Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[N:28]([S:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[CH:27]([C:39]([NH:41]O)=[NH:40])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>CN(C=O)C>[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[N:28]([S:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[CH:27]([C:39]3[N:40]=[C:1]([CH3:2])[O:4][N:41]=3)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(C(=N)NO)CCC2c2ccc(F)cc2)cc1
Reactant: CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2C(c3ccc(F)cc3)CCC2c2noc(C)n2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 67.9 %

Procedure:
A solution of acetic acid (0.11 ml, 1.99 mmol), 1,1′-carbonyl-diimidazole (0.32 g, 1.99 mmol) in DMF (12 ml) was stirred at room temperature for 2 h and subsequently (2RS,5SR)-5-(4-fluoro-phenyl)-N-hydroxy-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxamidine (0.50 g, 1.32 mmol) was added. The reaction mixture was stirred at 80° C. for 16 h and evaporated. Acetic acid (10 ml) was added and the stirred mixture was heated under reflux conditions for 2 h. Aqueous work-up, column chromatography on silica gel (ethyl acetate/hexane 1:1) and crystallization from ethyl acetate/hexane yielded the title compound (0.36 g, yield 68%) as a white solid, m.p. 115° C. and MS: m/e=246.1 (M+H+).
Reaction SMILES: [CH2:1]1[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]3[CH:18]=[CH:19][C:20]([NH:22][C:14]=3[CH:13]=2)=[O:21])[CH2:5][CH2:4][N:3]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[Cl:30])[CH2:2]1.CC(C)([O-])C.[K+].CC1CCCO1.Cl[C:44]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:45]>O>[C:44](=[O:45])([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[O:21][C:20]1[CH:19]=[CH:18][C:15]2[C:14](=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]3[CH2:5][CH2:4][N:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=4[Cl:30])[CH2:2][CH2:1]3)=[CH:17][CH:16]=2)[N:22]=1
Reactant: CCCCCCOC(=O)Cl
Reactant: O=c1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC1CCCO1
Solvent: O
Product: CCCCCCOC(=O)Oc1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of dehydro-aripiprazole (1.5 g, 3.4 mmol), potassium tert-butoxide (0.75 g, 6.7 mmol) and 2-methyltetrahydrofuran (30 mL) at 0° C. was added hexyl chloroformate (1.32 mL, 8.1 mmol). The reaction mixture was stirred for 2 h, allowed to self warm to room temperature and stirred for a further 4 h. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and evaporated. The residue was further purified on silica eluting with ethyl acetate/tetrahydrofuran and the major product containing fractions evaporated to give a yellow solid. This was triturated in heptane (30 mL) for 2.5 h, filtered and dried to give Compound-328 (1.55 g) as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH:11]([CH3:13])[CH3:12])[C:5]([CH3:14])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH:18]([NH2:21])([CH3:20])[CH3:19]>C1(C)C=CC=CC=1>[CH:18]([NH:21][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH:11]([CH3:13])[CH3:12])[C:5]([CH3:14])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])([CH3:20])[CH3:19]
Reactant: CC(C)N
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C(C)C
Solvent: Cc1ccccc1
Product: Cc1cc([N+](=O)[O-])c(NC(C)C)c([N+](=O)[O-])c1C(C)C
Temperature: 100 °C
Yield: 73.4 %

