Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([N:8]([CH3:31])[C@@H:9]2[CH2:13][CH2:12][N:11]([C:14]3[C:15]4[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:16]=4[N:17]=[CH:18][N:19]=3)[CH2:10]2)=[N:6][CH:7]=1.[NH:32]1[CH:36]=[CH:35][N:34]=[CH:33]1.C([O-])([O-])=O.[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>CN1C(=O)CCC1.O.[Cu]I>[N:32]1([C:2]2[N:3]=[CH:4][C:5]([N:8]([CH3:31])[C@@H:9]3[CH2:13][CH2:12][N:11]([C:14]4[C:15]5[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:28])[CH3:30])[C:16]=5[N:17]=[CH:18][N:19]=4)[CH2:10]3)=[N:6][CH:7]=2)[CH:36]=[CH:35][N:34]=[CH:33]1
Reactant: c1c[nH]cn1
Reactant: CN(c1cnc(Br)cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CN(c1cnc(-n2ccnc2)cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Temperature: 25 °C
Yield: 41 %

Procedure:
A mixture of (R)-5-bromo-N-methyl-N-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)pyrazin-2-amine (50 mg, 0.0991 mmol), imidazole (14 mg, 0.198 mmol), CuI (9.4 mg, 0.050 mmol), Cs2CO3 (32 mg, 0.0991 mmol), and 1,10-phenanthroline (9 mg, 0.050 mmol), in NMP (2 mL) was stirred at 180° C. for 45 minutes in a microwave reactor. It was then cooled to the ambient temperature and diluted with H2O, extracted with EtOAc, washed with brine, dried, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to give the title compound (20 mg, 41%).
Reaction SMILES: [NH2:1][C:2](=[O:46])[CH2:3][C:4]1[C:41]([C:42]([F:45])([F:44])[F:43])=[CH:40][CH:39]=[CH:38][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:28]1[CH2:29][CH2:30][CH:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:10]3[N:9]=[C:8]([CH2:7][CH2:6][C:5]4[CH:38]=[CH:39][CH:40]=[C:41]([C:42]([F:43])([F:44])[F:45])[C:4]=4[CH2:3][C:2]([NH2:1])=[O:46])[C:13]([C:14]([F:17])([F:15])[F:16])=[CH:12][N:11]=3)=[CH:20][CH:21]=2)[CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4cccc(C(F)(F)F)c4CC(N)=O)n3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Cc1c(CCc2nc(Nc3ccc(C4CCNCC4)cc3)ncc2C(F)(F)F)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.6 %

Procedure:
To a solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)-3-(trifluoromethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A97) (0.075 g, 0.12 mmol) in DCM (5 mL) was added TFA (0.20 mL, 2.6 mmol) and the resulting mixture was stirred at room temperature for 16 hours. The volatiles were evaporated under reduced pressure and the residue partitioned between water (20 mL) and EtOAc. The layers were separated and the aqueous layer extracted with EtOAc (2×20 mL). The combined organic extracts were dried using a phase separation cartridge then the volatiles were removed under reduced pressure. The residue was triturated with Et2O and the resulting precipitate collected by filtration to give the title compound 22 (56 mg, 88%); 1H NMR (400 MHz, d6-DMSO) δ 10.22 (s, 1H), 8.67 (s, 1H), 8.29 (brs, 1H), 7.68 (d, J=8.6 Hz, 2H), 7.57 (d, J=7.9 Hz, 1H), 7.52 (d, J=7.6 Hz, 1H), 7.48 (s, 1H), 7.41 (t, J=7.8 Hz, 1H), 7.19 (d, J=8.6 Hz, 2H), 6.94 (s, 1H), 3.73 (s, 2H), 3.38 (m, 2H), 3.10 (m, 4H), 2.98 (td, J=12.8, 2.6 Hz, 2H), 2.79 (tt, J=11.7, 2.7 Hz, 1H), 1.93 (d, J=15.8 Hz, 2H), 1.74 (qd, J=13.8, 4.0 Hz, 2H). LCMS-A: rt 4.99 min; m/z 552.3 [M+H]+.
Reaction SMILES: CN([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1P(C1CCCCC1)C1CCCCC1)C.B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].ClC1C=CC(C)=CC=1.[O:48]1CCOC[CH2:49]1>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:5]([C:10]1[CH:15]=[CH:14][C:13]([O:48][CH3:49])=[CH:12][CH:11]=1)[CH2:4][CH2:9][CH2:8][CH2:7][CH3:6]
Reactant: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: C1COCCO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccc(Cl)cc1
Product: CCCCCCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
General procedure for K3PO4 promoted Suzuki coupling of aryl chlorides: An oven-dried resealable Schlenk tube was purged with argon and charged with Pd(OAc)2 (0.01 mmol, 0.5 mol %), ligand 2 (0.015 mmol, 0.75 mol %), the boronic acid (3.0 mmol), and potassium phosphate (4.0 mmol). The tube was purged with argon, and dioxane (6 mL) and 4-chlorotoluene (2.0 mmol) were added through a rubber septum. The septum was removed, the tube was sealed with a teflon screw cap and the mixture was stirred at room temperature for 2 min, then heated to 100° C. with stirring until the starting aryl chloride had been completely consumed as judged by GC analysis. The reaction mixture was then cooled to room temperature, diluted with ether (20 mL) and poured into a separatory funnel. The mixture was washed with 1 M NaOH (20 mL), and the layers were separated. The aqueous layer was extracted with ether (20 mL), and the combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was then purified by flash chromatography on silica gel.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Br[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1>>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:7]1
Reactant: Brc1ccccn1
Reactant: C[C@@H]1CNCCN1
Product: C[C@@H]1CN(c2ccccn2)CCN1
Temperature: 120 °C
Yield: 89.1 %

