Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([C:12]3[CH:17]=[C:16]([S:18]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=3[O:27][CH2:28][CH2:29][CH3:30])[NH:11][C:5]=2[N:4]([CH2:31][CH2:32][CH3:33])[C:3]1=[O:34].[CH2:35]=O>[Pd]>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([C:12]3[CH:17]=[C:16]([S:18]([N:21]4[CH2:26][CH2:25][N:24]([CH3:35])[CH2:23][CH2:22]4)(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=3[O:27][CH2:28][CH2:29][CH3:30])[NH:11][C:5]=2[N:4]([CH2:31][CH2:32][CH3:33])[C:3]1=[O:34]
Reactant: CCCOc1ccc(S(=O)(=O)N2CCNCC2)cc1-c1cc2c(=O)n(C)c(=O)n(CCC)c2[nH]1
Reactant: C=O
Agent: [Pd]
Product: CCCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1cc2c(=O)n(C)c(=O)n(CCC)c2[nH]1
Reaction time: 2 h
Yield: 17 %

Procedure:
A mixture of the title compound of Example 87 (0.4 g, 0.82 mmol), formaldehyde (0.14 mL, 37% in water, 1.63 mmol) and palladium 10% on activated carbon (40 mg) was hydrogenated for 2 h. The catalyst was removed by filtration through celite and the filtrate was evaporated under reduced pressure. The resulting crude product was purified by flash column chromatography on silica-gel (dichloromethane-ethanol-ammonium hydroxide 180:8:1) to yield the title compound (0.07 g, 17%) as an off-white solid.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:14]=[C:13]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:5])C.[OH-].[Na+]>>[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:15]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:14]=[C:13]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)CCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1

Procedure:
Reaction of 1-(6-ethoxycarbonylhexyl)-2,4,5-triphenylimidazole (0.4 g) with sodium hydroxide in a method similar to Example 10 gave, after recrystallisations from ethanol and isopropanol, 1-(6-carboxyhexyl)-2,4,5-triphenylimidazole (0.19 g, 51%) as a white solid, m.p. 149°-150°; Found: C, 79.34; H, 6.65; N, 6.48%; C28H28N2O2 requires: C, 79.22; H, 6.65; N, 6.60%.
Reaction SMILES: [N:1]([C@H:4]1[C:7](=[O:8])[N:6]([Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[C@@H:5]1[C:16]([O:18][CH3:19])=[O:17])=[N+]=[N-].CO>C(O)(C(F)(F)F)=O.[Pd].O1CCOCC1>[NH2:1][C@H:4]1[C:7](=[O:8])[N:6]([Si:9]([C:12]([CH3:14])([CH3:15])[CH3:13])([CH3:10])[CH3:11])[C@@H:5]1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)[C@@H]1[C@@H](N=[N+]=[N-])C(=O)N1[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1[C@@H](N)C(=O)N1[Si](C)(C)C(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of 132 (5.85 mmol) in 3:1 methanol:dioxane (25 mL) was added a few drops of TFA and 10% Pd/C (10 wt %). The reaction was stirred under atmospheric hydrogen for one hour and then filtered through Celite. The solvent was removed and the residue triturated with diethyl ether to afford 133, which was used in the next step without further purification.
Reaction SMILES: N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:16]1[CH:17]=[C:18]([N:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([Cl:32])[CH:28]=3)[C:23]2=[O:33])[CH:19]=[N:20][CH:21]=1.[CH2:34]([S:36]([NH2:39])(=[O:38])=[O:37])[CH3:35]>[Cu]I.O1CCOCC1>[Cl:32][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:33])[N:22]([C:18]1[CH:17]=[C:16]([NH:39][S:36]([CH2:34][CH3:35])(=[O:38])=[O:37])[CH:21]=[N:20][CH:19]=1)[CH2:31][CH2:30]2
Reactant: CCS(N)(=O)=O
Reactant: O=C1c2ccc(Cl)cc2CCN1c1cncc(Br)c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCS(=O)(=O)Nc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Yield: 20 %

