Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:6][CH2:5][CH2:4][O:3]1.[OH-].[Na+].[C:13](=[S:15])=[S:14].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH2:16]([SH:14]=[C:13]([N:6]1[CH2:5][CH2:4][O:3][C:2]1([CH3:1])[C:7]([CH3:10])([CH3:9])[CH3:8])[SH:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: S=C=S
Reactant: ClCc1ccccc1
Reactant: CC(C)(C)C1(C)NCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)C1(C)OCCN1C(S)=[SH]Cc1ccccc1
Reaction time: 2 h

Procedure:
28.6 g (0.2 mole) of 2-methyl-2-(tert.butyl)-oxazolidine and 8.0 g (0.2 mole) of sodium hydroxide dissolved in 80 cm3 of water were placed into a round-bottom flask equipped with a reflux condenser, a thermometer, a dropping funnel and a stirrer. With continuous stirring and cooling, 15.2 g (12.05 cm3, 0.2 mole) of carbon disulphide was introduced dropwise while the temperature was not allowed to rise above 20° C. As the introduction of carbon disulphide had been completed, the mixture was continued to stir at room temperature for 2 hours. Under cooling and stirring, 25.2 g (22.96 cm3, 0.2 mole) of benzylchloride was added dropwise below 10° C. Stirring was continued for 2 hours after the introduction had been completed. The organic layer was separated from the aqueous one and the latter was extracted by chloroform. The unified organic phases were washed with water, dried above sodium sulphate, and then the solvent was distilled off. Yield: 36.8 g (61.8%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[O:6]1[C:11]([C:12](=[N:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:13]([OH:15])=O)=[CH:10][S:9][CH2:8][CH2:7]1.[NH2:24][CH:25]1[C:42](=[O:43])[N:27]2[C:28]([C:39]([OH:41])=[O:40])=[C:29]([CH2:32][S:33][C:34]3[S:35][CH:36]=[N:37][N:38]=3)[CH2:30][S:31][C@H:26]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.CN(C)C=O>[O:6]1[C:11]([C:12](=[N:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:13]([NH:24][CH:25]2[C:42](=[O:43])[N:27]3[C:28]([C:39]([OH:41])=[O:40])=[C:29]([CH2:32][S:33][C:34]4[S:35][CH:36]=[N:37][N:38]=4)[CH2:30][S:31][C@H:26]23)=[O:15])=[CH:10][S:9][CH2:8][CH2:7]1
Reactant: CCCCCCON=C(C(=O)O)C1=CSCCO1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)C1=CSCCO1
Yield: 77.6 %

Procedure:
Phosphoryl chloride (1.214 g.), N,N-dimethylformamide (0.579 g.) and ethyl acetate (3 ml.) were treated in a conventional manner to give a Vilmeier reagent. To the solution were added ethyl acetate (7 ml.) and 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-hexyloxyiminoacetic acid (syn isomer, 2.18 g.) and treated in a similar manner to that of Example 24 to give an activated acid solution. The solution was added to a solution of 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (2.18 g.) and trimethylsilylacetamide (6.93 g.) in ethyl acetate (50 ml.), and the mixture was treated in a similar manner to that of Example 24 to give 7-[2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-hexyloxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 3.00 g.)
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH:31]=[O:32].O>C1COCC1>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:31]([C:30]1[CH:33]=[CH:34][CH:35]=[C:28]([F:27])[CH:29]=1)[OH:32])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1ccccc1OCc1ccccc1
Reactant: O=Cc1cccc(F)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: OC(c1cccc(F)c1)c1ccccc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (2.44 M, 5.65 mL) was added dropwise to a solution of 1-benzyloxy-2-bromobenzene (3.3 g, 12.5 mmol) in THF (40 mL) at −78° C. and the mixture solution was stirred at the same temperature for 30 minutes. To this mixture, a solution of 3-fluorobenzaldehyde (1.40 g, 11.3 mmol) in THF (5 mL) was added dropwise at −78° C. The reaction mixture was stirred at the same temperature for one hour, and then water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:10)] to obtain the title compound (2.26 g, 65%).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[C:10]([OH:12])=O.[ClH:13].Cl.[NH2:15][C@@H:16]1[CH:21]2[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]2)[CH2:17]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[ClH:13].[N:18]12[CH2:23][CH2:22][CH:21]([CH2:20][CH2:19]1)[C@@H:16]([NH:15][C:10]([C:2]1[NH:3][C:4]3=[N:5][CH:6]=[CH:7][CH:8]=[C:9]3[N:1]=1)=[O:12])[CH2:17]2
Reactant: O=C(O)c1nc2cccnc2[nH]1
Reactant: N[C@H]1CN2CCC1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1nc2cccnc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To 3H-imidazo[4,5-b]pyridine-2-carboxylic acid (90 mg, 0.55 mmol) in DMF (4 mL) is added (R)-(+)-3-aminoquinuclidine dihydrochloride (0.11 g, 0.56 mmol), DIEA (0.25 g, 0.35 mL, 1.9 mmol) and HATU (0.21 g, 0.56 mmol). The mixture is stirred overnight at rt, diluted with CH2Cl2 (50 mL) and washed with 1 N NaOH (2×50 mL) followed by sat. aq. NaHCO3 (50 mL). The material is purified by passage through acidic ion exchange resin. The free base is taken up in 3 M HCl/MeOH (10 mL) and stirred for 1.5 hr. Isopropanol and Et2O are added and the solid is isolated by vacuum filtration to afford Example 1004 in 57% yield. MS for C14H17N5O: 272 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]([NH:15][OH:16])=[NH:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH:17](OC)(OC)OC.B(F)(F)F.CCOCC>CO>[O:16]1[CH:17]=[N:14][C:13]([C:4]2[S:3][C:2]([NH2:1])=[N:6][C:5]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:15]1
Reactant: N=C(NO)c1sc(N)nc1-c1ccccc1
Reactant: COC(OC)OC
Agent: FB(F)F
Solvent: CO
Solvent: CCOCC
Product: Nc1nc(-c2ccccc2)c(-c2ncon2)s1