Procedure:
(R)-(−)-2-Methylpiperazine (0.50 g, 0.005 mol, Aldrich) and 2-bromopyridine (5 mL, 0.05 mol) were combined and heated at 120° C. for 14 hours. The reaction mixture was allowed to cool to 23° C. and partitioned between a large volume of ethyl acetate and water. The layers were separated, and then additional water was added to the ethyl acetate solution. Drops of 1 N HCl solution were added to the water/ethyl acetate mixture with vigorous mixing. The layers were separated, and the combined aqueous phases were basified to pH ˜11 with a solution of saturated sodium bicarbonate and solid sodium carbonate. Sodium chloride was added, and the saturated aqueous solution was extracted with chloroform containing a few drops of isopropyl alcohol (5×). The combined organic extracts were dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to afford 0.79 g (89% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 1.02 (d, J=6.0 Hz, 3H), 2.27 (dd, J=10, 12 Hz, 1), 2.67 (m, 3H), 2.92 (m, 1H), 4.07 (m, 2H), 6.58 (dd, J=6, 8 Hz, 1H), 6.77 (d, J=8 Hz, 1H), 7.49 (m, 1H), 8.08 (m, 1H); MS (ESI) m/e 178 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[C:41](O)(=[O:48])[C:42]1[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=1.[OH-].[Na+]>>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]([C@@H:2]([NH:1][C:41](=[O:48])[C:42]2[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=2)[CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:4])(=[O:20])=[O:19])=[CH:26][CH:25]=1
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)C(c1ccccc1)c1ccccc1)S(=O)(=O)c1ccc(N)cc1
Reactant: O=C(O)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](NC(=O)c1ccncc1)C(c1ccccc1)c1ccccc1)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was then obtained in 76% yield using (2S,5S)-2-amino-N-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3,3-diphenyl-propionamide (product of example 72) and isonicotinic acid with general procedure A. However, 1.0N NaOH was used instead of 1.0N hydrochloric acid for the preparation of the title compound.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6]([CH3:9])([CH3:8])[N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:4]1[CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([O:24]C)[CH:19]=1.[CH3:26]I>CO>[OH:1][CH2:2][C@H:3]1[O:7][C:6]([CH3:9])([CH3:8])[N:5]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[C@H:4]1[CH2:17][C:18]1[CH:23]=[CH:22][N:21]([CH3:26])[C:20](=[O:24])[CH:19]=1
Reactant: COc1cc(C[C@H]2[C@@H](CO)OC(C)(C)N2C(=O)OC(C)(C)C)ccn1
Reactant: CI
Solvent: CO
Product: Cn1ccc(C[C@H]2[C@@H](CO)OC(C)(C)N2C(=O)OC(C)(C)C)cc1=O

