride are successively added. After stirring at a temperature in the region of 22° C. for 15 hours, concentrating the reaction medium to dryness under reduced pressure (2.7 kPa) gives 0.418 g of 3-chlorocarbonyl-1-(quinol-8-yl)-1H-pyrrole hydrochloride in the form of a cream-coloured solid which is used directly in the following step.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][C:4](=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[C:3]1=[O:15].[OH-].[K+].[I-].[K+].[CH3:20]Cl>C(O)(C)(C)C>[CH3:1][C:2]1([CH3:20])[CH2:6][CH2:5][C:4](=[CH:7][C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)[C:3]1=[O:15]
Reactant: CCl
Reactant: CC1CCC(=Cc2ccc(Cl)cc2)C1=O
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: CC1(C)CCC(=Cc2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 23 h
Yield: 100.1 %

Procedure:
106 g of 2-methyl-5-(4-chlorobenzylidene)-cyclopentanone, 49.5 g of 85% strength aqueous potassium hydroxide solution, 8.3 g of potassium iodide and 400 g of tert-butanol were weighed in succession into a 700 ml stainless steel autoclave, and 50.5 g of methyl chloride were injected at 20° C. The mixture was stirred at room temperature for 23 hours and then 300 ml of tert-butanol were distilled off at 20 mbar up to an overhead temperature of max. 50° C. 400 ml of water were added to the residue, and the mixture was stirred thoroughly. The resulting suspension was filtered off over a suction filter, and the filter cake was washed twice with 200 ml of water each time and dried. 112.8 g of a pale beige solid were thus obtained with a purity of 89.5%. The yield of the crude product was 90.2% of theory.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[C:8](=[NH:18])(OCC)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O.CO>[C:8]([NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[NH:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=N)c1ccccc1
Reactant: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N=C(NCC(=O)O)c1ccccc1
Temperature: 25 °C

Procedure:
A white suspension of glycine (3.81 g, 50 mmol) in water (0.9 g) and methanol (16 ml) was stirred at room temperature, adjusted to pH 9.6 by the addition of sodium hydroxide solution and admixed with ethyl benzimidate (7.69 g, 50 mmol). The mixture was heated for 1 hour at 50° C. and allowed to cool at room temperature. The solid was filtered off, washed with toluene and dried at room temperature/30 mbar. The yield of the title compound was 6.81 g (approximately 95 percent pure by H-NMR), 74 percent based on glycine. Other data concerning the title compound was:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH3:31][C:32]([CH3:34])=O>>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH:32]([CH3:34])[CH3:31])[CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: O=C(NC(COCC1CCNCC1)c1ccccc1F)c1ccc2c(Cl)c[nH]c2c1
Reactant: CC(C)=O
Product: CC(C)N1CCC(COCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccc2F)CC1
Yield: 77.6 %

Procedure:
Using alkylation method A, 3-chloro-N-[1-(2-fluoro-phenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (303 mg, 0.71 mmol) and acetone (2 mL, 27 mmol) afforded 260 mg (78%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16]CC3C=CC(OC)=CC=3)[CH:11]=2)=[CH:4][CH:3]=1.C(OC1C=CN([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][N:49]3[CH2:53][CH2:52][CH2:51][CH2:50]3)=[CH:42][CH:41]=2)C(=O)C=1)C1C=CC=CC=1.FC1C=CC(/C=C/C2C=CNC(=O)C=2)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][N:13]([C:40]3[CH:41]=[CH:42][C:43]([O:46][CH2:47][CH2:48][N:49]4[CH2:50][CH2:51][CH2:52][CH2:53]4)=[CH:44][CH:45]=3)[C:12](=[O:16])[CH:11]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(COc2cc(/C=C/c3ccc(F)cc3)ccn2)cc1
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc(OCCN2CCCC2)cc1
Agent: O=c1cc(/C=C/c2ccc(F)cc2)cc[nH]1
Product: O=c1cc(/C=C/c2ccc(F)cc2)ccn1-c1ccc(OCCN2CCCC2)cc1

