Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Br[C:26]1[C:31]([F:32])=[CH:30][C:29]([F:33])=[CH:28][N:27]=1>>[F:32][C:31]1[C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[O:11])=[N:27][CH:28]=[C:29]([F:33])[CH:30]=1
Reactant: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Fc1cnc(Br)c(F)c1
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(F)cc2F)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone and 2-bromo-3,5-difluoropyridine. MS (ESI) 438 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2[C:25](=[O:55])[N:26]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[N:27]([CH2:30][C@H:31]([O:33][C:34](=[O:48])[C@@H:35]([NH:37]C(OCC3C=CC=CC=3)=O)[CH3:36])[CH3:32])[C:28]=2[CH3:29])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1>CCOC(C)=O.CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2[C:25](=[O:55])[N:26]([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[N:27]([CH2:30][C@H:31]([O:33][C:34](=[O:48])[C@@H:35]([NH2:37])[CH3:36])[CH3:32])[C:28]=2[CH3:29])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)OC(=O)[C@H](C)NC(=O)OCc5ccccc5)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)OC(=O)[C@H](C)N)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (S)—((R)-1-(4-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)phenyl carbamoyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydropyrazol-1-yl)propan-2-yl)2-(benzyloxy-carbonyl-amino)propanoate (74.7 mg, 0.1 mmol) in a mixture of EtOAc (15 mL) and MeOH (10 mL) was added catalytic amount Pd/C (10%, ˜55% w/w water content, 20 mg) under N2 atmosphere. The suspension was degassed under vacuum and then purged with H2. The reaction mixture was stirred at rt for 20 minutes under H2 balloon. The mixture was filtered and the residue was washed with MeOH (5 mL×3). The filtrate used for the next step immediately.
Reaction SMILES: C(O[C:6](=[O:13])[NH:7][C@@H:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)(C)(C)C.Cl[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[NH2:7][CH2:8][CH2:9][NH:10][C:6]([NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:9]1)=[O:13]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: Clc1ccccn1
Product: NCCNC(=O)N[C@@H]1CCN(c2ccccn2)C1

Procedure:
The titled compound is prepared analogously to Intermediate D by replacing (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester with (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester and replacing 2-bromopyridine with 2-chloropyridine.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:11]([CH:12]=O)=[CH:10][N:9]=[C:8]([Cl:14])[CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>CC(O)=O>[C:1]([NH:5][C:6]1[C:11]([CH2:12][NH:20][C:19]2[CH:21]=[CH:22][C:16]([F:15])=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=2)=[CH:10][N:9]=[C:8]([Cl:14])[CH:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)(C)Nc1cc(Cl)ncc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)(C)Nc1cc(Cl)ncc1CNc1ccc(F)c([N+](=O)[O-])c1
Temperature: 80 °C
Yield: 64.5 %