Procedure:
A mixture of 5-chloro-4,6-dinitro-o-cymene (4.0 g, 0.0155 mole) and isopropylamine (3.2 g, 0.054 mole) in toluene is heated in a bomb at 100° C. for 4 hours. The cooled mixture is washed with aqueous bicarbonate solution, dried over magnesium sulfate, and concentrated to leave the crude product which is purified by dry column chromatography to yield 3.2 g of product with mp 54°-55° C. By using one of the aforementioned procedures for the dinitration of the appropriate N-alkyl-4-alkyl-m-toluidines or by reacting the appropriate amine with the desired 3-chloro-2,4-dinitro-6-alkyltoluene the following compounds are prepared. ##STR41##Ex. No. R1 R2 Y MP° C.______________________________________201 H C3H7 -i C2H5 46°-46.5°202 H C4H9 -sec " 37.5°-38°203 H CH(C2H5)2 " 51°-53°204 H C3H7 -i C3H7 -n 55°205 H CH(C2H5)2 " orange oil206 H C3H7 -i C3H7 -i 54°-55°207 H C3H7 -n " orange-red oil208 H C4H9 -sec " orange oil209 H CH(C2H5)2 " red oil210 H CH(C2H5)2 C4H9 -n 47.5°-50°211 H CH(C2H5)2 C 4 H9 -sec orange oil______________________________________
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[N:12]=[CH:11][NH:10][N:9]=1.Br[CH:14]([CH2:24][CH2:25]Cl)[C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=[O:16]>CC(C)=O>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]([C:14]2([N:10]3[CH:11]=[N:12][C:8]([Cl:7])=[N:9]3)[CH2:25][CH2:24]2)=[O:16])=[CH:18][CH:19]=1
Reactant: O=C(c1ccc(Cl)cc1)C(Br)CCCl
Reactant: Clc1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(c1ccc(Cl)cc1)C1(n2cnc(Cl)n2)CC1
Yield: 45 %

Procedure:
34 g (246 mmol) of potassium carbonate and 35 g (338 mmol) of 3-chloro-1,2,4-triazole are initially introduced into 130 ml of acetone under reflux and 50 g (169 mol) of 2-bromo-4-chloro-1-(4-chlorophenyl)-butan-1-one in 60 ml of acetone are added dropwise. The mixture is boiled under reflux for 8 hours, the solution is filtered off with suction from the residue and the solvent is stripped off in vacuo. The residue is taken up in ethyl acetate, washed with water and dried over sodium sulphate, and the solvent is evaporated. Chromatography on silica gel (eluent: dichloromethane) gives 42.9 g of the title compound (90% of theory) of m.p. 85° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH3:10])=[N:6][CH:7]=1.[CH2:11]([O:13][C:14](=[O:50])[CH2:15][C:16]1[CH:17]=[C:18]([C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][C:25]=2[CH2:39][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:41][CH3:42])[C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[CH3:12].C(=O)([O-])[O-].[K+].[K+]>COCCOC.C(OCC)(=O)C.O.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>[CH2:11]([O:13][C:14](=[O:50])[CH2:15][C:16]1[CH:17]=[C:18]([C:24]2[CH:29]=[CH:28][C:27]([C:2]3[CH:7]=[N:6][C:5]([O:8][CH2:9][CH3:10])=[CH:4][CH:3]=3)=[CH:26][C:25]=2[CH2:39][N:40]([C:43]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:44])[CH2:41][CH3:42])[C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[CH3:12]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN(CC)C(=O)OC(C)(C)C)c1
Reactant: CCOc1ccc(Br)cn1
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: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ccc(OCC)nc3)cc2CN(CC)C(=O)OC(C)(C)C)c1
Temperature: 85 °C

Procedure:
5-Bromo-2-ethoxypyridine (0.235 g, 1.16 mmol), [2′-[(tert-butoxycarbonyl-ethyl-amino)-methyl]-6-methoxy-4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-3-yl]-acetic acid ethyl ester (0.500 g, 0.903 mmol), and potassium carbonate (0.313 g, 2.3 mmol) were combined in DME (5 mL) and water (2.5 mL) under nitrogen. The mixture was purged with nitrogen, and then tetrakis(triphenylphosphine)palladium(0) (0.052 g, 0.045 mmol) was added, and the reaction was heated to 85° C. for 6 hours. Once no starting material was seen by analytical LCMS, the mixture was cooled to room temperature and diluted with ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate, and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-40% ethyl acetate in hexanes) to give the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[NH2:9][C@@H:10]([C:15]([OH:17])=[O:16])[C:11]([SH:14])([CH3:13])[CH3:12]>O>[CH3:12][C:11]1([CH3:13])[S:14][CH:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[NH:9][C@H:10]1[C:15]([OH:17])=[O:16]
Reactant: O=Cc1cccnc1
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Solvent: O
Product: CC1(C)SC(c2cccnc2)N[C@H]1C(=O)O
Reaction time: 0.17 h

