Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2C=C(C=CC=2)N)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.NC1C=C2C(CCCC2=O)=CC=1.[OH:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([NH:36][C:37]2[CH:46]=[C:45]3[C:40]([CH2:41][CH2:42][CH2:43][C:44]3=[O:47])=[CH:39][CH:38]=2)=[O:35])=[CH:29][C:28]=1[O:48][CH3:49].C(=O)C1C=CC=CC=1>Cl.C(O)C>[OH:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([NH:36][C:37]2[CH:46]=[C:45]3[C:40]([CH2:41][CH2:42][C:43](=[CH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:44]3=[O:47])=[CH:39][CH:38]=2)=[O:35])=[CH:29][C:28]=1[O:48][CH3:49]
Reactant: COc1cc(CC(=O)Nc2ccc3c(c2)C(=O)CCC3)ccc1O
Reactant: Nc1cccc(C2=CCCCC2)c1
Agent: Cl
Agent: Nc1ccc2c(c1)C(=O)CCC2
Solvent: O=Cc1ccccc1
Solvent: CCO
Product: COc1cc(CC(=O)Nc2ccc3c(c2)C(=O)C(=Cc2ccccc2)CC3)ccc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Instead of 3-(cyclohexen-1-yl)aniline (Intermediate 2) in Example 9, 7-amino-1-tetralone is treated in a similar manner to Example 9. The resulting 4-hydroxy-3-methoxy-N-[1-oxo-1,2,3,4-tetrahydronaphthalen-7-yl]phenylacetamide (1 g) is dissolved in 30% hydrogen chloride-ethanol (5 ml), and thereto is added benzaldehyde (433 mg). The mixture is stirred at 25° C. for 18 hours. The precipitated crystals are collected by filtration, and washed with diethyl ether to give the desired compound (700 mg).
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].[CH3:20][N:21]=[C:22]=[O:23]>>[NH2:17][C:16]1[C:4]([C:2]#[N:3])=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:22]([NH:21][CH3:20])=[O:23]
Reactant: CN=C=O
Reactant: N#Cc1c(OC[C@@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Agent: [Cl-]
Product: CNC(=O)N1CCC[C@H]1COc1cccc(N)c1C#N
Yield: 53 %

