Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F-].[Cs+].Cl[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>CN(C=O)C>[C:1]1([S:7][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCc1ccccn1
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: c1ccc(SCc2ccccn2)cc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
Thiophenol 2(2) (2.77 g, 0.025 mol), cesium carbonate (24.65 g, 0.075 mol) and catalytical amount of cesium fluoride were added successively to a solution of 2-chloromethylpyridine 6(1) (1.13 g, 0.017 mol) in absolute DMF (28 ml). The reaction mixture was stirred at 50-60° C. for 2 h in argon current and left for night at 20° C. Solvent was removed in vacuo, the residue was dissolved in water, the reaction product was extracted with CH2Cl2, dried over MgSO4, solvent was evaporated in vacuo. It gave 2-phenylsulphanylmethylpyridine 6(2), 3.2 g, (95%).
Reaction SMILES: C1N=CN([C:6]([N:8]2[CH:12]=[N:11][CH:10]=[CH:9]2)=[O:7])C=1.[CH:13]([OH:16])([CH3:15])[CH3:14]>C(Cl)Cl>[CH:13]([O:16][C:6]([N:8]1[CH:9]=[CH:10][N:11]=[CH:12]1)=[O:7])([CH3:15])[CH3:14]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)O
Solvent: ClCCl
Product: CC(C)OC(=O)n1ccnc1
Temperature: 25 °C
Yield: 17.4 %

Procedure:
To a solution of CDI (2 g, 12.33 mmol), in DCM (25 mL) was added isopropyl alcohol (0.95 mL, 12.33 mmol) at 0° C. The reaction mixture was stirred at r.t. and progress of the reaction was monitored by TLC. On completion, the reaction mixture was diluted with DCM (100 mL). The organic layer was washed with water (25 mL), brine (25 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 1:10 ethyl acetate:Pet. ether) to provide title compound (330 mg, 77%) as colourless viscous oil.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:27][CH2:26][CH2:25][C@H:6]1[C:7]([N:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])([OH:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH3:43][CH:44]([CH3:53])[C@H:45]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)O>ClCCl>[CH3:43][CH:44]([CH3:53])[C@H:45]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[O:2][C:1](=[O:3])[CH2:4][N:5]1[CH2:27][CH2:26][CH2:25][C@H:6]1[C:7]([N:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8]
Reactant: CC(C)[C@@H](O)c1ccccc1
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O[C@@H](c1ccccc1)C(C)C
Yield: 29.6 %

Procedure:
Using the procedure described previously, a solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (298 mg, 0.73 mmol), 4-N,N-dimethylaminopyridine (100 mg, 0.82 mmol, 1.3 eq), 1,3-dicyclohexylcarbodiimide (242 mg, 1.17 mmol, 1.8 eq) in dichloromethane (10 mL) was treated with (R)-2-methyl-1-phenyl-1-propanol (100 mg, 0.64 mmol, 1.3 eq). After TLC indicated the reaction was complete, the mixture was purified by HPLC to provide 96.2 mg (30%) of L-isoleucine, N-[1-(2-(2-methyl-1-(R)-phenyl-1-propoxy)-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][C:11]2=[O:14])=[CH:6][CH:5]=1
Reactant: O=C1NCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)C(=O)NCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
A suspension of 7-nitro-3,4-dihydro-2H-isoquinolin-1-one (11.6 g, 60 mmol) and 10% Pd/C (1.2 g,) in MeOH was stirred overnight at RT under H2 (40 psi). The mixture was filtered through Celite® and washed with MeOH. The filtrate was evaporated under vacuum to afford 8.2 g of 7-amino-3,4-dihydro-2H-isoquinolin-1-one, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:11][C:10]=2[CH2:20][OH:21])=[CH:4][CH:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27](O)=[CH:28][CH:29]=2)[CH:24]=[N:23]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([CH:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[N:11][C:10]=2[CH2:20][O:21][C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[NH:22][N:23]=[CH:24]3)=[CH:4][CH:3]=1
Reactant: OCc1nc(C2CCOCC2)oc1Sc1ccc(Cl)cc1
Reactant: Oc1ccc2[nH]ncc2c1
Product: Clc1ccc(Sc2oc(C3CCOCC3)nc2COc2ccc3[nH]ncc3c2)cc1

