Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[ClH:51].C(N(CC)CC)C.[CH3:59][O:60][CH2:61][CH2:62][NH:63][CH2:64][CH2:65][O:66][CH3:67]>CN(C=O)C.O>[ClH:51].[CH3:59][O:60][CH2:61][CH2:62][N:63]([CH2:64][CH2:65][O:66][CH3:67])[C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([C:18]2[N:17]=[C:16]3[N:12]([CH2:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)[N:13]=[N:14][C:15]3=[CH:20][CH:19]=2)=[CH:22][CH:23]=1
Reactant: O=C(O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Reactant: COCCNCCOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COCCN(CCOC)C(=O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Reaction time: 0.08 h
Yield: 19.1 %

Procedure:
To a solution of example 8 (0.150 g, 0.393 mmol) in DMF (1 ml), HOBT (0.063 g, 0.471 mmol), EDC-HCl (0.187 g, 0.983 mmol) and triethylamine (0.16 ml, 1.17 mmol) were added and stirred for 5 min. Bis(2-methoxyethyl)amine (0.104 g, 0.786 mmol) was added at RT and the reaction mixture was stirred for 12 h. To the reaction mixture water was added and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the amide as a yellow solid (0.04 g). The amide was dissolved in THF (2 ml), ether saturated with HCl (2 ml) was added at 0° C. and stirred for 15 min. The precipitate formed was washed with ether and dried under vacuum to afford the title compound as a yellow solid (0.035 g, 17%). M.P.: 126-129° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.07 (m, 1H), 8.74 (m, 1H), 8.70 (d, J=8.7 Hz, 1H), 8.29 (d, J=8.3 Hz, 2H), 8.19 (m, 3H), 8.02 (m, 1H), 7.78 (m, 1H), 7.53 (d, J=8.2 Hz, 2H), 6.27 (s, 2H), 3.64 (bs, 2H), 3.58 (br.s, 2H), 3.41 (br.s, 4H), 3.30 (s, 3H), 3.16 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]3[CH:18]=[C:19]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[S:20][C:13]=13)=[CH:6][CH:5]=2.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]3[CH:18]=[C:19]([C:21]4[CH:28]=[CH:27][C:24]([CH2:25][N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[CH:23][CH:22]=4)[S:20][C:13]=13)=[CH:6][CH:5]=2
Reactant: Cc1cc2cc(Nc3ccnc4cc(-c5ccc(C=O)cc5)sc34)ccc2[nH]1
Reactant: C1COCCN1
Product: Cc1cc2cc(Nc3ccnc4cc(-c5ccc(CN6CCOCC6)cc5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 4-[7-(2-methyl-1H-Indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-benzaldehyde(60 mg, 0.156 mmol) and morpholine (82 mg, 0.939 mmol) by a procedure analogous to example 89. RP18-HPLC RT: 4.652 minutes; API MS: 454.59 (M+1).
Reaction SMILES: Br[CH:2]([C:4]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=O)[CH3:3].Cl.[Cl:16][C:17]1[CH:18]=[C:19]([CH:28]([NH2:30])[CH3:29])[CH:20]=[N:21][C:22]=1[O:23][CH2:24][CH:25]([F:27])[F:26]>>[Cl:14][C:13]1[C:4]2[CH:2]([CH3:3])[N:30]([CH:28]([C:19]3[CH:20]=[N:21][C:22]([O:23][CH2:24][CH:25]([F:26])[F:27])=[C:17]([Cl:16])[CH:18]=3)[CH3:29])[C:6](=[O:8])[C:5]=2[CH:10]=[CH:11][N:12]=1
Reactant: COC(=O)c1ccnc(Cl)c1C(C)Br
Reactant: CC(N)c1cnc(OCC(F)F)c(Cl)c1
Agent: Cl
Product: CC(c1cnc(OCC(F)F)c(Cl)c1)N1C(=O)c2ccnc(Cl)c2C1C
Yield: 17 %