Procedure:
(4S,5S)-Tert-butyl 5-(hydroxymethyl)-4-((2-methoxypyridin-4-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate (0.281 g, 0.797 mmol) was refluxed in methanol (17 mL) with MeI (0.0798 ml, 1.28 mmol) for 48 hrs. Concentration and purification by silica gel chromatography (20:1 DCM/MeOH) afforded the titled compound along with recovered starting material.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[N:18][C:19]=1[CH:20]([O:23][CH3:24])[O:21][CH3:22])[N:16]([C:25](OC1C=CC=CC=1)=[O:26])[CH2:15][CH2:14][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:34][C:35]1[CH:42]=[C:41]([N:43]2[CH2:48][CH2:47][O:46][CH:45]([CH2:49][N:50]([CH3:52])[CH3:51])[CH2:44]2)[C:38]([C:39]#[N:40])=[CH:37][N:36]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CC1CCCCC1.[NH4+].[Cl-]>C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[N:18][C:19]=1[CH:20]([O:21][CH3:22])[O:23][CH3:24])[N:16]([C:25]([NH:34][C:35]1[CH:42]=[C:41]([N:43]3[CH2:48][CH2:47][O:46][CH:45]([CH2:49][N:50]([CH3:52])[CH3:51])[CH2:44]3)[C:38]([C:39]#[N:40])=[CH:37][N:36]=1)=[O:26])[CH2:15][CH2:14][CH2:13]2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2C(=O)Oc1ccccc1
Reactant: CN(C)CC1CN(c2cc(N)ncc2C#N)CCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CC1CCCCC1
Solvent: C1CCOC1
Product: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2C(=O)Nc1cc(N2CCOC(CN(C)C)C2)c(C#N)cn1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Dry THF (5 ml) was added to a mixture of phenyl 6-(((tert-butyldimethylsilyl)oxy)methyl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (intermediate 38, 120 mg, 0.254 mmol) and racemic 6-amino-4-(2-((dimethylamino)methyl)morpholino)nicotinonitrile (intermediate 77, 66 mg, 0.254 mmol). The resulting solution was evaporated, the flask flushed with argon, THF (1.3 ml) added and then cooled to −78° C. A solution of LHMDS in methylcyclohexane (0.9 M, 0.62 ml, 0.559 mmol) was added drop wise over 5 minutes, the reaction mixture stirred at −78° C. for a further 15 minutes then allowed to warm to 0° C. and aqueous NH4Cl (1 M) added. The mixture was extracted with DCM (3×), dried over MgSO4 and evaporated. The residue was applied to a 4 g RediSep® silica column as a DCM solution and purified by normal phase chromatography, eluting with a gradient from DCM to 10% MeOH in DCM. Product containing fractions were combined and evaporated to give the title compound as a clear brown glass. (UPLC-MS 6) tR 1.21; ESI-MS 640.5 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][CH:14]=[C:15]([CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]3=[O:24])[N:16]=2)=[CH:8][CH:7]=1.[CH3:25][CH:26]1[CH2:30][CH2:29][CH2:28][NH:27]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[CH3:25][CH:26]1[CH2:30][CH2:29][CH2:28][N:27]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][CH:14]=[C:15]([CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]3=[O:24])[N:16]=2)=[CH:8][CH:7]=1
Reactant: CC1CCCN1
Reactant: O=C1CCCCN1Cc1coc(-c2ccc(OCCCCl)cc2)n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC1CCCN1CCCOc1ccc(-c2nc(CN3CCCCC3=O)co2)cc1
Reaction time: 45 h
Yield: 41 %

Procedure:
1-({2-[4-(3-chloropropoxy)phenyl]-1,3-oxazol-4-yl}methyl)piperidin-2-one i55 (0.564 g, 1.62 mmol, 1 eq) is reacted with 2-methylpyrrolidine (0.19 ml, 1.94 mmol, 1.2 eq) in the presence of potassium carbonate (0.45 g, 3.24 mmol, 2 eq) and a catalytic quantity of sodium iodide in refluxing acetonitrile (20 ml). After 45 h, the solvent is evaporated. The residue is then taken up in ethyl acetate and washed two times with an aqueous solution of sodium hydrogenocarbonate. The organic layer is dried over magnesium sulfate, filtered and concentrated under vacuum. Purification by chromatography over silicagel (eluent: dichloromethane/methanol/ammonia 95:4.5:0.5) affords 0.27 g of 1-[(2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1,3-oxazol-4-yl)methyl]piperidin-2-one 122.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][OH:10].[O:11]=[S:12]1(=[O:34])[C:17]2[CH:18]=[C:19]([O:22][C:23]3[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=3)[C:26]#[N:27])[CH:20]=[CH:21][C:16]=2[N:15]2[CH2:31][CH2:32][CH2:33][C:14]2=[N:13]1>CS(C)=O>[O:34]=[S:12]1(=[O:11])[C:17]2[CH:18]=[C:19]([O:22][C:23]3[CH:24]=[C:25]([C:26](=[N:9][OH:10])[NH2:27])[CH:28]=[CH:29][CH:30]=3)[CH:20]=[CH:21][C:16]=2[N:15]2[CH2:31][CH2:32][CH2:33][C:14]2=[N:13]1
Reactant: N#Cc1cccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)c1
Reactant: NO
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: NC(=NO)c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)c1
Reaction time: 0.17 h

