Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([CH2:12][C:13]1([C:18](O)=[O:19])[CH2:17][CH2:16][S:15][CH2:14]1)(O)=[O:10].C(N1C=CN=C1)(N1C=CN=C1)=O>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9](=[O:10])[CH2:12][C:13]3([CH2:14][S:15][CH2:16][CH2:17]3)[C:18]2=[O:19])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CC1(C(=O)O)CCSC1
Reactant: Nc1cccc(Br)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: Cc1ccccc1C
Product: O=C1CC2(CCSC2)C(=O)N1c1cccc(Br)c1
Yield: 92.9 %

Procedure:
A solution of 3-bromo-phenylamine (1.0 g, 5.81 mmol) and 3-carboxymethyl-tetrahydro-thiophene-3-carboxylic acid (1.15 g, 6.05 mmol, [Rice, L. M. et al; J. Med Chem; 6; 1963; 388-402]) in xylene (10 ml) was heated for 2 hours (oil bath, 180° C.) with fitted Dean-Stark trap to remove water. The material was cooled to ambient and the xylene stripped (rotovap/pump). The material was covered with dry CH2Cl2 (10 ml). Carbonyldiimidazole (1.18 g, 7.26 mmol) was added with vigorous stirring and a homogeneous solution was rapidly obtained. After over night stirring the material was adsorbed onto silica (12 g). The crude was purified by chromatography on silica gel, eluting with a gradient of 100% CH2Cl2 to 0.12% MeOH/CH2Cl2, to afford 1.76 g of 7-(3-bromo-phenyl)-2-thia-7-aza-spiro[4.4]nonane-6,8-dione as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([O:19]CC)=[O:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6](=[O:22])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([OH:19])=[O:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)Cc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)O)cs1
Reaction time: 3 h
Yield: 89.2 %

Procedure:
2-{[4-(2-Ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (150 g) synthesized in Example 2 was dissolved in methanol (700 mL), a 1N aqueous sodium hydroxide solution (448 mL) was added at room temperature, and the mixture was stirred for 3 hr. The reaction solution was concentrated under reduced pressure, an aqueous 10% citric acid solution (1 L) was added, and the mixture was extracted with ethyl acetate (1 L). The organic layer was washed three times with water (500 mL) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (123 g) as a slightly yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][NH2:14])[CH:6]=1)=[O:4].[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([C:25](O)=[O:26])[CH:16]=1.C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][NH:14][C:25]([C:17]2[CH:16]=[N:15][C:24]3[C:19]([CH:18]=2)=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:26])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(=O)n(CCN)c1
Reactant: O=C(O)c1cnc2ccccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(=O)n(CCNC(=O)c2cnc3ccccc3c2)c1
Reaction time: 17 h

Procedure:
1-(2-aminoethyl)-1,6-dihydro-6-oxo-3-pyridinecarboxylic acid methyl ester (0.400 g, 2.0 mmol) was coupled with 3-quinolinecarboxylic acid (0.373 g, 2.2 mmol) in dichloromethane (35 ml) with triethylamine (1.40 ml, 10.0 mmol) and propylphosphoric acid anhydride (0.65 ml, added as a 0.65 ml ethyl acetate solution). After 17 hours, the solution was filtered through a pad of celite and the filtrate concentrated. Dichloromethane and aqueous sodium bicarbonate were added the layers separated. The aqueous layer was extracted with dichloromethane (2X) and the combined organic layers washed with aqueous sodium bicarbonate, brine, dried (Na2SO4), filtered, and concentrated. Recrystallisation from 1,2-dichloroethane gave the pure product, MP: 174°-175° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N:22]2[C:30]3[CH2:29][CH2:28][CH2:27][NH:26][C:25]=3[N:24]=[N:23]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N:22]2[C:30]3[CH2:29][CH2:28][CH2:27][N:26]([S:32]([CH3:31])(=[O:34])=[O:33])[C:25]=3[N:24]=[N:23]2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3c2CCCN3)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3c2CCCN3S(C)(=O)=O)cc1
Reaction time: 1 h