Procedure:
Prepared as in Example 191a from (S)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (Example 191b) and methyl isocyanate in 53% yield as a white solid. MS 275 (MH+).
Reaction SMILES: ClC1C=CC=[C:4]([C:8]([O:10]O)=[O:9])C=1.[CH2:12]([NH:19][CH2:20][CH2:21][C:22]1[CH:37]=[CH:36][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30](C(=O)C)=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl.ClCCl>[CH2:12]([NH:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:10][C:8](=[O:9])[CH3:4])=[CH:31][CH:32]=2)=[CH:36][CH:37]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)c1ccc(Oc2ccc(CCNCc3ccccc3)cc2)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(=O)Oc1ccc(Oc2ccc(CCNCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
Metachloroperbenzoic acid (0.23 g) was added to a solution of 1-{4-[4-(2-benzylamino-ethyl)-phenoxy]-phenyl}-ethanone (0.36 g) in chloroform (25 mL) while stirring at room temperature. Stirring was continued overnight then the reaction was diluted with dichloromethane, washed with saturated aqueous sodium thiosulfate, dried over sodium chloride/magnesium sulfate, filtered, and concentrated on a rotary evaporator. The residue was diluted with methanol (5 mL) and saturated aqueous sodium bicarbonate (5 mL) then stirred overnight at room temperature. The methanol was removed on a rotary evaporator and the pH of the residue was adjusted to 7-8 then extracted with dichloromethane (3×30 mL). The combined dichloromethane extracts were dried over sodium chloride/magnesium sulfate, filtered, and concentrated on a rotary evaporator to yield 0.4 g of crude product, which was purified by flash column chromatography on silica gel eluting with ethanol in dichloromethane to yield Acetic acid 4-[4-(2-benzylamino-ethyl)-phenoxy]-phenyl ester (117 mg), 1H NMR (CDCl3, 300.00 MHz): 8.01-7.93 (m, 2H), 7.42-7.21 (m, 7H), 7.06-6.97 (m, 4H), 3.87 (s, 2H), 3.02-2.94 (m, 4H), 2.61 (s, 3H); m/z=361.85(M+1).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[C:29]([F:31])[C:28]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=3)=[C:27]([F:44])[CH:26]=2)[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH2:16][C:17]([NH:19][C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH:26]=[C:27]([F:44])[C:28]([O:32][CH2:33][C:34]5[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:41])[F:42])=[CH:36][CH:35]=5)=[C:29]([F:31])[CH:30]=4)[N:24]=3)=[O:18])[C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14]
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Reactant: O=C(CBr)Nc1nc(-c2cc(F)c(OCc3ccc(C(F)(F)F)cc3)c(F)c2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ccn2CC(=O)Nc2nc(-c3cc(F)c(OCc4ccc(C(F)(F)F)cc4)c(F)c3)cs2)n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (33 mg, 0.184 mmol) with 2-bromo-N-{4-[3,5-difluoro-4-[4-(trifluoromethyl)benzyloxy)phenyl]-1,3-thiazol-2-yl}acetamide (112 mg, 0.221 mmol) in the presence of NaH (11 mg, 0.276 mmol) in dry DMF (3.0 mL) to give 25 mg of the product as a white solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 3.17 (s, 3H), 3.39 (s, 3H), 5.32 (br s, 4H), 6.22 (s, 1H), 7.35 (s, 1H), 7.70-7.72 (m, 4H), 7.78-7.80 (m, 3H), 12.68 (br s, 1H); ESI-MS (m/z) 606.15 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH:5]=[CH:6][C:7]1[C:8]([C:13]([OH:15])=[O:14])=[CH:9][CH:10]=[CH:11][CH:12]=1.[C:19](C1C=CC=CC=1CCC1C=C(C)C=CC=1)(O)=O>[Pd].CN(C)C=O>[C:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1[CH:1]=[CH:19][CH:16]=[CH:17][CH:18]=1)([OH:15])=[O:14]
Reactant: Cc1cccc(CCc2ccccc2C(=O)O)c1
Reactant: Cc1cccc(C=Cc2ccccc2C(=O)O)c1
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1CCCCc1ccccc1

Procedure:
A solution of 53.0 gm. of 3'-methylstilbene-2-carboxylic acid in 230 ml. dimethylformamide containing 2.0 gm. of 5% palladium on carbon is hydrogenated in a Parr shaker at 60 p.s.i. for 11/2 hours. The solution is filtered and added to ether and water. The organic layer is washed with water, then dried and evaporated. The product is recrystallized from ether-hexane to give 48 gm., 90%, of 3-(o-carboxyphenethyl)toluene, m.p. 82°-84° C. Use of 3'-ethylenestilbene-2-carboxylic acid gives a similar yield of 3-(o-carboxyphenethyl)ethylbenzene.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH2:8][S:9][CH3:10])[NH2:6].[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[S:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[O:34][C:33](=[O:35])[C:32]5([CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)[N:31]=4)=[CH:26][CH:25]=3)[N:23]=2)[CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH2:8][S:9][CH3:10])[NH:6][C:33]([C:32]1([NH:31][C:30]([C:27]2[CH:28]=[CH:29][C:24]([C:22]3[N:23]=[C:19]([N:16]4[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]4)[S:20][CH:21]=3)=[CH:25][CH:26]=2)=[O:34])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1)=[O:35]
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: CN1CCN(c2nc(-c3ccc(C4=NC5(CCCCC5)C(=O)O4)cc3)cs2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCSC)NC(=O)C1(NC(=O)c2ccc(-c3csc(N4CCN(C)CC4)n3)cc2)CCCCC1
Temperature: 80 °C
Reaction time: 15 h
Yield: 33.3 %

