Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[SH:14].C(N(CC)CC)C>O1CCCC1>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[S:14][CH:3]([CH2:2][C:1]([OH:8])=[O:7])[C:4]([OH:6])=[O:5]
Reactant: O=C(O)/C=C\C(=O)O
Reactant: Sc1cccs1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)CC(Sc1cccs1)C(=O)O
Yield: 93 %

Procedure:
To a stirred solution of maleic acid (6.38 g, 0.055 mol) in tetrahydrofuran (50 ml) under nitrogen atmosphere was added 2-thiophenethiol (5.0 ml, 0.055 mol) and triethylamine (14.2 g, 0.14 mol). The mixture was stirred at gentle reflux for 16 hours overnight. The solvent was removed in vacuo and the residual oil was poured into 3NHCl (200 ml). The product was extracted into ethyl acetate (125 ml) in three portions, washed with saturated NaCl solution and dried over Na2SO4. The solution was filtered and concentrated in vacuo. This procedure gave the product as a light beige solid, 11.9 g, m.p. 136°-138.5° C. of 95% purity by HPLC. Yield was 93%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C[O-].[Na+]>CO.[OH-].[Na+].[Cu]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1
Reactant: Sc1ccccc1
Reactant: Clc1ccc(I)cn1
Agent: [Cu]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Clc1ccc(Sc2ccccc2)cn1
Temperature: 80 °C
Yield: 59.9 %

Procedure:
A mixture of 3.4 g (14.3 mmol) of 2-chloro-5 iodopyridine, 1.9 g (17.2 mmol) of thiophenol, 0.93 g (17.2 mmol) of sodium methoxide and 0.36 g (5.7 mmol) of copper in 18 mL of MeOH is heated for 12 hours at 80° C. After cooling to room temperature, the medium is taken up in 100 mL of 1N NaOH and the MeOH is evaporated off under reduced pressure. The reaction medium is extracted with EtOAc (2×100 mL), the organic phase is washed with 0.1N NaOH (2×30 mL), and then dried over Na2SO4, concentrated under reduced pressure and purified by chromatography on a column of silica gel, eluting with a cyclohexane/EtOAc mixture (8/2). 1.90 g of 2-chloro-5-(phenylsulfanyl)pyridine are obtained in the form of a white powder.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19].[CH3:20][O:21][C:22]([CH3:24])=[CH2:23]>P(Cl)(Cl)(Cl)=O.C(N(CC)CC)C>[CH3:20][O:21][C:22]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])([CH3:24])[CH3:23]
Reactant: C=C(C)OC
Reactant: CCCCCCCCCCCCCCCCCCO
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOC(C)(C)OC

Procedure:
2-methoxy-2-(octadecyloxy)propane was prepared by reacting stearic alcohol (0.025 mole) with 2-methoxypropene (4 equivalents) for 2 hours at 20° C. in the presence of one drop of phosphoryl chloride (POCl3) then adding 5 drops of triethylamine and distilling the excess enol ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([O:22]C1C=CC=CC=1)=O.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:22]
Reactant: C1CNCCN1
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Product: Cn1c(Nc2ccc(I)cc2F)c(C(=O)N2CCNCC2)c(=O)n(C)c1=O

Procedure:
Example 43 was synthesized following a similar procedure described in the synthesis of Example 5 by reaction of compound 2A and piperazine. 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J=8.0 Hz, 1H) 7.56 (d, J=8.0 Hz, 1H) 6.99 (t, J=8.0 Hz, 1H) 3.93 (m, 1 H) 3.77 (m, 1H) 3.51 (s, 3H) 3.25 (s, 3H) 3.17 (m, 4H) 2.98 (m, 1H) 2.52 (m, 1H). [M+H] calc'd for C17H19FIN5O3, 488; found, 488.
Reaction SMILES: C(NC([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:19][C:20](=O)C)[C:13]=2[CH2:15][CH:16]2C[O:17]2)[CH:8]=[N:7]1)=O)C.C(=O)([O-])[O-].[K+].[K+].O.Cl>CO>[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[O:19][CH2:20][CH:16]([OH:17])[CH2:15][C:13]3=2)[CH:8]=[N:7]1
Reactant: CCNC(=O)n1ncc2ccc(OC(C)=O)c(CC3CO3)c21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: OC1COc2ccc3cn[nH]c3c2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the product of Step E (1.44 g, 4.75 mmol) in methanol (100 mL) was added saturated aqueous potassium carbonate (10 mL) and the mixture stirred for 18 h at ambient temperature. Water (200 mL) was added to the reaction mixture and the pH adjusted to 7 with conc HCl followed by extraction ethyl acetate (5×100 mL). The combined extracts were dried (MgSO4) and evaporated to tan solid (0.84 g, 93%): 1H NMR (DMSO-d6) δ 12.77 (s, 1H), 7.94 (s, 1H), 7.49 (d, J=6.0 Hz, 1H), 6.66 (d, J=6.0 Hz, 1H), 5.02 (t, J=6.0 Hz, 1H), 4.85-4.95 (m, 1H), 3.62 (m, 2H), 2.9-3.4 (m, 2H); LC/MS (+APCI) m/z 191 (M+H).
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[CH:14]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH:15]1.O>CN(C)C=O>[CH3:3][N:4]([CH:20]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=[CH:14]1)[C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrC1C=CCCCC1
Reactant: CNC(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)c1ccccc1)C1C=CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.1 %