Procedure:
The title compound is prepared in 17% yield (100 mg, colorless amorphous solid) from methyl 3-(1-bromoethyl)-2-chloroisonicotinate (400 mg, 1.4 mmol, Step-1 of Intermediate-6, racemate) and 1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (431 mg, 1.6 mmol, Amine-16, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: C([O:3][C:4](=[O:13])[C:5]([CH3:12])([CH3:11])[CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10])C.[OH-].[Na+].Cl>CO>[CH3:11][C:5]([CH3:12])([CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10])[C:4]([OH:13])=[O:3]
Reactant: C=CCCCC(C)(C)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCCCC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,2-dimethyl-hept-6-enoic acid ethyl ester (600 mg, 3.3 mmol) in MeOH (10 mL) is added 6N NaOH (5 mL) and the suspension is stirred at RT for 18 h. The solution is acidified with 1N HCl and extracted with EtOAc. The organic layer is dried, filtered and the solvent is removed under reduced pressure to afford the product which is used directly in the next step.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[N:3]=1.[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[C:19]([F:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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:13][C:10]1[C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:17]2[CH:16]=[C:15]([F:14])[CH:20]=[C:19]([F:21])[CH:18]=2)[C:11]=1[CH3:12]
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: Cc1c(Cl)nc2cnccc2c1Cl
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: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(F)cc(F)c2)nc2cnccc2c1Cl

Procedure:
Prepared according to procedure F using 2,4-dichloro-3-methyl-1,7-naphthyridine (0.18 g, 0.845 mmol), 3,5-difluorophenylboronic acid (0.147 g, 0.929 mmol), Pd(PPh3)4 (0.098 g, 0.084 mmol), potassium carbonate (0.519 g, 3.75 mmol) in toluene (6 mL) at 95° C. for 18 h. Purification by column chromatography (silica gel; 0-25% EtOAc in hexanes) gave 4-chloro-2-(3,5-difluorophenyl)-3-methyl-1,7-naphthyridine as a yellow amorphous solid. Mass Spectrum (ESI) m/e=291.0 (M+1).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:12])[C@@H:6]1[CH2:10][C@@H:9]([OH:11])[CH2:8][NH:7]1)[CH3:3].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1>[CH2:2]([O:4][C:5](=[O:12])[C@@H:6]1[CH2:10][C@@H:9]([OH:11])[CH2:8][N:7]1[S:14]([CH3:13])(=[O:16])=[O:15])[CH3:3]
Reactant: CCOC(=O)[C@@H]1C[C@@H](O)CN1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)[C@@H]1C[C@@H](O)CN1S(C)(=O)=O

Procedure:
In 200 ml of pyridine was placed 19.56 g (0.1 mol) of (2S,4R)-4-hydroxyproline ethyl ester hydrochloride, and 12.03 g (0.105 mol) of methanesulfonyl chloride was slowly added dropwise to the mixture under agitation and ice-cooling. After stirring the mixture under ice-cooling for 6 hours, the mixture was further stirred overnight at room temperature. After distilling off the pyridine under reduced pressure, 10% hydrochloric acid was added to the reaction mixture under ice-cooling. The mixture was extracted three times with 200 ml of ethyl acetate in each case and the ethyl acetate extracts were combined, washed with 40 ml of a saturated aqueous solution of sodium chloride and then dried over magnesium sulfate. The extract was concentrated under reduced pressure and dried until dryness whereby a solid substance having a melting point of 111°-113° C. was obtained in a yield of 18.7 g (78.9%) which, after recrystallization from ethyl acetate, showed a melting point of 118°-120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:17][C:11]3[C:12](=[O:16])[NH:13][CH2:14][CH2:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]([C:22]1[CH:27]=[CH:26][C:25](Br)=[CH:24][N:23]=1)=[O:21].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:18][O:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([N:13]2[CH2:14][CH2:15][C:10]3[CH:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[S:17][C:11]=3[C:12]2=[O:16])=[CH:24][N:23]=1)=[O:21]
Reactant: O=C1NCCc2cc(-c3ccc(Cl)cc3)sc21
Reactant: COC(=O)c1ccc(Br)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(N2CCc3cc(-c4ccc(Cl)cc4)sc3C2=O)cn1
Yield: 76.5 %