Procedure:
Operations similar to Steps (1), (2) and (3) of Example 12 were conducted except that 4-[(E)-2-(4-fluorophenyl)vinyl]-1H-pyridin-2-one was used in place of 4-benzyloxy-1H-pyridin-2-one in Example 12, to provide the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N+:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])([O-:22])=[O:21].O1CCOCC1>N1CCCCC1.C(O)C>[N+:20]([CH:23]([CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH2:11][C:12](=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])([O-:22])=[O:21]
Reactant: O=C(C=Cc1cccc([N+](=O)[O-])c1)c1ccccc1
Reactant: CCOC(=O)C[N+](=O)[O-]
Solvent: C1CCNCC1
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)C(C(CC(=O)c1ccccc1)c1cccc([N+](=O)[O-])c1)[N+](=O)[O-]
Temperature: 25 °C
Yield: 19.7 %

Procedure:
A mixture of 3-(3-nitrophenyl)-1-phenyl-2-propen-1-one (0.5 g), ethyl nitroacetate (0.29 g), piperidine (3 drops), dioxane (5 ml) and ethanol (5 ml) was refluxed for 2 hours. After allowing to cooling at ambient temperature, the reaction mixture was evaporated in vacuo. The residue was subjected to a column chromatography on silica gel (50 ml) eluting with benzene. The fractions containing the object compound were combined and concentrated under reduced pressure to give ethyl 2-nitro-3-(3-nitrophenyl)-5-oxo-5-phenylpentanoate (0.15 g).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:15])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH3:7]>O1CCCC1.O.CO>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([CH:6]([CH3:7])[C:5]([OH:15])=[O:4])=[CH:13][CH:12]=1
Reactant: COC(=O)C(C)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C(=O)O)c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
Lithium hydroxide (0.17 g, 7.10 mmol) was added to a stirred solution of 2-(4-chloro-phenyl)-propionic acid methyl ester (0.47 g, 2.366 mmol) in tetrahydrofuran, water and methanol (4:1:1, 12 ml). The mixture was stirred overnight and the volatiles evaporated in vacuo. The mixture was basified by addition of aqueous sodium hydrogencarbonate and washed with ethyl acetate. The aqueous was then acidified with 2M HCl and the product extracted into ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the desired product. Yield 0.4 g, 91%. NMR 1H (300 MHz, DMSO): 1.36 (d, 3H), 3.72 (q, 1H), 7.23-7.38 (m, 4ArH), 12.48 (bs, 1H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[N:12]=[C:11]([NH2:13])[S:10][N:9]=1)[C:5]([OH:7])=O.P(Cl)(Cl)(Cl)=O.[NH2:19][CH:20]1[C:38](=[O:39])[N:22]2[C:23]([C:35]([OH:37])=[O:36])=[C:24]([CH:27]([S:29][C:30]3[NH:34][N:33]=[N:32][N:31]=3)[CH3:28])[CH2:25][S:26][C@H:21]12.C[Si](CC(N)=O)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C)C=O>[CH3:1][O:2][N:3]=[C:4]([C:8]1[N:12]=[C:11]([NH2:13])[S:10][N:9]=1)[C:5]([NH:19][CH:20]1[C:38](=[O:39])[N:22]2[C:23]([C:35]([OH:37])=[O:36])=[C:24]([CH:27]([S:29][C:30]3[NH:31][N:32]=[N:33][N:34]=3)[CH3:28])[CH2:25][S:26][C@H:21]12)=[O:7]
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CON=C(C(=O)O)c1nsc(N)n1
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.3 %

