Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:10]([C:13]1[CH:14]=[CH:15][C:16]([OH:23])=[C:17]([CH:22]=1)[C:18]([O:20][CH3:21])=[O:19])(=[O:12])=[O:11].[O:28]1[CH2:33][CH2:32][CH:31]([CH2:34]O)[CH2:30][CH2:29]1.C(P(CCCC)(CCCC)=CC#N)CCC>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:10]([C:13]1[CH:14]=[CH:15][C:16]([O:23][CH2:34][CH:31]2[CH2:32][CH2:33][O:28][CH2:29][CH2:30]2)=[C:17]([CH:22]=1)[C:18]([O:20][CH3:21])=[O:19])(=[O:12])=[O:11]
Reactant: COC(=O)c1cc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)ccc1O
Reactant: OCC1CCOCC1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)ccc1OCC1CCOCC1
Temperature: 20 °C
Reaction time: 24 h

Procedure:
To a solution of methyl 5-(N-(2,4-dimethylphenyl)-N-isobutylsulfamoyl)-2-hydroxybenzoate (100 mg, 0.255 mmol) and (tetrahydro-2H-pyran-4-yl)methanol (29.7 mg, 0.255 mmol) in toluene (1.5 mL) stirred in air at room temperature was added a solution of 2-(tributylphosphoranylidene)acetonitrile (61.7 mg, 0.255 mmol) in toluene (0.5 mL). The reaction mixture was then stirred at 20° C. for 24 hours. After this time, additional 2-(tributylphosphoranylidene)acetonitrile (61.7 mg, 0.255 mmol) was added and the reaction stirred for a further 2 hours. The solvent was evaporated and the purification attempted by mass directed autoprep (ammonium carbonate modifier). The relevant fractions were concentrated under a stream of nitrogen to give a mixture of two products. Further purification was carried out by mass directed autoprep (Method O), to provide the desired product, 25 mg. LCMS [LCMS2] Rt 1.44 min, m/z (ES+) 490 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1C2C(=CC=C(C(=O)C)C=2)N[CH:5]=1.[F:16][C:17]1[C:18](I)=[C:19]([CH:21]=[C:22]([F:25])[C:23]=1[F:24])[NH2:20]>>[F:16][C:17]1[C:23]([F:24])=[C:22]([F:25])[CH:21]=[C:19]2[C:18]=1[C:4]([CH2:3][CH2:2][NH2:1])=[CH:5][NH:20]2
Reactant: Nc1cc(F)c(F)c(F)c1I
Reactant: CC(=O)c1ccc2[nH]cc(CCN)c2c1
Product: NCCc1c[nH]c2cc(F)c(F)c(F)c12