Procedure:
CuI (1.9 mg, 0.01 mmol), L-proline (2.3 mg, 0.02 mmol) and Cs2CO3 (65 mg, 0.2 mmol) were added to a dioxane (3 mL) solution of 2-(5-bromo-pyridin-3-yl)-6-chloro-3,4-dihydro-2H-isoquinolin-1-one (example 7) (33.7 mg, 0.1 mmol) and ethanesulfonic acid amide (10.9 mg, 0.1 mmol). The resulting reaction mixture was subject to microwave reaction at 150° C. for 2.5 hours. The reaction mixture was filtered and concentrated in vacuo to give a crude product which was then purified by prep-HPLC to give title compound (7.3 mg, 20%) as a white solid. MS: 366.1 (M+H+).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=1.[NH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:10][O:9][C:7]([C:4]1[S:3][C:2]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][NH2:11])[CH2:15][CH2:16]2)=[N:6][CH:5]=1)=[O:8]
Reactant: NCCN1CCNCC1
Reactant: COC(=O)c1cnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cnc(N2CCN(CCN)CC2)s1
Temperature: 80 °C
Yield: 65.1 %

Procedure:
To a solution of methyl 2-bromothiazole-5-carboxylate 1 (222 mg, 1.00 mmol) in acetonitrile (20 mL) were added N-(2-amino ethyl)piperazine 14d (155 mg, 1.20 mmol) and potassium carbonate (152 mg, 1.10 mmol) under a N2 atmosphere. The reaction mixture was heated to reflux at 80° C. for 10 h. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using silica gel to give the compound 15d (176 mg, 65.2%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[Si](C)(C)[O:9][C:10]1([C:20]#[N:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1.[F-].[Na+].O>O1CCCC1>[NH2:21][CH2:20][C:10]1([OH:9])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: C[Si](C)(C)OC1(C#N)CCCc2ccccc21
Agent: [Al+3]
Agent: [F-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: NCC1(O)CCCc2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.4 %

Procedure:
Under nitrogen, to the suspension of lithium aluminum hydride (8.4 g) in tetrahydrofuran (120 ml) was dropwise added 1-trimethylsilyloxy-1-cyano-1,2,3,4-tetrahydronaphthalene (27 g) in tetrahydrofuran (120 ml) at 5° C., and the mixture was stirred at room temperature for 24 hours. To the mixture were added sodium fluoride (37 g) and water (12 ml) at 5° C., and the mixture was vigorously stirred at room temperature for 30 minutes. The precipitate was removed by filtration. The filtrate was evaporated in vacuo to give 1-aminomethyl-1-hydroxy-1,2,3,4-tetrahydronaphthalene (19 g)
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([CH:15]=O)[C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1)[CH3:2].[C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N+:27]1[CH:32]=[C:31]([S:33]([O-:36])(=[O:35])=[O:34])[CH:30]=[CH:29][C:28]=1[CH3:37])([OH:21])=[O:20].[CH3:38][N+:39]([CH2:42][C:43]([OH:45])=[O:44])([CH3:41])[CH3:40]>CO.O>[C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N+:27]1[CH:32]=[C:31]([S:33]([O-:36])(=[O:35])=[O:34])[CH:30]=[CH:29][C:28]=1/[CH:37]=[CH:15]/[C:9]1[C:10](=[O:14])[O:11][C:12]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[C:4]([N:3]([CH2:17][CH3:18])[CH2:1][CH3:2])[CH:13]=2)([OH:21])=[O:20].[CH3:38][N+:39]([CH2:42][C:43]([OH:45])=[O:44])([CH3:41])[CH3:40]
Reactant: CCN(CC)c1ccc2cc(C=O)c(=O)oc2c1
Reactant: Cc1ccc(S(=O)(=O)[O-])c[n+]1CCCCCC(=O)O
Agent: C[N+](C)(C)CC(=O)O
Solvent: CO
Solvent: O
Product: CCN(CC)c1ccc2cc(/C=C/c3ccc(S(=O)(=O)[O-])c[n+]3CCCCCC(=O)O)c(=O)oc2c1