Procedure:
To a suspension (10 ml) of sodium hydride (0.24 g, 10 mmoles) in dimethylformamide was added dropwise at 0° C. a dimethylformamide solution (1 ml) of N-methylbenzamide (1.35 g, 10 mmoles). After completion of the addition, the temperature was raised to room temperature, and after stirring for 15 minutes, 3-bromocycloheptene (1.75 g, 10 mmoles) was added dropwise. The resulting mixture was stirred at room temperature for 24 hours, poured into water (20 ml) and extracted with ether. The oily product obtained by concentration was purified by chromatography on silica gel to obtain 0.92 g of N-methyl-N-(2-cycloheptenyl)benzamide [Compound (54)].
Reaction SMILES: S(Cl)(Cl)(=O)=O.C(S[S:9][CH2:10][CH3:11])C.[CH3:12][NH:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([Cl:25])[CH:18]=1)=[O:15].Cl>C(Cl)Cl.N1C=CC=CC=1>[CH3:12][N:13]([S:9][CH2:10][CH3:11])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([Cl:25])[CH:18]=1)=[O:15]
Reactant: CNC(=O)Nc1ccc(OC)c(Cl)c1
Reactant: CCSSCC
Agent: Cl
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Solvent: c1ccncc1
Product: CCSN(C)C(=O)Nc1ccc(OC)c(Cl)c1
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
A mixture of 67 g of sulfuryl chloride and 100 ml of methylene chloride was slowly added at -40° C. to 68 g of diethyl disulfide in 600 ml of methylene chloride and after the temperature was slowly raised to -5° C., the mixture was stirred at -5° C. for 5 minutes. The mixture was then cooled to -40° C. and a solution of 56 g of N-methyl-N'-(3-chloro-4-methoxyphenyl)-urea in 800 ml of pyridine was added thereto. The mixture was stirred at -20° C. for 2 hours and was then added to a water-ice mixture. The pH of the mixture was adjusted to 5 by addition of an aqueous concentrated solution of hydrochloric acid and was extracted with methylene chloride. The combined organic extracts were washed with water until the wash water was neutral, then dried and distilled to dryness under reduced pressure. The residue was chromatographed over silica gel and eluted with a 7-3 benzene-ethyl acetate mixture. The product was crystallized from isopropyl ether to obtain 23.5 g of N-methyl-N-ethylthio-N'-(3-chloro-4-methoxyphenyl)-urea melting at 60° C.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([CH3:20])[C:9]=2[C:21](=[O:31])[NH:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:5][CH:4]=1)=O.Cl.[NH2:33]O.C(OC(=O)C)(=O)C.Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.N1C=CC=CC=1.C(OCC)(=O)C.O>[C:1]([C:3]1[O:7][C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([CH3:20])[C:9]=2[C:21](=[O:31])[NH:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:5][CH:4]=1)#[N:33]
Reactant: NO
Reactant: Cc1nc(-c2ccccc2)cc(-c2ccc(C=O)o2)c1C(=O)NCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(-c2ccccc2)cc(-c2ccc(C#N)o2)c1C(=O)NCCN1CCOCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 55.4 %