Procedure:
A 4 mL scintillation vial was charged with 4-tert-butyl-N-[4-chloro-2-(4,5,6,7-tetrahydro-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-phenyl]-benzenesulfonamide (synthesized according to general procedure M, 13 mg, 0.029 mmol), MeSO2Cl (5 mg, 0.04 mmol), and pyridine (500 μL). The reaction was stirred for 1 hour. The solvent was subsequently removed in vacuo and the residue purified by preparative TLC to afford 4-tert-butyl-N-[4-chloro-2-(4-methanesulfonyl-4,5,6,7-tetrahydro-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-phenyl]-benzenesulfonamide: MS (ES) M+H expected 524.1, found 524.0.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18]>>[Cl:1][C:2]1[S:3][C:4]2[C:10]([N+:17]([O-:19])=[O:18])=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(Cl)ccc2nc(Cl)sc12

Procedure:
This compound was prepared in the manner of Step D, Example 6, with 8.0 grams (39 mmole) of 2,6-dichlorobenzothiazole, 45 mL of concentrated sulfuric acid, and 3.8 mL (60 mmole) of concentrated nitric acid as reagents. The material was purified by column chromatography on silica gel. Elution was accomplished with 3:1 heptane:ethyl acetate. The product-containing fractions were combined and concentrated under reduced pressure, yielding 2,6-dichloro-7 nitrobenzothiazole. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[CH:6]1[C:22]2[CH2:21][C@H:20]3[N:23]([CH2:25][CH2:26][C@@:12]45[C@H:19]3[CH:18]=[CH:17][C@H:15]([OH:16])[C@@H:13]4[O:14][C:10]([C:11]=25)=[C:8](O)[CH:7]=1)[CH3:24].O.CN1[C@@H]2CC3=CC=C(O)C4O[C@H]5C(CC[C@@H]2[C@]5(C=43)CC1)=O>CCO.C(#N)C>[CH3:24][N:23]1[C@@H:20]2[CH2:21][C:22]3=[CH:6][CH:7]=[C:8]([O:2][S:1]([OH:5])(=[O:4])=[O:3])[C:10]4[O:14][C@H:13]5[C:15]([CH2:17][CH2:18][C@@H:19]2[C@:12]5([C:11]=43)[CH2:26][CH2:25]1)=[O:16]
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Reactant: O=S(=O)(O)O
Agent: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@H]3[C@H]1C5
Solvent: CCO
Solvent: O
Solvent: CC#N
Product: CN1CC[C@]23c4c5ccc(OS(=O)(=O)O)c4O[C@H]2C(=O)CC[C@H]3[C@H]1C5
Temperature: 81 °C
Yield: 48.3 %

Procedure:
Morphine sulfate (30.0 g), water (30 mL), and EtOH (60 mL) were added to a reaction flask. The reaction mixture was agitated to form a suspension. The reactor was flushed with nitrogen and the reaction mixture was kept under nitrogen throughout the reaction. The reaction flask was charged with the catalyst (RuCl3.xH2O, 0.60 g), and the mixture was heated to reflux (80-82° C.) for 16 h. HPLC analysis indicated that 94.5% (area) hydromorphone was formed. Acetonitrile (30 mL) was added to the reaction mixture and the mixture was heated for 1 h. EtOH (90 mL) was added to the mixture, which was then cooled to 15° C. for 2 h. The mixture was filtered, and the solid was washed with 95% EtOH (2×15 mL). The solid was dried under vacuum at 65° C. for 18 h to give 13.8 g of hydromorphone sulfate as solids (purity>99% area).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[S:8][C:9]3[N:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Li+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:12]1[C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[N:17][C:9]=2[S:8][C:7]1=[N:6][C:5]1[CH:18]=[CH:19][C:2]([Br:1])=[CH:3][CH:4]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=c1nc(Nc2ccc(Br)cc2)sc2ncccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Li+]
Product: O=c1c2cccnc2sc(=Nc2ccc(Br)cc2)n1Cc1ccccc1
Yield: 65.4 %

