Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5](SC)[C:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:7])(=[O:3])[CH3:2].CCO.[BH4-].[Na+].Cl>O.CCOC(C)=O>[C:1]([O:4][CH2:5][CH:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[OH:7])(=[O:3])[CH3:2]
Reactant: CSC(OC(C)=O)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)OCC(O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a suitable reactor was added 3g (1.19 g, 1.0 equiv) and EtOH (6 mL) was added at 20-30° C. under N2. The mixture was cooled to −25 to −15° C., and NaBH4 (107.1 mg, 0.8 equiv) in H2O (2.4 mL) was added at below −15° C. The reaction mixture was warmed to −5-5° C. and stirred for 1 hr. The reaction was deemed completed as determined by TLC. 1N HCl aqueous solution (11 mL) was added at below 10° C., and the mixture was warmed to 20-30° C. EtOAc (100 mL) was added at 20-30° C., and the mixture was stirred at this temperature for 30 min. The separated organic portion was concentrated under reduced pressure to afford crude 4g. The diastereomeric ratio of crude 4g was determined to be 95/5 by HPLC analysis. The residue was purified by flash column chromatography (EtOAc/n-heptane=1/1) to give a diastereomeric mixture of 4g (0.84 g, 82% yield) as a yellow oil.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:7][CH:8]([NH:18][CH2:19][CH:20]([OH:35])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27]CC1C=CC=CC=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1>[C].[Pd].C(O)C>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:7][CH:8]([NH:18][CH2:19][CH:20]([OH:35])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1
Reactant: COc1ccc(CC(C)NCC(O)c2ccccc2OCc2ccccc2)cc1
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: COc1ccc(CC(C)NCC(O)c2ccccc2O)cc1
Yield: 84.4 %

Procedure:
A mixture of 0.7 g of α-[(α-methyl-4-methoxyphenethylamino)methyl]-2-benzyloxybenzylalcohol oxalate [the diastereoisomer of M.p. 143°-144° C. (decomp.)], 0.15 g of 10% palladium-carbon and 15 ml of 90% aqueous ethanol is treated in the same manner as described in Example 1-(4-a). The crude product thus obtained is recrystallized from ethanol. 0.48 g of α-[(α-methyl-4-methoxyphenethylamino)methyl]-2-hydroxybenzylalcohol oxalate [the diastereoisomer of M.p. 193°-194° C. (decomp.)] is thereby obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:8][NH2:9])=[CH:6][CH:7]=1.[CH2:10]([O:12][C:13](=[O:25])[C:14](=O)[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=O)[CH3:11].Cl>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:8]([C:5]2[N:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]=1)=[O:25])[CH3:11]
Reactant: CCOC(=O)C(=O)CC(=O)c1ccccn1
Reactant: NNc1ccc(Cl)nn1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccn2)n(-c2ccc(Cl)nn2)n1

Procedure:
3-Chloro-6-hydrazinopyridazine (1.59 g) and the 4-(2-pyridyl)-2,4-dioxobutanoic acid ethyl ester (2.45 g) obtained from Referential Example 31 in ethanol (60 mL) was refluxed under heat for 6 hours. To the reaction mixture, concentrated hydrochloric acid (1 mL) was added, and the mixture was refluxed under heat for 1 hour, and then cooled in air. The reaction solvent was removed under reduced pressure, and the residue was partitioned by use of ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated brine, and then dried over magnesium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, and the residue was purified through silica gel chromatography (ethyl acetate-hexane), to thereby give 1-(6-chloro-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid ethyl ester as a solid (1.50 g, 41%).
Reaction SMILES: [CH2:1]([O:5][CH:6]([CH3:11])[C:7]([O:9]C)=[O:8])[CH2:2][CH2:3][CH3:4].[OH-].[K+]>CO>[CH2:1]([O:5][CH:6]([CH3:11])[C:7]([OH:9])=[O:8])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(C)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCOC(C)C(=O)O

