Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4]([NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.O.[NH2:39][NH2:40].C(O)(C)C.C(O)=O>C(#N)C>[C:26]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:24][NH:23][C:4]2[N:3]=[C:2]([NH:39][NH2:40])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: NN
Solvent: CC#N
Solvent: O=CO
Solvent: O
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(NN)nc32)[C@H](O)[C@@H]1O
Reaction time: 12 h

Procedure:
N-{(1S,2R,3S,4R)-4-[2-Chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (Intermediate J) (1.0 g, 1.91 mmol) and hydrazine monohydrate (12 ml) is stirred for 72 h and then isopropyl alcohol (10 ml) is added. The solvent is removed in vacuo and the residue is water (10 ml) and stirred for 12 h. The fine solid obtained is filtered, washed with water and dried in vacuo to afford the product. LC-MS (0.1% formic acid, acetonitrile) (MH+ 517)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH:12]=O)=[CH:9][CH:8]=[CH:7]2.[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:25]3([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:24](=[O:31])[NH:23][CH2:22]2)=[CH:17][CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>C(Cl)Cl.C(OCC)C.CC(O)=O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:25]3([CH2:26][CH2:27][N:28]([CH2:12][C:10]4[C:11]5[C:6](=[CH:5][CH:4]=[CH:3][C:2]=5[CH3:1])[CH:7]=[CH:8][CH:9]=4)[CH2:29][CH2:30]3)[C:24](=[O:31])[NH:23][CH2:22]2)=[CH:17][CH:16]=1
Reactant: O=C1NCN(c2ccc(F)cc2)C12CCNCC2
Reactant: Cc1cccc2cccc(C=O)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cccc2cccc(CN3CCC4(CC3)C(=O)NCN4c3ccc(F)cc3)c12
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
A 1-L 3-neck flask equipped with an overhead stirrer and a thermocouple was charged with 8-methyl-naphthalene-1-carbaldehyde (13.75 g, 0.08 mol) and 1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (21.5 g, 0.085 mol) under N2 in CH2Cl2 (500 mL). After stirring for 20 min, HOAc (1 mL) was added followed by careful addition of solid NaBH(OAc)3 (33.4 g, 0.157 mol). The mixture was stirred for 16 h at room temperature (suspension becomes a solution). The reaction was then warmed at 50° C. for 2 h, cooled down to room temperature and then treated with 0.5 N NaOH (50 mL), stirred for 10 min and then diluted with CH2Cl2 (100 mL). The organic layer was isolated and dried over MgSO4. The solvent was evaporated to yield a residue, which was suspended in diethyl ether, stirred for 20 min, filtered and dried in a 60° C. vacuum oven to yield 1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]-decan-4-one as a white solid;
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([O:16][CH3:17])[C:4]=1[C:5](O)=[O:6].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.Cl.[N:55]1([C@H:60]2[CH2:65][CH2:64][CH2:63][CH2:62][C@H:61]2[NH2:66])[CH2:59][CH2:58][CH2:57][CH2:56]1>CN(C)C=O>[CH3:17][O:16][C:8]1[CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=[C:3]([C:2]([F:1])([F:18])[F:19])[C:4]=1[C:5]([NH:66][C@@H:61]1[CH2:62][CH2:63][CH2:64][CH2:65][C@@H:60]1[N:55]1[CH2:56][CH2:57][CH2:58][CH2:59]1)=[O:6]
Reactant: N[C@@H]1CCCC[C@@H]1N1CCCC1
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
2,4-Bis(trifluoromethyl)-6-methoxy-benzoic acid (200 mg, 0.69 mmol) was dissolved in 5 mL dimethylformamide. N,N-Diisopropyl ethyl amine (359 mg, 2.8 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (264 mg, 0.69 mmol) were added. After 5 minutes of stirring at room temperature cis-2-pyrrolidin-1-yl-cyclohexylamine dihydrochloride (intermediate F) (171 mg, 0.71 mmol) was added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated off. The residue was taken up in 2N sodium carbonate solution and ethyl acetate and was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (dichloromethane/methanol/ammonia 100:0:0->140:10:1) yielded cis-2-methoxy-N-(2-pyrrolidin-1-yl-cyclohexyl)-4,6-bis-trifluoromethyl-benzamide as a white solid (158 mg, 52%), MS: m/e=439.2 [(M+H)+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:19]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:20]([C:22]2([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.[CH3:35][C:36]([N:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)([C:38]#[CH:39])[CH3:37]>>[F:1][C:2]1[CH:3]=[C:4]([N:19]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:20]([C:22]2([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:39]#[C:38][C:36]([CH3:37])([N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)[CH3:35])[S:17][C:10]=12
Reactant: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4cc(I)sc34)c(F)c2)CC1
Reactant: C#CC(C)(C)N1CCCCC1
Product: CC(C)(C#Cc1cc2nccc(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)cc3F)c2s1)N1CCCCC1
Yield: 38.5 %

