Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:23])([CH2:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:6]1=[O:24])[CH2:2]CC.[Cl:25]C1C=C2C(=CC=1)N(CC)C(=O)C2=O.C(C1C=CC=CN=1)(=O)C>>[Cl:25][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:1][CH3:2])[C:6](=[O:24])[C:7]2([OH:23])[CH2:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CCCCN1C(=O)C(O)(CC(=O)c2ccccn2)c2ccccc21
Reactant: CCN1C(=O)C(=O)c2cc(Cl)ccc21
Agent: CC(=O)c1ccccn1
Product: CCN1C(=O)C(O)(CC(=O)c2ccccn2)c2cc(Cl)ccc21

Procedure:
This compound was made in a similar manner to 1-butyl-3-hydroxy-3-(2-oxo-2-(pyridin-2-yl)ethyl)indolin-2-one using 5-chloro-1-ethylindoline-2,3-dione and 2-acetyl pyridine (purchased from Fisher Scientific). 1H-NMR δ 8.70 (ddd, 1H), 8.11 (dd, 1H), 7.93 (ddd, 1H), 7.57 (ddd, 1H), 7.31-7.27 (m, 2H), 6.79 (d, 1H), 5.5 (bs, OH), 3.77 (d, 1H), 3.74 (m, 2H), 3.53 (d, 1H), 1.27 (t, 3H). calculated mass for C17H15ClN2O3, 330.08, observed, 331.0 (M+1).
Reaction SMILES: Cl.[Ti:2](Cl)(Cl)(Cl)Cl.[P:7]([O-:11])([O-:10])([OH:9])=[O:8].[NH4+].[NH4+]>O>[P:7]([O-:11])([O-:10])([O-:9])=[O:8].[Ti+4:2].[P:7]([O-:11])([O-:10])([O-:9])=[O:8].[P:7]([O-:11])([O-:10])([O-:9])=[O:8].[P:7]([O-:11])([O-:10])([O-:9])=[O:8].[Ti+4:2].[Ti+4:2]
Reactant: Cl[Ti](Cl)(Cl)Cl
Reactant: O=P([O-])([O-])O
Agent: Cl
Agent: [NH4+]
Solvent: O
Product: O=P([O-])([O-])[O-]
Product: [Ti+4]
Reaction time: 3 h

Procedure:
Titanium phosphate was prepared by the following procedure. Hydrochloric acid (500 g) was added to 5 liters of water, and 500 g of titanium tetrachloride was added dropwise at room temperature. After allowing the mixture to stand for 3 hours, a 10% aqueous solution containing 356 g of diammonium hydrogen phosphate was gradually added dropwise to the mixture with thorough stirring. After the formation of a precipitate, the system was allowed to stand at 70° C. for 6 hours. The precipitate was separated by filtration, and washed with water by means of a centrifugal separator until there was no chlorine ion in the filtrate. It was dried at 120° C., and then calcined at 550° C. for 3 hours. The resulting powder had the composition 2TiO2.P2O5 and a surface area, measured by the BET method, of 72 m2 /g.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][NH:23][CH2:24][CH:25]1[CH2:29][CH2:28][NH:27][CH2:26]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([N:27]4[CH2:28][CH2:29][CH:25]([CH2:24][NH:23][CH3:22])[CH2:26]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CNCC1CCNC1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2OC)C1
Yield: 49.3 %

Procedure:
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), 3-methylaminomethylpyrrolidine (90 mg), DBU (110 mg) and anhydrous acetonitrile (3 ml) was refluxed for 75 minutes. After cooling, the resulting precipitate was collected by filtration and recrystallized from a solution of dichloromethane-methanol (1:1) to give the title compound (130 mg) as white powdery crystals, mp 226.5°-230° C.
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([C:13]2S[C:15]([C:19](O)=O)=[C:16](C)[N:17]=2)N=N1)C1C=CC=CC=1.[F:22][C:23]1[CH:44]=[CH:43][C:26]([CH2:27][CH2:28][N:29]2[CH:33]=[C:32]([C:34]3[S:35][C:36]([C:40]([OH:42])=O)=[C:37]([CH3:39])[N:38]=3)[N:31]=[N:30]2)=[CH:25][CH:24]=1.N1C=CC=C(CN)C=1>>[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][CH2:28][N:29]2[CH:33]=[C:32]([C:34]3[S:35][C:36]([C:40]([NH:8][CH2:12][C:11]4[CH:13]=[N:17][CH:16]=[CH:15][CH:19]=4)=[O:42])=[C:37]([CH3:39])[N:38]=3)[N:31]=[N:30]2)=[CH:43][CH:44]=1
Reactant: Cc1nc(-c2cn(Cc3ccccc3)nn2)sc1C(=O)O
Reactant: Cc1nc(-c2cn(CCc3ccc(F)cc3)nn2)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1nc(-c2cn(CCc3ccc(F)cc3)nn2)sc1C(=O)NCc1cccnc1
Yield: 53 %

