Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Br:8])=[CH:5][CH:4]=1.[O:13]1[CH2:17][CH2:16][O:15][CH:14]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[Br-:8].[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N+:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH:14]2[O:13][CH2:17][CH2:16][O:15]2)=[CH:5][CH:4]=1
Reactant: c1ccc(C2OCCO2)nc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Product: FC(F)(F)c1ccc(C[n+]2ccccc2C2OCCO2)cc1
Product: [Br-]
Temperature: 25 °C
Yield: 80.9 %

Procedure:
A mixture of 4.8 g (0.02 mol) of p-trifluoromethylbenzyl bromide and 3 g (0.019 mol) of 2-(1,3-dioxolan-2-yl)pyridine was allowed to stir at room temperature and then filtered. The solid residue was washed with ether and dried in vacuo to afford 6 g (76.9%) of 1-(p-trifluoromethylbenzyl)-2-(1,3-dioxolane-2-yl)pyridinium bromide (Formula IX: R1 =R7 =H; R2 =4--CF3 ; Z- =Br-).
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([NH:11][NH2:12])[CH2:8][CH2:9][CH3:10].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=O)[CH2:21][N:22]2C(=O)CS[C:23]2=[O:28])=[CH:16][CH:15]=1.C(N(CC)CC)C.O>CO>[CH2:7]([N:11]1[C:23](=[O:28])[NH:22][CH2:21][C:20]([C:17]2[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][CH:18]=2)=[N:12]1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCNN
Reactant: O=C(CN1C(=O)CSC1=O)c1ccc(Cl)cc1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCN1N=C(c2ccc(Cl)cc2)CNC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.4 %

Procedure:
Butylhydrazine oxalate (41 g, 230 mmol) and 40 g of 3-(2-(4-chlorophenyl)-2-oxo-ethyl)-thiazolidine-2,4-dione (161 mmol) in 2200 mL of methanol were cooled in an ice bath and treated with 30.3 g (300 mmol) of triethylamine. The reaction mixture was stirred at room temperature for 30 minutes, then refluxed overnight. The reaction mixture was cooled and 400 mL of water was added. This mixture was extracted with ethyl acetate. The organic phase was washed twice with 10% aqueous sodium hydroxide solution, then dried and stripped. The solids obtained were recrystallized from ethyl acetate/hexane to give 9.6 g of 2-n-butyl-6-(4-chlorophenyl)-4,5-dihydro-1,2,4-triazin-3-one.
Reaction SMILES: [CH2:1]([O:4][C:5]1[N:10]=[C:9]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[OH:22])=[O:13])[CH:8]=[N:7][C:6]=1[C:23]#[N:24])[CH:2]=[CH2:3].[C:25]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:30]=CC=C[CH:26]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C(O)C=C>O1CCCC1>[CH2:30]([O:22][C:16]1[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=1[NH:14][C:12]([NH:11][C:9]1[CH:8]=[N:7][C:6]([C:23]#[N:24])=[C:5]([O:4][CH2:1][CH:2]=[CH2:3])[N:10]=1)=[O:13])[CH:25]=[CH2:26]
Reactant: C=CCOc1nc(NC(=O)Nc2cc(Cl)ccc2O)cnc1C#N
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: C=CCO
Solvent: C1CCOC1
Product: C=CCOc1ccc(Cl)cc1NC(=O)Nc1cnc(C#N)c(OCC=C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 27.6 %

Procedure:
To a solution of Example 55A (456 mg, 1.32 mmol) in anhydrous tetrahydrofuran (18 mL) was added polymer supported triphenylphosphine (659.5 mg, 1.98 mmol), di-tert-butyl azodicarboxylate (455.5 mg, 1.98 mmol), and allyl alcohol (76.6 mg, 1.32 mmol). The reaction mixture was shaken at room temperature for 5 hours. The solution was filtered, dried with silica gel powder (10 g), and purified by flash chromatography eluting with 20% ethyl acetate in hexanes (2 L) to give the title compound (140.8 mg, 28%). MS (ESI) m/z 385.95 (M+H)+; 1H NMR (500 MHz, DMSO-D6) δ ppm 4.71 (d, J=5.62 Hz, 2 H) 4.95 (d, J=5.30 Hz, 2 H) 5.29–5.36 (m, 2 H) 5.40–5.48 (m, 2 H) 6.00–6.16 (m, 2 H) 7.04–7.10 (m, 2 H) 8.20 (d, J=2.50 Hz, 1 H) 8.88 (s, 1 H) 9.05 (s, 1 H) 10.71 (s, 1 H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])[CH2:13]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[NH2:8][C:6]1[N:7]=[C:2]([N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]([N:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)=[O:19])[CH2:13]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: O=C([C@@H]1CCCNC1)N1CCCC1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 16 h
Yield: 89.6 %