Procedure:
0.2 mmol 7-diethylamino-2-oxo-2H-chromene-3-carbaldehyde and 0.2 mmol 1-(5-carboxy-pentyl)-2-methyl-5-sulfonato-pyridinium betaine are converted according to the general directions above. Column chromatography: SiO2 (RP18), eluent: methanol/water.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([Si:18]([CH3:21])([CH3:20])[CH3:19])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])=[O:5].C1COCC1.[Li]C(CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1CCCCC1>[CH3:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[NH:6][C:4](=[O:5])[C:3]1[CH:2]=[CH:17][CH:16]=[CH:15][C:14]=1[Si:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1ccccc1NC(=O)c1c(Br)cccc1[Si](C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccccc1NC(=O)c1ccccc1[Si](C)(C)C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
The compound of Example 120 (0.0021 mol, 0.75 g) and 50 mL THF were cooled to -78° C. in a nitrogen atmosphere with magnetic stirring. 1.3M s-BuLi (0.0026 mol, 2 mL) in cyclohexane was added dropwise. After stirring for 30 min, 25 mL of 25% citric acid were added. The mixture was then extracted three times with ethyl acetate, the extracts combined and washed with brine and twice with water, dried (MgSO4) and concentrated. The title compound was recrystallized as a white solid from ethyl acetate/hexanes in 54% yield. m.p. 117-119° C.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([CH2:20][C:21](OCC)=[O:22])[CH2:4]1)[CH3:2].O/[N:27]=[C:28](\[NH2:32])/[CH2:29][O:30][CH3:31].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CO>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([CH2:20][C:21]2[O:22][N:32]=[C:28]([CH2:29][O:30][CH3:31])[N:27]=2)[CH2:4]1)[CH3:2]
Reactant: CCOC(=O)C[C@H]1C[C@@H](CC)[C@@H](c2nnc3cnc4[nH]ccc4n23)C1
Reactant: COC/C(N)=N/O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC[C@@H]1C[C@H](Cc2nc(COC)no2)C[C@@H]1c1nnc2cnc3[nH]ccc3n12
Temperature: 130 °C
Yield: 55.5 %