Procedure:
A solution of 4-(5-formyl-2-furyl)-2-methyl-3-(2-morpholinoethylcarbamoyl)-6-phenylpyridine (1.2 g) and hydroxylamine hydrochloride (0.26 g) in a mixture of N,N-dimethylformamide (5 ml) and pyridine (4 ml) was stirred at ambient temperature for 2.5 hours. To the reaction mixture was added acetic anhydride (5 ml) and the resulting solution was stirred at 80° C. for 1 hour. The mixture was poured into a mixture of water and ethyl acetate and adjusted to pH 1.0 with 10% hydrochloric acid. The separated aqueous layer was adjusted to pH 8.0 with 20% aqueous potassium carbonate and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was subjected to column chromotography on silica gel. The column was eluted with a mixture of ethyl acetate and tetrahydrofuran (85:15 V/V) and the fraction was evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 4 -(5-cyano-2-furyl)-2-methyl-3-(2-morpholinoethylcarbamoyl)-6-phenylpyridine (0.66 g).
Reaction SMILES: COC(CCC/C=[C:9]1/[C:10](=[O:17])[CH:11]2[CH:15]([CH2:16]/1)[CH2:14][CH2:13][CH2:12]2)=O.C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].C(O)(=O)C.O>O1CCCC1>[OH:17][CH:10]1[CH2:9][CH2:16][CH:15]2[CH:11]1[CH2:12][CH2:13][CH2:14]2
Reactant: COC(=O)CCC/C=C1\CC2CCCC2C1=O
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: OC1CCC2CCCC12
Reaction time: 2 h
Yield: 100.6 %

Procedure:
A stirred solution of 6-[(E)-3-cyclohexyl-(mixture of 3α and 3β)-hydroxyprop-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one (6.7 mg), prepared as described in Example 8 and predominantly in the 6β-configuration, otherwise known as (±)-methyl(5E,13E)-(9S),[mixture of (15R) and (15S)]-6a-oxo-6,9-methano-15-cyclohexyl-15-hydroxy-16,17,18,19,20-pentanorprosta-5,13-dienoate, in tetrahydrofuran (0.5 ml) at -78° C. was treated dropwise with a solution of lithium tri-sec-butylborohydride in tetrahydrofuran (0.0196 ml; 1.0M). The stirred solution was allowed to warm to 0° during 2 hours and then it was stirred for a further period of 2 hours. Glacial acetic acid (0.15 ml) and water (0.2 ml) were then added to the mixture, which was then concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (10 ml), washed with aqueous sodium bicarbonate solution (2M) and then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and concentrated in vacuo. The resulting oil was treated with a solution of sodium hydroxide in 50% v/v aqueous methanol (0.1 ml; 2.5N) and stirred for 150 minutes at 20° C. The mixture was then carefully concentrated in vacuo, and diluted with water (6 ml) and diethyl ether (3 ml). The aqueous phase was separated, acidified to pH 3 by treatment with hydrochloric acid (2N), and extracted with ethyl acetate (4×10 ml). The combined organic extracts were dried over sodium sulphate and concentrated in vacuo. The resulting residue was subjected to chromatography on a silica gel column, using a mixture of ethyl acetate, hexane and glacial acetic acid (50:50:1 by volume) as eluant, to give 3-[(E)-4-carboxybutylidene]-6-[(E)-3-cyclohexyl-(mixture of 3α and 3β)-hydroxyprop-1-enyl]-2-hydroxybicyclo[3,3,0]octane (3.6 mg), predominantly in the 6β,6α-configuration, otherwise known as (±)-(5E,13E)-(6aS,9S),[mixture of (15R) and (15S)]-6a,15-dihydroxy-6,9-methano-15-cyclohexyl-16,17,18,19,20-pentanorprosta-5,13-dienoic acid [NMR in deuterochloroform: multiplets at 5.5, 3.5, 2.7-0.7 p.p.m⟧
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19](Cl)=[O:20])[CH2:15][CH2:14]1)([CH3:12])([CH3:11])[CH3:10].N1C=CC=CC=1>ClCCl>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:19]([C@H:16]2[CH2:17][CH2:18][C@H:13]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:14][CH2:15]2)=[O:20])=[CH:3][CH:4]=1
Reactant: Nc1ccc(O)cc1
Reactant: CC(C)(C)[C@H]1CC[C@H](C(=O)Cl)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[C@H]1CC[C@H](C(=O)Nc2ccc(O)cc2)CC1
Reaction time: 8 h