Procedure:
16.5 g of the compound (5d) was stirred together with 18.0 g of potassium hydroxide in methanol for 40 hours at room temperature.
Reaction SMILES: [C:1]([C:3](=[C:9]([CH3:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[ClH:12]>CCO.O=[Pt]=O>[ClH:12].[NH2:2][CH2:1][CH:3]([CH:9]([CH3:10])[CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C#N)=C(C)C
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(CN)C(C)C
Reaction time: 5 h

Procedure:
Ethyl 2-cyano-3-methylbut-2-enoate (5.0 g, 32.6 mmol) was dissolved in 320 mL of absolute EtOH. 700 mg of PtO2 and 12 mL of 4M HCl were added. The reaction mixture was hydrogenated at room temperature for 5 hours (30 psi). Filtration on a celite pad and evaporation of the solvent afforded crude title compound (quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[NH:14][C:13](=O)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:27])=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:27][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:14]=1
Reactant: O=c1ccnc(Nc2cccc(Cl)c2)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: Clc1cccc(Nc2nccc(Cl)n2)c1
Yield: 61 %

Procedure:
To 2-(3-chlorophenylamino)pyrimidin-4(3H)-one, 2, (3.00 g, 13.5 mmol) in toluene (30 mL) is added N,N-dimethyl-aniline (3.57 mL, 28.4 mmol) and phosphorus oxychloride (1.24 mL, 13.5 mmol). The resulting mixture is heated to reflux for 15 minutes, cooled to room temperature and neutralized to pH 7 with 1M NaOH (aqueous). The organic layer is extracted with EtOAc (3×250 mL). The combined organic layers are dried (MgSO4) and concentrated in vacuo. The residue is purified over silica (5% EtOAc in hexanes) to afford 2.0 g (61% yield) of the desired compound. 1H NMR (DMSO-d6, 300 MHz): δ 7.06-7.04 (m, 2H), 7.34 (t, J=8.1, 1H), 7.65-7.61 (m, 1H), 7.93 (m, 1H), 8.50 (d, J=5.1 Hz, 1H), 10.26 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:7][C:6](=[CH:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5](=[O:15])[CH:4]=1.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH2:7][CH:6]([CH2:8][CH:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[C:5](=[O:15])[CH:4]=1
Reactant: COC1=CC(=O)C(=CC2CCOCC2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC1=CC(=O)C(CC2CCOCC2)C1
Yield: 95.8 %