Procedure:
To a solution of ethyl 2-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetate (0.100 g, 0.293 mmol) in toluene (0.20 mL) and MeOH (0.20 mL) was added (Z)-N′-hydroxy-2-methoxyacetimidamide (0.300 g, 2.89 mmol, Tyger) and K2CO3 (0.100 g, 0.726 mmol). The solution was heated in a CEM microwave at about 130° C. for about 1 h (250 psi maximum pressure, 1 min ramp, 300 max watts). The solvent was removed under reduced pressure. The residue was diluted with DCM (3 mL) and a small amount of MeOH. The crude material was purified by flash chromatography on silica gel eluting with a gradient of 0-10% MeOH in DCM. The residue was dissolved in EtOAc and heptane was added. The solvent was concd. The solid was dried in a heated vacuum oven (about 70° C.) for about 20 h to afford 5-(((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methyl)-3-(methoxymethyl)-1,2,4-oxadiazole (0.062 g, 56%) as a white solid: LC/MS (Table 1, Method a) Rt=1.79 min; MS m/z: 382 (M+H)+.
Reaction SMILES: [CH:1]1([C@H:7]([NH:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][NH2:27])[CH:21]=3)=[CH:18][CH:19]=2)=[O:14])[C:8](=[O:11])[NH:9][CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:28]([CH:31]([CH3:33])[CH3:32])=[C:29]=[O:30]>CN(C=O)C>[CH:1]1([C@H:7]([NH:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][NH:27][C:29](=[O:30])[NH:28][CH:31]([CH3:33])[CH3:32])[CH:21]=3)=[CH:18][CH:19]=2)=[O:14])[C:8]([NH:9][CH3:10])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNC(=O)[C@@H](NC(=O)c1ccc(-c2cccc(CN)c2)o1)C1CCCCC1
Reactant: CC(C)N=C=O
Solvent: CN(C)C=O
Product: CNC(=O)[C@@H](NC(=O)c1ccc(-c2cccc(CNC(=O)NC(C)C)c2)o1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(3-aminomethyl-phenyl)-furan-2-carboxylic acid ((S)-cyclohexyl-methylcarbamoyl-methyl)-amide (20 mg, 0.05 mmol) in DMF (0.5 mL) is added 2-isocyanato-propane (5.8 μL, 0.06 mmol). After 2 h stirring at room temperature, the mixture evaporated in vacuo and purified on reverse phase HPLC. The product is obtained as a pale yellow solid, 16 mg, 63%, LC/MS ESI m/z (M+H)+=455.5.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]([F:34])([F:33])[C:10]1[CH:11]=[N:12][C:13]([N:16]2[CH2:32][CH2:31][C:19]3([CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:14][CH:15]=1>C(Cl)Cl>[F:33][C:9]([F:8])([F:34])[C:10]1[CH:11]=[N:12][C:13]([N:16]2[CH2:32][CH2:31][C:19]3([CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(c3ncc(C(F)(F)F)cn3)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1cnc(N2CCC3(CCNC3)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (1.5 ml) was added to a solution of tert-butyl 8-(5-(trifluoromethyl)pyrimidin-2-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (300 mg, 0.78 mmol, 1.0 eq.) in methylene chloride (6 ml) at 0° C. and the reaction mixture was stirred at 25° C. for 1 h. After completion of the reaction, the solvent was evaporated under reduced pressure to give the desired product as a yellow sticky solid which was directly used in the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.[CH3:13][S:14]([O-:16])=[O:15].[Na+]>CS(C)=O>[CH2:8]([C:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=[C:2]([S:14]([CH3:13])(=[O:16])=[O:15])[CH:7]=1)[CH3:9]
Reactant: CCc1cc(Br)ncc1[N+](=O)[O-]
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCc1cc(S(C)(=O)=O)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 2-bromo-4-ethyl-5-nitro-pyridine (4.35 mmol) and sodium methanesulfinate (4.35 mmol) in DMSO (10 mL) was stirred at room temperature for 1.5 h. The mixture was poured into ice-water and stirred until the ice had melted. The mixture was filtered and the solid (the desired product) was collected.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH3:18][N:19]([CH3:29])[CH2:20][CH2:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:26][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][CH2:20][N:19]([CH3:18])[CH3:29])=[CH:28][CH:27]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CN(C)CCc1ccc(N)cc1
Product: CN(C)CCc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cc1
Yield: 73.9 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with 4-(2-(dimethylamino)ethyl)aniline (247 mg, 1.5 mmol) to afford the desired product (324 mg, 73%) as a yellow solid: ESI MS m/z 438 [C23H24BrN3O+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[CH3:26][O:27][C:28]1[N:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][C:29]=1[C:30]([O:32][CH3:33])=[O:31].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:35]5[CH:36]=[N:37][C:28]([O:27][CH3:26])=[C:29]([C:30]([O:32][CH3:33])=[O:31])[CH:34]=5)[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cnc1OC
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: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cnc1OC
Yield: 83.3 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (0.26 g, 0.7 mmol) in 1,2-dimethoxyethane (7 mL) was added methyl 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (0.25 g, 0.86 mmol), tetrakis(triphenylphosphine)palladium (0) (42 mg, 0.04 mmol), and 2 M sodium carbonate (0.70 mL, 1.4 mmol). The reaction mixture was irradiated in the microwave at 120° C. for twenty minutes. The reaction mixture was diluted with ethyl acetate (5 mL) and washed with water (5 mL). The organics were dried over sodium sulfate and evaporated to dryness. The crude reaction mixture was purified by silica gel chromatography (eluting with 0-100% ethyl acetate in hexanes) to yield the product (0.29 g, 81%). ESI-MS m/z calc. 497.45. found 498.3 (M+1)+. Retention time 2.14 minutes.
Reaction SMILES: O.[OH-].[Li+].[O:4]=[C:5]1[CH2:10][CH2:9][C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:11]([O:13]C)=[O:12])[CH2:7][CH:6]1C(OC)=O>CO.O.O1CCCC1>[O:4]=[C:5]1[CH2:10][CH2:9][C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]1
Reactant: COC(=O)C1CC(C(=O)OC)(c2ccccc2)CCC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CCC(C(=O)O)(c2ccccc2)CC1
Yield: 99 %