Procedure:
Prepared from N-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Example 12, Step A, 20 mg, 0.0338 mmol) and 1-(2-methylbut-3-yn-2-yl)piperidine (10.2 mg, 0.0676 mmol) using the procedure described for Example 6, Step B. The crude was purified by preparative TLC (1 mm thickness, Rf=0.34) eluting with 10% MeOH/DCM. A second purification by preparative TLC was conducted (0.5 mm thickness, Rf=0.49), eluting with 15% MeOH in EtOAc, in order to obtain product of adequate purity. The product was obtained as a beige powder (8 mg, 38%). HPLC: 98% purity (254 nm); LCMS (APCI−): 100% purity, 220 nm, m/z 613 (M−1) detected; 1H NMR (400 MHz, CDCl3) δ 10.04 (s, 1H), 8.48 (d, J=6 Hz, 1H), 8.15 (s, 1H), 7.74 (m, 1H), 7.55 (s, 1H), 7.45 (m, 2H), 7.24 (m, 2H), 7.07 (t, J=9 Hz, 2H), 6.50 (d, J=6 Hz, 1H), 2.66 (br s, 4H), 1.81 (m, 2H), 1.64 (m, 6H), 1.51 (m, 8H).
Reaction SMILES: [CH3:1][C:2]([N:7]1[C:12](=[O:13])[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:10]([CH3:20])[O:9][CH2:8]1)([CH3:6])[C:3]([OH:5])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:33]([NH2:36])([CH3:35])[CH3:34].O>O1CCCC1>[CH:33]([NH:36][C:3](=[O:5])[C:2]([CH3:1])([N:7]1[C:12](=[O:13])[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:10]([CH3:20])[O:9][CH2:8]1)[CH3:6])([CH3:35])[CH3:34]
Reactant: CC(C)N
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)O)CO1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)NC(C)C)CO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.8 %

Procedure:
To a solution of 2-methyl-2-(6-methyl-5-phenyl-2,3-dihydro-4-oxo-4H-1,3-oxazin-3-yl)-propionic acid (0.83 g) in 6 ml of tetrahydrofuran (THF) was added carbonyldiimidazole (0.59 g). After stirring at room temperature for 30 min., isopropylamine (0.23 g) was added and the reaction mixture was stirred at 60° C. for 5 h. Then it was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on a silica gel column to get the captioned compound (0.38 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:23]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)([C:14]([NH2:23])=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccncc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C(N)=O)(c2ccncc2)CC1

Procedure:
Prepare by the method of example 20.8 using 1-tert-butoxycarbonyl-4-(pyridin-4-yl)-piperidine-4-carboxylic acid (4.0 mmol) and NH3 (gas). Purify to give the title compound.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:30][C:21]3=[N:22][CH:23]=[C:24]([CH2:26][C:27]([OH:29])=O)[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:32][NH:33][CH3:34].CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:30][C:21]3=[N:22][CH:23]=[C:24]([CH2:26][C:27]([N:33]([CH3:34])[CH3:32])=[O:29])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:12][CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(CC(=O)O)cnc3[nH]2)cc1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)Cc1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 58.4 %