Procedure:
1-(3-(2-aminoethyl)-1H-indol-5-yl)ethanone can be prepared according to method D step II, III, IV and V starting from 3,4,5-trifluoro-2-iodoaniline.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:60])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:32]=[C:33]5[C:57](=[CH:58][CH:59]=4)[C:37]4[NH:38][C:39]([CH:41]6[CH2:45][CH2:44][CH2:43][N:42]6[C:46](=[O:56])[CH:47]([NH:51][C:52]([O:54][CH3:55])=[O:53])[CH:48]([CH3:50])[CH3:49])=[N:40][C:36]=4[CH2:35][CH2:34]5)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]>C(Cl)Cl.O=[Mn]=O>[CH3:55][O:54][C:52]([NH:51][C@@H:47]([CH:48]([CH3:50])[CH3:49])[C:46]([N:42]1[CH2:43][CH2:44][CH2:45][C@H:41]1[C:39]1[NH:38][C:37]2[C:57]3[C:33]([CH:34]=[CH:35][C:36]=2[N:40]=1)=[CH:32][C:31]([C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([C:18]1[NH:17][C:16]([C@@H:12]4[CH2:13][CH2:14][CH2:15][N:11]4[C:9](=[O:10])[C@@H:5]([NH:4][C:3](=[O:60])[O:2][CH3:1])[CH:6]([CH3:8])[CH3:7])=[N:20][CH:19]=1)[CH:30]=[CH:29]2)=[CH:59][CH:58]=3)=[O:56])=[O:53]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc5c(c4)CCc4nc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]c4-5)ccc3c2)[nH]1)C(C)C
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc5c(ccc6nc([C@@H]7CCCN7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c65)c4)ccc3c2)[nH]1)C(C)C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
To (1-{2-[5-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl}-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (13.0 mg, 0.016 mmol) in CH2Cl2 (1 mL) was added MnO2 (2.8 mg, 0.032 mmol). The reaction was stirred overnight then additional MnO2 (1.4 mg, 0.016 mmol) was added. After stirring for 3 hours, the reaction was filtered through a Whatman 0.45 mM PTFE filter. The filtrate was concentrated then purified by preparative reverse phase HPLC (Gemini, 10 to 45% ACN/H2O+0.1% TFA) to yield methyl (S)-1-((S)-2-(5-(6-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (6.3 mg, 48%). LCMS-ESI+: calculated for C46H53N8O6: 813.4; observed [M+1]+: 813.4.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][C:20]1[NH:24][CH:23]=[N:22][C:21]=1[C:25]#[N:26]>>[C:25]([C:21]1[N:22]=[CH:23][NH:24][C:20]=1[NH:19][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)(=[O:8])=[O:9])[CH:11]=1)#[N:26]
Reactant: N#Cc1nc[nH]c1N
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Product: N#Cc1nc[nH]c1NC(=O)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 5-amino-1H-imidazole-4-carbonitrile as the starting materials.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11](=[O:19])[N:12]([C:13]([CH3:18])([CH3:17])[CH2:14][O:15][CH3:16])[C:8]=2[CH:7]=1)[CH3:4].[CH3:22][O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[C:28]([O:36][CH3:37])[CH:27]=1)=[O:25]>C1COCC1>[CH2:3]([O:5][C:6]1[CH:21]=[CH:20][C:9]2[N:10]([S:32]([C:29]3[CH:30]=[CH:31][C:26]([C:24]([O:23][CH3:22])=[O:25])=[CH:27][C:28]=3[O:36][CH3:37])(=[O:34])=[O:33])[C:11](=[O:19])[N:12]([C:13]([CH3:17])([CH3:18])[CH2:14][O:15][CH3:16])[C:8]=2[CH:7]=1)[CH3:4]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)c(OC)c1
Reactant: CCOc1ccc2[nH]c(=O)n(C(C)(C)COC)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccc2c(c1)n(C(C)(C)COC)c(=O)n2S(=O)(=O)c1ccc(C(=O)OC)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
0.12 g of sodium hydride as a 60% dispersion in oil is added in portions to a mixture of 1 g of 5- ethoxy-1,3-dihydro-3-(2-methoxy-1,1-dimethylethyl)-2H-benzimidazol-2-one and 30 ml of THF and the mixture is stirred for 30 minutes at RT. 1.2 g of 4-methoxycarbonyl-2-methoxybenzenesulfonyl chloride are then added and the mixture is stirred for 2 hours at RT. It is concentrated under vacuum, the residue is extracted with AcOEt, washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (98/2; v/v) as the eluent to give 1.7 g of the expected product, which is used as such in the next step.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].C([O:13][C:14](=O)[CH:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16](=O)[CH3:17])C>>[OH:13][C:14]1[N:1]([C:3]2[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=2)[N:2]=[C:16]([CH3:17])[C:15]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(C(C)=O)c1ccccc1
Reactant: N#Cc1ccnc(NN)c1
Product: Cc1nn(-c2cc(C#N)ccn2)c(O)c1-c1ccccc1
Yield: 29 %

Procedure:
The title compound was prepared in 29% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and 3-oxo-2-phenyl-butyric acid ethyl ester according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C16H12N4O, 277. Found, 277.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:13]2[CH2:17][C@H:16]([CH2:18][N:19]3[CH:23]=[CH:22][N:21]=[N:20]3)[O:15][C:14]2=[O:24])[CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[N:10][NH:11][CH:12]=1.[H-].[Na+].Br[CH2:28][C:29]#[N:30]>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[C:4]([N:13]2[CH2:17][C@H:16]([CH2:18][N:19]3[CH:23]=[CH:22][N:21]=[N:20]3)[O:15][C:14]2=[O:24])[CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[N:10][N:11]([CH2:28][C:29]#[N:30])[CH:12]=1
Reactant: N#CCBr
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2c[nH]nn2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCn1cc(-c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 108.6 %