Procedure:
A solution of 3-methoxy-5-[1-(tetrahydro-pyran-4-yl)-methylidene]-cyclopent-2-enone (938 mg, 4.5 mmol) in ethanol (45 ml) was added to 5% palladium on activated charcoal (94 mg) and the reaction stirred for 7.5 hours under 3 bar of hydrogen. The reaction was then filtered through a pad of Celite, washed with ethanol and concentrated in vacuo to give 3-methoxy-5-(tetrahydro-pyran-4-ylmethyl)-cyclopent-2-enone (906 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17](=[O:19])[NH2:18])[CH:12]=1)[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2]>CO.C(O)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([CH:11]1[CH2:16][CH2:15][NH:14][CH:13]([C:17](=[O:19])[NH2:18])[CH2:12]1)[CH2:9][CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)c1ccnc(C(N)=O)c1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC[C@H](NC(=O)OC(C)(C)C)C1CCNC(C(N)=O)C1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A solution of [(S)-1-(2-carbamoyl-pyridin-4-yl)-propyl]-carbamic acid tert-butyl ester (1 g, 3.58 mmol) in MeOH (16.6 mL) and glacial acetic acid (3.3 mL) was added to a flask containing 10% palladium on carbon (0.38 g, 0.36 mmol) under nitrogen. The reaction was stirred at 60° C. under hydrogen at 400 psi using a Biotage Endeavour Argonaut instrument. After 20 hours, the reaction was filtered and concentrated. The crude material was diluted with EtOAc (100 mL), washed with saturated sodium carbonate solution (20 mL), brine, dried over sodium sulfate, filtered and concentrated to afford [(S)-1-(2-carbamoyl-piperidin-4-yl)-propyl]carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C1C=CC2N(O)N=NC=2C=1.[CH3:29][CH2:30][N:31](C(C)C)[CH:32](C)[CH3:33].CCN=C=NCCCN(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[C:6]([CH:10]=1)[C:7]([N:31]([CH2:32][CH3:33])[CH2:30][CH3:29])=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1Oc1ccc(Cl)nc1
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCN(CC)C(=O)c1cc(Br)ccc1Oc1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
A mixture of compound 5-bromo-2-(6-chloropyridin-3-yloxy)benzoic acid (1.28 Kg, 4.44 mol), DEA (461 mL, 4.44 mol), HOBT (600 g, 4.44 mol), DIPEA (1.547 L, 8.88 mol) in anhydrous DCM (8 L) was cooled to 0° C. and EDCI (851.2 g, 4.44 mol, 1 eq) was added. The mixture was stirred at 0° C. for 30 minutes and then at RT overnight. The reaction mixture was washed with an aqueous, saturated solution of NaHCO3, brine and water. The organic phase was separated, dried over MgSO4 and concentrated under reduced pressure. The resulting crude mixture was purified by silica gel chromatography (5 to 20% ethyl acetate in hexane) to afford 950 g of 5-bromo-2-(6-chloropyridin-3-yloxy)-N,N-diethylbenzamide as a yellow oil.
Reaction SMILES: C([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]([S:24]([CH3:26])=O)[CH:11]=1)(=O)C1C=CC=CC=1.[Na]>O.O.O.O.O.O.[Co](Cl)Cl>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([OH:9])=[CH:11][C:12]=1[S:24][CH3:26])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CS(=O)c1cc(OC(=O)c2ccccc2)ccc1OCc1ccccc1
Agent: Cl[Co]Cl
Agent: [Na]
Solvent: O
Product: CSc1cc(O)ccc1OCc1ccccc1

Procedure:
It is contemplated that reacting 4-benzyloxy-3-(methylsulfinyl)phenyl benzoate prepared according to the procedure of Example 3A with cobalt chloride hexahydrate and sodium bobohydride according to the procedure described in Example 1H will give 4-benzyloxy-3-(methylthio)-phenol and that substituting the latter for 4-benzyloxy-3-(methylsulfinyl)phenol in the procedures of Examples 3C and 3D will afford 1-[4-hydroxy-3-(methylthio)phenoxy]-3-[[3-(4-methoxyphenyl)-1-methylpropyl]-amino]-2-propanol (Formula I: Y=CH3S, R1 =H, ##STR16##
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:15]([NH2:19])[CH:16]([CH3:18])[CH3:17]>C(O)C.[Pd]>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:19][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)CN
Agent: [Pd]
Solvent: CCO
Product: CC(C)CNC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1.5 h
Yield: 80.8 %

Procedure:
To 10% Pd/C (3.0 g, 10% wt), under nitrogen, is added a solution of the 1-Boc-4-piperidone (30 g, 150.6 mmol, 1.0 eq.) and isobutylamine (11.2 g, 180.3 mmol, 1.2 eq) in ethanol (300 ml). This is hydrogenated for 1.5 h at 65 psi using a Parr hydrogenator. The catalyst is removed by filtration through Celite. Solvent is removed under vacuum to give 4-isobutylamino-piperidine-1-carboxylic acid tert-butyl ester as a colourless oil (31.2 g) with >98% purity. Mass spectrum (LCMS) Rt=2.79 (6 min gradient) (M++1) 257.2; 1H NMR (CDCl3): δ=4.01 (2H, brs), 2.82-2.75 (2H, m), 2.61-2.54 (1H, m), 2.43 (2H, d), 1.85-1.81 (2H, m), 1.76-1.67 (1H, m), 1.56 (1H, br s), 1.45 (9H, s), 1.31-1.18 (2H, m), 0.91 (6H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9](O)[CH2:10][CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:13]1(=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[NH:14]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH-].[Na+]>C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([N:14]2[C:15](=[O:22])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]2=[O:23])[CH2:10][CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC[C@H](O)c1ccc(Cl)c(Cl)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC[C@H](c1ccc(Cl)c(Cl)c1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.2 %