Procedure:
To a solution of {2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-acetic acid (75 mg, 0.17 mmol) and dimethylamine hydrochloride (43 mg, 0.53 mmol) in N,N-dimethylformamide (2 mL) and N-methylmorpholine (97 uL, 0.88 mmol) was added 1-hydroxybenzotriazole hydrate (110 mg, 0.81 mmol) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (68 mg, 0.35 mmol) in one portion. The mixture was stirred at 25° C. for 6 h. The mixture was diluted with ethyl acetate (100 mL), washed with a 1 N aqueous sodium bicarbonate solution, 1N aqueous hydrochloric acid solution, brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-{2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N,N-dimethyl-acetamide (45 mg, 56%) as a light yellow solid: LC/MS m/e calcd for C25H31N3O3S [M+H]+ 454.61, observed 454.1; 1H NMR (400 MHz, CDCl3) δ ppm 1.18 (m, 2H), 1.48 (m, 2H), 1.56-1.85 (m, 5H, H), 2.10 (m, 1H), 2.23 (m, 1H), 2.99 (s, 3H), 3.04 (s, 3H), 3.10 (s, 3H), 3.81 (s, 2H), 4.29 (t, J=7.8 Hz, 1H), 6.35 (s, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.86 (d, J=8.3 Hz, 2H), 7.96 (s, 1H), 8.02 (s, 1H), 10.99 (br, 1H).
Reaction SMILES: Cl.C(OC([NH:9][C:10]1([C:40]([O:42][CH3:43])=[O:41])[CH2:15][CH2:14][N:13]([C:16]([C:18]2[CH:19]=[N:20][N:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[C:32]4[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=4[F:39])=[CH:23][C:22]=23)=[O:17])[CH2:12][CH2:11]1)=O)(C)(C)C>O1CCOCC1.O>[NH2:9][C:10]1([C:40]([O:42][CH3:43])=[O:41])[CH2:11][CH2:12][N:13]([C:16]([C:18]2[CH:19]=[N:20][N:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[C:32]4[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=4[F:39])=[CH:23][C:22]=23)=[O:17])[CH2:14][CH2:15]1
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCN(C(=O)c2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)cc23)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C1(N)CCN(C(=O)c2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)cc23)CC1
Temperature: 27.5 °C
Reaction time: 3 h
Yield: 36.5 %

Procedure:
A mixture of 4M HCl solution in Dioxane (1 mL) and (R)-methyl 4-((tert-butoxycarbonyl)amino)-1-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)piperidine-4-carboxylate (50 g, 0.085 mmol) was stirred at 20-35° C. for 3 h. After which the reaction mixture was concentrated under reduced pressure to afford the crude. The residue obtained was dissolved in water, extracted with ethylacetate, washed with saturated NaHCO3 solution followed by brine and dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford 15 mg of the title compound.
Reaction SMILES: [F-].[Cs+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[CH:14]1[C:23]2[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[N:21][N:20]([CH3:30])[C:19]=2[CH2:18][C:17](=[O:31])[CH2:16][CH2:15]1)[C:7]([O:9][CH3:10])=[O:8].[F:32][C:33]([Si](C)(C)C)([F:35])[F:34].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>COCCOC>[OH:31][C@:17]1([C:33]([F:35])([F:34])[F:32])[CH2:18][C:19]2[N:20]([CH3:30])[N:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[C:23]=2[C@@H:14]([C:13]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=2[CH3:3])[CH2:15][CH2:16]1
Reactant: COC(=O)c1ccc(C2CCC(=O)Cc3c2c(-c2ccccn2)nn3C)c(C)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: C1CCOC1
Product: COC(=O)c1ccc([C@H]2CC[C@@](O)(C(F)(F)F)Cc3c2c(-c2ccccn2)nn3C)c(C)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 8 %