Procedure:
Following the procedure as described in Example 4, making variations as necessary to replace 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-methylthiazole-5-carboxylic acid with 2-(1-(4-fluorophenethyl)-1H-1,2,3-triazol-4-yl)-4-methylthiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a white solid in 53% yield: mp 149-150° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.50 (br s, 1H), 8.42 (br s, 1H), 7.84 (s, 1H), 7.70-7.62 (m, 1H), 7.27-7.16 (m, 1H), 7.12-6.99 (m, 3H), 6.95-6.85 (m, 2H), 4.56 (t, J=7.1 Hz, 2H), 4.55 (d, J=5.5 Hz, 2H), 3.16 (t, J=7.1 Hz, 2H), 2.63 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.0, 161.9, 157.9, 157.1, 149.2, 148.8, 142.4, 135.7, 133.9, 132.2, 132.1, 130.1, 124.1, 121.9, 115.8, 52.0, 41.5, 35.7, 17.3; MS (ES+) m/z 423.3 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[Br-:10].C([NH+](CCCC)CCCC)CCC>C(Cl)(Cl)Cl>[Br:10][C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:9])[CH3:1])=[N:4][CH:5]=1
Reactant: [Br-]
Reactant: CN(C)c1ccccn1
Agent: CCCC[NH+](CCCC)CCCC
Solvent: ClC(Cl)Cl
Product: CN(C)c1ccc(Br)cn1
Yield: 72 %

Procedure:
2-Dimethylaminopyridine (1.0 ml) was dissolved in chloroform (60 ml). After adding tributylammonium bromide (3.88 g) thereto, the resultant mixture was stirred for 7 min. Then the reaction solution was washed with an aqueous solution of sodium thiosulfate and water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate-methanol system) to give the title compound (1.097 g) as yellow crystals (yield: 72.0%).
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: CCOc1ccc(Br)cn1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN(CC)C(=O)OC(C)(C)C)c1
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: COCCOC
Solvent: O
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: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][C:17]([CH3:21])([CH3:20])[C:18]#[N:19]>>[C:18]([C:17]([NH:16][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:21])[CH3:20])#[N:19]
Reactant: CC(C)(N)C#N
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Product: CC(C)(C#N)NC(=O)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and 2-amino-2-methyl-propanenitrile (CAN 19355-69-2 as starting materials and isolated (50 mg, 78%) as colorless oil; LC-MS (UV peak area, m/z) 93.8%, 294.1001 (MH+).
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][CH3:10])=[N:7][CH:8]=1)[NH2:2].[CH2:11]([O:13][C:14](=[O:27])[C:15](=O)[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=O)[CH3:12]>>[CH2:11]([O:13][C:14]([C:15]1[CH:16]=[C:17]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[N:1]([C:3]2[CH:8]=[N:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=2)[N:2]=1)=[O:27])[CH3:12]
Reactant: COc1ccc(NN)cn1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(F)cc1
Product: CCOC(=O)c1cc(-c2ccc(F)cc2)n(-c2ccc(OC)nc2)n1

Procedure:
The general procedure of Referential. Example 3-2) was repeated through use of the 5-hydrazino-2-methoxypyridine (1.0 g) prepared in Referential Example 2 and the 4-(4-fluorophenyl)-2,4-dioxobutanoic acid ethyl ester (1.88 g) prepared in Referential Example 134, to thereby give the title compound as an oily product (2.12 g, 86%).
Reaction SMILES: FC(F)(F)C1C=CC(C=C)=CC=1.Br[C:14]1[CH2:18][CH2:17][O:16][N:15]=1.COC(=O)[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][N:23]=1>>[N:23]1[CH:22]=[CH:27][CH:26]=[C:25]([O:28][C:14]2[CH2:18][CH2:17][O:16][N:15]=2)[CH:24]=1
Reactant: COC(=O)c1ccc(O)cn1
Reactant: BrC1=NOCC1
Agent: C=Cc1ccc(C(F)(F)F)cc1
Product: c1cncc(OC2=NOCC2)c1