Procedure:
A solution of 6-chloro-3-nitropyridin-2-amine (0.175M, 20 mL, 3.5 mmol) in anhydrous N,N-dimethylformamide was added to (R)-piperidin-3-yl(pyrrolidin-1-yl)methanone, followed by diisopropylethylamine (1.3 mL, 7.0 mmol). The reaction mixture was stirred at 80° C. for 16 h. The solvent was removed under reduced pressure and the residue was purified via preparative HPLC to afford (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidine-3-yl)(pyrrolidin-1-yl)methanone (1.0 g, 89.6%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:27])[NH:17][C:18]1[N:19]=[C:20]2[N:24]([CH:25]=1)[CH:23]=[C:22](Br)[S:21]2)=[O:10])([CH3:4])([CH3:3])[CH3:2].[C:35]([NH:42][C:43]1[CH:48]=[CH:47][C:46](B2OC(C)(C)C(C)(C)O2)=[CH:45][CH:44]=1)([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>>[C:38]([O:37][C:35](=[O:36])[NH:42][C:43]1[CH:44]=[CH:45][C:46]([C:22]2[S:21][C:20]3=[N:19][C:18]([NH:17][C:16]([C@@H:12]4[CH2:13][CH2:14][CH2:15][N:11]4[C:9](=[O:10])[C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:34])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:27])=[CH:25][N:24]3[CH:23]=2)=[CH:47][CH:48]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1cn2cc(Br)sc2n1)c1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cn3cc(NC(=O)[C@@H]4CCCN4C(=O)[C@@H](NC(=O)OC(C)(C)C)c4ccccc4)nc3s2)cc1
Yield: 5 %

Procedure:
Compound A37 was synthesized from compound 23 (0.100 mmol) and 4-(Boc-amino)benzeneboronic acid pinacol ester (0.150 mmol), following the procedure as described for compound A1, as a white lyophilized powder in 5% yield. MS (ESI, EI+) m/z=661.27 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[O:19]=[C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:29])[NH:21]1.[CH3:30][CH2:31][C:32]([Cl:34])=[O:33]>ClCCl>[ClH:34].[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N:9]([CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[C:32](=[O:33])[CH:31]([CH3:30])[N:21]1[C:22](=[O:29])[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]1=[O:19]
Reactant: CCC(=O)Cl
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1cccc(C)c1NCCCc1cccnc1
Solvent: ClCCl
Product: Cc1cccc(C)c1N(CCCc1cccnc1)C(=O)C(C)N1C(=O)c2ccccc2C1=O
Product: Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78.4 %

Procedure:
A solution of 10 g of N-(2,6-dimethylphenyl)-3-pyridine propanamine in dichloromethane was cooled in an ice bath and was treated with 10.4 g of 2,3-dihydro-1,3-dioxo-1H -isoindole-alpha-methylacetyl chloride. The reaction mixture was stirred at 0° C. for 10 minutes and allowed to warm to room temperature overnight. The solvent was evaporated and the residue was crystallized from methanol-ether to give 15.6 g of rac.-2,3-dihydro-N -(2,6-dimethylphenyl)-alpha-methyl-1,3-dioxo-N-[3-(3-pyridinyl) propyl]-1H-isoindole-2-acetamide-hydrochloride, mp 220°-223° C. Recrystallization from methanol-ether afforded 13.55 g of captioned product, mp 223°-225° C.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:15])=O.[Br-].[CH2:17]([O:19][C:20]([CH2:22][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:21])[CH3:18].C(=O)([O-])[O-].[K+].[K+].CO>CN(C=O)C>[C:13]([C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[C:3]([CH:1]=[CH:22][C:20]([O:19][CH2:17][CH3:18])=[O:21])=[C:4]([OH:15])[CH:5]=[CH:6]2)#[N:14]
Reactant: CCOC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc2c(C=O)c(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCOC(=O)C=Cc1c(O)ccc2cc(C#N)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.2 %