Procedure:
Lithium hydroxide monohydrate (11.08 g, 264 mmol) was added to a suspension of dimethyl 4-oxo-1-phenyl-1,3-cyclohexanedicarboxylate (Description 1, 25.5 g, 87.9 mmol) in methanol (250 mL), water (83 mL) and tetrahydrofuran (83 mL) and the mixture was heated under reflux for 3 days. The mixture was cooled and the tetrahydrofuran and methanol were evaporated under reduced pressure. The pH was adjusted to 1 with hydrochloric acid (5M) and the mixture was extracted with dichloromethane. The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a light yellow solid (19 g, 99%). 1H NMR (400 MHz, CDCl3) δ 7.50-7.29 (5H, m), 2.29-2.73 (2H, m), 2.62-2.55 (2H, m), 2.47-2.41 (2H, m), and 2.35-2.27 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:23])[CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=2)[OH:12])=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH3:34][S:35]([O:12][CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)[CH2:10][CH2:9][CH:8]([O:23][S:35]([CH3:34])(=[O:37])=[O:36])[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:24]([O-:26])=[O:25])[CH:4]=1)(=[O:37])=[O:36]
Reactant: O=[N+]([O-])c1cc(C(O)CCC(O)c2ccc(Cl)c([N+](=O)[O-])c2)ccc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
The product of Example 28B (4.81 g, 11.99 mmol) and triethylamine (5.85 mL, 42.0 mmol) were dissolved in dichloromethane (80 mL) at room temperature and treated with methanesulfonyl chloride (2.34 mL, 30.0 mmol) dropwise over 10 minutes. The resulting solution was stirred for 2 h then concentrated to dryness and used directly in the next step.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[C:8]([CH:17]=[O:18])[NH:9][C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:6]2[C:5](=[O:19])[N:4]([CH3:20])[C:3]1=[O:21].[F:22]C1C=C(C2NC=C3C=2C(=O)N(C)C(=O)N3C)C=CC=1.CN1C2=CNC(C3C=C(C=CC=3)C#N)=C2C(=O)N(C)C1=O>>[F:22][C:13]1[CH:12]=[C:11]([C:10]2[NH:9][C:8]([CH:17]=[O:18])=[C:7]3[C:6]=2[C:5](=[O:19])[N:4]([CH3:20])[C:3](=[O:21])[N:2]3[CH3:1])[CH:16]=[CH:15][CH:14]=1
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]cc2n(C)c1=O
Reactant: Cn1c(=O)c2c(-c3ccccc3)[nH]c(C=O)c2n(C)c1=O
Agent: Cn1c(=O)c2c(-c3cccc(C#N)c3)[nH]cc2n(C)c1=O
Product: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]c(C=O)c2n(C)c1=O

Procedure:
The title compound was prepared in a similar manner to 1,3-dimethyl-2,4-dioxo-5-phenyl-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidine-7-carbaldehyde (Intermediate Na), starting from 5-(3-fluorophenyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (prepared in a similar manner to 3-(1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (Example 9.0 Step 4) using the appropriate halo compound in step 3 and omitting Step 1.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:14])[O:5][C:6]2[C:11]([C:12]=1[CH3:13])=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].[N-:15]=[N+:16]=[N-:17].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH3:13][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:14])[C:3]=1[C:1]1[NH:17][N:16]=[N:15][N:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1c(C#N)c(=O)oc2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2nnn[nH]2)c(=O)oc2ccccc12