Procedure:
Prepared from {5-[(4-chlorophenyl)sulfanyl]-2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazol-4-yl}methanol (INTERMEDIATE C6.1) and 1H-indazol-5-ol using a similar procedure as described in the preparation of example B2.1. MS: M+H=442.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[C:5](C)=[CH:6][CH:7]=1.[Mg]>O1CCCC1.[Cu](Cl)Cl>[C:9]1([C:4]2[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=2)[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: Cc1ccc(Br)cc1C
Agent: Cl[Cu]Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 50.8 %

Procedure:
A solution of 13.7 g of 4-bromo-o-xylene in 50 ml of dry tetrahydrofuran is added dropwise to a suspension of magnesium filings (1.95 g) in 50 ml of dry tetrahydrofuran in the course of 1 hour. After refluxing in an argon atmosphere for 2 hours, the mixture is cooled to room temperature and 9.4 g of anhydrous copper(II) chloride are added in portions. The mixture is poured onto ice-water and extracted twice with 100 ml of diethyl ether each time. The organic phase is washed with 2N hydrochloric acid and saturated sodium chloride solution. Drying with magnesium sulfate, evaporation and crystallisation of the residue from ethanol gives 2.9 g of biphenyl.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Br[CH2:32][CH:33]1[CH2:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH:33]1([CH2:32][N:17]([CH2:16][C:14]2[S:15][C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=3)=[CH:12][CH:13]=2)[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:28])[F:29])(=[O:20])=[O:19])[CH2:36][CH2:35][CH2:34]1
Reactant: BrCC1CCC1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3C(F)(F)F)s2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1cccc(-c2ccc(CN(CC3CCC3)S(=O)(=O)c3ccccc3C(F)(F)F)s2)c1

Procedure:
In analogy to example 10, step 3, N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide (example 27, step 1) was reacted with (bromomethyl)-cyclobutane and cesium carbonate in N,N-dimethylacetamide to give N-cyclobutylmethyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide as a light yellow semi-solid. MS: 560.7 ([M+NH4]+)
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[CH2:5][C:6]2=[O:11].[N+:13]([O-])([OH:15])=[O:14]>CCOCC>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[CH:5]([N+:13]([O-:15])=[O:14])[C:6]2=[O:11]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc2c1C(=O)CC2=O
Solvent: CCOCC
Product: Cc1cccc2c1C(=O)C([N+](=O)[O-])C2=O
Reaction time: 0.17 h