Procedure:
0.94 ml (1.07 g, 10 mmoles) of pyridine-3-aldehyde is added to a solution containing 1.5 g (10 mmoles) of D-penicillamine in 30 ml of water at room temperature while stirring. After 10 minutes, the title product begins to crystallize. The mixture is stirred for 1 additional hour, the precipitate is filtered, washed with water and dried. The thus-obtained crude product is dissolved in hot water, filtered and cooled down to give the crystalline title compound in a yield of 1.9 g (79.7%), m.p.: 164°-165° C., [α]D20 =+145° (c=0.556, dimethylsulphoxide).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[OH:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH2:34][CH2:35][NH:36][CH2:37][CH:38]=2)=[CH:29][CH:28]=1>CN(C)C=O>[OH:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:35][CH:34]=2)=[CH:29][CH:28]=1
Reactant: Oc1ccc(C2=CCNCC2)cc1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CC=C(c2ccc(O)cc2)CC1
Temperature: 20 °C
Reaction time: 12 h
Yield: 18.4 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (12 g), triethylamine (6 cc) and 4-(4-hydroxyphenyl)-1,2,3,6-tetrahydropyridine (7.5 g) in dimethylformamide (120 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is continued for 12 hours at this temperature. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling acetonitrile (80 cc), 2-{3-[4-(4-hydroxyphenyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (3.3 g) is obtained, m.p. 198° C.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:19]([CH:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)[Si](C(C)(C)C)(C)C>C1COCC1>[OH:19][CH:27]1[CH2:28][CH2:29][N:30]([C:33]2[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=2)[CH2:31][CH2:32]1
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(c2ccc(C#N)cc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1ccc(N2CCC(O)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.9 %

Procedure:
Tetra-n-butylammonium fluoride (1M) THF solution (10.6 ml, 10.2 mmol) was added to a mixture of 4-[4-(tert-butyldimethylsiloxy)piperidin-1-yl]benzonitrile (2.8 g, 8.85 mmol) prepared in Reference Example 28 in THF (30 ml) while cooling in an ice-bath, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate twice. The extract was washed with water and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/2) to afford 4-(4-hydroxypiperidin-1-yl)benzonitrile (1.52 g, yield 85%) as a colorless crystalline powder.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:11]([CH2:12][CH3:13])[C:10]([C:14](=[N:17][OH:18])[C:15]#[N:16])=[N:9][C:4]=2[C:5]([Cl:8])=[N:6][CH:7]=1.C([N:21](CC)CC)C.NO>O1CCOCC1.CO>[Br:1][C:2]1[C:3]2[N:11]([CH2:12][CH3:13])[C:10]([C:14]3[C:15]([NH2:21])=[N:16][O:18][N:17]=3)=[N:9][C:4]=2[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: CCn1c(C(C#N)=NO)nc2c(Cl)ncc(Br)c21
Agent: NO
Solvent: C1COCCO1
Solvent: CO
Product: CCn1c(-c2nonc2N)nc2c(Cl)ncc(Br)c21
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a mixture of (7-bromo-4-chloro-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)hydroxyimino-acetonitrile (V, 545 g, 1.45 mol) in dioxane (5 L) was added triethylamine (1 L) and hydroxylamine (143 g, 55% in water). The reaction was heated at reflux for 6 h. After cooling the reaction to ambient temperature, the mixture was filtered and the filtrate concentrated under reduced pressure to give a brown solid. The solid was suspended in methanol (1 L) and the suspension was stirred at 65° C. for 0.5 h. The solid was collected by filtration and dried to give 321 g (70% yield) of the desired compound (VI). This was used in the next step without further purification. MS (ES+) m/z 343 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2.[CH3:12][S:13]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[C:21]2Cl)(=[O:15])=[O:14]>>[CH3:12][S:13]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([C:10]1[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:11])[CH:8]=3)[NH:3][C:2]=1[CH3:1])[CH:22]=[CH:21]2)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1cccc2c(Cl)ccnc12
Reactant: Cc1ccc2[nH]c(C)cc2c1
Product: Cc1ccc2[nH]c(C)c(-c3ccc4cccc(S(C)(=O)=O)c4n3)c2c1