Procedure:
200 mg (1.00 mmol) of L-methionine methyl ester hydrochloride was added to a solution of 411 mg (1.00 mmol) of 2-[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one and 258 mg (2.00 mmol) of N,N-diisopropylethylamine in 20 ml of dimethylformamide. After the mixture was stirred at 80° C. for 15 hours, the reaction solution was concentrated under reduced pressure, ethyl acetate was added thereto, and the mixture was successively washed with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine and dried with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, it was purified by silica gel chromatography to obtain 191 mg (33%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:13]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[N+:12]([O-])[CH:11]=[C:10]([O:24][CH3:25])[C:9]=3[C:8]2=[O:26])=[CH:4][CH:3]=1.[C:29]([O:32]C(=O)C)(=[O:31])[CH3:30]>>[C:29]([O:32][C:11]1[N:12]=[C:13]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[C:14]2[CH2:15][CH2:16][N:7]([CH2:6][C:5]3[CH:27]=[CH:28][C:2]([F:1])=[CH:3][CH:4]=3)[C:8](=[O:26])[C:9]=2[C:10]=1[O:24][CH3:25])(=[O:31])[CH3:30]
Reactant: COc1c[n+]([O-])c(N(C)S(C)(=O)=O)c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Reactant: CC(=O)OC(C)=O
Product: COc1c(OC(C)=O)nc(N(C)S(C)(=O)=O)c2c1C(=O)N(Cc1ccc(F)cc1)CC2

Procedure:
A solution of N-[6-(4-fluorobenzyl)-4-methoxy-2-oxido-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl]-N-methylmethanesulfonamide (0.36 g, 0.889 mmol) in acetic anhydride (10 mL) was heated to 110° C. for 3 hours, then evaporated to dryness to give the intermediate 6-(4-fluorobenzyl)-4-methoxy-1-[methyl(methylsulfonyl)amino]-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl acetate (ES MS (M+1)=452). The crude material was dissolved in methanol (6 mL) and treated with sodium methoxide (30% by weight in methanol, 0.5 mL, 2.6 mmol). After 1 hour, the product mixture was neutralized with 6 N HCl, then concentrated. The residue was partitioned between CHCl3 and 10% KHSO4. The organic extract was dried with Na2SO4, filtered, and concentrated under vacuum to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.IC.[C:11](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH3:11])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1ccc(Br)c[nH]1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(Br)ccc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Bromopyridin-2(1H)-one (0.250 g, 1.44 mmol) was dissolved in DMF (3 mL) then added iodomethane (0.0943 ml, 1.51 mmol) and potassium carbonate (0.218 g, 1.58 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum. The remaining residue was dissolved in ethyl acetate then washed with water and brine. The aqueous layer was back-extracted with ethyl acetate (3×). The organic layers were combined and dried over sodium sulfate then concentrated under vacuum to afford 5-bromo-1-methylpyridin-2(1H)-one as an orange waxy solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C@H:23]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:24][OH:25].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>ClCCl>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([C:19]([NH:22][C@H:23]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:24][OH:25])=[O:21])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2c(OCc3ccccc3)cccn2c1C(=O)O
Reactant: CCCC[C@@H](N)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCC[C@H](CO)NC(=O)c1c(C)nc2c(OCc3ccccc3)cccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, 4 g (14.17 mmol) of 8-(benzyloxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid, 1.83 g (15.59 mmol) of (R)-(−)-2-aminohexanol and 7.166 g (70.85 mmol) of 4-methylmorpholine were suspended in 28 ml of dichloromethane. 5 g (15.59 mmol) of TBTU were then added, and the mixture was stirred at room temperature overnight. After 16 h, the mixture was diluted with 200 ml of dichloromethane and washed with 10% strength aqueous citric acid solution, with water and with saturated aqueous sodium chloride solution. The organic phase was concentrated and the residue obtained was purified on a silica gel cartridge (mobile phase dichloromethane:methanol=100:3). Concentration of the product fractions thus gave 3.83 g (71% of theory) of 8-(benzyloxy)-N-[(2R)-1-hydroxyhexan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][O:37][CH2:38][CH2:39][CH2:40][NH2:41]>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:41][CH2:40][CH2:39][CH2:38][O:37][CH3:36])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Reactant: COCCCN
Product: COCCCNCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 5 using tert-butyl (3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (488 mg, 0.96 mmol) and 3-methoxypropylamine (325 mg, 3.84 mmol) as starting materials.
Reaction SMILES: C([C:4]1[C:5](=[O:16])[O:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10](Cl)=[C:9](O)[CH:8]=2)(O)=O.C([N:20](C(C)C)CC)(C)C.ClCOCC1C=CC=CC=1.CN(C)CCN>C1COCC1.CN(C=O)C>[O:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[C:4]([NH2:20])[C:5]1=[O:16]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cc2cc(Cl)c(O)cc2oc1=O
Agent: CN(C)CCN
Agent: ClCOCc1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1cc2ccccc2oc1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 117.9 %