Procedure:
616 μl (4.42 mmol) of triethylamine are added to a solution of hydroxylamine hydrochloride (307 mg, 4.42 mmol) in 1.5 ml of DMSO and the suspension is stirred for 10 minutes. The precipitate is filtered off and the filtrate is concentrated. 250 mg (0.737 mmol) of the product obtained in Step B of Example 1 are then added to that filtrate and the solution is stirred at 75° C. for 16 hours. The reaction mixture is allowed to return to ambient temperature, and precipitation is brought about using water. A gummy white paste is observed which is made harder by adding CH2Cl2. The precipitate is filtered off to yield the title product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:16]([CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1)[C:17]([O:19]CC1C=CC=CC=1)=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[CH2:9]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:16]([C:17]([OH:19])=[O:18])[CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@@H](Cc1ccc2ccccc2c1)C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
Benzyl (2S)-2- [N-(tert-butoxycarbonyl)-N-benzylamino]-3-(2-naphthyl)propionate (10.5 g) was dissolved in methanol (100 ml) and aqueous 1N sodium hydroxide solution (20 ml) was added at ice-bath temperature. The mixture was stirred at room temperature overnight. The reaction mixture was poured into ice-water and extracted with diisopropyl ether. The aqueous layer was adjusted to pH 3 by adding dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave N-benzyl-N-(tert-butoxycarbonyl)-3-(2-naphthyl)-L-alanine (3.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH:8]3[NH2:15])[CH2:6]1)[CH2:12]2)=[O:4].[F:16][C:17]([F:29])([F:28])[C:18]1[CH:23]=[CH:22][C:21]([S:24](N)(=[O:26])=[O:25])=[CH:20][CH:19]=1.ClC1C=CC(S(N[C@H]2CC[C@H](C(OC)=O)CC2)(=O)=O)=CC=1[N+]([O-])=O>>[F:29][C:17]([F:16])([F:28])[C:18]1[CH:19]=[CH:20][C:21]([S:24]([NH:15][CH:8]2[CH:9]3[CH2:14][C:5]4([C:3]([O:2][CH3:1])=[O:4])[CH2:12][CH:11]([CH2:13][CH:7]2[CH2:6]4)[CH2:10]3)(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C12CC3CC(C1)C(N)C(C3)C2
Agent: COC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Product: COC(=O)C12CC3CC(C1)C(NS(=O)(=O)c1ccc(C(F)(F)F)cc1)C(C3)C2