Procedure:
A solution prepared by dissolving 19.3 g of 1-formyl-6-cyano-2-naphthol and 42.1 g of ethoxycarbonylmethyltriphenylphosphonium bromide in 140 ml of DMF was added dropwise to a solution comprising 13.6 g of anhydrous potassium carbonate and 250 ml of anhydrous methanol, followed by stirring for 3 hours under cooling with ice in a nitrogen stream and 24 hours at room temperature. The precipitate was filtered, and 2.7 liters of water was added to the filtrate, followed by stirring for 2 hours. Then, the precipitate was collected by filtration and washed with 90 ml of methanol to obtain 12.6 g of the desired product.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[N:26]=2)[N:4]=1)[CH3:2].CS(O[CH2:37][CH2:38][CH2:39][NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.C(OCC)(=O)C.CO>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[N:26]=[C:27]([O:31][CH2:37][CH2:38][CH2:39][NH:40][C:41](=[O:42])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH:28]=[CH:29][CH:30]=2)[N:4]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCOS(C)(=O)=O
Reactant: CCc1nn(Cc2cccc(O)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCc1nn(Cc2cccc(OCCCNC(=O)OC(C)(C)C)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 82.5 °C
Yield: 25 %

Procedure:
To a solution of N-(3-ethyl-1-((6-hydroxypyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (50 mg, 0.121 mmol) (Prepared as in Example 17, Step A) and 3-(tert-butoxycarbonylamino)propyl methanesulfonate (107 mg, 0.422 mmol) in N,N-dimethylacetamide (2.0 mL) was added cesium carbonate (79.0 mg, 0.242 mmol). The mixture was heated at 80-85° C. for 90 minutes. The mixture was allowed to cool and diluted with ethyl acetate and methanol. The suspension was filtered and concentrated under a stream of nitrogen. The material was purified using preparative thin layer chromatography on silica, eluting with 5% methanol and 1% triethylamine in ethyl acetate to give the product (17.2 mg).
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[N:7]([CH2:22][CH2:23][OH:24])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].ClC(Cl)(Cl)[C:27]([N:29]=C=O)=[O:28].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.O>[C:27](=[O:28])([O:24][CH2:23][CH2:22][N:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[S:9]/[C:8]/1=[N:10]\[C:11](=[O:21])[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])[NH2:29]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1CCOC(N)=O
Reaction time: 2 h

Procedure:
To a solution of Example 60A (110 mg, 0.298 mmol) in CH2Cl2 (2 mL) was added trichloroacetyl isocyanate (67.4 mg, 0.358 mmol) and the mixture was stirred for 2 hr. The reaction was concentrated and dissolved in methanol (0.5 mL). A solution of potassium carbonate (140 mg, 1.013 mmol) in water was added and the mixture was stirred for 24 hr. The reaction was concentrated, partitioned between ethyl acetate (3×10 mL) and water (10 mL). The organics were combined, dried, filtered, concentrated and the residue was trituated with CH2Cl2 and hexane (1:3). The solid was collected by filtration (80 mg, 70%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.32 (s, 9H) 3.79 (s, 3H) 4.29-4.38 (m, 4H) 6.55 (s, 1H) 7.10 (d, J=9.12 Hz, 1H) 7.19 (s, 1H) 7.44 (dd, J=9.12, 2.78 Hz, 1H) 7.67 (d, J=2.78 Hz, 1H); MS (DCI) m/z 412 (M+H)+. Anal calcd C18H22ClN3O4S.0.5 H2O: C, 51.36; H, 5.51; N, 9.98. Found: C, 51.23; H, 5.33; N, 9.92.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.[OH2:23]>C(OCC)(=O)C>[ClH:1].[CH:11]1([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19][CH2:18]2)=[N:3][C:4]=3[NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O
Reactant: Clc1nc(Nc2ccccc2)c2ncn(C3CCCC3)c2n1
Solvent: CCOC(C)=O
Product: Cl
Product: O[C@H]1CC[C@H](Nc2nc(Nc3ccccc3)c3ncn(C4CCCC4)c3n2)CC1
Reaction time: 20 h

Procedure:
575 mg of trans-1,4-aminocyclohexanol are mixed together and the reaction medium is taken to a temperature of 50 to 60° C. then 313 mg of the product obtained in Stage 1 above is added and agitation is carried out at a temperature of 150 to 160° C. for approximately 20 hours. The reaction medium is then left to return to ambient temperature, taken up in ethyl acetate and water and then taken to a temperature of approximately 60° C. and left to settle, followed by re-extracting with ethyl acetate, washing with a saturated aqueous solution of sodium chloride, drying and evaporating to dryness. The residue is chromatographed on silica (eluent: CH2Cl2/MeOH 95/5), taken up in an ethanolic solution of hydrochloric acid and left to crystallize, followed by separating, drying under reduced pressure and 266 mg of expected product is recovered.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[N:11]1([C:7]2[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH:6]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C1CCNC1
Reactant: CC(=O)N1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)N1CC=C(N2CCCC2)CC1