Procedure:
The reaction procedure of Example 11 was followed except that 900 mg (2.69 mmol) of 2-(4-bromoanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 24 mg of lithium hydride and 507 mg of benzyl bromide were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform) to obtain 746 mg of 3-benzyl-2-[(4-bromophenyl)imino]-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one (recrystallized from a mixture of ether and hexane) as a low polarity substance and 163 mg of 2-[N-benzyl-N-(4-bromophenyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (recrystallized from a mixture of ether and ethanol) as a high polarity substance.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[NH:13][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: Brc1ccccn1
Product: c1ccc(COc2ccc(Nc3ccccn3)cc2)cc1
Reaction time: 1 h

Procedure:
A mixture of 19.93 g. of 4-benzyloxyaniline and 4.77 ml. of 2-bromopyridine was stirred and gradually heated over a period of 21/2 hours to 150°C. The mixture was held at 160°C. for 1 hour and at 130°C. for one and three-quarters hours, and then steam distilled. The residue was filtered and the filtrate made alkaline. The combined solid products were recrystallized from cyclohexane to give N-(2-pyridyl)-4-benzyloxyaniline, tan prisms, m.p. 110°-111.5°C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([NH:14][C@H:15]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:16][O:17][CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:13])=[CH:9][CH:10]=2)[NH:5][CH:4]=1.[C:31]1(=O)[CH2:35][CH2:34][CH2:33][CH2:32]1>>[Cl:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([NH:14][C@H:15]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:16][O:17][CH2:18][CH:19]3[CH2:20][CH2:21][N:22]([CH:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[CH2:23][CH2:24]3)=[O:13])=[CH:9][CH:10]=2)[NH:5][CH:4]=1
Reactant: O=C1CCCC1
Reactant: O=C(N[C@@H](COCC1CCNCC1)c1ccccc1)c1ccc2c(Cl)c[nH]c2c1
Agent: Cl
Product: O=C(N[C@@H](COCC1CCN(C2CCCC2)CC1)c1ccccc1)c1ccc2c(Cl)c[nH]c2c1

Procedure:
Using alkylation method A, 3-chloro-N-[(R)-1-phenyl-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide hydrochloride (150 mg, 0.33 mmol) and cyclopentanone (0.5 mL, 5.7 mmol) afforded, after purification (SiO2: 8:2:1 hexane:EtOAc:isopropylamine), 78 mg (49%) of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[C:10](\[CH3:13])/[CH2:11][OH:12])=[CH:5][CH:4]=1)[CH3:2].[C:14](OC(=O)C)(=[O:16])[CH3:15].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.ClCCl>[C:14]([O:12][CH2:11]/[C:10](/[CH3:13])=[CH:9]/[C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)(=[O:16])[CH3:15]
Reactant: CCc1ccc(/C=C(\C)CO)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1ccc(/C=C(\C)COC(C)=O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 1790 %