Procedure:
2-Amino-N-hydroxy-4-phenyl-thiazole-5-carboxamidine (1.0 g, 4.3 mmol) was dissolved in methanol (20 mL), and trimethyl orthoformate (1.2 mL, 11 mmol) containing boron trifluoride etherate (0.2 mL, 1.6 mmol) was added End the mixture was heated at reflux for 3 h. The reaction mixture was cooled, and the solvent was removed under reduced pressure at 20° C. The residue was extracted with ethyl acetate, and the solution was washed with saturated aqueous NaHCO3 dried over sodium sulfate and evaporated. The crude product was purified by flash column chromatography, eluted with the gradient of 10-18% ethyl acetate in hexanes to get the product (the product was eluted by 18% ethyl acetate in hexanes). Yield: 0.1 g, 10%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1B(O)O.[N+:14]([C:17]1[CH:18]=[CH:19][C:20](Br)=[C:21]([CH:26]=1)[C:22]([O:24][CH3:25])=[O:23])([O-:16])=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=2[O:9][CH3:10])=[C:21]([CH:26]=1)[C:22]([O:24][CH3:25])=[O:23])([O-:16])=[O:15]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Reactant: COc1cccc(OC)c1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1c(OC)cccc1OC
Temperature: 23 °C
Reaction time: 2 h

Procedure:
A mixture of Example 1A, methyl 5-nitro-2-bromobenzoate (25.8 g, 99.2 mmol), (21.7 g, 119 mmol), cesium carbonate (97.1 g, 298 mmol), and dichlorobis(triphenylphosphine)palladium(II) (3.5 g, 5.0 mmol) in DMF (300 mL) was stirred for 24 hours at 80° C., cooled to 23° C., treated with water (600 mL), and extracted with ethyl acetate. The extract was dried (Na2SO4), filtered, and concentrated, during which a light yellow solid precipitated. The mixture was placed in a freezer (−20° C.) for 2 hours and filtered to provide the desired compound. MS (DCI/NH3) m/z 318 (M+H)+and 335 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[CH:5][S:4][N:3]=1.[F:8][S:9]([O:12][CH3:13])(=[O:11])=[O:10]>>[F:8][S:9]([O-:12])(=[O:11])=[O:10].[Cl:1][C:2]1[C:6]([Cl:7])=[CH:5][S:4][N+:3]=1[CH3:13]
Reactant: Clc1csnc1Cl
Reactant: COS(=O)(=O)F
Product: C[n+]1scc(Cl)c1Cl
Product: O=S(=O)([O-])F
Yield: 63 %