Procedure:
N-Acetyl-4-piperidinone (1.3 g, 9.2 mmol) was dissolved in toluene (10 ml), and pyrrolidine (0.72 g, 10.13 mmol) and p-toluenesulfonic acid hydrate (catalytic) were added. The reaction mixture was refluxed under an inert gas for 2 hours using a water separator, cooled slowly under an inert gas and concentrated in vacuo and the residue was dried. The crude product was employed immediately without purification. The yield was 1.87 g (>99%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([NH:21][CH2:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[N:16][CH:17]=[N:18][C:19]=2[NH2:20])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[C:34](Cl)(=[O:37])[CH:35]=[CH2:36]>C1COCC1.O>[C:34]([N:26]1[CH2:27][CH2:28][CH:23]([CH2:22][NH:21][C:15]2[C:14]([C:11]3[CH:12]=[CH:13][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:9][CH:10]=3)=[C:19]([NH2:20])[N:18]=[CH:17][N:16]=2)[CH2:24][CH2:25]1)(=[O:37])[CH:35]=[CH2:36]
Reactant: C=CC(=O)Cl
Reactant: Nc1ncnc(NCC2CCNCC2)c1-c1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC(=O)N1CCC(CNc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 36.8 %

Procedure:
Into a 20 mL reaction vial was added 5-(4-phenoxyphenyl)-N-(piperidin-4-ylmethyl)pyrimidine-4,6-diamine (70.00 mg; 0.19 mmol), sodium bicarbonate (23.49 mg; 0.28 mmol) suspended in THF (3.00 ml) and water (0.30 ml). The mixture was cooled to 0° C. Acryloyl chloride (0.02 ml; 0.22 mmol) was added. The ice bath was left to melt. The reaction mixture was then stirred at rt overnight. The crude mixture was purified using Biotage column chromatography eluting 0-50% MeOH/EtOAc. Fractions containing the desired product were combined and concentrated under reduced pressure. The residue was lyophilized overnight to afford N-[(1-acryloylpiperidin-4-yl)methyl]-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine as a white solid (30.00 mg, 37% yield). HPLC purity: 97%, RT=3.665 min. MS: m/z=430 [M+H]+, RT=1.53 min. 1H-NMR (DMSO-d6) δ 7.93 (s, 1H), 7.40 (t, 2H), 7.21-7.08 (m, 8H), 6.76 (dd, 1H), 6.04 (d, 1H), 5.61 (d, 1H), 5.43 (s, 2H), 4.34 (d, 1H), 3.98 (d, 1H), 3.12 (t, 2H), 2.95 (t, 1H), 2.56 (t, 1H), 1.81 (m, 1H), 1.59 (m, 2H), 0.92 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:28]([CH3:30])[CH3:29])[NH:11]1.[CH2:31]=O.[CH3:33][NH:34][CH3:35].O>CC(O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:33][N:34]([CH3:31])[CH3:35])=[C:23]([OH:27])[CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:28]([CH3:30])[CH3:29])[NH:11]1
Reactant: C=O
Reactant: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3cccc(O)c3)nc(=O)c1-2
Reactant: CNC
Solvent: O
Solvent: CC(=O)O
Product: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(CN(C)C)c(O)c3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 464 mg (1.0 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 10 mL of glacial HOAc was added 0.4 mL of 37% aq. formaldehyde followed by 0.5 mL of 40% aq. dimethylamine. The solution was stirred overnight at RT, and it was then heated to just below reflux for 20 min. The solution was poured into water and extracted with EtOAc. The organic extract was washed (brine), dried (MgSO4), and chromatographed on silica gel (elution with EtOAc) to afford, after removal of solvent, 135 mg (26%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(dimethylaminomethyl)-3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one as an off-white, amorphous solid. Mass spec. (ESI+): 520 (M+H)−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[CH2:10]1N2CN3CN(C2)CN1C3.[OH2:20].S(=O)(=O)(O)O>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([OH:8])=[C:6]([CH:7]=1)[CH:10]=[O:20]
Reactant: Oc1ccc(Br)cc1F
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1cc(Br)cc(F)c1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 43 %