Procedure:
Cesium fluoride (0.037 g, 0.244 mmol) was added to a solution of rac-methyl 3-methyl-4-(1-methyl-7-oxo-3-(pyridin-2-yl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)benzoate (0.190 g, 0.488 mmol) in DME (50 mL). The mixture was stirred at rt for about 20 min then it was cooled in an ice bath and (trifluoromethyl)trimethylsilane (1.44 mL, 9.76 mmol) was added in a dropwise manner. After about 30 min, (trifluoromethyl)trimethylsilane (1.44 mL, 9.76 mmol) was added. After about 45 min, the mixture was partitioned between EtOAc (100 mL) and saturated aqueous NH4Cl solution (100 mL). The organic layer was washed with brine (100 mL), dried with Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in EtOAc (20 mL) and 1 M tetrabutylammonium fluoride in THF (0.54 mL, 0.54 mmol) was added. The mixture was stirred at rt for about 1 h then it was washed with saturated NH4Cl (2×50 mL) and brine (50 mL). The organic layer was dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 25-50% EtOAc/heptane) to give rac-methyl 4-((4R,7S)-7-hydroxy-1-methyl-3-(pyridin-2-yl)-7-(trifluoromethyl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)-3-methylbenzoate (0.018 g, 8%): LC-MS (Table 1, Method g) Rt=2.28 min, m/z 460 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 8.31-8.27 (m, 1H), 7.75-7.72 (m, 1H), 7.69-7.67 (m, 1H), 7.65-7.60 (m, 1H), 7.53-7.49 (m, 1H), 7.10-7.05 (m, 1H), 6.95 (d, J=8.1 Hz, 1H), 6.30 (s, 1H), 5.22-5.14 (m, 1H), 3.85 (s, 3H), 3.76 (s, 3H), 3.34-3.32 (m, 2H), 2.62 (s, 3H), 2.20-2.08 (m, 1H), 1.98-1.90 (m, 1H), 1.86-1.74 (m, 2H). and rac-methyl 4-((4R,7R)-7-hydroxy-1-methyl-3-(pyridin-2-yl)-7-(trifluoromethyl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)-3-methylbenzoate (0.034 g, 15%): LC-MS (Table 1, Method g) Rt=2.28 min, m/z 460 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 8.35-8.38 (m, 1H), 7.77-7.74 (m, 1H), 7.71-7.69 (m, 1H), 7.68-7.63 (m, 1H), 7.57-7.52 (m, 1H), 7.14-7.10 (m, 1H), 6.96-6.93 (m, 1H), 6.18 (s, 1H), 5.51-5.45 (m, 1H), 3.90 (s, 3H), 3.76 (s, 3H), 3.36-3.17 (m, 2H), 2.56 (s, 3H), 2.29-2.20 (m, 1H), 1.90-1.79 (m, 1H), 1.76-1.65 (m, 2H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21].O.Cl>N1C=CC=CC=1>[C:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)=CCc1cc(C(=O)O)ccc1O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Oc1ccc(C(=O)O)cc1CC=C(C)C
Reaction time: 48 h
Yield: 51 %