Procedure:
To a solution of 4-aminophenol (3.08 g, 28.2 mmol) in dichloromethane (50 ml) were added cis/trans-4-tert-butyl-cyclohexanecarbonyl chloride (11.43 g, 56.4 mmol) and pyridine (4.56 ml, 56.4 mmol), while cooling the reaction mixture in an ice bath. After the addition was completed, the cooling bath was removed and stirring was continued overnight at room temperature. The solvent was removed by evaporation and the residue was dissolved in THF (300 ml). 6N NaOH (aq, 33 ml) was added and the mixture was stirred at room temperature overnight. The organic phase was removed by evaporation. Water (200 ml) was added and the solid material collected by filtration, washed with water, dried and dissolved in methanol (100 ml). A solution of KOH (2.4 g) in methanol (50 ml) was added. After stirring for 2 h at room temperature water (200 ml) was added and the organic solvent was removed by evaporation. The aqueous phase was acidified with 1 N HCl and extracted with ethyl acetate (3×300 ml). The combined organic phases were dried and evaporated, yielding a pink oil, which was dried in vacuo. The solid material was crystallised from ethyl acetate/heptane yielding the title compound (2.03 g, 26%) as pink crystals. From the first aqueous extract a second portion of product was isolated by extraction with ethyl acetate (3×250 ml). The combined organic layers were washed with water (400 ml), saturated sodium bicarbonate (2×400 ml), dried, filtered and evaporated, yielding a pink thick oil. Crystallisation from ethyl acetate/heptane yielded a second amount of the title compound (2.75 g, 35%).
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[F:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][C:18]2[C:19]([NH:28][CH3:29])=[CH:20][C:21]([N:24]([O:26][CH3:27])[CH3:25])=[N:22][CH:23]=2)=[CH:12][C:11]=1[N+:30]([O-:32])=[O:31].CCN(CC)CC.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:17][C:18]3[CH:23]=[N:22][C:21]([N:24]([O:26][CH3:27])[CH3:25])=[CH:20][C:19]=3[N:28]([CH3:29])[C:4]2=[O:3])=[CH:12][C:11]=1[N+:30]([O-:32])=[O:31]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CNc1cc(N(C)OC)ncc1CNc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CON(C)c1cc2c(cn1)CN(c1ccc(F)c([N+](=O)[O-])c1)C(=O)N2C
Temperature: 30 °C
Reaction time: 10 h
Yield: 64.6 %

Procedure:
To a solution of diphosgene (1.15 mL, 9.5 mmol) in anhydrous dioxane (100 mL) was added a mixture of 5-((4-fluoro-3-nitrophenylamino)methyl)-N2-methoxy-N2,N4-dimethylpyridine-2,4-diamine (3.0 g, 9.0 mmol) and Et3N (2.5 mL, 18.0 mmol) in dioxane (200 mL) at 10° C. After addition, the resulting mixture was stirred at 30° C. for 10 h. H2O was added to quench the above reaction and the mixture was neutralized to pH 7 with saturated Na2CO3 solution. The dioxane was removed under reduced pressure and the remaining aqueous solution was extracted with EtOAc (3×50 mL). The combined organics were washed with brine, dried over MgSO4 and concentrated to give 3-(4-fluoro-3-nitrophenyl)-7-(methoxy(methyl)amino)-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (2.1 g, 65% yield), which was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6): δ 8.15 (m, 1 H), 7.97 (s, 1 H), 7.80 (m, 1 H), 7.62 (t, J=9.3 Hz, 1 H), 6.58 (s, 1 H), 4.80 (s, 2 H), 3.72 (s, 3 H), 3.27 (s, 3 H), 3.15 (s, 3 H); MS (ESI) m/z: 362.2 (M+H+).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30])=[CH:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]([C:21]([OH:23])=[O:22])[CH2:16]1.C(OCC)(=O)C.CC(C)=O>CO.[Pd]>[ClH:1].[CH3:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH3:2])[CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]([C:21]([OH:23])=[O:22])[CH2:16]1
Reactant: Cc1ccccc1C(=CCOCCN1CCC[C@@H](C(=O)O)C1)c1ccccc1C
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(C)=O
Product: Cc1ccccc1C(CCOCCN1CCC[C@@H](C(=O)O)C1)c1ccccc1C
Yield: 66.8 %

Procedure:
The acid prepared in Example 32 (1.1 g, 2.6 mmol) was dissolved in methanol (25 ml) and stirred under an atmosphere of hydrogen for 1 h at room temperature in the presence of 10% palladium on carbon catalyst (35% aqueous paste) and then filtered. The filtrate was evaporated to dryness leaving a residue which was treated with a mixture of ethyl acetate and acetone and filtered to give a solid which was recrystallised from a mixture of methanol and toluene to give 0.75 g (67%) of the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([CH3:23])=[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.S([O-])([O-])(=O)=O.[Mg+2].F[C:31](F)(F)[C:32](O)=O.C([BH3-])#N.[Na+]>O.CO.C(Cl)(Cl)Cl>[CH2:31]([NH:1][C:2]1[C:6]2[C:7]([CH3:23])=[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)[CH3:32]
Reactant: Cc1nc(NC(=O)N[C@H](C)c2ccccc2)cc2[nH]nc(N)c12
Reactant: O=C(O)C(F)(F)F
Agent: O=S(=O)([O-])[O-]
Agent: [BH3-]C#N
Agent: [Mg+2]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: CCNc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)nc(C)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.2 %