Procedure:
The sub-title compound was prepared by the method of Example 40 step a, using 2,5-dimethyl indole and 8-methanesulphonyl-4-chloroquinoline.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1>[Pd]>[C:6]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=[CH:2][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Agent: [Pd]
Product: NS(=O)(=O)c1ccccc1-c1ccccc1

Procedure:
In Scheme 1 the compounds of the invention, 1, are prepared in 4 steps. Sulfonylation of valine methyl ester with 4-Bromo-benzenesulfonyl chloride was carried out under Hunig base condition to give sulfonamide intermediate 1. This 4-Bromo-benzenesulfonamide was furthered coupled with boronate ester using Palladium catalyst under Suzuki coupling condition to provide biphenyl sulfonamide Intermediate 2. Biphenyl sulfonamide intermediate 2 was then alkylated with various alkylating reagents to provide biphenyl sulfonamide ester (Intermediate 3). Hydrolysis of intermediate 3 was carried out using bases such as NaOH, or LiOH to afford the final product 1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[NH:5][C:4](=O)[CH:3]=1.P(Br)(Br)([Br:21])=O>>[Br:21][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=1
Reactant: O=P(Br)(Br)Br
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)[nH]c(=O)c1
Product: Cc1cc(Br)nc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
The title compound was prepared from 4-methyl-6-(4-trifluoromethyl-phenyl)-1H-pyridin-2-one (example A.23 step 1) (25.32 g, 100 mmol) and phosphoryl bromide (86.0 g, 300 mmol) according to the general procedure Ia to d preparation of bromides. Obtained as a light yellow solid (29.27 g, 93%). MS (ISP) 316.0 [(M+H)+] and 318.0 [(M+2+H)+].
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[Cl:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]([NH:17][CH:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:19](O)=[O:20])=[O:16])=[CH:9]2>>[CH3:2][N:3]([CH3:4])[C:19]([CH:18]([NH:17][C:15]([C:10]1[NH:11][C:12]2[C:8]([CH:9]=1)=[CH:7][C:6]([Cl:5])=[CH:14][CH:13]=2)=[O:16])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20]
Reactant: CNC
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Product: CN(C)C(=O)C(Cc1ccccc1)NC(=O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
Dimethylamine hydrochloride (0.96 mmol) and 2-[(5-chloro-1H-indole-2-carbonyl)-amino]-3-phenyl-propionic acid (0.90 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, 60 hour reaction time, washed first with acid, then base), and the resulting solid triturated with ether: Yield 320 mg, 99%; HPLC (60/40) 5.87 minutes (100%);
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([CH3:30])[C:14]=1[O:15][C@H:16]1[C@@H:21]3[O:22]C(=O)[O:24][C@@H:20]3[C@@H:19]([O:26][CH3:27])[C:18]([CH3:29])([CH3:28])[O:17]1)[O:11][C:10](=[O:31])[C:9]([NH:32][C:33](=O)[O:34]CC1C=CC=CC=1)=[CH:8]2)([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.[NH:54]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:56]=[C:55]1C(O)=O.C(=O)([O-])[O-]>[Pd].C1COCC1.N1C=CC=CC=1.C(Cl)Cl.CO.C(Cl)Cl.C(N(CC)CC)C>[OH:22][C@@H:21]1[C@H:20]([OH:24])[C@@H:19]([O:26][CH3:27])[C:18]([CH3:29])([CH3:28])[O:17][C@H:16]1[O:15][C:14]1[C:13]([CH3:30])=[C:12]2[C:7]([CH:8]=[C:9]([NH:32][C:33]([C:55]3[NH:54][C:62]4[C:57]([CH:56]=3)=[CH:58][CH:59]=[CH:60][CH:61]=4)=[O:34])[C:10](=[O:31])[O:11]2)=[CH:6][C:5]=1[O:4][CH:1]([CH3:2])[CH3:3]
Reactant: CO[C@@H]1[C@H]2OC(=O)O[C@H]2[C@H](Oc2c(OC(C)C)cc3cc(NC(=O)OCc4ccccc4)c(=O)oc3c2C)OC1(C)C
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CO[C@@H]1[C@@H](O)[C@@H](O)[C@H](Oc2c(OC(C)C)cc3cc(NC(=O)c4cc5ccccc5[nH]4)c(=O)oc3c2C)OC1(C)C
Reaction time: 12 h
Yield: 32.1 %