Procedure:
Combine 2-(4-chloro-phenyl)-5,6-dihydro-4H-thieno[2,3-c]pyridin-7-one (0.351 g, 1.32 mmol) and 5-bromo-pyridine-2-carboxylic acid methyl ester (Song, J.; Yee, N. K. J. Org. Chem. 2001, 66, 605) (0.345 g, 1.59 mmol) in dioxane (20 mL). Treat the solution with Xantphos (38 mg, 0.066 mmol) and Cs2CO3 (0.647 g, 1.97 mmol). Degas the reaction by purging with nitrogen for 5 min. Add Pd2(dba)3 (12 mg, 0.0132 mmol) and reflux the reaction mixture overnight. Dilute with EtOAc (100 mL) and water (100 mL). Collect the insoluble material by filtration. Wash with water (2×20 mL) and EtOAc (2×20 mL) and dry in a vacuum oven to give 0.403 g (76%) of the title compound. LC-MS/ES (35Cl) 399.0 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6](=O)[CH3:7])(=[O:4])=[O:3].[ClH:9].[CH2:10]([NH:17][NH2:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CO>[ClH:9].[CH2:10]([NH:17][N:18]=[C:6]([CH3:7])[CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)CS(C)(=O)=O
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: CO
Product: CC(CS(C)(=O)=O)=NNCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 102.8 %

Procedure:
To a 50 ml volume three-necked flask, 1-methylsulfonyl-2-propanone (7-2-1) (2.01 g), methanol (10 ml) and benzylhydrazine monohydrochloride (14-c) (2.56 g) were added under a nitrogen atmosphere at room temperature, then additional methanol (10 ml) was added. The resulting reaction mixture was stirred at room temperature for three days, and filtered to give the primary crystal. The filtrate was concentrated under reduced pressure, and filtered again to give the crystal. The crystal was combined with the primary crystal to give 4.2 g of 1-benzyl-2-(1-methylsulfonyl-2-propylidene)hydrazine monohydrochloride (5-2-3). Additionally, the hydrochloride (5-2-3) (0.28 g) was dissolved in saturated aqueous sodium hydrogen carbonate solution (5.0 ml), and extracted with tert-butyl methyl ether (5.0 ml) 2 times. Then, the organic layer was concentrated under reduced pressure to give 0.22 g of 1-benzyl-2-(1-methylsulfonyl-2-propylidene)hydrazine (5-2-3′). NMR data of Compound (5-2-3′) is shown below.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:8][C:6]1[CH:7]=[C:2]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)[CH:3]=[N:4][CH:5]=1
Reactant: CN1CCNCC1
Reactant: Brc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(c2cncc(Br)c2)CC1
Temperature: 120 °C
Reaction time: 24 h
Yield: 79.7 %

Procedure:
To a solution of 3,5-dibromopyridine (XXXVIII) (2.90 g, 12.24 mmol) in dry DMF (20 mL) was added 1-methylpiperazine (2.987 mL, 26.93 mmol) and K2CO3 (5.58 g, 40.39 mmol). The reaction was heated at 120° C. overnight. An additional portion of 1-methylpiperazine (6 mL) was added and heating was continued for another 24 h. The reaction was poured into ice water and filtered. The filtrate was extracted with 66% MeOH/CHCl3. The organic layer was dried over MgSO4, filtered and concentrated under vacuum to yield 1-(5-bromopyridin-3-yl)-4-methylpiperazine (XL) as a brown viscous oil (2.49 g, 9.76 mmol, 79.8% yield). ESIMS found for C10H14BrN3 m/z 256 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:6]=2[CH:16]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1[O:31][CH3:32].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=4[O:31][CH3:32])[CH2:14][CH2:15]3)[C:6]=2[CH:16]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: Fc1ccc2onc(C3CCNCC3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2noc3ccc(F)cc23)CC1
Yield: 93.8 %