Procedure:
3,4-Dichloroisothiazole (3.1 g, 0.02 mol) and 4 ml of methyl fluorosulfonate were heated at 40° for 15 min under a nitrogen atmosphere. The resulting solid was washed with ether and benzene to yield 3.4 g (63%) of 3,4-dichloro-2-methylisothiazolium fluorosulfonate, mp 159-164. Analysis--Calculated for C4H4Cl2FNO3S2 : C, 17.90; H, 1.49; Cl, 26.45; F, 7.90; N, 5.22. Found C, 17.74; H, 1.49; Cl, 26.49; F, 7.24; N, 5.13.
Reaction SMILES: Br[C:2]12[CH2:9][CH2:8][C:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.[C:15]1([CH:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>[N+](C1C=CC=CC=1)([O-])=O.ClCCl.[Fe](Cl)(Cl)Cl>[CH2:10]([C:5]12[CH2:8][CH2:9][C:2]([C:18]3[CH:19]=[CH:20][C:15]([CH:21]4[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]4)=[CH:16][CH:17]=3)([CH2:3][CH2:4]1)[CH2:7][CH2:6]2)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCC12CCC(Br)(CC1)CC2
Reactant: O=C1CCC(c2ccccc2)CC1
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCCCC12CCC(c3ccc(C4CCC(=O)CC4)cc3)(CC1)CC2
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 66.6 %

Procedure:
A solution of 1-bromo-4-pentylbicyclo[2.2.2]octane (6 g, 23 mmol) in sieve-dried nitrobenzene (100 cm3) is added dropwise to a stirred solution of 4-phenylcyclohexanone (3.9 g, 23 mmol) and anhydrous iron(III)chloride (1.2 g, 9 mmol) in sieve-dried nitrobenzene (100 cm3) maintained at 80° C. through the addition and overnight. The cooled solution is added to a small volume of hydrochloric acid and stirred for 20 min. The organic layer is separated off and steam-distilled to yield a solid residue. This is taken up in dichloromethane and dried (MgSO4). The raw product is crystallised from ethanol to yield the desired 4-[4-(4-pentylbicyclo[2.2.2]octyl)phenyl]cyclohexanone (5.4 g, 69%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH:22]1[CH2:27][CH2:26][CH2:25][N:24]([C:28](=[O:30])[CH3:29])[CH2:23]1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH:22]2[CH2:27][CH2:26][CH2:25][N:24]([C:28](=[O:30])[CH3:29])[CH2:23]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)N1CCCC(O)C1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Product: CC(=O)N1CCCC(Oc2ccccc2N2CCN(C(=O)OC(C)(C)C)CC2)C1

Procedure:
The title compound was prepared by using mitsonobu condition from 4-(2-hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester and 1-(3-Hydroxy-piperidin-1-yl)-ethanone.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10](O)=[O:11])(=[O:4])=[O:3].[CH3:15][NH2:16].O1CCCC1>ClCCl>[NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([NH:16][CH3:15])=[O:11])(=[O:4])=[O:3]
Reactant: CN
Reactant: NS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)c1cc(S(N)(=O)=O)ccc1F
Reaction time: 16 h
Yield: 23 %

Procedure:
To a suspension of 5-(aminosulfonyl)-2-fluorobenzoic acid [prepared according to Chem. Pharm. Bull. 1995, 43(4), 582-7] (3.0g, 13.7mmol) in dichloromethane (100 mL) at room temperature under nitrogen was added 1-(3-dimethylaminopropyl)-3-ethylcarbodlimide hydrochloride (WSCDI) (2.89 g, 15.06 mmol) followed by a solution of methylamine in tetrahydrofuran (2 M, 8.21 mL, 16.42 mmol), dropwise and the reaction allowed to stir for 16 hours. The crude reaction mixture was then evaporated to dryness and the residue chromatographed on silica gel, eluting with dichloromethane:methanol:ammonia (84:14:2) as solvent to give the amide (732mg, 23%) as a white powder. 1H NMR (300 MHz, d4-MeOH): δ=2.97 (3 H, s), 7.40 (1 H, t), 8.05 (1 H, m), 8.29 (1 H, d). MS m/z 250 (MNH4)+
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[N:7]([CH2:23][CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([N+:34]([O-:36])=[O:35])[CH:32]=2)[NH:27][C:26]=1[C:37]1[CH:42]=[C:41]([CH3:43])[CH:40]=[C:39]([CH3:44])[CH:38]=1)[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18]S(C)(=O)=O)=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:45])[N:7]([CH2:23][CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([N+:34]([O-:36])=[O:35])[CH:32]=2)[NH:27][C:26]=1[C:37]1[CH:38]=[C:39]([CH3:44])[CH:40]=[C:41]([CH3:43])[CH:42]=1)[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[C:16]([S:47]([CH3:46])(=[O:49])=[O:48])[C:17]=1[S:47]([CH3:46])(=[O:49])=[O:48])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc([N+](=O)[O-])cc3c2CCN(CCCCc2ccc(NS(C)(=O)=O)cc2)C(=O)OC(C)(C)C)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(-c2[nH]c3ccc([N+](=O)[O-])cc3c2CCN(CCCCc2ccc(N)c(S(C)(=O)=O)c2S(C)(=O)=O)C(=O)OC(C)(C)C)c1
Reaction time: 0.5 h