Procedure:
Methyl 4-(4-(trifluoromethyl)phenylsulfonamido)-adamantane-1-carboxylate was prepared from 4-amino-adamantane-1-carboxylic acid methyl ester and 4-trifluoromethylbenzene sulfonamide using a method analogous to the method used to prepare Intermediate 1.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[C:15]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1)(O)=[O:16]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:15](=[O:16])[C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:25])=[O:26])=[CH:20][CH:19]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: NS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (30 mg) and 4-carboxybenzenesulfonamide to produce N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(aminosulfonyl)-benzamide. MS (Q1) 388.0 (M)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([C@H:12]1[CH2:16][C@@H:15]([O:17][CH2:18][O:19][CH3:20])[CH2:14][N:13]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=O)C.[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>CCOCC.O>[OH:9][CH2:10][C@H:12]1[CH2:16][C@@H:15]([O:17][CH2:18][O:19][CH3:20])[CH2:14][N:13]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1
Reactant: CCOC(=O)[C@H]1C[C@@H](OCOC)CN1CCc1ccc(OC)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: COCO[C@@H]1C[C@H](CO)N(CCc2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
To an ice-cooled suspension of 690 mg of LiAlH4 (18.1 mmol) in 15 ml of dry ether was added 6.10 g (18.1 mmol) of (2R, 4R)-(+)-2-(ethoxycarbonyl)-4-(methoxymethoxy)-1-(4-methoxyphenethyl) pyrrolidine in 15 ml of dry ether and the mixture was stirred on ice for 30 min and at room temperature for 30 min. To the ice-cooled mixture 0.7 ml of water and 1N NaOH were added and the mixture was stirred for 30 min on ice, and for 30 min at room temperature. Magnesium sulfate was added and after stirring for 30 min, insoluble materials were filtered off on celite. The filtrate was concentrated in vacuo to give 5.30 g of (2R,4R)-(+)-2-(hydroxymethyl)-4-(methoxymethoxy)-1-(4-methoxyphenethyl)pyrrolidine (99.3%) as pale yellow oil.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[C:11]([O:15][C:16]([O:18][C:19]1[C:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][C:36]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[C:23]([CH3:55])[C:22]([OH:56])=[C:21]([O:57][CH3:58])[C:20]=1[O:59][CH3:60])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16]([O:18][C:19]1[C:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][C:36]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[C:23]([CH3:55])[C:22]([O:56][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=2)=[C:21]([O:57][CH3:58])[C:20]=1[O:59][CH3:60])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(Cl)c1cccnc1
Reactant: COc1c(O)c(C)c(CCCCCCCCCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c(OC(=O)OC(C)(C)C)c1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(OC(=O)c2cccnc2)c(C)c(CCCCCCCCCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c(OC(=O)OC(C)(C)C)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
Nicotinoyl chloride hydrochloride (2 g) was added under ice-cooling to a mixture of 1-tert-butoxycarbonyloxy-2,3-dimethoxy-4-hydroxy-6-(10-trityloxydecyl)-5-methylbenzene (10 g), triethylamine (2 g) and dichloromethane (30 ml), and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with water followed by an aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with ethyl acetate/hexane (1:1) to obtain 1-tert-butoxycarbonyloxy-2,3-dimethoxy-6-(10-trityloxydecyl)-5-methyl-4-nicotinoyloxybenzene (5.1 g). This compound was dissolved in methanol (35 ml). Concentrated hydrochloric acid (2 ml) was added, and the mixture was heated under reflux for 30 minutes. The mixture was concentrated under reduced pressure. Ether was added to the residue which was then separated by filtration to obtain the desired compound (2.9 g).
Reaction SMILES: [C:1]([N:9]1[CH2:19][CH2:18][C:12]2[N:13]=[N:14][C:15](Cl)=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][NH:21][NH2:22]>>[C:1]([N:9]1[CH2:19][CH2:18][C:12]2[N:13]=[N:14][C:15]([N:21]([CH3:20])[NH2:22])=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNN
Reactant: O=C(c1ccccc1)N1CCc2nnc(Cl)cc2C1
Product: CN(N)c1cc2c(nn1)CCN(C(=O)c1ccccc1)C2

Procedure:
13.7 g of 6-benzoyl-3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine in 40 cc of methyl hydrazine are stirred at a bath temperature of 50° for 61/2 hours. The oil resulting after concentrating the reaction solution is dissolved in 200 cc of chloroform, the solution is dried with sodium sulphate and again concentrated to an oil. This is boiled for a short time with 12.0 g of gentisic acid in 100 cc of methanol on a water bath. After concentrating the solution to approximately 2/3 of its volume, and cooling with ice, the bisgentisinate of the title compound precipitates. M.P. 166°-168° (decomp., from absolute ethanol).
Reaction SMILES: BrC1C(OC)=C(C=CC=1C[S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1C)C(OCC)=O.[Br:24][C:25]1[C:26]([O:37][CH3:38])=[C:27]([C:32]([CH2:35]Br)=[CH:33][CH:34]=1)[C:28]([O:30][CH3:31])=[O:29].C1(S)C=CC=CC=1>>[Br:24][C:25]1[C:26]([O:37][CH3:38])=[C:27]([C:32]([CH2:35][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:33][CH:34]=1)[C:28]([O:30][CH3:31])=[O:29]
Reactant: CCOC(=O)c1ccc(CSc2ccccc2C)c(Br)c1OC
Reactant: COC(=O)c1c(CBr)ccc(Br)c1OC
Agent: Sc1ccccc1
Product: COC(=O)c1c(CSc2ccccc2)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 77, starting from methyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 89) and thiophenol and used without further characterization.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=2[F:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[F:24])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2F)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2F)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.7 %

Procedure:
To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-3-fluoronitrobenzene (3.71 g) in methanol (50 ml) was added palladium on carbon (0.30 g) and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hours. The reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=1/1 as an eluant to give the desired compound (3.27 g, yield 97%) as a pale red solid.