Procedure:
To a stirred suspension of 4-methyl-1,3-indanedione (1.02g.0.006 mole) in anhydrous ether (5 ml) at ca 10°C was added dropwise and with stirring fuming nitric acid (2.0 ml). After 10 mins. a clear, dark solution formed followed by precipitation of a bright yellow solid. The mass was filtered and washed with 5N hydrochloric acid. Recrystallisation from water/hydrochloric acid afforded the title compound, m.p. 108°-9°C. (Found; C, 56.16; H, 3.74; N, 6.32; C10H7NO4.1/2H2O requires; C, 56.07; H, 3.76; N, 6.54%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:20]=[CH:19][C:8]2[C:9]([CH2:13]/[CH:14]=[CH:15]/[CH2:16][CH2:17][CH3:18])([CH3:12])[CH2:10][O:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].C(O)C.Cl>O1CCCC1.O>[CH2:13]([C:9]1([CH3:12])[C:8]2[CH:19]=[CH:20][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[O:11][CH2:10]1)/[CH:14]=[CH:15]/[CH2:16][CH2:17][CH3:18]
Reactant: CCC/C=C/CC1(C)COc2cc(C(=O)OC)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCC/C=C/CC1(C)COc2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 3-((E)-Hex-2-enyl)-3-methyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (200 mg, 0.73 mmol), sodium hydroxide (200 mg, 5 mmol), ethanol (7 ml) and water (1 ml) in tetrahydrofuran (7 ml), was stirred for 12 h at room temperature. The reaction medium was acidified by adding a 1.2 M hydrochloric acid solution and extracted with ethyl acetate. The organic phase was washed with water, dried (Na2SO4), and concentrated in a rotary evaporator. The product was obtained as colorless oil which crystallized (M: 155 mg, 82%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[CH:7]/[CH:8]([N:25]([OH:28])[CH:26]=[O:27])[CH2:9][S:10]([N:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[CH:18][CH:19]=2)[CH2:14]1)(=[O:12])=[O:11].[H][H]>CO.[Pd]>[OH:28][N:25]([CH:8]([CH2:9][S:10]([N:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[CH:18][CH:19]=2)[CH2:14]1)(=[O:11])=[O:12])[CH2:7][CH2:6][CH:2]1[CH2:3][CH2:4][CH2:5][O:1]1)[CH:26]=[O:27]
Reactant: COc1ccc2c(c1)CN(S(=O)(=O)CC(/C=C/c1ccco1)N(O)C=O)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1)CN(S(=O)(=O)CC(CCC1CCCO1)N(O)C=O)CC2
Yield: 33.2 %

Procedure:
A solution of N-((2E)-3-(2-furyl)-1-{[(7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]methyl}prop-2-en-1-yl)-N-hydroxyformamide (30 mg, 0.073 mmol) in MeOH (3 ml) was hydrogenated over 10% Pd/C under 5 bars of hydrogen for 2 hours. The reaction mixture was filtered and the solvent was evaporated under reduced pressure to give the title compound (33) as a colorless oil (10 mg, 33%). HPLC, Rt: 3.2 min (purity: 84.3%). LC/MS, M+(ESI): 413.3, M−(ESI): 411.2.
Reaction SMILES: [C:1]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:13][CH:12]=1)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.[Pd]>[C:4]1([CH2:3][CH2:2][C:1]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:16]=2)=[O:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)CCCc1ccc(C(=O)C=Cc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCc1ccc(C(=O)CCc2ccccc2)cc1
Reaction time: 5 h
Yield: 98.8 %

Procedure:
To a solution of 3.89 g of methyl 4-(4-cinnamoylphenyl)butyrate in 50 ml of methanol, 0.25 g of 10% palladium on carbon was added, and hydrogenation was carried out at an ordinary temperature and under ordinary pressure for 5 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give 3.87 g of pale brown oil.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH:21]4[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=[CH:5]1.[CH3:28][S:29]([CH2:32][C:33](O)=[O:34])(=[O:31])=[O:30]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33](=[O:34])[CH2:32][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=[CH:5]1
Reactant: NC1CCC(CCN2CCN(c3nccc4ccoc34)CC2)CC1
Reactant: CS(=O)(=O)CC(=O)O
Agent: Cl
Product: CS(=O)(=O)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4ccoc34)CC2)CC1

Procedure:
The title compound, white solid (72 mg, 80%), MS (ISP) m/z=449.3 [(M+H)+], mp 182° C., was prepared in accordance with the general method of example 6 from 4-[2-(4-furo[2,3-c]pyridin-7-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate C) (88 mg, 0.2 mmol) and 2-methanesulfonyl-acetic acid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.Cl.Cl[CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]1[CH3:25]>C(N(CC)CC)C>[CH3:25][N:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH:19]1[CH2:18][CH2:17][N:2]1[CH:3]=[C:4]([B:6]2[O:7][C:8]([CH3:9])([CH3:10])[C:11]([CH3:13])([CH3:12])[O:14]2)[CH:5]=[N:1]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CN1CCCCC1CCCl
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCCCC1CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 90 °C