Procedure:
241 mg 3-carboxy-6-chloro-7-hydroxy coumarin (1 mmol) dissolved in the mixture of 5 ml THF and 5 ml DMF was added 200 ul diisopropylethylamine (DIEA, 1.1 mmol) and 330 mg O-(N-succinium)-N,N,N′,N′-tetramethyl uronium tetrafluoroborate (TSTU, 1.1 mmol). After stirring at room temperature for 20 minutes under nitrogen atmosphere, the reaction mixture was added 400 ul of DIEA and 460 ul benzyl chloromethyl ether (BOM-Cl) and stirred for another 2 hours at room temperature. The resulted mixture was then pulled high vacuum for 2 hours and 1 ml THF, 480 ul 2-dimethyaminoethylamine was added into the solution afterwards. After the reaction mixture was allowed to react at room temperature for 1 hour, the crude product was pulled high vacuum again overnight and purified on a silica gel column (chloroform: methanol=95:5 as eluent). 190 mg colorless solid was obtained as product, 44% yield. 1H NMR (CDCl3, ppm): 2.32 (d, 6H), 2.56 (t, 2H), 2.16 (t, 2H), 4.76 (s, 2H), 5.46 (s, 2H), 7.33 (m, 7H), 7.68 (s, 1H), 8.76 (s, 1H). MS: C22H23O5N2Cl, 430.3 calculated; 431.2 (M+1) found.
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15](C2C=CC=CC=2C([O-])=O)=[CH:14][C:13]=1[N+:27]([O-:29])=[O:28])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1C[O:33]CC1.Cl>CO.O>[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:33])=[CH:14][C:13]=1[N+:27]([O-:29])=[O:28])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C1CCOC1
Reactant: O=C([O-])c1ccccc1-c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1cc(O)ccc1OCc1ccccc1
Reaction time: 8 h
Yield: 95 %

Procedure:
Lithium hydroxide monohydrate (5.632 g, 134.2 mmol) was added to a stirred solution of compound 53 (2.343 g, 6.71 mmol) in 150 ml methanol and 50 ml water. THF (50 ml) was added after 20 minutes to increase solubility. The reaction mixture was stirred overnight and was then acidified with concentrated HCl. The reaction mixture was extracted five times with dichloromethane, and the combined organic layers were washed with brine and dried over MgSO4. The crude product was purified via flash chromatography over silica gel with gradual elutions from 80/10-50/50 (Hex/EtOAc). Evaporation of solvent yielded 1.567 g (95%) of a yellow solid.
Reaction SMILES: C([S:5]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[CH:19]=[CH:20][C:21](=[O:24])[NH:22][N:23]=3)[CH:15]=2)[CH2:10]1)(=[O:7])=[O:6])CCC.C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O>CN(C)C=O>[CH2:17]([CH:10]1[CH2:11][C:12]2[C:17](=[CH:16][CH:15]=[C:14]([C:18]3[CH:19]=[CH:20][C:21](=[O:24])[N:22]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:23]=3)[CH:13]=2)[CH:9]1[N:8]=[S:5](=[O:7])=[O:6])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCS(=O)(=O)NC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC1Cc2cc(-c3ccc(=O)n(Cc4ccccc4)n3)ccc2C1N=S(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 183.5 %