Procedure:
(5R)-3-[3-Fluoro-4-(1H-1,2,3-triazol4-yl)phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 7, 1.5 g, 4.6 mmol) was stirred in N,N-dimethylformamide at 0° C. Sodium hydride (0.35 g, 9.2 mmol) was added and the mixture was stirred 30 minutes. Bromoacetonitrile (0.66 g, 5.5 mmol) was added and the reaction was stirred overnight, slowly warming to room temperature. Starting material was present so additional bromoacetonitrile (0.33 g, 2.8 mmol) was added and the reaction was stirred for two additional days. The mixture was diluted with water and extracted using ethyl acetate. The organic layer was washed with water, dried (magnesium sulfate) and concentrated under vacuum to give a yellow solid (1.84 g). The solid was dissolved in dimethylsulfoxide (18 ml) and water (5 ml) and the isomers were separated using Gilson HPLC. Peaks 1 and 2 were collected, concentrated and lyophilized to give a light yellow solid (Example 10, peak 1, 36 mg; Example 11, peak 2, 182 mg). NOE experiments were used to distinguish the two isomers with the cyano group of peaks 1 and 2 corresponding to the 1 and 2 positions of the nitrogen, respectively.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH:5]=[C:6]([C:23]1[CH:24]=[N:25][C:26]([NH2:29])=[CH:27][CH:28]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH:6]([C:23]1[CH:24]=[N:25][C:26]([NH2:29])=[CH:27][CH:28]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[CH2:19][CH2:18][CH2:17][NH:16][C:15]=2[N:14]=1)[CH3:2]
Reactant: CCOC(=O)C=C(CCCCCCc1ccc2cccnc2n1)c1ccc(N)nc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC(CCCCCCc1ccc2c(n1)NCCC2)c1ccc(N)nc1

Procedure:
A mixture of 28-5 (0.1 g, 0.3 mmol) and 10% Pd/C (0.1 g) in 10 mL methanol was purged with argon under vacuum and then treated under balloon hydrogenation conditions for 40 hr. It was filtered through a pad of celite. The solution was concentrated. The residue was purified by silica gel chromatography (100% CHCl3 to CHCl3/MeOH 5:1) to afford the desired product 28-6 as an oil.
Reaction SMILES: [ClH:1].[NH:2](C(OC(C)(C)C)=O)[C@H:3]([C:8]([NH:10][C@H:11]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].C(OCC)(=O)C>COC(C)(C)C>[NH2:2][C@H:3]([C:8]([NH:10][C@H:11]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH:13]([CH3:14])[CH3:15])=[O:9])[CH2:4][CH:5]([CH3:6])[CH3:7].[ClH:1]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
Gaseous HCl (10.2 g, 279 mmol) was infused into a mixture of Boc-Leu-Leu-OMe (17.9 g, 50.0 mmol) and ethyl acetate (71.4 g) at 20 to 25° C. After 30 min, t-butyl methyl ether (142.9) was added to the resulting solution followed by a seed crystal. The resulting solid crystalline product was filtered at 0 to 5° C. and dried in vacuo to give H-Leu-Leu-OMe.HCl (14.1 g, 95.7%).
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][CH:18]([C:22]3[N:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[S:25][CH:26]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)([O:3]C)=[O:2].[OH-].[Na+]>CO>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][CH:18]([C:22]3[N:23]=[C:24]([C:27]([F:28])([F:29])[F:30])[S:25][CH:26]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)([OH:3])=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)N2CCOC(c3csc(C(F)(F)F)n3)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(Cc1ccc(OCC(=O)O)cc1)N1CCOC(c2csc(C(F)(F)F)n2)C1