Procedure:
The title compound was prepared from pyrazole-4-boronic acid pinacol ester and 2-(2-chloroethyl)-1-methylpiperidine hydrochloride according to Method AC (heating to 90° C. for 6 days before addition of further 2-(2-chloroethyl)-1-methylpiperidine hydrochloride and triethylamine, then heating to 90° C. for a further 3 days) and was isolated as a brown oil (quantitative). LCMS (ES+) 320 (M+H)+, RT 1.85 minutes (Method 1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:17][CH:18]1[CH2:23][CH2:22][CH:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:20][CH2:19]1>CN1C(=O)CCC1.O>[N:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:17][CH:18]3[CH2:23][CH2:22][CH:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:20][CH2:19]3)[N:7]=2)[N:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=12
Reactant: CS(=O)(=O)NC1CCC(N)CC1
Reactant: Clc1nccc(-c2cnc3ccccn23)n1
Solvent: CN1CCCC1=O
Solvent: O
Product: CS(=O)(=O)NC1CCC(Nc2nccc(-c3cnc4ccccn34)n2)CC1
Temperature: 105 °C
Reaction time: 10 h
Yield: 2.8 %

Procedure:
A mixture of 3-(2-chloropyrimidin-4-yl)-imidazo[1,2-a]pyridine (0.125 g), N-(4-amino-cyclohexyl)-methanesulfonamide (0.372 g), and TEA (0.38 mL) in NMP (3 mL) was stirred at 105° C. for 10 h. The reaction mixture was cooled to RT, diluted with water, and the resulting solid filtered, washed with water, and dried. The product was purified by ISCO using 100% DCM to 15% MeOH/DCM, the pure fractions combined and concentrated, then titurated with EtOAc. The resulting solid was filtered and dried at 50° C. under vacuum overnight to provide N-[4-(4-imidazo[1,2-a]pyridin-3-yl-pyrimidin-2-ylamino)-cyclohexyl]-methanesulfonamide (compound 10, 5.8 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17]>C1COCC1>[CH3:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8])=[O:17]
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)Nc2ccc(Cl)c(C(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a stirring solution of 5-amino-2-chlorobenzoic acid (880 mg, 5.1 mmol) in anhydrous THF (45 mL), 3-methylbenzoyl chloride (870 mg, 5.6 mmol) was added slowly. The mixture was stirred at room temperature under argon for overnight. The solvent was removed under reduced pressure and re-crystallized from chloroform to afford the title compound as a white solid (1.2 g, 80%).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].O.[N+:9]([C:12]1[CH:21]=[C:20]2[C:15]([NH:16][C:17](=[O:23])[C:18](=[O:22])[NH:19]2)=[CH:14][C:13]=1[S:24](Cl)(=[O:26])=[O:25])([O-:11])=[O:10]>>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[S:24]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:12]=1[N+:9]([O-:11])=[O:10])[NH:19][C:18](=[O:22])[C:17](=[O:23])[NH:16]2)(=[O:25])=[O:26]
Reactant: OCCNCCO
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c(S(=O)(=O)Cl)cc2[nH]c1=O
Solvent: O
Product: O=c1[nH]c2cc([N+](=O)[O-])c(S(=O)(=O)N(CCO)CCO)cc2[nH]c1=O
Reaction time: 16 h
Yield: 52 %

Procedure:
To a solution of 10,5 g (0.1 mole) of diethanolamine in 40 ml of water 6.11 g (0.02 mole) of 1,2,3,4-tetrahydro-7-nitro-2,3-dioxo-6-quinoxalinesulfonyl chloride are added under stirring, the reaction mixture is stirred at room temperature for 6 hours and then allowed to stand for 16 hours. The separated crystals are filtered off, washed with water, dried and recrystallized from acetone. Thus 3.90 g (52%) of N,N-bis(2-hydroxyethyl)-1,2,3,4-tetrahydro-7-nitro-2,3-dioxo-6-quinoxaline sulfonamide are obtained, m.p.: 310-321° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][N:4]=1.[Br:10][C:11]1[CH:12]=[C:13]([CH2:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=1.O.[OH-].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Br:10][C:11]1[CH:12]=[C:13]([CH:17]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][N:4]=2)[C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)Cc1cccc(Br)c1
Reactant: Clc1ccc(CBr)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cs+]
Agent: [I-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)C(Cc1ccc(Cl)cn1)c1cccc(Br)c1