Procedure:
A mixture of 4-(tert-butylamino)-6-chloronicotinaldehyde (4.0 g, 18.9 mmol), 4-fluoro-3-nitroaniline (2.9 g, 18.9 mmol) and NaBH(OAc)3 (7.1 g, 37.8 mmol) in CH3COOH (80 mL) was heated to 80° C. for 10 h. The reaction was concentrated under reduced pressure to give a sticky solid, which was suspended in ice water. The mixture was neutralized (pH 7) with 2N aqueous NaOH solution and was extracted with EtOAc. The extracts were washed with brine, dried Na2SO4) and concentrated in vacuo. Purification of the residue by chromatography provided N-tert-butyl-2-chloro-5-((4-fluoro-3-nitrophenylamino)methyl)pyridin-4-amine (4.3 g, 65% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.87 (s, 1 H), 7.32 (m, 1 H), 7.27 (m, 1 H), 7.04 (m, 1 H), 6.68 (s, 1 H), 6.52 (m, 1 H), 5.46 (s, 1 H), 4.17 (d, J=4.8 Hz, 2 H), 1.36 (s, 9 H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[CH:18][N:19]([CH3:21])[CH3:20])[C:10]2=[O:22])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[CH:18][N:19]([CH3:20])[CH3:21])[C:10]2=[O:22])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N2C(=O)C(=CN(C)C)c3ccccc32)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CN(C)C=C1C(=O)N(c2cccc(O)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Under nitrogen, a solution of title product of Example C1 (0.468 g, 1.59 mmoles) in 5 ml CH2Cl2 was cooled to -78°. Boron tribromide (0.45 ml, 4.77 mmoles) was added. After stirring 20 minutes at -78°, the reaction mixture was allowed to warm to room temperature, stirred 2 hours, diluted with 25 ml. of water and then 20 ml CH2Cl2, stirred 15 minutes, and the pH adjusted to 6-7 with saturated NaHCO3. The aqueous layer was separated and extracted 2×25 ml CH2Cl2. The three organic layers were combined, dried over MgSO4, and concentrated to solids in vacuo, 0.402 g. Recrystallization from CH2Cl2 /hexane gave purified title product, 0.320 g, m.p. 200°-203°.
Reaction SMILES: S=[C:2]1[CH2:6][O:5][C:4](=[O:7])[NH:3]1.[CH2:8]([NH2:11])[C:9]#[CH:10]>C(O)C>[CH2:8]([NH:11][C:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]=1)[C:9]#[CH:10]
Reactant: O=C1NC(=S)CO1
Reactant: C#CCN
Solvent: CCO
Product: C#CCNC1=NC(=O)OC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
To a solution of 4-thioxooxazolidin-2-one (180 mg) in ethanol (3 mL) was added prop-2-yn-1-amine (85 mg) at room temperature. The reaction mixture was stirred at room temperature for 2 hr. The precipitated white solid was collected by filtration, and washed with ethyl acetate/hexane to give the title compound (168 mg).
Reaction SMILES: ClC1C=CC([C@@H]([N:10]2[C:22]3[C@@H:21]([CH2:23][C:24]([OH:26])=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]3[C:11]2=[C:12]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:13]=[C:14]([F:27])[CH:15]=3)C)=CC=1.[CH3:32]O>[Pd]>[CH3:32][O:26][C:24](=[O:25])[CH2:23][C@@H:21]1[C:22]2[NH:10][C:11]3[C:16](=[CH:15][C:14]([F:27])=[CH:13][C:12]=3[S:28]([CH3:31])(=[O:29])=[O:30])[C:17]=2[CH2:18][CH2:19][CH2:20]1
Reactant: CO
Reactant: C[C@@H](c1ccc(Cl)cc1)n1c2c(c3cc(F)cc(S(C)(=O)=O)c31)CCC[C@@H]2CC(=O)O
Agent: [Pd]
Product: COC(=O)C[C@H]1CCCc2c1[nH]c1c(S(C)(=O)=O)cc(F)cc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of [(1R)-9-[(1S)-1-(4-chlorophenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetic acid ([α]D=−226° in MeOH) in MeOH (0.1M) was added 10% palladium on carbon (10% wt/wt). A stream of N2 was bubbled through the mixture for 5 min. The reaction was stirred at rt under H2 atmosphere (balloon) for 24 hrs and filtered through a celite pad eluted with CH2Cl2. The solvents were removed by evaporation under reduced pressure and the residue was swished in MeOH to give the title compound.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10](=[O:12])[CH3:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N:13]1([C:18]2[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1.[OH-].[Na+]>CO>[N:13]1([C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[CH:11][C:10]([C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[CH2:1][CH2:2][CH2:3]4)=[O:12])=[CH:20][CH:19]=2)[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: O=Cc1ccc(N2CCCC2)cc1
Reactant: CC(=O)c1ccc2c(c1)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(C=Cc1ccc(N2CCCC2)cc1)c1ccc2c(c1)CCC2