Procedure:
(E)-3-(4-Ethylphenyl)-2-methyl-2-propen-1-ol (4.6 g, 26 1 mmol, obtained by LiAlH4 reduction of (E)-3-(4-ethylphenyl)-2-methyl-2-propenal as described for (E)-2-Ethyl-3-(4-methylphenyl)-2-propen-1-ol) was added to a mixture of acetic anhydride (4.0 g, 39 mmol), pyridine (3.5 g, 44 mmol) and DMAP (0.46 g, 3.7 mmol) in 50 ml of dichloromethane. The mixture was stirred for 20 hours at room temperature. The dichloromethane was removed on a rotary evaporator, and the residue dissolved in EtOAc. This solution was washed with aqueous 10% HCl, aqueous 10% NaOH, and saturated aqueous NaCl. The organic phase was dried (MgSO4), filtered and concentrated. The product was purified by silica gel flash chromatography (hexane/EtOAc=80:20) followed by Kugelrohr distillation (140-160° C., 0.05 mbar) yielding 3.9 g (17.9 mmol, 69% yield) of the product as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15](OS(C(F)(F)F)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:25]([OH:29])[CH2:26][C:27]#[CH:28]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:28]#[C:27][CH2:26][CH2:25][OH:29])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(Br)cc3)nsc2c1)C(F)(F)F
Reactant: C#CCCO
Product: OCCC#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 13.1, Trifluoro-methanesulfonic acid 3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl ester and 3-butyn-1-ol were converted to yield 4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-ol as orange solid, MS: 357 (M, 1Br).
Reaction SMILES: [C-:1]#[N:2].[K+].[Cl:4][C:5]1[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18]Cl)=[CH:14][C:13]=2[O:20][CH3:21])=[C:9]([CH3:22])[N:8]=[C:7]([NH2:23])[N:6]=1>CS(C)=O.CN(C=O)C.O>[NH2:23][C:7]1[N:6]=[C:5]([Cl:4])[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:1]#[N:2])=[CH:14][C:13]=2[O:20][CH3:21])=[C:9]([CH3:22])[N:8]=1
Reactant: COc1cc(CCl)ccc1Cc1c(C)nc(N)nc1Cl
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(CC#N)ccc1Cc1c(C)nc(N)nc1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Potassium cyanide (0.17 g) was added to a stirred solution of the product from step (ii) (0.40 g) in DMSO (5 mL) and DMF (5 mL). The mixture was stirred at rt for 15 h, diluted with water and then extracted with EtOAc. The combined organic phase was dried, filtered and evaporated to give the subtitle compound, 0.20 g.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)Cl>[C:1]1([CH:7]2[CH2:8][CH2:9][N:10]([C:19](=[O:21])[CH3:20])[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Cl
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCC(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Phenylpiperidine (87 mmol) and pyridine (96 mmol) are dissolved in dry CH2Cl2 (100 ml) and acetylchloride (96 mmol) in CH2Cl2 (40 ml) is added dropwise to the stirred solution at 10° C. The reaction is stirred for 1 hour at rt. The mixture is extracted three times with water and the water phase is extracted again with CH2Cl2. The combined organic phases are dried over sodium sulfate and evaporated. A pale brown oil with Rf=0.13 (ethyl acetate/hexane=1:1) is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:14])[CH:12]=[CH2:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[OH-].[Na+]>CCOC(C)=O.O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:14])[CH:12]=[CH2:13])[CH:7]=[CH:8][CH:9]=1
Reactant: C=CC(=O)Nc1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: C=CC(=O)Nc1cccc(N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of N-(3-nitrophenyl)-acrylamide (1.1 g, 5.61 mmol), iron powder (1.88 g, 33.7 mmol), FeSO4 (3.12 g, 11.2 mmol), Celite® (1.0 g) and H2O (45 mL) was heated to reflux with stirring for 2 h. The reaction mixture was cooled to RT and the solution was made basic to pH 13-14 by the addition of 2N NaOH. The reaction mixture was diluted with EtOAc and water. The solution was filtered to remove the solids and the solids were washed with EtOAc. The aqueous layer was extracted three times with EtOAc (100 mL) and the combined organics were dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography using EtOAc as the solvent to give N-(3-aminophenyl)acrylamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3I)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C@@H:22]12[CH2:28][N:27](C(OC(C)(C)C)=O)[C@@H:26]1[CH2:25][NH:24][CH2:23]2.[ClH:36]>C(O)(C)C>[ClH:36].[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[N:24]2[CH2:25][C@@H:26]3[C@@H:22]([CH2:28][NH2+:27]3)[CH2:23]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1cccc(F)c1)c1cnc2c(I)cccc2c1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@H]21
Agent: Cl
Solvent: CC(C)O
Product: O=S(=O)(c1cccc(F)c1)c1cnc2c(N3C[C@@H]4C[NH2+][C@@H]4C3)cccc2c1