Procedure:
Prepared analogously to Example 16 by reaction of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl) morpholine in methanol with 1N sodium hydroxide solution. After neutralisation with 1N hydrochloric acid, the mixture is extracted by shaking with methylene chloride, the extract is evaporated to dryness, and the remaining residue is triturated with petroleum ether and filtered off with suction.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[CH3:17][O:18][C:19]([C:21]1[O:22][C:23]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][C:24]=2[CH:25]=1)=[O:20]>>[F:16][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[N:7][C:2]([NH:30][C:27]2[CH:28]=[CH:29][C:23]3[O:22][C:21]([C:19]([O:18][CH3:17])=[O:20])=[CH:25][C:24]=3[CH:26]=2)=[N:3][CH:4]=1
Reactant: COC(=O)c1cc2cc(N)ccc2o1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2o1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine with 2-methoxycarbonyl-5-aminobenzofuran gave 5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 9.42 (s, 1H), 9.33 (s, 1H), 9.23 (s, 1H), 8.26 (s, 1H), 8.09 (d, 1H, J=3.6 Hz), 7.59 (m, 3H), 7.13 (m, 3H), 6.53 (d, 1H, J=7.5 Hz), 3.87 (s, 3H), 3.87 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH2:20][O:21][C:22]1[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=1)[C:13]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:12]2Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:38][C:39]([F:50])([F:49])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1B(O)O.[F-].[Cs+]>C(COC)OC.CO.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>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH2:20][O:21][C:22]1[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=1)[C:13]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:12]2[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[C:39]([F:50])([F:49])[F:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: CCOC(=O)c1c(Br)c2cc(OCc3ccccc3)ccc2n1CCCOc1cccc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CO
Product: CCOC(=O)c1c(-c2ccccc2C(F)(F)F)c2cc(OCc3ccccc3)ccc2n1CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 135B (30 mg), 2-(trifluoromethyl)phenylboronic acid (15.3 mg), tetrakis(triphenylphosphine)palladium(0) (3.1 mg) and cesium fluoride (16.3 mg) in dimethoxyethane (1.4 ml) and methanol (0.7 ml) was heated at 100° C. in a microwave reactor (CEM Discover) for 30 minutes and was concentrated. The residue was purified by flash chromatography, eluting with 0%-100% dichloromethane in hexane, to provide ethyl 5-(benzyloxy)-1-(3-(naphthalen-1-yloxy)propyl)-3-(2-(trifluoromethyl)phenyl)-1H-indole-2-carboxylate. This ester was hydrolyzed with aqueous NaOH in tetrahydrofuran and methanol to provide the title compound. 1H NMR (500 MHz, dimethyl sulfoxide-d6) δ 12.67 (s, 1H), 8.04-8.40 (m, 1H), 7.87 (d, J=7.32 Hz, 1H), 7.82 (d, J=7.63 Hz, 1H), 7.69 (t, J=7.32 Hz, 1H), 7.57-7.65 (m, 2H), 7.44-7.56 (m, 3H), 7.26-7.41 (m, 7H), 6.97 (dd, J=9.00, 2.29 Hz, 1H), 6.85 (d, J=7.93 Hz, 1H), 6.55 (d, J=2.14 Hz, 1H), 4.83-4.98 (m, 4H), 4.05-4.24 (m, 2H), 2.28-2.40 (m, 2H).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][OH:21])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:21][S:36]([CH3:35])(=[O:38])=[O:37])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CO)nn23)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COS(C)(=O)=O)nn23)CC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 106.5 %

Procedure:
To a solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(hydroxymethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.50 g, 1.054 mmol) in DCM (6 ml) cooled to 0° C. were added DMAP (0.013 g, 0.105 mmol) and TEA (0.294 ml, 2.107 mmol) followed by methanesulfonyl chloride (0.098 ml, 1.264 mmol) and the resulting solution was stirred at 0° C. After 45 min, the reaction was diluted with DCM and quenched with sat'd aq NaHCO3. The organic phase was washed with water, dried and concentrated to give (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methyl-2-(((methylsulfonyl)oxy)methyl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.62 g, 1.122 mmol, 106% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.63 (s, 1H), 6.15-5.97 (m, 1H), 5.98-5.81 (m, 1H), 5.55-5.38 (m, 3H), 5.29-5.20 (m, 1H), 4.32-4.11 (m, 2H), 4.02 (d, J=4.9 Hz, 2H), 3.06 (s, 3H), 2.63 (s, 3H), 1.93 (br. s., 4H), 1.35 (s, 3H), 1.29-1.19 (m, 12H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-])=O)(=[O:11])=[O:10])[O:4][N:3]=1.[H][H]>[Pd].CO>[NH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][C:5]1[O:4][N:3]=[C:2]([CH3:1])[C:6]=1[CH3:7])(=[O:11])=[O:10]
Reactant: Cc1noc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])c1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1noc(NS(=O)(=O)c2ccccc2N)c1C
Yield: 111.1 %

Procedure:
To a suspension of 135 mg of 10% palladium on carbon in 20 mL of methanol under argon, 0.9 g (3.03 mmol) of N-(3,4-dimethyl-5-isoxazolyl)-2-nitrobenzenesulfonamide (Example 9)in 20 mL of methanol was added. The solution was hydrogenated with a balloon filled with hydrogen for 90 minutes. The mixture was filtered through Celite® and the filtrate was concentrated to afford 0.9 g of a gum. This material was chromatographed on silica initially with 9:1 methylene chloride:methanol and then with 1:1 hexanes:ethyl acetate to provide 0.2 g (24%) of Example 10 as a white solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:15](=[O:16])[NH:14][C:13]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:12][C:11]=1[NH:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1.F[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:15](=[O:16])[NH:14][C:13]([CH:17]2[CH2:18][CH2:19][N:20]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)[CH2:21][CH2:22]2)=[N:12][C:11]=1[NH:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1
Reactant: Fc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nc(C3CCNCC3)[nH]c(=O)c2-c2nc3ccccc3s2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nc(C3CCN(c4ccccn4)CC3)[nH]c(=O)c2-c2nc3ccccc3s2)C1
Temperature: 100 °C
Reaction time: 24 h
Yield: 41.1 %