Procedure:
A mixture of 5-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 0.01 mole), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (2.4 g, 0.01 mole), K2CO3 (1.4 g), a few crystals of KI and acetonitrile (100 ml) was stirred and refluxed for 8 hours. The reaction was poured into water and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed (brine), dried (MgSO4), and concentrated to afford 4.0 g of a white solid. The solid was chromatographed on a Waters Prep 500 HPLC utilizing silica gel columns and eluting with methylene chloride/methanol (5%). Concentration of the appropriate fractions afforded 2.0 g (47%) of 1-[4-[3-[4-(5-fluoro-1,2-benzisoxazol-3-yl-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone as a white crystalline solid, m.p.=103°-105° C.
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]([CH:21]3[CH2:24][CH2:23][CH2:22]3)[CH3:20])=[N:18][C:12]=2[O:11][C@@H:10]([CH2:25][O:26][CH3:27])[CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C.[ClH:34]>CO.[OH-].[OH-].[Pd+2]>[ClH:34].[CH:21]1([N:19]([CH3:20])[C:17]2[CH:16]=[N:15][C:13]3[CH2:14][NH:8][CH2:9][C@H:10]([CH2:25][O:26][CH3:27])[O:11][C:12]=3[N:18]=2)[CH2:22][CH2:23][CH2:24]1
Reactant: COC[C@H]1CN(Cc2ccccc2)Cc2ncc(N(C)C3CCC3)nc2O1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC[C@H]1CNCc2ncc(N(C)C3CCC3)nc2O1
Temperature: 50 °C
Reaction time: 6 h
Yield: 62 %

Procedure:
To a solution of (6R)-8-benzyl-N-cyclobutyl-6-(methoxymethyl)-N-methyl-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepin-3-amine (390 mg) in methanol (10 mL) was added 20% Pd(OH)2/C (50 mg), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 6 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To a solution of the obtained crude product in ethyl acetate (10 ml) was added a 4 N hydrogen chloride-ethyl acetate solution (291 μL) and the mixture was stirred for 5.5 hr. The reaction mixture was filtered, and the obtained crystals were washed with ethyl acetate to give the title compound (206 mg, 62%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N+:13]([C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[S:26](Cl)(=[O:28])=[O:27])([O-:15])=[O:14].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:26]([C:17]2[CH:18]=[CH:19][C:20]([C:22]([F:24])([F:25])[F:23])=[CH:21][C:16]=2[N+:13]([O-:15])=[O:14])(=[O:27])=[O:28])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Cl
Reactant: Nc1ccc(F)c2cccnc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Nc1ccc(F)c2cccnc12
Yield: 58.5 %

Procedure:
In a similar fashion using route 14 general procedure 27, 5-fluoro-quinolin-8-ylamine (Intermediate 50) (280 mg, 1.73 mmol), 2-nitro-4-trifluoromethylbenzenesulfonyl chloride (0.6 g, 2.07 mmol), DMAP (cat), pyridine (0.42 ml, 5.19 mmol) and DCM (5 ml) gave the title compound (420 mg, 59%) after purification by column chromatography with DCM/MeOH (98:2) as the eluent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:12]=2[OH:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1OCCOCCOCCOCCOCCOC1.Cl[C:48]1[C:53]([CH3:54])=[CH:52][C:51]([N+:55]([O-:57])=[O:56])=[CH:50][C:49]=1[CH3:58]>CN1CCCC1=O>[CH3:54][C:53]1[CH:52]=[C:51]([N+:55]([O-:57])=[O:56])[CH:50]=[C:49]([CH3:58])[C:48]=1[O:17][C:15]1[CH:14]=[CH:13][C:12]([OH:18])=[C:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH:16]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Cl
Reactant: O=S(=O)(c1ccc(F)cc1)c1cc(O)ccc1O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)c(S(=O)(=O)c2ccc(F)cc2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 73.8 %