Procedure:
A solution of 3-cyano-4-methyl coumarin (7.94 g; 0.043 mole) in cimethylformamide (DMF) (45 ml) was added to a mixture of sodium azide (2.92 g; 0.044 mole) and ammonium chloride (2.36 g; 0.044 mole) and the stirred mixture heated on a steam bath for 24 hours. After removal of the solvent under reduced pressure, water (100 ml) was added and the solid filtered off. Acidification of the filtrate, and further aqueous extracts, afforded the title compound; m.p. (EtOH) 213°-4° C (Found: C, 57.58; H, 3.51; N, 24.41; C11H8N4O2 requires; C, 57.89; H, 3.53; N, 24.55%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=[O:7])[CH2:5][C:4]([CH3:9])([CH3:8])[O:3]1.[Br:11]Br>ClCCl>[Br:11][CH:5]1[C:4]([CH3:9])([CH3:8])[O:3][C:2]([CH3:10])([CH3:1])[C:6]1=[O:7]
Reactant: CC1(C)CC(=O)C(C)(C)O1
Reactant: BrBr
Solvent: ClCCl
Product: CC1(C)OC(C)(C)C(Br)C1=O
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a solution of 2,2,5,5-tetramethyldihydrofuran-3(2H)-one (Aldrich) (10.0 g, 0.07 mol) in dichloromethane (100 mL) was added bromine (3.6 mL, 0.07 mol) drop wise at room temperature. The reaction mixture was stirred for 2 hours as the brown reaction mixture became a clear solution. The reaction mixture was quenched with the addition of NaHCO3 powder in small portions, filtered and concentrated to provide the title compound as viscous oil (14.1 g, 90%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([NH:13][C@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)=[N:10][C:9]([C:19]1[NH:23][C:22](=[O:24])[NH:21][N:20]=1)=[CH:8]2.CC1C=CC=C(C)N=1.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>C(Cl)Cl>[C:33]([N:16]1[CH2:17][CH2:18][C@H:14]([NH:13][C:11]2[C:12]3[C:7](=[CH:6][CH:5]=[CH:4][C:3]=3[F:2])[CH:8]=[C:9]([C:19]3[NH:23][C:22](=[O:24])[NH:21][N:20]=3)[N:10]=2)[CH2:15]1)(=[O:36])[CH:34]=[CH2:35]
Reactant: O=c1[nH]nc(-c2cc3cccc(F)c3c(N[C@H]3CCNC3)n2)[nH]1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C=CC(=O)N1CC[C@H](Nc2nc(-c3n[nH]c(=O)[nH]3)cc3cccc(F)c23)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 15.5 %

Procedure:
To a mixture of (S)-3-(8-fluoro-1-(pyrrolidin-3-ylamino)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one hydrochloride (250 mg, 0.71 mmol) in DCM (15 mL) was added a solution of 2,6-dimethylpyridine (192 mg, 1.8 mmol) in DCM (1 mL). Acryloyl chloride (135 mg, 1.5 mmol) in DCM (1.35 mL) was added dropwise via syringe at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes. Additional 2,6-dimethylpyridine (32 mg, 0.3 mmol) in DCM (0.32 mL) was added followed by acryloyl chloride (45 mg, 0.50 mmol) in DCM (0.45 mL). The reaction mixture was stirred at −10° C. for 20 minutes. The reaction was quenched with MeOH (1 mL) and the mixture was concentrated under vacuum. The crude product was purified by preparative HPLC to give the title compound as a white solid (40.58 mg, 15.5%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.91 (s, 1H), 11.78 (s, 1H), 7.69-7.63 (m, 3H), 7.60-7.58 (m, 1H), 6.61-6.55 (m, 2H), 6.18-6.13 (m, 1H), 5.67-5.64 (m, 1H), 5.30-5.10 (m, 1H), 4.17-4.15 (m, 1H), 3.66-3.63 (m, 2H), 3.28-3.25 (m, 1H), 2.25-2.03 (m, 2H); ESI-MS m/z [M+H]+ 369.1.
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:22])=[O:4].[NH2:23][CH:24]1[CH2:28][CH2:27][O:26][CH2:25]1>>[O:26]1[CH2:27][CH2:28][CH:24]([NH:23][C:3]([C:5]2[S:9][C:8](/[CH:10]=[CH:11]/[C:12]3[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=3[CH3:17])=[N:7][C:6]=2[CH3:22])=[O:4])[CH2:25]1
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)OC)s1
Reactant: NC1CCOC1
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)NC2CCOC2)s1
Yield: 46 %

Procedure:
As described for example 93d, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid methyl ester (80 mg, 0.25 mmol) was converted, using 3-amino-tetrahydrofuran instead of isopropylamine, to the title compound (43 mg, 46%) which was obtained as a white solid. MS: m/e=376.3 [M+H]+.