Procedure:
A suspension of 5-chloro-2-methylpyridine (Reference Example 66, Step A, 6.4 g, 50 mmol) and N-bromosuccinimide (12.5 g, 70 mmol) in 100 mL carbon tetrachloride was heated to gentle reflux (bath temperature 90° C.), and 2,2′-azobisisobutyronitrile (0.74 g) was added in several portions over 30 min. After stirring at this temperature for 5 h, the reaction mixture was concentrated. The resulting slurry was diluted with EtOAc (100 mL) and was washed with water (100 mL), saturated aqueous sodium bicarbonate/saturated aqueous sodium thiosulfate, and brine. The organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 2 to 15% ether in CH2Cl2/hexane (1:1) to afford 2-bromomethyl-5-chloropyridine (6.0 g, 60%), which was used immediately for the ensuing reaction. Thus, to a vigorously stirred solution of 2-bromomethyl-5-chloropyridine (6.0 g, 29 mmol) and 3-bromophenyl acetone (Step A, 6.0 g, 28 mmol) and tetrabutylammonium iodide (20 mg) in 30 mL CH2Cl2 at −78° C. was added cesium hydroxide monohydrate (10 g, 60 mmol), and the reaction was allowed to slowly warm to room temperate overnight. The reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2×100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 5 to 40% EtOAc in hexane to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 8.44 (d, 1H), 7.66 (dd, 1H), 7.46-7.41 (m, 2H), 7.24 (t, 1H), 7.22 (d, 1H), 7.15 (d, 1h), 4.42 (dd, 1H), 3.54 (dd, 1H), 3.07 (dd, 1H), 2.12 (s, 3H). LC-MS: m/e 338 (M+H)+ (3.0 min).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:5][CH:4]=1)=O.[S:24]1[CH2:28][C:27](=[O:29])[NH:26][C:25]1=[O:30].C([O-])(=O)C.[NH2+]1CCCCC1>C1(C)C=CC=CC=1>[O:30]=[C:25]1[NH:26][C:27](=[O:29])[C:28](=[CH:1][C:3]2[S:7][C:6]([C:8]3[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=3)[CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:5][CH:4]=2)[S:24]1
Reactant: O=C1CSC(=O)N1
Reactant: CC(C)(C)OC(=O)NCCc1cccc(-c2ccc(C=O)s2)c1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCc1cccc(-c2ccc(C=C3SC(=O)NC3=O)s2)c1
Yield: 74.2 %