Procedure:
To a solution of 4-bromo-2-fluorophenol (100 g, 0.52 mol) in trifluoroacetic acid (TFA) (400 mL) , hexamethylenetetramine (HMT) (146.8 g, 1.05 mol) was added under a nitrogen atmosphere in three portions over 20 minutes, the mixture was stirred at room temperature for 20 minutes, and then at 90° C. for 13 hours, and then cooled to room temperature. Water (600 mL) and a 50% aqueous solution of sulfuric acid (300 ML) were sequentially added thereto at room temperature, and the mixture was stirred at room temperature for two hours. The resultant mixture was extracted three times with ethyl acetate (1 L), the organic layer was washed four times with 1 N aqueous solution of hydrochloric acid (1 L), twice with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off from the organic layer under reduced pressure and the residue was azeotroped twice with toluene. Ethanol (20 mL) was added to the residue, and the solid obtained after filtration of the suspended solution was washed twice with ethanol (10 mL) to give 49.6 g of the title compound (yield: 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=3[OH:31])[C:5]2=[CH:4][CH:3]=1.[CH3:33][Si:34]([C:37]#[CH:38])([CH3:36])[CH3:35].CCN(CC)CC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:38]#[C:37][Si:34]([CH3:36])([CH3:35])[CH3:33])[CH:27]=[CH:26][C:25]=3[OH:31])[C:5]2=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2O)N1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccc(O)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Temperature: 83 °C

Procedure:
To a stirred solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-hydroxy-5-iodo-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′-dione (100 mg) in DMF (2 mL) were added PdCl2(PPh3)2 (18 mg), CuI (4 mg), trimethylsilyl acetylene (Aldrich, 0.40 mL) and Et3N (Aldrich, 0.62 mL) and the mixture was purged with nitrogen and then heated at 83° C. for 3 hrs. The solvent was removed and the crude was directly used for next step. MS (H+), 549.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[O:12]1[CH2:17][CH2:16][CH:15]([CH:18]=[O:19])[CH2:14][CH2:13]1.[CH2:20]1COCC1>>[OH:19][CH:18]([CH:15]1[CH2:16][CH2:17][O:12][CH2:13][CH2:14]1)[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH2:9][CH3:20])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: C1CCOC1
Reactant: O=CC1CCOCC1
Product: CCOC(=O)c1ccc(C(O)C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 4-iodobenzoate (1.21 mL, 7.24 mmol) in THF (12 ml) at −40° C. was added TurboGrignard (1.3 M in THF, 6.13 ml, 7.97 mmol) dropwise. The mixture was stirred for approximately 60 minutes whereupon, tetrahydro-2H-pyran-4-carbaldehyde (0.761 ml, 0.724 mmol) was added dropwise. The mixture was stirred for 15 minutes and slowly warmed to rt over 12 hours. The reaction was quenched with HCl (1N, aq.) and the aq. layer was extracted with EtOAc (3×75 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide ethyl 4-(hydroxy(tetrahydro-2H-pyran-4-yl)methyl)benzoate. Crude mixture used into the next step without any further purification. Step B: A round bottom flask was charged with ethyl 4-(hydroxy(tetrahydro-2H-pyran-4-yl)methyl)benzoate (1.9 g, 72 mmol), the Dess-Martin reagent (3.66 g, 8.63 mmol) and DCM (15 mL). The reaction was stirred at room temperature overnight. Reaction diluted with DCM and solid filtered off. The mother liquor concentrated and loaded onto a silica gel column. Purification by silica gel flash chromatography (ethyl acetate/DCM) provide methyl 4-(tetrahydro-2H-pyran-4-carbonyl)benzoate (290 mg, mmol) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.75-1.96 (m, 4H) 3.45-3.62 (m, 3H) 3.97 (s, 3H) 4.07 (dt, J=11.88, 325 Hz, 2H) 7.98-8.02 (m, 2H) 8.12-8.17 (m, 2H); MS (M−1): 246.8.
Reaction SMILES: Cl.[CH2:2]([C@@H:9]1[CH2:13][NH:12][C@H:11]([C:14]([OH:16])=[O:15])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:24]([O:28][C:29](ON=C(C1C=CC=CC=1)C#N)=[O:30])([CH3:27])([CH3:26])[CH3:25]>O.O1CCOCC1>[CH3:25][C:24]([CH3:27])([O:28][C:29]([N:12]1[CH2:13][C@@H:9]([CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:10][C@H:11]1[C:14]([OH:16])=[O:15])=[O:30])[CH3:26]
Reactant: O=C(O)[C@@H]1C[C@H](Cc2ccccc2)CN1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](Cc2ccccc2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of cis-4-benzyl-L-proline hydrochloride (3 g) and triethylamine (5 g) in water (10 ml) is added a solution of 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (3.5 g) in dioxane (10 ml). The mixture is stirred at ambient temperature for 4 hours. After the addition of water (30 ml), and washing with ether, the mixture is acidified to a pH of 3-4 with 10% citric acid. The oil that separates is extracted into ethyl acetate, washed with brine, and dried (MgSO4). After concentration in vacuo, the residue (3.7 g) solidifies at room temperature, melting point 145°-149° C. dec.