Procedure:
Palladium on carbon (10%, 4 mg) was added to 25c (19.0 mg, 0.033 mmol) in anhydrous THF (220 μL) and the solution was placed under an atmosphere of H2. After 12 hours, the solution was filtered through SiO2 (1:1 CH2Cl2:Acetone) and the eluent was concentrated to afford a yellow solid, which was used without further purification (14.5 mg, 99%). EDCI (15.6 mg, 0.081 mmol) and 1H-indole-2-carboxylic acid (10.5 mg, 0.065 mmol) was added to the amine (14.5 mg, 0.033 mmol) in 30% pyridine/CH2Cl2 (1.00 mL). After 12 hours, the solvent was concentrated and the residue purified via column chromatography (SiO2, 40:1 CH2Cl2:Acetone) to afford a colorless solid, which was used without further purification (10.0 mg, 50%). Triethylamine (150 μL) was added to the carbonate (10.0 mg, 0.017 mmol) in MeOH (2.5 mL) and CH2Cl2 (2.50 mL). After 12 hours, the solvent was concentrated and the residue purified via column chromatography (SiO2, 10:1 CH2Cl2:Acetone) to afford 26k as a colorless amorphous solid (6.00 mg, 46%, 23% over 3 steps): 1H NMR (CDCl3, 500 MHz) δ 8.16 (s, 1H), 7.52 (s, 1H), 7.34-7.30 (m, 5H), 6.75 (s, 1H), 4.93 (d, J=5.0 Hz, 1H), 4.56-4.51 (m, 1H), 4.23 (t, J=4.0 Hz, 1H), 3.98-3.96 (m, 1H), 3.76 (s, 1H), 3.43 (s, 3H), 3.06 (d, J=4.3 Hz, 1H), 2.65 (s, 1H), 2.38 (s, 3H), 1.33 (dd, J=11.2, 6.1 Hz, 6H), 1.29 (s, 3H), 1.27 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 157.6, 152.1, 146.6, 146.0, 142.1, 134.5, 127.7, 127.5, 127.2, 122.2, 121.3 (2C), 120.2 (2C), 115.0 (2C), 108.1 (2C), 101.2, 81.6, 71.2, 68.9, 68.1, 66.5, 59.0, 24.8, 23.6, 20.8 (2C), 9.1; IR (film) νmax cm−1 3406, 2930, 2375, 1705, 1522, 1394, 1229, 1205, 1111, 1078, 1049, 933, 793, 739, 698; HRMS (ESI+) m/z: [M+Na]+ calcd for C30H34N2O9, 589.2162. found, 589.2111.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:16]=[C:17]([OH:24])[CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])([O-:14])=[O:13]>C(Cl)Cl.[OH-].[Na+]>[N+:12]([C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[O:24][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(O)cc1[N+](=O)[O-]
Reactant: Clc1ccnc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Oc2ccnc3ccccc23)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
4-Chloroquinoline (4.3 g, 26.3 mmol) and 3,4-dinitrophenol (41.5 g, 24.4 mmol) were heated at 150° C. for 30 min. The mixture was cooled to RT and the residue was dissolved in CH2Cl2. The mixture was diluted in NaOH 2 M and extracted with CH2Cl2. The organic phase was dried, filtered and evaporated. The residue was diluted in EtOAc and filtered through a silica pad. The solvent was removed to give the title compound as a brown solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:16][CH2:15][C:14](=[O:17])[N:13]([CH3:18])[C:12]3[C:7]2=[N:8][C:9]([NH:19][C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][C:21]=2[O:29][CH3:30])=[N:10][CH:11]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:64][CH:65]1[CH2:70][CH2:69][N:68]([CH2:71][CH2:72][CH3:73])[CH2:67][CH2:66]1>CC(N(C)C)=O.CO>[CH:1]1([N:6]2[CH2:16][CH2:15][C:14](=[O:17])[N:13]([CH3:18])[C:12]3[C:7]2=[N:8][C:9]([NH:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([NH:64][CH:65]4[CH2:70][CH2:69][N:68]([CH2:71][CH2:72][CH3:73])[CH2:67][CH2:66]4)=[O:25])=[CH:22][C:21]=2[O:29][CH3:30])=[N:10][CH:11]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C
Reactant: CCCN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CC(=O)N(C)C
Product: CCCN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CCC(=O)N4C)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.7 %