Procedure:
3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-170a and I-170b were prepared in 3 steps from 1-(trifluoromethyl)-4-vinylbenzene using the cycloaddition conditions from Method 5. The resulting bromo-4,5-dihydroisoxazole was reacted with 5-hydroxypicolinic acid methyl ester using Method 5 followed by hydrolysis using the analogous conditions as in example 94. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=353.0 m/z. Activity: A
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CO>[CH2:15]([NH:14][C:12]([NH:11][C:8]1[S:9][C:10]2[C:2]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[F:23])=[CH:3][C:4]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:5][C:6]=2[N:7]=1)=[O:13])[CH3:16]
Reactant: OB(O)c1ccccc1F
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(Br)c2s1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3ccccc3F)c2s1
Temperature: 80 °C
Yield: 23 %

Procedure:
A stirred mixture of 1-(7-Bromo-5-pyridin-3-yl-benzothiazol-2-yl)-3-ethyl-urea (50 mg, 0.133 mmol), 2-fluorobenzeneboronic acid (19 mg, 0.139 mmol), powdered potassium phosphate tribasic (34 mg, 0.160 mmol) and 1,1′-bis(diphenylphosphino)ferrocene palladium(II)chloride complex (16 mg, 0.01995 mmol) in anhydrous 1,4-dioxane (1 ml) and anhydrous methanol (2 ml) was purged with nitrogen for 5 min and heated in a sealed vessel for 16 h at 80° C. After cooling to ambient temperature, the mixture was filtered through kieselguhr. The kieselguhr was thoroughly washed with methanol and the combined filtrates evaporated to dryness in vacuo to give the crude 1-Ethyl-3-[7-(2-fluoro-phenyl)-5-pyridin-3-yl-benzothiazol-2-yl]-urea which was purified by “flash” silica chromatography eluting with 0 to 30% methanol in ethyl acetate. 12 mg of a pale-brown solid was obtained.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:28]([C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1)([O-:30])=[O:29]>>[N+:28]([C:31]1[CH:32]=[CH:33][C:34]([S:37]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:25]([OH:27])=[O:26])[NH:18][C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])(=[O:39])=[O:38])=[CH:35][CH:36]=1)([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Product: O=C(N[C@@H](CCCCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 89 %

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-L-lysine was reacted with 4-nitrobenzenesulfonyl chloride under the conditions used in example 2 giving 89% of the title compound.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([OH:14])=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH:2]=[CH:3][CH3:4].[CH2:16](Br)[CH:17]([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:14][CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH:2]=[CH:3][CH3:4]
Reactant: CC=CCC1Cc2ccc(O)cc2C1=O
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC=CCC1Cc2ccc(OCC(C)C)cc2C1=O
Yield: 93 %

Procedure:
A solution of 4.74 g of (RS)-2-(2-buten-1-yl)-6-hydroxy-1-indanone, 5.18 ml of isobutyl bromide and 5.98 g of potassium carbonate in 40 ml of N,N-dimethylformamide was heated to 60° for 48 hours. After cooling, the solution was poured into 100 ml of water and extracted twice with 70 ml of ethyl acetate each time. The combined organic phases were washed once with 70 ml of water and once with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. 5.2 g (93%) of (RS)-2-(2-buten-1-yl)-6-isobutoxy-1-indanone were obtained as a red-brown oil which was used directly in the next reaction.
Reaction SMILES: [CH:1]1([CH2:4]Br)[CH2:3][CH2:2]1.[CH2:6]([O:8][C:9]([C:11]1[N:12]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([OH:20])=[CH:15][CH:14]=2)=[O:10])[CH3:7].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C.O>[CH2:6]([O:8][C:9]([C:11]1[N:12]([S:21]([C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)(=[O:23])=[O:22])[C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([O:20][CH2:4][CH:1]1[CH2:3][CH2:2]1)=[CH:15][CH:14]=2)=[O:10])[CH3:7]
Reactant: BrCC1CC1
Reactant: CCOC(=O)c1cc2cc(O)ccc2n1S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(OCC3CC3)ccc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
Cyclopropylmethyl bromide (0.072 ml, 0.75 mmol) was added to a suspension (5.0 ml) of 5-hydroxy-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylic acid ethyl ester (173 mg, 0.48 mmol) and potassium carbonate (276 mg, 1.0 mmol) in acetonitrile, and stirred at 80° C. for five hours. After cooling to room temperature, the reaction mixture was combined with ethyl acetate and water and extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 5-cyclopropylmethoxy-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylic acid ethyl ester as a colorless gum-like material (112.5 mg, 56%).
Reaction SMILES: ClCS([NH:6]C1C=C2C(=CC=1)C=NC=C2)(=O)=O.N[C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([NH:23][CH3:24])=[O:22]>CO>[NH3:6].[CH3:24][NH:23][C:21](=[O:22])[C:20]1[CH:25]=[CH:26][CH:27]=[CH:18][CH:19]=1
Reactant: CNC(=O)c1cccc(N)c1
Reactant: O=S(=O)(CCl)Nc1ccc2cnccc2c1
Solvent: CO
Product: CNC(=O)c1ccccc1
Product: N
Temperature: 60 °C
Reaction time: 3 h
Yield: 2 %