Procedure:
0.081 g of (1S,5S)-3-(3-(3-fluorophenylsulfonyl)quinolin-8-yl)-3-aza-6-azoniabicyclo[3.2.0]heptane hydrochloride were prepared by analogy to the methods of Examples 27 and 28 by coupling of 3-(3-fluorophenylsulfonyl)-8-iodoquinoline with (1R,5S)-tert-butyl 3,6-diazabicyclo[3.2.0]heptane-6-carboxylate and subsequent deprotection of the tert-butyl-oxycarbonyl derivative with HCl in isopropanol.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[N:39][C:40]([N:43]2[CH:47]=[CH:46][N:45]=[C:44]2[CH3:48])=[N:41][CH:42]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:38]=[N:39][C:40]([N:43]4[CH:47]=[CH:46][N:45]=[C:44]4[CH3:48])=[N:41][CH:42]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: Cc1nccn1-c1ncc(Br)cn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: Cc1nccn1-c1ncc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 5-bromo-2-(2-methyl-1H-imidazol-1-yl)-pyrimidine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=0.932 min, m/z=512.3; 1H NMR (CD3OD) 0.86 (s, 3H), 1.16 (s, 3H), 1.49 (m, 3H), 2.15 (m, 2H), 2.18 (m, 1H), 2.37-2.49 (m, 2H), 2.79 (s, 3H), 3.03 (m, 1H), 5.53 (m, 1H), 7.01-7.06 (m, 3H), 7.21-7.29 (m, 5H), 7.44 (m, 2H), 7.97 (m, 1H), 8.95 (s, 2H).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.CCOCC.[Br:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[N:18][CH:19]=1>C1(C)C=CC=CC=1.CO>[CH3:1][O:22][C:21](=[O:23])[CH2:20][C:16]1[CH:17]=[N:18][CH:19]=[C:14]([Br:13])[CH:15]=1
Reactant: O=C(O)Cc1cncc(Br)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CO
Product: COC(=O)Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
A 2.0 M solution of trimethylsilyldiazomethane in ether (10.3 mL, 20.5 mmol) was added dropwise to a mixed solution of (5-bromo-pyridin-3-yl)-acetic acid (4.04 g, 18.7 mmol) in toluene (17.3 mL) and methanol (11.5 mL), and the mixture was stirred at room temperature for 10 minutes. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=1:3) to give the title compound (3.12 g, 72%).
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[C:42]3[N:41]=[CH:40][N:39]=[C:29]([NH:30][C:31](=[O:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:28]=3[N:27]=[CH:26]2)[C@H:22]([O:43][CH2:44][CH2:45][O:46][N:47]([CH3:49])[CH3:48])[C@@H:21]1[OH:50])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[C:31]([NH:30][C:29]1[C:28]2[N:27]=[CH:26][N:25]([C:42]=2[N:41]=[CH:40][N:39]=1)[C@@H:23]1[O:24][C@H:20]([CH2:19][OH:18])[C@@H:21]([OH:50])[C@H:22]1[O:43][CH2:44][CH2:45][O:46][N:47]([CH3:49])[CH3:48])(=[O:38])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CN(C)OCCO[C@@H]1[C@H](O)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O[C@H]1n1cnc2c(NC(=O)c3ccccc3)ncnc21
Solvent: C1CCOC1
Product: CN(C)OCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(NC(=O)c3ccccc3)ncnc21
Reaction time: 24 h
Yield: 86.5 %