Procedure:
Into a 25-mL round-bottom flask, was placed a solution of tert-butyl (3R)-3-[[5-(1,3-benzothiazol-2-yl)-6-oxo-2-(piperidin-4-yl)-1,6-dihydropyrimidin-4-yl]amino]piperidine-1-carboxylate (150 mg, 0.29 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL) and 2-fluoropyridine (114 mg, 1.17 mmol, 4.00 equiv). This was followed by the addition of potassium carbonate (81 mg, 0.59 mmol, 2.00 equiv). The resulting solution was stirred for 24 h at 100° C. The solids were filtered out. The resulting mixture was concentrated under reduced pressure. The residue was purified through a silica gel column with dichloromethane/methanol (50:1-20:1) to afford 70 mg of tert-butyl (3R)-3-[[5-(1,3-benzothiazol-2-yl)-6-oxo-2-[1-(pyridin-2-yl)piperidin-4-yl]-1,6-dihydropyrimidin-4-yl]amino]piperidine-1-carboxylate as a light yellow solid.
Reaction SMILES: C(O[C:4]1([CH2:12][C:13]([O:15]CC)=O)[CH2:8][C:7](=[O:9])[NH:6][C:5]1=C=O)C.[OH-:18].[Na+].Cl>>[CH2:5]([N:6]1[C:13](=[O:15])[CH2:12][C:4]2([CH2:8][C:7](=[O:9])[NH:6][CH2:5]2)[C:7]1=[O:18])[CH3:4]
Reactant: CCOC(=O)CC1(OCC)CC(=O)NC1=C=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CCN1C(=O)CC2(CNC(=O)C2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 24.3 g (0.10 mmole) 3-ethoxy-carbonyl-5-oxo-3-pyrrolidineacetic acid, ethyl ester in an excess of 2 N sodium hydroxide, was stirred three hours at room temperature, acidified with dilute hydrochloric acid, and evaporated to dryness in vacuo. The product, 3-carboxy-5-oxo3-pyrrolidineacetic acid, was taken up in isopropyl alcohol, separated from insoluble sodium chloride by filtration, concentrated to a syrup and dissolved in 100 ml 70% ethylamine. The solution was gradually heated in an oil bath up to 230° C. allowing volatiles to distill and then maintained at 230°-240° C. for ten minutes. After cooling, the product was crystallized from isopropyl alcohol to afford 10.1 g of 2-ethyl-2,7-diazaspiro[4.4]nonane-1,3,8-trione, mp 168°-169° C.
Reaction SMILES: [C:1]([OH:9])(=O)[C@H:2]([CH2:4][C:5](O)=[O:6])[OH:3].[CH3:10][NH2:11]>C1(C)C=CC=CC=1>[OH:3][C@H:2]1[CH2:4][C:5](=[O:6])[N:11]([CH3:10])[C:1]1=[O:9]
Reactant: O=C(O)C[C@H](O)C(=O)O
Reactant: CN
Solvent: Cc1ccccc1
Product: CN1C(=O)C[C@H](O)C1=O

Procedure:
To a stirred solution of 134 g (1 mole) of (S)-malic acid in 700 ml of toluene was added 97 ml of 40% aqueous methylamine. The temperature slowly rose to 50° C. After 0.5 hr the stirred mixture was heated to reflux and the water was collected in a Dean-Stark trap for 48 hr. A total of 93 ml of water was collected. The toluene residue was treated with 300 ml of ethanol and concentrated on the rotary evaporator. The residue was distilled. The yield of product obtained was 101 g (78%), b.p 140°/2 mm; 145°/0.5 mm.
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[CH2:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:8]([F:15])[CH:7]=1>C(O)C.[Cl-].[Na+].O>[F:15][C:8]1[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=[C:6]([CH2:5][S:2][CH3:1])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(F)cc(CCl)c1
Reactant: C[S-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CSCc1cc(F)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 106.9 %

Procedure:
Sodium methanethiolate (1.22 g; 17.4 mmol) was added in three portions to a stirred solution of 1-(chloromethyl)-3-fluoro-5-nitrobenzene (3.00 g; 15.8 mmol, HE Chemical) in ethanol (33 mL) at 0° C. The ice bath was removed and the batch was stirred at room temperature for 18 hours. Further sodium methanethiolate (0.33 g; 4.7 mmol) was added and the batch was stirred for 5 additional hours at room temperature. The batch was diluted with brine and extracted with ethyl acetate (2×). The combined organic phases were washed with water, dried (sodium sulfate), filtered and concentrated to give the desired product (3.4 g) that was used without further purification.