Procedure:
To 1-chloro-N-(isoquinolin-6-yl)methanesulfonamide in MeOH is added KI and the solution is heated to 60° C. for 40 minutes. The mixture is cooled to 45° C. and 3-amino-N-methylbenzamide is added and stirred at 45° C. After 2-4 hours or when TLC indicated completion of the reaction, the solvents are evaporated and the residue is taken up in EtOAc and extracted with NaHCO3 (sat). The organics are dried (Na2SO4), filtered and evaporated. Flash chromatography (SiO2, 2% NH3(2M) in MeOH/3% MeOH/CH2Cl2) gives 34N-isoquinolin-6-ylsulfamoyl)methylamino)-N-methylbenzamide.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[C:8]([O:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:20]=3)=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH:13]=[C:12]([OH:17])[CH:11]=[CH:10]3)=[CH:4][CH:3]=1.C(OCC)(=O)C.[CH3:40][S:41](O)(=[O:43])=[O:42]>O1CCCC1>[CH3:40][S:41]([O:17][C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:5]3[S:6][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:8]=2[O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=2)[CH:13]=1)(=[O:43])=[O:42]
Reactant: Cc1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)s1
Reactant: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3cc(OS(C)(=O)=O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)s1
Temperature: 60 °C

Procedure:
Place 6-(5-methylthiophen-2-yl)-5-(4-(2-(piperidin-1-yl)ethoxy)phenoxy)naphthalen-2-ol (105.7 mg, 0.23 mmol) in a vial. Add ethyl acetate (2 mL) and methanesulfonic acid (18 μL). Warm the resulting mixture to ˜60° C. with stirring. Add tetrahydrofuran (1 mL) to the resulting burnt orange solution with some dark brown gum on the bottom of the vial. Sonicate the resulting solution for 15 minutes. Carefully decant the suspension from gum that forms on the flask. Carefully collect the resulting solids by vacuum filtration and wash the resulting cake with pentane (2×2 mL). Dry the resulting solids in a 40° C. vacuum oven overnight to obtain the title compound. MP (DSC)=161.90° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[C:12]([Cu])#[N:13]>CN1CCCC1=O>[Cl:11][C:4]1[N:3]=[C:2]([C:12]#[N:13])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: N#C[Cu]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CN1CCCC1=O
Product: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 41.4 %

Procedure:
A mixture of 2,6-dichloro-3-nitropyridine (40 g, 207 mmol) and CuCN (22.32 g, 248 mmol) in 1-methyl-2-pyrrolidinone (160 ml) was quickly heated to 180° C. for 25 minutes. The mixture was cooled to room temperature and the deep brown solution was poured into ice water (1200 ml) and stirred for 30 min. The aqueous solution was extracted with ethyl acetate and boiling toluene, the organic layer was dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (5% to 25% Ethyl Acetate gradient in Pentane) to give 6-chloro-3-nitropicolinonitrile as a yellow solid. (15.75 g, 41.4% yield)
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@H:14](O)[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C1(P([N:35]=[N+:36]=[N-:37])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([N:35]=[N+:36]=[N-:37])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)COc1cccc2c1CCC[C@@H]2O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)COc1cccc2c1CCC[C@H]2N=[N+]=[N-]
Temperature: 2.5 °C
Reaction time: 0.75 h