Procedure:
Acetic anhydride (1 mL) was added dropwise to a solution of acid 8 (178 mg, 2.00 mmol) in pyridine (3 mL) at room temperature. After stirring for 48 hours, the mixture was poured into water (6 mL) and acidified to pH=2 by the dropwise addition of 6 M HCl. The suspension was extracted with EtOAc (2×10 mL), and the combined organic fractions were dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography (5:1, hexanes:EtOAc) to afford acetate 9 (223 mg, 51%) as a white solid: 1H NMR (CDCl3, 400 MHz) δ 8.01-7.96 (m, 2H), 7.15 (dd, J=3.5, 8.2 Hz, 1H), 5.24 (tt, J=1.3, 7.2 Hz, 1H), 3.30 (d, J=7.2 Hz, 2H), 2.34 (s, 3H), 1.97 (s, 3H), 1.76 (s, 3H).
Reaction SMILES: O[C:2]1[C:3](O)=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11](O)=[O:12])[C:7](=[O:14])[C:6]=2[CH:15]=1.S(Cl)([Cl:19])=O>>[O:14]=[C:7]1[C:6]2=[CH:15][CH2:2][CH2:3][CH:4]=[C:5]2[S:10][CH:9]=[C:8]1[C:11]([Cl:19])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1csc2cc(O)c(O)cc2c1=O
Product: O=C(Cl)c1csc2c(c1=O)=CCCC=2

Procedure:
6,7-Dihydroxy-4-oxo-4H-1-benzothiopyran-3-carboxylic acid (100 mg) was heated under reflux for 2 hours in thionyl chloride (5 mL), and then the thionyl chloride was distilled off. To the residue was added benzene (20 mL). Benzene was distilled off again and the residue was vacuum dried to give 6,7-dihydro-4-oxo-4H-1-benzothiopyran-3-carbonyl chloride.
Reaction SMILES: [N+:1]([C:4]1[N:5]([CH2:9][C:10]([O:12]CC)=[O:11])[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2]>[OH-].[Na+]>[N+:1]([C:4]1[N:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)Cn1ccnc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cn1ccnc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Ethyl 2-(2-nitro-1H-imidazol-1-yl)acetate was suspended in 1N NaOH (100 mL) and stirred at room temperature until it turned into a clear solution. The solution was cooled in an ice-bath and neutralized to pH~2 to give a white precipitate. The solid was filtered and washed with water (3×25 mL). Yield: 11.5 g (97%). MS: 189 (M+NH4)+, 172 (M+H)+, 170 (M-H)-. 1H NMR (DMSO-d6) δ5.22 [s, 2H, C H2 -(2-nitroimidazole)], 7.22 and 7.65 (s, 2H, 2-nitroimidazolyl- H).
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1[CH:5]=[C:6]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:11][N:10]([C:18]3[C:19]4[C@H:26]([CH3:27])[CH2:25][C@@H:24]([OH:28])[C:20]=4[N:21]=[CH:22][N:23]=3)[C:7]2=[CH:8][CH:9]=1.[CH3:29]CN(C(C)C)C(C)C.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].Cl>ClCCCl.C1COCC1.C(Cl)Cl.CCOCC>[ClH:3].[ClH:1].[Cl:3][C:4]1[CH:5]=[C:6]2[C:12]3([CH2:17][CH2:16][N:15]([CH3:29])[CH2:14][CH2:13]3)[CH2:11][N:10]([C:18]3[C:19]4[C@H:26]([CH3:27])[CH2:25][C@@H:24]([OH:28])[C:20]=4[N:21]=[CH:22][N:23]=3)[C:7]2=[CH:8][CH:9]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CC4(CCNCC4)c4cc(Cl)ccc43)c21
Reactant: CCN(C(C)C)C(C)C
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CC4(CCN(C)CC4)c4cc(Cl)ccc43)c21