Procedure:
A mixture of 2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (100 mg) and phosphorus oxychloride (306 mg) in methylene chloride (5 ml) was stirred for 30 minutes at ambient temperature. To the mixture was added N,N-dimethylformamide (0.2 ml) under cooling in an ice-bath, followed by stirring for 30 minutes. A mixture of 7-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (300 mg) and trimethylsilylacetamide (0.9 g) in methylene chloride (9 ml) was warmed to make a clear solution. The solution was cooled in an ice-bath and added to the above obtained solution, followed by stirring for 30 minutes at 0° C. The reaction mixture was poured into a cold aqueous solution of sodium bicarbonate. The aqueous layer was separated, adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated with diethyl ether to give a crude product of the title compound (120 mg). The crude material was dissolved in an aqueous solution of sodium bicarbonate and reprecipitated with diluted hydrochloric acid to give the pure title compound (60 mg), mp. 170° to 175° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[N+:12]=[N-:13])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[C:15]#[CH:16]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:12]([N:13]=[C:15]([C:14]([O:18][CH2:19][CH3:20])=[O:17])[CH:16]=3)[C:7](=[O:11])[N:8](/[CH:16]=[CH:15]\[C:14]([O:18][CH2:19][CH3:20])=[O:17])[C:9]=2[CH:10]=1
Reactant: C#CC(=O)OCC
Reactant: [N-]=[N+]=C1C(=O)Nc2cc(Cl)ccc21
Solvent: Cc1ccccc1C
Product: CCOC(=O)/C=C\n1c(=O)n2nc(C(=O)OCC)cc2c2ccc(Cl)cc21
Temperature: 25 °C
Yield: 59 %

Procedure:
7.5 g (0.039 mole) of 6-chloro-3-diazooxindole is suspended in 400 ml of xylene and 8.4 g (0.086 mole) of ethyl propiolate added. The reaction mixture is heated 7 hours in a 160° silicone oil bath under nitrogen. A brown solid forms on cooling to room temperature (9.0 g, 59% yield). Recrystallization from dichloromethanemethanol gives 8.5 g of analytically pure title compound, m.p. 215°-217°.
Reaction SMILES: S[C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:5]=2[N:6]=1.O=P(Cl)(Cl)[Cl:14].P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[Cl:14][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:5]=2[N:6]=1
Reactant: Fc1ccc2oc(S)nc2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: Fc1ccc2oc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 86.9 %