Procedure:
A solution of 1.47 g (9.14 mmoles) of 5, 1.60 g (9.14 mmoles) of p-pyrrolidinylbenzaldehyde and two pellets of sodium hydroxide (about 0.4 g) in 20 ml of methanol was stirred under nitrogen at room temperature for 112 hr. The reaction mixture was cooled in an ice bath and the precipitated solid 3-[4-(1-pyrrolidinyl)phenyl]-1-(2,3-dihydro-1H-inden-5-yl)-2-propen-1-one was filtered and washed with cold methanol. Yield: 1.2 g (41%); m.p. 162° to 164°. Evaporation of the filtrate gave a residue which was dissolved in methanol-toluene (9:1). The solution was filtered, evaporated to 100 ml, and cooled. The precipitated product was collected by filtration and washed with cold methanol. Yield: 0.9 g (31%); m.p. 177° to 179°. λmax (EtOH): 275 nm (ε=16,600); 328 nm (4170); 425 nm (37,800). Calcd for C 22 H23NO: C, 83.24; H, 7.30; N, 4.41. Found: C, 82.99; H, 7.49; N, 4.32.
Reaction SMILES: Br[C:2]1[C:3]([NH2:11])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[CH:13]>[Cu]I.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>[N+:8]([C:6]1[CH:7]=[C:2]([C:13]#[C:12][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]([NH2:11])=[N:4][CH:5]=1)([O-:10])=[O:9]
Reactant: C#Cc1ccccc1
Reactant: Nc1ncc([N+](=O)[O-])cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: Nc1ncc([N+](=O)[O-])cc1C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
A solution of 3-bromo-5-nitropyridin-2-amine (655 mg, 3.0 mmol, 1.0 eq.) in 1:1 TEA/DMF (40 mL) was degassed with argon for 10 minutes, and ethynylbenzene (1.5 eq.), CuI (0.04 eq.), and PdCl2(PPh3)2 (0.04 eq.) were sequentially added. The mixture was degassed with argon for 10 minutes, and then stirred at room temperature for 16 hours. The volatiles were removed under reduced pressure, and CH2Cl2 (25 mL) was added. The mixture was sonicated for 15 minutes, cooled to 0° C., and collected by vacuum filtration to afford 5-nitro-3-(phenylethynyl)pyridin-2-amine (356 mg, 50%).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O-:16])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].[Cl-].[CH:31]12[CH2:37][CH:34]([CH2:35][CH2:36]1)[CH2:33][CH:32]2[CH2:38][CH3:39]>>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:16][CH2:39][CH2:38][CH:32]2[CH2:33][CH:34]3[CH2:37][CH:31]2[CH2:36][CH2:35]3)[N:10]=[CH:9]1
Reactant: CCC1CC2CCC1C2
Reactant: [O-]CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Cl-]
Agent: [Na+]
Product: c1nc(CCCOCCC2CC3CCC2C3)c[nH]1

Procedure:
5 mmol of sodium 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanolate and 5 mmol of 2-(bicyclo[2.2.1]hept-2-yl)ethane chloride are treated as described in Example 5.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([CH2:37][O:38]C(=O)C)=[O:36]>>[OH:38][CH2:37][C:35]([NH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)=[O:36]
Reactant: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c13)OCO2
Reactant: CC(=O)OCC(=O)Cl
Product: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)CO)CC4)c[nH]c13)OCO2

Procedure:
Starting from cis-4-[5-(2-methoxy-ethoxy)-benzo[1,3]dioxol-4-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A186) and acetic acid chlorocarbonyl-methyl ester the title compound was obtained as colorless solid.
Reaction SMILES: [CH2:1]([C:8]1(O)[CH2:15][CH2:14][CH2:13][CH:12](C(C)(C)C)[CH2:11][CH2:10][CH:9]1O[SiH](C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=[O:26]>N1C=CC=CC=1>[CH2:1]([CH:8]1[CH2:15][CH2:14][CH2:13][CH:12]([OH:26])[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[SiH](C)OC1CCC(C(C)(C)C)CCCC1(O)Cc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: OC1CCCC(Cc2ccccc2)CCC1
Temperature: 0 °C