Procedure:
A solution of 2-(4-Fluoro-benzenesulfonyl)-benzene-1,4-diol (10.0 grams, 37 mmol) in dry 1-methyl-2-pyrrolidinone (100 mL) with 3° A molecular sieves (3.0 grams) was sparged with dry nitrogen for 15 minutes at room temperature. The solution was cooled to 0° C. and potassium bis(trimethylsilyl)amide (18.6 grams, 93.2 mmol) was added in a single portion to give a deep red suspension. The suspension was warmed to room temperature with continued sparging. 18-Crown-6 (10.8 grams 41.0 mmol) was added in a single portion and the resulting solution was cooled to 0° C. To the cooled suspension was added 2-chloro-1,3-dimethyl-5-nitro-benzene (8.30 grams, 44.7 mmol) to give a brown solution and sparging was ceased. The solution was allowed to warm to room temperature and stirred under dry nitrogen for 3 hours. The reaction mixture was poured into 1M hydrochloric acid (1 L) at 0° C. and extracted with ethyl acetate (3 times 300 ml). The combined organic extracts were washed with 1 M hydrochloric acid (4 times 1 L), brine (1 L), dried over anhydrous sodium sulfate and filtered. The filtrate was treated with activated carbon, filtered, and concentrated. The crude product was purified by chromatography on silica gel (150 grams) (methanol:hexanes:methylene chloride=1:9:10, 1.5 L) to give the title compound as a tan solid (11.4 grams). 1H NMR (400 MHz, CD3OD) δ8.05 (s, 1H), 8.00-7.95 (m, 2H), 7.28 (d, 1H), 7.26-7.20 (m, 2H), 6.93 (dd, 1H), 6.82 (d, 1H), 2.19 (s, 6H). MS (APCI−) Calc.: 417.1, Found: 416.0 (M−1).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[C:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11](=[O:21])[C:10]([C:22](=[O:30])[CH:23]=[C:24]([OH:29])[C:25]([O:27]C)=[O:26])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1>[CH2:1]([N:8]1[CH:13]=[C:12]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:11](=[O:21])[C:10]([C:22](=[O:30])[CH:23]=[C:24]([OH:29])[C:25]([OH:27])=[O:26])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(O)=CC(=O)c1cn(Cc2ccccc2)cc(Cc2ccccc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(O)=CC(=O)c1cn(Cc2ccccc2)cc(Cc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A mixture of methyl-4-(1,5-dibenzyl-1,4-dihydro-4-oxopyridin-3-yl)-2-hydroxy-4-oxobut-2-enoate 15, (0.080 g, 0.19 mmol) and 1 N NaOH (4 mL) in THF (12 mL) was stirred at 0° C. for 4 h. THF was distilled off and the residue acidified with 1 N HCl and extracted with EtOAc (2×25 mL), washed with brine solution (1×25 mL), dried over anhydrous Na2SO4 and EtOAc distilled off to give a yellow solid. The crude solid was triturated with diethylether, filtered and dried under vacuum. Finally the solid was triturated with chloroform, filtered and dried under vacuum for 24 h. Yield 0.065 g (84%), yellow solid, mp 140-142° C. 1H NMR (CDCl3+MeOH-d4, 500 MHz): δ 3.80 (s, 2H, CH2), 4.97 (s, 2H, CH2), 6.95 (t, 1H, CH, J=1 Hz), 7.13-7.40 (m, 11H, Ar—H and olefenic CH), 8.36 (d, 1H, CH, J=2.5 Hz). 13C NMR (CDCl3, 125 MHz): δ 33.4, 61.2, 120.5, 126.5, 127.5, 127.6, 128.6, 128.7, 128.7, 129.1, 129.1, 129.2, 129.2, 129.2, 129.4, 133.8, 135.9, 137.2, 138.2, 143.8, 163.8, 175.4. HRMS (M+H)+ calcd for C23H20NO5 390.1341, found 390.1343.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:23][CH2:22]2)[CH2:10]1)=O)(C)(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>>[CH3:37][S:38]([NH:8][C@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:23][CH2:22]2)[CH2:10]1)(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](CN2CCC(CCCc3ccc(F)cc3)CC2)[C@@H](c2ccccc2)C1
Product: CS(=O)(=O)N[C@@H]1C[C@H](CN2CCC(CCCc3ccc(F)cc3)CC2)[C@@H](c2ccccc2)C1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-(N-(t-butoxycarbonyl)amino)-3-(S)-((4-(3-(4-fluorophenyl)prop-1-yl)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 30 in Step A and methylsulfonyl chloride in Step B, the title compound can be prepared.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH:11](O)[CH3:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:16])=O>ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH:11]([Cl:16])[CH3:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1cc(C(C)(C)C)ccn1
Solvent: ClCCl
Product: CC(Cl)c1cc(C(C)(C)C)ccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
4-t-Butyl-2-(1-hydroxyethyl)-pyridine (3.6 g, 20.1 mmole) is dissolved in 60 ml dichloromethane in a 200 ml one neck round bottom flask under nitrogen. The solution is cooled to 0° C., is treated with thionyl chloride (2.2 ml, 30 mmole) in 10 ml dichloromethane, and the reaction is stirred 1 h at 0° C. followed by 2 h at room temperature. The reaction is quenched with 1×75 ml saturated sodium bicarbonate, the layers are separated and the aqueous layer is extracted with 3×25 ml dichloromethane. The combined organics are dried over potassium carbonate and are concentrated in vacuo to give 3.9 g (98%) of 4-t-Butyl-2-(1-chloroethyl)-pyridine as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].O.[NH2:13][C:14]1[NH:18][N:17]=[N:16][N:15]=1>C(O)C.C(O)(=O)C>[NH:15]1[C:14]([NH:13][CH2:7][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=[CH:10][CH:9]=2)=[N:18][N:17]=[N:16]1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: Nc1nnn[nH]1
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cccc(CNc2nnn[nH]2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 19.1 %