Procedure:
A solution of 2.4 g (7.2 mmol) of tert-butyl [3-(5-formylthiophen-2-yl)benzyl]methylcarbamate, 0.85 g (7.2 mmol) of 2,4-thiazolidinedione and 0.2 g (1.4 mmol) of piperidinium acetate in 50 ml of toluene is refluxed for 4 hours in Dean-Stark apparatus. After cooling, the product precipitates. The precipitate is filtered off and washed with ethyl ether. 2.3 g (76%) of tert-butyl {3-[5-(2,4-dioxothiazolidin-5-ylidenemethyl)thiophen-2-yl]benzyl}methylcarbamate are obtained.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([O:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=2)=[CH:15][CH:16]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
A mixture of 4-(trifluoromethoxy)phenol (2.50 g, 14.036 mmol), 4-fluoro-1-nitrobenzene (1.98 g, 14.036 mmol), potassium carbonate (2.90 g, 20.982 mmol) and N,N-dimethylacetamide (15 ml) was stirred at 160° for 2 hours under argon atmosphere. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=10:1) to give the title compound (4.18 g, 100%) as a pale yellow solid.
Reaction SMILES: ClC1C=C(S(NC23CCC(C4N5C6C=CN(S(C7C=CC(C)=CC=7)(=O)=O)C=6N=CC5=NN=4)(CC2)CC3)(=O)=O)C=CC=1.[NH:42]([C:44]1[N:45]=[C:46]2[CH:52]=[CH:51][N:50]([S:53]([C:56]3[CH:62]=[CH:61][C:59]([CH3:60])=[CH:58][CH:57]=3)(=[O:55])=[O:54])[C:47]2=[N:48][CH:49]=1)[NH2:43].[C:63]([O:67][C:68]([NH:70][C:71]12[CH2:78][CH2:77][C:74]([C:79](O)=[O:80])([CH2:75][CH2:76]1)[CH2:73][CH2:72]2)=[O:69])([CH3:66])([CH3:65])[CH3:64]>>[S:53]([N:50]1[C:47]2=[N:48][CH:49]=[C:44]([NH:42][NH:43][C:79]([C:74]34[CH2:75][CH2:76][C:71]([NH:70][C:68](=[O:69])[O:67][C:63]([CH3:65])([CH3:64])[CH3:66])([CH2:72][CH2:73]3)[CH2:78][CH2:77]4)=[O:80])[N:45]=[C:46]2[CH:52]=[CH:51]1)([C:56]1[CH:62]=[CH:61][C:59]([CH3:60])=[CH:58][CH:57]=1)(=[O:54])=[O:55]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Reactant: CC(C)(C)OC(=O)NC12CCC(C(=O)O)(CC1)CC2
Agent: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C45CCC(NS(=O)(=O)c6cccc(Cl)c6)(CC4)CC5)n23)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(NNC(=O)C45CCC(NC(=O)OC(C)(C)C)(CC4)CC5)cnc32)cc1

Procedure:
The precursor to Example #H.1.1, 3-chloro-N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)benzenesulfonamide, was prepared as shown in Scheme B. 2-Hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (Preparation #9) and 4-(tert-butoxycarbonylamino)bicyclo-[2.2.2]octane-1-carboxylic acid are reacted following the conditions given in General Procedure A to give tert-butyl 4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)bicyclo[2.2.2]octan-1-ylcarbamate. This hydrazide is cyclized using the conditions given in General Procedure C to afford tert-butyl 4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-ylcarbamate. This carbamate is deprotected using General Procedure I to yield 4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-amine. This amine is sulfonylated using the conditions described in General Procedure N to give the precursor to Example #H.1.1. The reaction sequence detailed above is translated in the preparations and examples section to “using A from Preparation #9 and 4-(tert-butoxycarbonylamino)bicyclo-[2.2.2]octane-1-carboxylic acid [Prime Organics], C with TEA, I, N from 3-chlorobenzenesulfonyl chloride”.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1([CH2:11][C:12]([OH:14])=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.Cl>C(O)CCC>[ClH:1].[NH2:2][CH2:3][C:4]1([CH2:11][C:12]([O:14][CH2:3][CH2:4][CH2:5][CH3:6])=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: NCC1(CC(=O)O)CCCCCC1
Agent: Cl
Solvent: CCCCO
Product: CCCCOC(=O)CC1(CN)CCCCCC1

Procedure:
In an analogous manner as described in Example 7, 1-aminomethyl-1-cycloheptane-acetic acid hydrochloride is esterified with n-butanol in the presence of hydrogen chloride to give n-butyl 1-aminomethyl-1-cycloheptane-acetate hydrochloride in the form of a syrup, which is mixed with benzene and an equivalent amount of p-toluene-sulfonic acid. The mixture is evaporated in a vacuum to dryness. After crystallisation from chloroform/ether/hexane n-butyl 1-aminomethyl-1-cycloheptane-acetate .p-toluene-sulfonate is obtained. m.p. 116° - 118° C.