Procedure:
1.7 g of the above product (b) was dissolved in 40 ml of pyridine. To the solution was added 0.43 ml of thionyl chloride while cooling with an ice bath. After stirring at 0° C. for twenty minutes, the reaction solution was poured into ice water, and extracted with ether. The organic layer was washed with a saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, to afford 1.6 g of the titled compound as pale yellow liquid.
Reaction SMILES: [CH2:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][N:5]=1)[CH2:2][CH3:3].[C:12](Br)(Br)([Br:14])[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:13][C:12]([Br:14])=[CH:8][C:7]1[CH:10]=[CH:11][C:4]([CH2:1][CH2:2][CH3:3])=[N:5][CH:6]=1
Reactant: CCCc1ccc(C=O)cn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCc1ccc(C=C(Br)Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.2 %

Procedure:
6-Propylnicotinaldehyde (0.2 g, 0.00134 mol) was dissolved in DCM (4 mL). Carbon tetrabromide (0.887 g, 0.00268 mol) and triphenylphosphine (1.4 g, 0.00536 mol) were added to the solution followed by stirring at RT overnight. After insoluble matter was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was purified through column chromatography (3% ethylacetate:hexane in silica 100-200 mesh, diameter of column—5.0 cm, height of silica—approx. 5 inch) to provide the desired compound as a yellow colored oil (0.05 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:18]=[CH:17][N:16]=[C:15]3[C:10]=2[C:11]2[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=2[C:13](=[O:19])[NH:14]3)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[N:33]([CH3:36])=[C:34]=[O:35]>CS(C)=O>[CH3:36][NH:33][C:34]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:18]=[CH:17][N:16]=[C:15]3[C:10]=2[C:11]2[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=2[C:13](=[O:19])[NH:14]3)=[CH:6][CH:7]=1)=[O:35]
Reactant: CN=C=O
Reactant: Nc1ccc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CNC(=O)Nc1ccc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.2 %

Procedure:
340 (40 mg, 0.13 mmol), DIEA (34 mg, 0.26 mmol), and isocyanatomethane (11 mg, 0.18 mmol) were suspended in DMSO (1 mL), and stirred for 4 h at room temperature. The reaction mixture was quenched with H2O, filtered, washed with H2O and MeOH, and dried under vacuum to provide 342 (23 mg, 46% yield) as a solid. LC-MS (M+H=361, obsd.=361).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]#[N:13])[C:9]([Cl:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([F:22])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>O.O1CCOCC1.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>[Cl:14][C:9]1[C:10]([C:12]#[N:13])=[N:11][C:2]([C:18]2[CH:17]=[C:16]([F:15])[CH:21]=[C:20]([F:22])[CH:19]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)c(C#N)nc1Cl
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(Cl)c(C#N)nc1-c1cc(F)cc(F)c1
Temperature: 80 °C
Yield: 94.2 %