Procedure:
4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-3-methoxy-benzoic acid (Example 111; 231 mg, 0.56 mmol), DIPEA (0.3 mL, 1.68 mmol) and HATU (283 mg, 0.75 mmol) were stirred together in DMA (4 mL) at ambient temperature for 10 minutes. 4-amino-1-propylpiperidine (Fluorochem; 100 mg, 0.70 mmol) was added and the mixture stirred at room temperature for 4 hours. The reaction mixture was loaded onto an SCX-2 (10 g) column pre-wet with MeOH. The column was washed with MeOH (×2) and the product eluted with 2M NH3/MeOH. Product containing fractions were combined and evaporated and the residue purified by base modified reverse phase preparative HPLC. Product containing fractions were combined and evaporated to yield the title compound as a gum (194 mg, 65%).
Reaction SMILES: [CH:1]12[N:8]([C:9]3[N:14]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=4)[N:12]=[C:11]([NH:24][CH:25]([CH3:27])[CH3:26])[CH:10]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2>CC(O)C.ClCCl.[Pd]>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[N:12]=[C:11]([NH:24][CH:25]([CH3:27])[CH3:26])[CH:10]=[C:9]([N:8]3[CH:5]4[CH2:6][CH2:7][CH:1]3[CH2:2][O:3][CH2:4]4)[N:14]=2)=[CH:20][CH:19]=1
Reactant: CC(C)Nc1cc(N2C3CCC2COC3)nc(-c2ccc([N+](=O)[O-])cc2)n1
Agent: [Pd]
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)Nc1cc(N2C3CCC2COC3)nc(-c2ccc(N)cc2)n1
Reaction time: 16 h
Yield: 98.1 %

Procedure:
In a 250 mL round-bottomed flask was placed 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-isopropyl-2-(4-nitrophenyl)pyrimidin-4-amine (60, 196 mg, 0.53 mmol) in 2-propanol (5 mL) and dichloromethane (5 mL) to give a yellow solution. A catalytic amount of Pd on charcoal (wet) was added and the mixture was stirred under a hydrogen atmosphere for 16 hours. The mixture was filtered over Celite™, rinsed with dichloromethane and concentrated to give the title compound (176 mg, 0.52 mmol, 98%) as a yellow solid. HRMS: For [M+H]+ mass error=0.5 mDa or 1.46 ppm.