Procedure:
To 1.0 g of 2-n-butylsulfonylamino-5-[pyridazin-3(2H)-on-6-yl]indane dissolved in 30 ml of dimethylformamide were added 828 mg of potassium carbonate and 547 mg of benzyl bromide, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and crude crystals precipitated were collected by filtration, dried and then recrystallized from ethanol to obtain 1.15 g of 2-n-butyl sulfonylamino-5-[2-benzylpyridazin-3(2H)-on-6-yl]indane. This compound had the same physical property values as those of the compound obtained in Example 85.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:18][CH2:17][C@@H:16]([NH2:19])[CH2:15]2)=[N:12][CH:13]=1.C(N(CC)CC)C>ClCCl>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:18][CH2:17][C@@H:16]([NH:19][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH2:15]2)=[N:12][CH:13]=1
Reactant: COCC(=O)Cl
Reactant: N[C@@H]1CCN(c2ccc(Br)cn2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)N[C@@H]1CCN(c2ccc(Br)cn2)C1
Yield: 80.7 %

Procedure:
Add methoxyacetyl chloride (208 μL, 2.27 mmol) to a 0° C. solution of (R)-1-(5-bromo-pyridin-2-yl)-pyrrolidin-3-ylamine (0.5 g, 2.07 mmol) and triethylamine (317 μL, 2.27 mmol) in dichloromethane (10 mL). Remove the ice bath and stir the reaction overnight. Wash the reaction mixture with 10% aqueous NaHSO4 (20 mL). Separate the organic portion and extract the aqueous portion with dichloromethane (2×10 mL). Dry the combined organics over Na2SO4, filter, and concentrate to dryness. Purify using chromatography (0 to 5% MeOH/CH2Cl2) to afford 525 mg (81%) of the title compound. LC-MS/ES m/z (79Br) 314.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][O:6][C:7]([O:16][O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:15])[CH2:8][CH2:9][C:10](OCC)=[O:11])([CH3:4])([CH3:3])[CH3:2].[NH2:22][NH2:23].C(O)(C)C>O>[C:1]([O:5][O:6][C:7]([O:16][O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:15])[CH2:8][CH2:9][C:10]([NH:22][NH2:23])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CCC(C)(OOC(C)(C)C)OOC(C)(C)C
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)OOC(C)(CCC(=O)NN)OOC(C)(C)C
Reaction time: 20 h

Procedure:
4,4-Di-(t-butylperoxy)pentanohydrazide was prepared by reacting ethyl 4,4-di-(t-butylperoxy)pentanoate with 9 molar excess of 54% aqueous hydrazine. A 3-neck flask equipped with a magnetic stirrer, a thermometer and an addition funnel was charged with 125 mL of isopropanol (IPA), 15.3 g (0.05 mole) of 99% ethyl 4,4-di-(t-butylperoxy)pentanoate and 30 g (about 0.50 mole) of 54% aqueous hydrazine at 25° C. The solution was stirred for about 20 hours at 20°-25° C. Then the reaction mass was poured into 1000 mL of water and extracted once with 300 mL of methylene chloride. After drying over 10% by weight of anhydrous magnesium sulfate and separation of the spent desiccant by filtration, the methylene chloride was removed in vacuo leaving 14.4 g of liquid product. 30 mL of pentane were added and a solid was precipitated. The solid was separated by filtration and air dried, leaving 12.2 g (83.6% of theory, uncorrected) of a white solid having a melting point (mp) of 76°-78° C. An infrared (IR) spectrum of the product showed strong carbonyl absorption bands at 1640 cm-1 and at 1680 cm-1 and a strong NH band at 3300 cm-1. A DSC scan run on the product showed a peroxide decomposition exotherm at 170° C. These product data confirm that the product was 4,4-Di-(t-butylperoxy)pentanohydrazide (I-1).
Reaction SMILES: F.F.F.C(N(CC)CC)C.[B-](F)(F)(F)F.CCN([S+](F)[F:22])CC.[Cl:24][C:25]1[CH:26]=[C:27]([CH2:33]O)[C:28]([CH:31]=[CH2:32])=[N:29][CH:30]=1>C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[C:27]([CH2:33][F:22])[C:28]([CH:31]=[CH2:32])=[N:29][CH:30]=1
Reactant: C=Cc1ncc(Cl)cc1CO
Reactant: CCN(CC)[S+](F)F
Agent: F
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=Cc1ncc(Cl)cc1CF
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.2 %