Procedure:
To a stirred suspension of (5R,7R)-4-(5-chlorospiro[indoline-3,4′-piperidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (10 mg, 0.027 mmol) in DCE (0.5 mL) was added DIEA (0.009 mL, 0.05 mmol). The suspension was shaken until dissolved. Formaldehyde (37% w/w in water, 0.022 mL, 0.27 mmol) was added as a solution in THF (0.15 mL). The reaction was allowed to stir at about room temperature for about 15 minutes at which point Na(OAc)3BH was added and the reaction allowed to stir overnight. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3 solution and brine, dried and concentrated. The residue was purified by column chromatography (DCM:MeOH, 8:1) to give the free base, which was taken up in DCM and acidified with 2N HCl in ether. Removal of the solvents under reduced pressure afforded (5R,7R)-4-(5-chloro-1′-methylspiro[indoline-3,4′-piperidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride. LCMS (APCI+) m/z 385, 387 [M+H]+; Rt=2.18 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:24])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][OH:23])[CH:15]=1.[H-].[Na+].I[CH3:28].S([O-])(O)(=O)=O.[Na+]>CN(C)C=O>[CH3:28][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:24])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][OH:23])[CH:15]=1
Reactant: CI
Reactant: Cc1cc(O)c(C(=O)C=Cc2cccc(OCCO)c2)c(=O)n1C
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C)n(C)c(=O)c1C(=O)C=Cc1cccc(OCCO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
To a mixture of 1.41 g of 4-hydroxy-3-[3-[3-(2-hydroxyethoxy)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone and 14 ml of dimethylformamide was added 0.19 g of sodium hydride (60% oily) under ice-cooling. After stirred at room temperature for 1 hour, 1.82 g of iodomethane was added, and this was stirred at room temperature to 42° C. for 5 hours. The reaction solution was neutralized with sodium hydrogen sulfate under ice-cooling, this was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography to obtain 0.67 g of 4-methoxy-3-[3-[3-(2-hydroxyethoxy)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone [Compound No. (41a)] as a yellow crystal.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6](S(C2C=CC(C)=CC=2)(=O)=O)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:11]=2[O:19][CH3:20])[CH:9]=1)=[O:4].O.[OH-].[Li+].CN(C)C=O.Cl>O>[N+:16]([C:12]1[C:11]([O:19][CH3:20])=[C:10]([C:8]2[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[NH:6][CH:7]=2)[CH:15]=[CH:14][CH:13]=1)([O-:18])=[O:17]
Reactant: COC(=O)c1cc(-c2cccc([N+](=O)[O-])c2OC)cn1S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(-c2c[nH]c(C(=O)O)c2)cccc1[N+](=O)[O-]
Yield: 55.2 %

Procedure:
4-(3-Nitro-2-methoxy-phenyl)-1-(p-tolylsulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester 57f (1.04 g, 2.42 mmol) and lithium hydroxide monohydrate (1.01 g, 24.19 mmol) were added to a solvent mixture of 10 mL of N,N-dimethylformamide and 5 mL of water. The reaction mixture was reacted at 100° C. for 30 minutes under microwave. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was adjusted to pH 3 with hydrochloric acid (1 N) to form a lot of precipitates. The mixture was filtered and the filter cake was dried to obtain the title compound 4-(3-nitro-2-methoxy-phenyl)-1H-pyrrole-2-carboxylic acid 57g (350 mg, yield 50%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N+:6]([O-])=[CH:7]2.C[CH2:14][N:15](CC)CC.[Si](C#N)(C)(C)C>CC#N>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[C:14]#[N:15]
Reactant: [O-][n+]1ccc2c(Br)cccc2c1
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Product: N#Cc1nccc2c(Br)cccc12
Yield: 89.7 %

Procedure:
A mixture of Example 795A (0.30 g, 1.34 mmol), Et3N (0.270 g, 2.68 mmol) and TMSCN (0.18 g, 2 mmol) in CH3CN (10 mL) was heated under reflux overnight. More Et3N (0.27 g, 2.68 mmol) and TMSCN (0.18 g, 2 mmol) were added, and the reaction mixture was heated under reflux for another 16 hours. The reaction mixture was partitioned between water and EtOAc. The aqueous layer was extracted with additional EtOAc. The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 4:1 Hexanes/EtOAc to give 0.28 g of the title compound (90%). MS (APCI) m/e 234 (M+H)+, 1H NMR (500 MHz, DMSO-d6): □ 8.85 (d, J=5.62 Hz, 1H), 8.35 (d, J=7.49 Hz, 1H), 8.29-8.33 (m, 2H), 7.85 (m, 1H).