Procedure:
The 2-mercapto-5-fluorobenzoxazole (2.0 g, 11.8 mmol) is slurried into POCl3 (9.7 mL, 104 mmol). The slurry is treated with PCl5 (3.0 g, 14.2 mmol) and 5.0 mL of anhydrous CH2Cl2. The mixture is stirred at room temperature for 5.5 hours. After this time excess POCl3 is removed under reduced pressure. The residue is treated with saturated aqueous NaHCO3 and the mixture is poured into a separatory funnel. The mixture is extracted with EtOAc and the combined extracts are washed with brine and dried over anhydrous Na2SO4. Filtration and concentration gives 1.76 g of 2-chloro-5-fluorobenzoxazole as a waxy solid. The crude chloride is used in the piperazine displacement reaction.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=2)=[CH:3]1.[C:23](OC=C)(=[O:25])[CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(O)=O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CC(CC(C)C)=O>[C:23]([O:1][C@@H:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=2)=[CH:3]1)(=[O:25])[CH3:24]
Reactant: C=COC(C)=O
Reactant: O=C1CC(O)C=C1Cc1cccc(OCc2ccccc2)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: CC(=O)CC(C)C
Product: CC(=O)O[C@H]1C=C(Cc2cccc(OCc3ccccc3)c2)C(=O)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
4-Hydroxy-2-(3-Benzyloxybenzyl)cyclopent-2-enone (2.1 kg, 7.14 mol) was dissolved in isobutyl methyl ketone (21 L), and vinyl acetate (4.2 kg, 51.16 mol) and Lipase derived from Pseudomonas cepacia (210 g) was added to the solution, and the mixture was stirred at room temperature for 1 day. The reaction mixture was filtered to remove Lipase and the filtrate was evaporated. The resulting residue was dissolved in PhCH3 (20 L), and triphenylphosphine (625 g, 2.38 mol) and AcOH (145 g, 2.41 mol) was added to the solution. Then diisopropylazodicarboxylate (413 g, 2.04 mol) was added to the mixture at 5° C. After the reaction was completed, the reaction mixture was filtered to remove the precipitate and the filtrate was evaporated. The residue was dissolved in EtOAc (5 L) and hexane (5 L) was added. The mixture was stirred at room t temperature overnight. The mixture was filtered to remove the precipitate and the filtrate was evaporated. The residue was purified by chromatography on a silica gel column using hexane-EtOAc as eluent to give the (R)-3-(3-benzyloxybenzyl)-4-oxocyclopent-2-enyl acetate as yellow oil: 1.8 kg (yield: 75%, 97% ee by HPLC using a chiral column)
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:27][C:28](=[O:50])[CH2:29][NH:30][C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:4]=[N:3]1.[H-].[Na+].[CH3:53]I.O>CN(C)C=O>[CH3:53][N:27]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[NH:7][C:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:28](=[O:50])[CH2:29][NH:30][C:31]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: CI
Reactant: Cn1ncc(NC(=O)CNC(c2ccccc2)(c2ccccc2)c2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)CNC(c1ccccc1)(c1ccccc1)c1ccccc1)c1cnn(C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
To a stirred solution of N-[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]-2-(tritylamino)acetamide (2 g) in N,N-dimethylformamide (20 ml) was added sodium hydride (245 mg, 60% oil suspension) at 0° C., and the mixture was stirred for 30 minutes with warming to room temperature. The mixture was cooled to 0° C., and methyl iodide (1.3 g) was added. The whole mixture was stirred at room temperature overnight. Water (5 ml) was added, and the whole mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave N-methyl-N-[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]-2-(tritylamino)acetamide (2.05 g).
Reaction SMILES: [N+:1]([O-])([O-])=O.[Na+].[NH2:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[NH:17][C:18]1[CH:32]=[CH:31][C:21]([O:22][CH:23]([CH2:29][CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][CH:19]=1>O.Cl>[F:14][C:13]([F:16])([F:15])[C:11]1[CH:10]=[CH:9][C:8]2[N:17]([C:18]3[CH:19]=[CH:20][C:21]([O:22][CH:23]([CH2:29][CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:31][CH:32]=3)[N:1]=[N:6][C:7]=2[CH:12]=1
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)C(CC)Oc1ccc(Nc2ccc(C(F)(F)F)cc2N)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(CC)Oc1ccc(-n2nnc3cc(C(F)(F)F)ccc32)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 2.1 g of sodium nitrate in 10 ml of water was added drop-by-drop to a stirred solution of 5.0 g of 3B in 150 ml of 12% hydrochloric acid at 5° C. The resulting mixture was stirred at room temperature for 2 days, diluted with 100 ml of water and extracted with ether. The ether was evaporated from the extract and the residue was chromatographed over silica gel, using as eluent a 20/4/1 v/v/v mixture of hexane, ethyl acetate and tetrahydrofuran, to give 3, as a reddish syrupy liquid.
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[N:2]1.C(N(C(C)C)CC)(C)C.[CH3:39][N:40]1[CH:44]=[C:43]([S:45](Cl)(=[O:47])=[O:46])[N:42]=[C:41]1[CH3:49]>C(Cl)Cl>[S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[S:45]([C:43]2[N:42]=[C:41]([CH3:49])[N:40]([CH3:39])[CH:44]=2)(=[O:47])=[O:46])=[N:2]1
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Reactant: COc1ccc(-c2ccc(CNCCCNc3nsc4ncccc34)cc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2ccc(CN(CCCNc3nsc4ncccc34)S(=O)(=O)c3cn(C)c(C)n3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
N1-(Isothiazolo[5,4-b]pyridin-3-yl)-N3-((4′-methoxybiphenyl-4-yl)methyl)propane-1,3-diamine (100 mg, 0.25 mmol) was dissolved in anhydrous methylene chloride with diisopropylethylamine (0.11 mL, 0.63 mmol). The mixture was cooled in an ice-bath under nitrogen and a solution of 1,2-dimethylimidazole-4-sulfonyl chloride (58.4 mg, 0.30 mmol) in methylene chloride (5 mL) was added dropwise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride and then washed successively with saturated sodium bicarbonate solution and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-scale reverse phase high performance liquid chromatography to yield N-(3-(isothiazolo[5,4-b]pyridin-3-ylamino)propyl)-N-((4′-methoxybiphenyl-4-yl)methyl)-1,2-dimethyl-1H-imidazole-4-sulfonamide (45 mg). 1H NMR (300 MHz, DMSO-d6): 8.64-8.66 (d, 1H), 8.45-8.50 (d, 1H), 7.52-7.75 (m, 8H), 7.28 (s, 1H), 6.95 (s, 1H), 6.82 (s, 1H), 3.99 (s, 2H), 3.89 (s, 3H), 3.55-3.65 (m, 5H), 2.88-2.90 (t, 2H), 2.50 (s, 3H), 1.99-2.10 ppm (t, 2H). MW=563 confirmed by LC-MS, tr=4.31 min (Method E) MH+=564.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:23]([F:24])=[CH:22][C:18]([C:19]([OH:21])=O)=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:28]1[CH2:33][CH2:32][CH:31]([N:34]2[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[CH2:37][O:36][C:35]2=[O:44])[CH2:30][CH2:29]1>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[C:23]([F:24])=[CH:22][C:18]([C:19]([N:28]3[CH2:29][CH2:30][CH:31]([N:34]4[C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=5[CH2:37][O:36][C:35]4=[O:44])[CH2:32][CH2:33]3)=[O:21])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c(F)cc1C(=O)O
Reactant: O=C1OCc2ccccc2N1C1CCNCC1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c(F)cc1C(=O)N1CCC(N2C(=O)OCc3ccccc32)CC1