Procedure:
To a solution of triethylamine trihydrofluoride (Aldrich, 1.9 mL, 12 mmol) in DCM (30 mL) at −78° C., was added Xtalfluor-E (4.1 g, 18 mmol, Aldrich), followed by a solution of (5-chloro-2-vinylpyridin-3-yl)methanol (2 g, 12 mmol) in DCM (40 mL). The cold bath was removed and the reaction mixture was allowed to warm from −78° C. to rt over a period of 15 min. The reaction was quenched by the addition of aqueous saturated bicarbonate solution. After 15 min stirring at rt, the reaction mixture was diluted with EtOAc and water. The organic phase was separated and dried over MgSO4. The filtrate was absorbed onto a plug of silica gel and purified by chromatography through, eluting with a gradient of 5% to 45% EtOAc in hexane, to provide the title compound as colorless oil (1.22 g). LC/MS m/z=172.1 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][OH:12].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][O:12][S:21]([CH3:20])(=[O:23])=[O:22]
Reactant: OCCc1ccccc1CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccccc1CCO
Temperature: 0 °C
Yield: 23 %

Procedure:
2-[2-(2-Hydroxy-ethyl)-phenyl]-ethanol (6.77 g/40 mmol) was dissolved in methylene chloride (100 mL) and cooled to 0° C. Triethylamine (11.0 mL/80 mmol) and methanesulfonyl chloride (5.25 mL/65 mmol) were added sequentially via addition funnel (dropwise). After an hour the reaction was poured into a separatory funnel and sequentially washed with 1 N hydrochloric acid (100 mL), water (100 mL) and saturated aqueous sodium bicarbonate (100 mL). The resulting organic solution was dried over magnesium sulfate, filtered and concentrated. Column chromatography on silica gel (eluting with 0→10% methanol/methylene chloride afforded methanesulfonic acid 2-[2-(2-hydroxy-ethyl)-phenyl]-ethyl ester (2.25 g/23%). 1H NMR (400 MHz, CDCl3) δ 7.25 (m, 4H), 4.42 (t, J=7.1 Hz, 2H), 3.88 (m, 2H), 3.15 (t, J=7.1 Hz, 2H), 2.93 (t, J=7.1 Hz, 2H), 2.85 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].[Br:11]Br.O>C(O)(=O)C>[Br:11][C:8]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:6]=[O:7]
Reactant: BrBr
Reactant: COc1cccc(C=O)c1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Br)c(C=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
50 g of 3-methoxybenzaldehyde are dissolved in 245 ml of acetic acid. 22 ml of bromine are added dropwise at 0° C., the medium is stirred at room temperature for 4 hours, and then left overnight at room temperature. 300 ml of water are added to the solution and the expected product crystallizes. After filtration and washing with water and drying, 68 g of 2-bromo-5-methoxybenzaldehyde having the empirical formula C8H7Br.O2 are obtained (M=114 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[C:35]([NH2:39])([CH3:38])([CH3:37])[CH3:36]>ClCCl>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH:39][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:6]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: CC(C)(C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cc(Cl)ccc1N
Yield: 76.8 %

Procedure:
Stir and cool to 0° C. a solution of 2-amino-5-chlorobenzoic acid (1.21 g, 10 mmol) and N-hydroxysuccinimide (1.38 g, 12 mmol) in dichloromethane (12 mL). Add, dropwise, a 1M solution of dicyclohexylcarbodiimide in dichloromethane (12 mL, 12 mmol), and stir at 0° C. for 1 h. Add tert-butyl amine (1.74 g, 23.79 mmol) by syringe and stir at ambient temperature overnight. Filter the reaction mixture and wash the filtrate with aqueous sodium bicarbonate. Dry the organic phase with MgSO4 and chromatograph over silica gel eluting with 4% ethyl acetate/dichloromethane to afford 1.74 g of the title compound: MS 227(M+H), m.p. 126–127° C.