Procedure:
5′-O-t-Butyldiphenylsilyl-N6-benzoyl-2′-O-(dimethylaminooxyethyl)adenosine (7.77 g, 11.15 mmol) was dissolved in THF (110 mL), and tetrabutylammonium fluoride (TBAF)on silica (1.0-1.5 mmol/g silica, 10.1 g) was added. After stirring for 24 hours the solid was filtered, washed with THF, and the solvent was evaporated in vacuo to give a solid which was purified by column chromatography using CH2Cl2—EtOAc—MeOH, 75:20:5, to give the title compound as a solid (4.42 g, 86%).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9](I)=[CH:8][N:7]=1)(=[O:5])=[O:4])[CH3:2].[C:13]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][C:17]=1[F:25])([OH:15])=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH2:1]([S:3]([C:6]1[N:7]=[CH:8][C:9]([C:19]2[CH:20]=[CH:21][C:16]([C:13]([OH:15])=[O:14])=[C:17]([F:25])[CH:18]=2)=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(I)cn1
Reactant: O=C(O)c1ccc(B(O)O)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(-c2ccc(C(=O)O)c(F)c2)cn1

Procedure:
Procedure VV: To a stirring solution of 2-Ethanesulfonyl-5-iodo-pyridine (1.0 mmol) and (4-carboxy-3-fluorophenyl)boronic acid (1.3 mmol) in dioxane (0.1M), add dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane complex (0.03 mmol) and 2M aqueous sodium carbonate (3.0 mmol). Heat the reaction to reflux for 4 hours. After this time, remove the heat and concentrate in vacuo. Wash with dichloromethane while extracting with water. Acidify the aqueous layer with 1N hydrochloric acid and extract with 10% isopropanol/dichloromethane four times. Combine the organics, dry with sodium sulfate, decant and concentrate in vacuo. MS (m/e): 310.3 (M+1)
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:4][N:3]=1.[C:19]1([CH2:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH:12][C:26](=[O:27])[CH2:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:4][N:3]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Cc1noc(-c2sc(N)nc2-c2ccccc2)n1
Product: Cc1noc(-c2sc(NC(=O)Cc3ccccc3)nc2-c2ccccc2)n1

Procedure:
Prepared from 5-(3-methyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-ylamine and phenyl-acetyl chloride.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:27])=[C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22](=[O:26])N(C)C)=[CH:18][N:17]=3)[CH:13]=2)[N:8]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=2)[C:7]=1[CH2:38][C:39]([O:41]CC)=[O:40])=[O:5])C.[OH-:44].[Na+].Cl>O1CCOCC1>[C:34]([C:31]1[CH:30]=[CH:29][C:28]([N:8]2[C:9]3[C:14](=[CH:13][C:12]([O:15][C:16]4[CH:21]=[CH:20][C:19]([C:22]([OH:26])=[O:44])=[CH:18][N:17]=4)=[C:11]([Cl:27])[CH:10]=3)[C:6]([C:4]([OH:3])=[O:5])=[C:7]2[CH2:38][C:39]([OH:41])=[O:40])=[CH:33][CH:32]=1)([CH3:35])([CH3:36])[CH3:37]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(=O)N(C)C)cn3)c(Cl)cc2n1-c1ccc(C(C)(C)C)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(-n2c(CC(=O)O)c(C(=O)O)c3cc(Oc4ccc(C(=O)O)cn4)c(Cl)cc32)cc1

Procedure:
A mixture of 1-(4-tert-butylphenyl)-6-chloro-5-(5-dimethylcarbamoyl-pyridin-2-yloxy)-2-ethoxycarbonylmethylindole-3-carboxylic acid ethyl ester (124 mg, 4.07 mmol; see step (c) above), NaOH (aq, 2 M, 1.0 mL) and dioxane (2.0 mL) was heated at reflux for 48 h, cooled, acidified to pH 2 with HCl (aq, 1 M) and extracted with EtOAc. The combined extracts were washed with H2O and brine, dried (Na2SO4), concentrated and purified by chromatography to give the title compound. Yield 40 mg (36%), mp 223-235° C.