Procedure:
A mixture of 3-nitrobenzaldehyde (1.51 g) and 5-aminotetrazole monohydrate (1.03 g)in absolute ethanol (30 ml) and glacial acetic acid (0.57 ml) was stirred at room temperature for 40 minutes and then refluxed under nitrogen for 5 hours 30 minutes. Solvents were removed under high vacuum and the remaining solid was suspended in absolute ethanol (50 ml) and treated at room temperature with solid sodium borohydride (1.2 g) over 20 minutes. After a further 15 hours of stirring, the solvent was removed under vacuum and the residue was dissolved in water (100 ml) and extracted with diethyl ether (2×30 ml). The basic aqueous phase was acidified to pH 2 with 2N hydrochloric acid and the precipitated solid was collected by filtration, washed with water, diethyl ether, and finally recrystallized from absolute ethanol to give the title compound (420 mg) as white needles; mp 208°-210° C.; δH (250 MHz, DMSO-d6) 8.21 (1H, br s, Ar--H), 8.12 (1H, br d, J=9 Hz, Ar--H), 7.80 (1H, d, J=8 Hz, Ar--H), 7.70 (1H, br t, J=6.3 Hz, --NH--), 7.64 (1H, t, J=8 Hz, Ar--H), 4.53 (2H, d, J=6.3 Hz, --CH2 --); m/z (CI) 220 (M-).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH3:15])[N:14]=1)[C:8]([NH:10][NH2:11])=[O:9])[CH:2]([CH3:4])C.[CH2:16](C(C1C=C(C=C(C)N=1)C(O)=O)CC)[CH3:17]>>[CH2:16]([CH:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH3:15])[N:14]=1)[C:8]([NH:10][NH2:11])=[O:9])[CH2:2][CH3:4])[CH3:17]
Reactant: Cc1cc(C(=O)NN)cc(CC(C)C)n1
Reactant: CCC(CC)c1cc(C(=O)O)cc(C)n1
Product: CCC(CC)c1cc(C(=O)NN)cc(C)n1

Procedure:
The title compound is prepared in analogy to 2-isobutyl-6-methyl-isonicotinic acid hydrazide starting from 2-(1-ethyl-propyl)-6-methyl-isonicotinic acid; LC-MS: tR=0.49 min, [M+1]+=222.02.