Procedure:
4-(N-t-butyloxycarbonyl-4-piperidinyloxy)-5-fluoro-2-methoxybenzoic acid from step 6 above and 1-(4-piperidinyl)-4H-3,1-benzoxazin-2(1H)-one hydrochloride from step 3 of Example 1 were coupled using the procedure given in step 6 of Example 1. 1-(1-(4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-5-fluoro-2-methoxy-benzoyl) piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one was obtained as an amorphous solid (TLC Rf = 0.17 (4:1 EtOAc:hexanes); HPLC (method A) retention time= 9.8 min); FAB MS m/z 584 (M+ +H)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)([CH3:22])[C:9]([CH:11]([C:17]([O:19]CC)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10])=[CH:4][CH:3]=1>OS(O)(=O)=O>[Cl:29][C:26]1[CH:25]=[C:24]2[C:23](=[CH:28][CH:27]=1)[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)([CH3:22])[C:9](=[O:10])[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:17]2[OH:19]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(c2ccc(Cl)cc2)C1=O
Reaction time: 0.25 h
Yield: 81 %

Procedure:
A solution of diethyl 2-(2,2-bis(4-chlorophenyl)propanoyl)malonate (2.00 g, 4.57 mmol) in H2SO4, 36N (10.0 mL, 180 mmol) in a 500 mL round bottom flask was stirred at 25° C. for 30 minutes. The reaction was quenched by adding 400 mL of ice and 100 mL of EtOAc and then stirring for 15 minutes. The layers were separated, and the aqueous solution was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (100 mL). The organic layer was then dried over MgSO4 and concentrated in vacuo to give 2.24 g of crude product which was purified by flash column chromatography (silica, 0-100% DCM in hexane) to give the title compound (1.448 g). MS m/e=391 (M+H)+.