Procedure:
The toluene solution of chiral alcohol XI prepared above (36.19 mmol, assumed 100% conversion) was diluted with an additional 100 mL of toluene, and cooled in an ice-water bath, then treated with diphenylphosphoryl azide (13.64 g, 49.57 mmol). To this solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 8.0 g, 52.46 mmol), dropwise over 20 minutes at such a rate so as to maintain the internal temperature between 1-4° C. The reaction mixture was then stirred at an internal temperature of 1-2° C. for an additional 45 minutes, then warmed to room temperature (with a water bath), and stirred at room temperature overnight. After 20 hours, the reaction mixture was treated with ice-cold water (50 mL), while maintaining the internal temperature below 24° C. The organic layer was separated and washed with 1 M aqueous citric acid solution (50 mL), saturated aqueous sodium bicarbonate (50 mL), and water (50 mL). The resulting organic phase was then concentrated under vacuum at 20 mmHg/26° C., to provide 15 g of an oil, which was used in the next step without further purification.
Reaction SMILES: C[N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][N:21]4[C:25]5=[N:26][C:27]([C:30]6[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=6)=[CH:28][N:29]=[C:24]5[N:23]=[N:22]4)[CH2:15]3)=[N:12][CH:13]=2)[CH2:4][CH2:3]1.[ClH:36]>C(Cl)Cl.O1CCOCC1>[ClH:36].[CH3:35][N:33]1[CH:34]=[C:30]([C:27]2[N:26]=[C:25]3[N:21]([CH2:20][CH:16]4[CH2:17][CH2:18][CH2:19][N:14]([C:11]5[N:12]=[CH:13][C:8]([C:5]6[CH2:6][CH2:7][NH:2][CH2:3][CH:4]=6)=[CH:9][N:10]=5)[CH2:15]4)[N:22]=[N:23][C:24]3=[N:29][CH:28]=2)[CH:31]=[N:32]1
Reactant: CN1CC=C(c2cnc(N3CCCC(Cn4nnc5ncc(-c6cnn(C)c6)nc54)C3)nc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1cc(-c2cnc3nnn(CC4CCCN(c5ncc(C6=CCNCC6)cn5)C4)c3n2)cn1
Temperature: 25 °C
Yield: 82 %

Procedure:
1-((1-(5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-2-yl)piperidin-3-yl)methyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (125 mg, 0.22 mmol) was dissolved in CH2Cl2 (5 ml), and then 4 N HCl dissolved in dioxane (1 ml) was added, followed by stirring at room temperature. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and then purified with ether, to give 6-(1-methyl-1H-pyrazol-4-yl)-1-((1-(5-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-2-yl)piperidin-3-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine hydrochloride (90 mg, 82%).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]([NH:15][C@@H:16]([CH2:20][NH:21][C:22](=[O:40])[C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31](=[O:39])[NH:32][C:33]4[NH:34][CH2:35][CH2:36][CH2:37][N:38]=4)=[CH:25][CH:24]=3)[C:17]([OH:19])=[O:18])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(=O)(=O)(O)O.[CH:46]([OH:49])([CH3:48])[CH3:47]>>[C:17]([OH:19])(=[O:18])[CH3:16].[CH:46]([O:49][C:17](=[O:18])[C@@H:16]([NH:15][C:13]([O:12][CH2:11][C:1]12[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2)=[O:14])[CH2:20][NH:21][C:22](=[O:40])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31](=[O:39])[NH:32][C:33]2[NH:38][CH2:37][CH2:36][CH2:35][N:34]=2)=[CH:25][CH:24]=1)([CH3:48])[CH3:47]
Reactant: CC(C)O
Reactant: O=C(CCc1ccc(C(=O)NC[C@H](NC(=O)OCC23CC4CC(CC(C4)C2)C3)C(=O)O)cc1)NC1=NCCCN1
Agent: O=S(=O)(O)O
Product: CC(=O)O
Product: CC(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)NC(=O)OCC12CC3CC(CC(C3)C1)C2

Procedure:
17.5 g of (2S)-2-(adamantan-1-ylmethoxycarbonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propionic acid were dissolved in 670 ml of isopropanol. 1.8 ml of concentrated sulfuric acid were added and the reaction mixture was refluxed for 24 h. The solvent was distilled off in vacuo, the residue was brought to pH 7 with an aqueous solution of sodium chloride and solid sodium bicarbonate and the mixture was extracted four times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, the ethyl acetate was distilled off, the residue was treated with 20 ml of glacial acetic acid and lyophilized.