Procedure:
To a solution of {2-[2-(3,5-dimethylphenyl)-5-nitro-1H-indol-3-yl]ethyl}-[4-(4-methanesulfonylaminophenyl)butyl]carbamic acid tert-butyl ester (300 mg in 7 mL methylene chloride) at 0° C. was added 0.135 mL triethylamine and 0.066 mL methanesulfonyl chloride and the mixture sired at low temperature. After 30 minutes, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate and partitioned between water and ethyl acetate. The organic portion was washed successively with saturated ammonium chloride, saturated sodium bicarbonate and brine, then dried over sodium sulfate and concentrated in vacuo to give the crude title compound (330 mg).
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[N:5][C:6]([Cl:19])=[CH:7][CH:8]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH:32]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:19][C:6]1[N:5]=[C:4]2[CH:3]=[C:2]([C:32]3[CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH:28]=3)[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[C:9]2=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)C1
Reactant: Clc1cccc(Cn2c(Br)cc3nc(Cl)ccc32)c1
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: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3nc(Cl)ccc3n2Cc2cccc(Cl)c2)C1
Temperature: 106 °C
Reaction time: 2 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.11 mmol, Strem) was added to a degassed mixture of 2-bromo-5-chloro-1-(3-chlorobenzyl)-1H-pyrrolo[3,2-b]pyridine (0.50 g, 1.1 mmol, prepared as in Example 103, Step 2), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (0.414 g, 1.40 mmol, Combi-Blocks) and Na2CO3 (0.60 g, 5.6 mmol) in 1,2-dimethoxyethane (10 mL) and water (2 mL), and the sealed reaction mixture was heated at 106° C. for two hours. Additional tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (0.33 g, 1.1 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.11 mmol) were added, and heating was continued for additional two hours. Upon cooling to room temperature, the reaction mixture was diluted with water, and the aqueous layer was extracted with three portions of EtOAc. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-30% EtOAc in hexanes. Yield: (0.12 g, 24%).
Reaction SMILES: [S:1](=[O:4])([OH:3])[O-:2].[Na+].[OH-].[Na+].Cl[C:9]1[CH:10]=[N+:11]([O-])[CH:12]=[CH:13][CH:14]=1.[H][H]>O.[Ni]>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([S:1]([OH:3])(=[O:2])=[O:4])[CH:10]=1
Reactant: [O-][n+]1cccc(Cl)c1
Reactant: [H][H]
Reactant: O=S([O-])O
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(O)c1cccnc1
Temperature: 145 °C
Reaction time: 17 h

Procedure:
18.7 kg of sodium bisulfite were dissolved in 55.8 liters of water and the pH was adjusted to a pH of 9 to 9.5 with 14.4 kg of sodium hydroxide. To the solution were added 11.7 kg of raw 3-chloro-pyridine-N-oxide and the mixture was heated in an autoclave to 145° C. The reaction mixture was stirred at 145° C. for 17 hours (during the reaction, a pressure of 4 to 5 bars resulted). After completion of the reaction, cooling to 90° C. took place. 1 kg of sodium hydroxide (50 weight %) was added to adjust to alkaline and in a nitrogen atmosphere, 0.5 kg of Raney nickel were added. The suspension was heated to 100° to 110° C. and at this temperature, hydrogen was pressed on with 7 bars. Hydrogenation was carried out for 16 hours and then the mixture was cooled to 70° C. and the catalyst was separated with a pressure filter. The pyridine-3-sulfonic acid was isolated as in Example 4 and purified.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:11]=[C:10]([C:21](O)=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.[NH2:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([Cl:39])=[C:30]([S:32]([NH:35][CH:36]2[CH2:38][CH2:37]2)(=[O:34])=[O:33])[CH:31]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:39][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][NH:24][C:21]([C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:11]=2)=[O:22])=[CH:31][C:30]=1[S:32](=[O:34])(=[O:33])[NH:35][CH:36]1[CH2:37][CH2:38]1
Reactant: NCc1ccc(Cl)c(S(=O)(=O)NC2CC2)c1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CCCC3)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(Cl)c(S(=O)(=O)NC4CC4)c3)cc(C(=O)N3CCCC3)c2)cc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-(pyrrolidine-1-carbonyl)biphenyl-3-carboxylic acid (60 mg, 0.19 mmol) in N,N-dimethylformamide (1.0 mL) were added 5-(aminomethyl)-2-chloro-N-cyclopropylbenzenesulfonamide (80 mg, 0.31 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (150 mg, 0.39 mmol) and N,N-diisopropylethylamine (150 μL, 0.86 mmol). The reaction mixture was stirred for 16 hours at 50° C. The reaction mixture was purified by preparative HPLC to afford a light colour solid.
Reaction SMILES: C1(C[O:8]C(=O)[NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:24][CH2:25][P:26]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[O:27])[C:15]2[C:18](=[O:19])[C:17](=[O:20])[C:16]=2OCC)C=CC=CC=1.C1CC=CCC=1>[Pd].C(O)C>[OH2:8].[CH2:29]([O:28][P:26]([CH2:25][CH2:24][N:14]1[CH2:13][CH2:12][CH2:11][NH:10][C:16]2[C:17](=[O:20])[C:18](=[O:19])[C:15]1=2)(=[O:27])[O:31][CH2:32][CH3:33])[CH3:30].[O:20]=[C:17]1[C:18](=[O:19])[C:15]2[N:14]([CH2:24][CH2:25][P:26](=[O:27])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])[CH2:13][CH2:12][CH2:11][NH:10][C:16]1=2
Reactant: CCOc1c(N(CCCNC(=O)OCc2ccccc2)CCP(=O)(OCC)OCC)c(=O)c1=O
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: CCOP(=O)(CCN1CCCNc2c1c(=O)c2=O)OCC
Product: O
Reaction time: 5 h
Yield: 60 %