Procedure:
A conical vial was charged with (R) -1-(3-amino-4-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (32 mg, 0.103 mmol) and magnesium sulfate (37.2 mg, 0.309 mmol). chloroform (666 μl), methanol (333 μl), magnesium sulfate (37.2 mg, 0.309 mmol) and trifluroacetic acid (23.83 μl, 0.309 mmol) were injected and the reaction was stirred at ambient temperature for 1 hour. Sodium cyanoborohydride (19.44 mg, 0.309 mmol) was then added and stirring was continued for one hour. The reaction was diluted with water and the aqueous layer was transferred to a separatory funnel and washed 3×chloroform/IPA. The combined organic washings were dried over magnesium sulfate and then filtered and concentrated. The residue was dissolved in DMSO (2 mL) filtered and delivered to the purification group. Reversed phase mass triggered HPLC was performed. The active fractions were dried down on the Genevac which was free-based with NH3 in MeOH (7N) and concentrated to yield a white solid (14 mg, 40.1%). MS ESI calc'd for C18H22N6O [M+H]+ 339. found 339. 1H NMR (ppm, 500 Mhz, DMSO-d6): δ 11.52 (s, 1H), 8.88 (s, 1H), 8.39 (s, 1H), 7.45-7.09 (m, 5H), 7.00-6.95 (m, 1H), 5.41 (q, J=5.6 Hz, 1H), 4.98-4.69 (m, 1H), 3.26-3.15 (m, 2H), 2.61 (s, 3H), 1.44-1.35 (m, 3H), 1.19 (dd, J=3.6 Hz, 3H).
Reaction SMILES: Br[C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[N:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1cccnc1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cccnc1-c1ccc(Cl)cc1
Yield: 93.5 %

Procedure:
To a solution of methyl 2-bromonicotinate (5.6 g, 25.9 mmol) in toluene (140 mL) was added 4-chlorophenylboronic acid (6.1 g, 38.9 mmol), potassium carbonate (5.4 g, 39 mmol), and tetrakis(triphenylphosphine) palladium (1.53 g. 1.3 mmol). The mixture was heated to reflux for 3.5 hours, evaporated in vacuo and then purified on a silica gel column using a 1:4 mixture of ethyl acetate:hexane as mobile phase. Pure fractions were combined and the solvent was removed in vacuo to yield methyl 2-(4-chlorophenyl)nicotinate (6.0 g, HPLC RT=3.04 min, method A; LC-MS m/z=248).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][CH:6]([C:33]#[CH:34])[NH:7][C:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:32])[CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH2:11]1)=[O:9])C.[OH-].[Li+].OS([O-])(=O)=O.[K+]>O1CCCC1.C(O)C.O>[C:28]([O:27][C:25]([N:22]1[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17][C:16]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:10]([C:8]([NH:7][CH:6]([C:33]#[CH:34])[CH2:5][C:4]([OH:35])=[O:3])=[O:9])[CH2:11]2)=[O:32])[CH2:24][CH2:23]1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: C#CC(CC(=O)OCC)NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: C#CC(CC(=O)O)NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 0 °C
Yield: 86.1 %

Procedure:
A solution of N-[(R)-1-{3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-3-ethynyl-β-alanine ethyl ester (1.38 g) in tetrahydrofuran (5 ml), ethanol (5 ml) and water (5 ml) was added lithium hydroxide (0.35 g) under stirring at 0° C. After stirring at ambient temperature for 1 hour, the mixture was acidified with 5% KHSO4 aqueous solution and extracted with ethyl acetate. The extract was washed with water, brine and dried over MgSO4, and evaporated in vacuo to give N-[(R)-1-{3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-3-ethynyl-β-alanine (1.12 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[C:8]1[C:16]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]1)=[O:17].C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[C:8]1[C:16]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)=[O:26])[CH2:22][NH:21][CH2:20]1)=[O:17]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)cc2c1CCCC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCOCC3)C2)cc2c1CCCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
tert-Butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (100 mg) was dissolved in dichloromethane (0.5 ml), TFA (0.5 ml) was added, to and the mixture was stirred at room temperature for 15 min. The solvent was evaporated under reduced pressure, and the residue was neutralized with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (10 ml×2), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dried under reduced pressure to give the object product (45 mg).