Procedure:
A solution of methyl 2,5-dichloro-6-cyanonicotinate (2.0 g, 8.6 mmol), (3,5-difluorophenyl)boronic acid (1.5 g, 9.5 mmol) and potassium carbonate (2.6 g, 19 mmol) in water (16 mL) and 1,4-dioxane (41 mL) were bubbled with nitrogen gas (10 minutes). Bis(triphenylphosphine)palladium(II) chloride (0.67 g, 0.95 mmol) was added and the mixture was bubbled with nitrogen gas (10 minutes). The mixture was heated at 80° C. for 1 hour and diluted with ethyl acetate and water. The aqueous layer was separated and extracted again with ethyl acetate. The combined extracts were washed with water, washed with brine, dried over sodium sulfate, filtered and evaporated. Purification on silica gel using ethyl acetate in hexanes (0-50%) gave the desired compound (2.5 g, 94%). LCMS calculated for C14H8ClF2N2O2 (M+H)+: m/z=309.0. found: 308.9.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[H-].[Na+].Cl[CH2:16][CH2:17][O:18]C1CCCCO1.[I-].[Na+]>CN(C)C=O>[CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:16][CH2:17][OH:18])[C:3]1=[O:11]
Reactant: ClCCOC1CCCCO1
Reactant: CC1(C)C(=O)Nc2ccccc21
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(CCO)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3,3-Dimethyl oxindole (1.1 equivalent) was dissolved in dry dimethyl formamide. Sodium hydride (60% dispersion in mineral oil) (1.1 equivalent) was added portionwise and the mixture was stirred under nitrogen for one hour at 25° C. 2-(2-Chloroethoxy)tetrahydro-2H-pyran (1 equivalent) was added with a catalytic amount of sodium iodide. The reaction mixture was stirred under nitrogen at 70° C. for 12 hours, then the solvent was removed under reduced pressure. The resulting oil was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4), filtered and evaporated to dry under reduced pressure. The resulting oil was taken up in methanol and stirred at room temperature with paratoluenesulfonic acid. After eight hours the solvent was removed and replaced with ethyl acetate. The solution was washed (×2) with saturated sodium hydrogen carbonate solution, dried (MgSO4), filtered and evaporated to dryness. Column chromatography of the resulting oil on silica gel (eluent ethyl acetate/hexane 1:1) gave 2((3,3-dimethyl)oxindolyl)ethanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:20][C:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=O)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])=O)[CH:5]=[CH:6][C:7]=1[F:8].CC(O)=O.C[N:35](C)C=O>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]2[N:35]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=3)[CH:20]=2)=[CH:24][CH:25]=1
Reactant: O=C(CC(CC(=O)c1ccccc1O)c1ccc(F)c(F)c1)c1ccc(Cl)cc1
Reactant: CN(C)C=O
Solvent: CC(=O)O
Product: Oc1ccccc1-c1cc(-c2ccc(F)c(F)c2)cc(-c2ccc(Cl)cc2)n1
Temperature: 100 °C

Procedure:
A mixture of 3-(3,4-difluorophenyl)-1-(2-hydroxyphenyl)-5-(4-chlorophenyl)-1,5-pentanedione on Wang resin (2.0 g, 1.76 mmol), NH4OAc (0.80 g), and AcOH (1.0 mL) in dimethylformamide (20 mL) was heated at 100° C. for 18 h. The resin was filtered, and washed with dimethylformamide (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight. The dried resin was treated with 50% TFA/CH2Cl2 (15 mL) for 1 h. After filtration of the reaction mixture, the filtrate was concentrated to dryness. The residue was repeatedly dissolved in CH2Cl2 (10 mL) and concentrated to remove traces of TFA, and lyophilized to give 2-[6-(4-chloro-phenyl)-4-(3,4-difluoro-phenyl)-pyridin-2-yl]-phenol; mp 146-148° C.; 1H NMR (DMSO-d6) d 6.75 (m, 1 H), 7.00 (m, 2 H), 7.35 (m, 2 H), 7.57 (m, 1 H), 7.69 (d, J=8.6 Hz, 2 H), 7.95 (d, J=8.6 Hz, 1 H), 8.18 (d, J=8.6 Hz, 2 H), 8.32 (m, 2 H), 14.00 (s, 1 H); IR (KBr) 1606 cm−1; MS [M+1] m/z=394. Anal. calcd for C23H14ClF2NO: C, 70.15; H, 3.58; N, 3.50; Found: C, 69.98; H, 3.51; N, 1.80.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.N[C:10](N)=[O:11]>O>[NH:7]1[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][C:3]=2[NH:8][C:10]1=[O:11]
Reactant: Nc1ccncc1N
Reactant: NC(N)=O
Solvent: O
Product: O=c1[nH]c2ccncc2[nH]1
Reaction time: 18 h