Procedure:
To a flask containing 10% palladium on carbon (2.11 g) under nitrogen was added [3-[[2-(diethoxyphosphinyl)ethyl](2-ethoxy-3,4-dioxo-1cyclobuten-1-yl)amino]propyl]carbamic acid phenylmethyl ester (2.11 g, 4.2 mmol) in absolute ethanol (180 mL), followed by 1,4-cyclohexadiene (4.3 mL, 45 mmol). After stirring for 5 hours, the reaction mixture was filtered through Celite® and concentrated in vacuo to yield a crude solid, which was recrystallized from methanol and ethyl acetate (total volume=20 mL), filtered, and washed with hexane to afford [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid diethyl ester hemihydrate as a cream colored solid (0.82 g, 62%, mp 148°-149° C.); IR (KBr, cm-1): 1810; 1H NMR (CDCl3, 400 MHz): δ 7.50 (br s, NH), 4.18-4.10 (m, 4H), 4.09-4.00 (m, 2H), 3.51-3.46 (m, 4H), 2.19 (d of t, J=18 and 7.5 Hz, 2H), 2.10-2.04 (m, 2H), 1.34 (t, J=7 Hz, 6H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C-:12]#[N:13].[Na+].ClC(Cl)C>CN(C)C=O>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[C:12]#[N:13]
Reactant: [C-]#N
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1c(Cl)cccc1[N+](=O)[O-]
Yield: 78.3 %

Procedure:
2,3-dichloronitrobenzene (19.2 g), cuprous chloride (2.4 g), anhydrous cupric sulfate (1.0 g), sodium cyanide (purity of 90%, 5.4 g) and dimethylformamide (3.0 g) were heated together to 190° C. and made to react for 3.5 hours at the temperature. After the reaction was over, 100 ml of dichloroethane were added to the reaction mixture and the mixture was filtered. After separating the filtrate, 100 ml of an aqueous 5% solution of ammonia were added to the filtrate and after well shaking the mixture, it was separated into layers. After distilling off dichloroethane from the organic layer and washing the residue with ethanol, 14.3 g of 2-chloro-6-nitrobenzonitrile was obtained as a pale yellow crystal. The yield was 78% theoretical.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:7]=1.[H-].[Na+].CS(C)=O.Cl[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1>O1CCCC1>[CH3:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH:7]=[C:2]([O:1][C:26]3[N:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)c1cc(O)cc(-c2ccc(C)cc2)c1
Reactant: Clc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Oc2ncccn2)cc(-c2ccc(C)cc2)c1

Procedure:
To a stirred solution of methyl 5-hydroxy-4′-methylbiphenyl-3-carboxylate (300 mg, 1.24 mmol) in tetrahydrofuran (20 mL) at 0° C. was added sodium hydride (60% in mineral oil, 55 mg, 1.37 mmol) over a period of 10 minutes. The reaction mixture was concentrated to afford a green solid. A microwave vial was charged with the resulting green solid, dimethyl sulfoxide (8 mL), and 2-chloropyrimidine (118 mg, 0.98 mmol). The mixture was subjected to microwave irradiation at 100° C. for 4 minutes. After cooling, the mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by flash chromatography to afford the title compound.