Procedure:
A combination of pyridine-3,4-diamine (1.0 g, 9.16 mmol) and urea (3.3 g, 54.9 mmol) were stirred as a melt at 165° C. for 4 h, then cooled and H2O (100 mL) was added. The aqueous mixture was heated at reflux until all solid dissolved and the solution was allowed to cool and aged for 18 h. The precipitate was isolated by filtration to give the title compound. MS: m/z=136 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[NH:4][N:3]=1.[C:23]1(=O)[CH2:27][CH2:26][C:25](=[O:28])[CH2:24]1.[O-]S([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1>[O:28]=[C:25]1[CH2:26][CH2:27][C:23]([NH:1][C:2]2[C:6]3[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH3:16])=[O:13])=[CH:10][C:5]=3[NH:4][N:3]=2)=[CH:24]1
Reactant: C[C@@H](NC(=O)Nc1cc2[nH]nc(N)c2cn1)c1ccccc1
Reactant: O=C1CCC(=O)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: C[C@@H](NC(=O)Nc1cc2[nH]nc(NC3=CC(=O)CC3)c2cn1)c1ccccc1
Temperature: 150 °C
Yield: 4.6 %

Procedure:
A mixture of (R)-1-(3-amino-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (52.9 mg, 0.179 mmol), cyclopentane-1,3-dione (34.1 mg, 0.348 mmol) and MgSO4 (167.7 mg, 1.393 mmol) in toluene (2 ml) was heated in a sealed 5 ml microwave vial to 150° C. for 1 hr. LCMS shows formation of product. The mixture was poured directly onto silica gel and purified via flash chromatography (Biotage SNAP 10 g, 0-20% MeOH/DCM) to provide (R)-1-(3-((3-oxocyclopent-1-en-1-yl)amino)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (3.11 mg, 8.26 μmol, 4.63% yield) as a yellow solid. MS ESI calc'd. For C20H21N6O2 [M+H]+ 377. found 377. 1H NMR (ppm, 500 MHz, DMSO-d6) δ 12.49 (s, 1H), 10.39 (s, 1H), 8.99 (s, 1H), 8.87 (s, 1H), 7.77 (br s, 1H), 1.53 (s, 1H), 7.34 (m, 5H), 7.23 (s, 1H), 6.11 (br s, 1H), 4.86 (t, J=6.5 Hz, 1H), 3.32 (s, 3H, overlaps with H2O peak), 2.81 (s, 2H), 2.26 (s, 2H), 1.40 (d, J=6.8 Hz, 3H).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][CH2:15][OH:16].N1C=CN=C1>CN(C)C=O>[C:4]([Si:1]([CH3:3])([CH3:2])[O:16][CH2:15][CH2:14][C:10]1[S:9][CH:13]=[CH:12][CH:11]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: OCCc1cccs1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCc1cccs1
Yield: 96 %

Procedure:
Tert-butyldimethylsilyl chloride (15.5 g, 103 mmol) was added portionwise to a solution of 2-(2-thienyl)ethanol (11.0 g, 85.9 mmol) and imidazole (7.0 g, 103 mmol) in N,N-dimethylformamide (35 mL). The resultant solution was stirred at room temperature for 18 h. The reaction mixture was partitioned between ethyl acetate (30 mL) and water (30 mL) and the organic phases washed with water (3×50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with 1-4% ethyl acetate in iso-hexane to give the title compound as a colourless oil (20 g, 96%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[Li+].[OH-].Cl>CCO.O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)CCCCCCBr
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCCCCCBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
to a solution of ethyl 7-bromoheptanoate (2.0 g, 8.43 mmol, 1 eq) in EtOH (15 mL) and H2O (10 mL) was added LiOH (2.0 g, 83.3 mmol, 10 eq). The mixture was stirred overnight at room temperature. The mixture was neutralized with 2N aqueous HCl with cooling in an ice-water bath, and the mixture was extracted with EtOAc. The EtOAc layer was separated, washed with water and brine, and dried over Na2SO4. Filtration and concentration in vacuo gave 1.7 g (96%) of the 7-Bromoheptanoic acid as a white solid.