Procedure:
To a solution of 158 (3.45 g, 16.5 mmol) and THF (45 mL) cooled to 0° C. was added isoindoline-1,3-dione (2.67 g, 18.1 mmol) and PPh3 (6.49 g, 24.7 mmol) followed by the dropwise addition of neat DIAD (6.67 g, 33.0 mmol). The reaction was warmed to RT and stirred 18 h. The reaction was stirred with NaOH 2N (50 mL) and DCM (50 mL) for 2 h (emulsion) and then extracted with DCM. The combined organic fractions were dried (Na2SO4), filtered, and concentrated. The residue was triturated with hexane/EtOAc (1:1) and the precipitated POPh3 was filtered. The filtrate was concentrated and chromatographed (Isolera) eluting with hexane/EtOAc (9:1) to afford 2.05 g (32%) of (R)-2-(1-(3,4-dichlorophenyl)propyl)isoindoline-1,3-dione (160)
Reaction SMILES: [CH3:1][C@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1.Cl>CN(C)C1C=CN=CC=1.ClCCl>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:30])=[CH:24][CH:23]=1
Reactant: CC1(C)C2CC[C@@]1(C)C(=O)CC2=O
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@@]1(C)C(=O)C(C(=O)Nc1ccc(Cl)cc1)C2=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice-cooled solution of (1R)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 4-chlorophenyl isocyanate (0.31 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting reaction mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature. It was then stirred at 30° C. for seven hours. The resulting mixture was treated with 2N aqueous HCl (30 mL) and the layers were separated. The aqueous layer was extracted with two additional portions of dichloromethane (50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The desired product was isolated by chromatography on silica gel (10% ethyl acetate/hexane) and recrystallized from 95% ethanol to yield the title compound as a tan solid (0.39 g, 56% yield), mp=88–90° C.; MS (−) ESI m/z=334 (M+H)+; [α]D25=+22.8° (c=1, EtOH).
Reaction SMILES: [CH:1]1([C:6]2[CH:29]=[CH:28][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([OH:27])=[O:26])[C:16]5=[CH:15][C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:30]([F:33])([F:32])[F:31])[CH2:5][CH2:4][CH2:3][CH2:2]1.[O-]S(C(F)(F)F)(=O)=O.F[N+:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(Cl)Cl.CCOC(C)=O>[CH:1]1([C:6]2[CH:29]=[CH:28][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([OH:27])=[O:26])[C:16]5=[C:15]([C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][N:43]=5)[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:30]([F:33])([F:31])[F:32])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CC1CCn2c1cc1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Reactant: F[n+]1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(O)CC1CCn2c1c(-c1ccccn1)c1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Temperature: 0 °C
Yield: 9.4 %

Procedure:
The 1st enantiomer (described as the enantiomer isolated and having the retention time of 15 min per the conditions reported in Example 1.7) of 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid (0.100 g, 0.219 mmol) was dissolved in anhydrous DCM (2.2 mL) using a plastic vial. The reaction was cooled to 0° C., and N-fluoropyridinium triflate (0.073 g, 0.295 mmol) was added. The reaction was allowed to warm to 25° C. and after 4 h there was a dark solution. The reaction was diluted with EtOAc (40 mL), washed with water/brine (2×10 mL), brine (10 mL), and dried over MgSO4. The solvent was evaporated in vacuo. The residue was purified by HPLC to give the titled compound (0.011 g) as a yellow solid. LCMS m/z=535.5 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.54-1.78 (m, 4H), 1.79-1.92 (m, 2H), 2.05 (dd, J=9.92, 4.48 Hz, 2H), 2.43-2.53 (m, 2H), 2.57-2.73 (m, 2H), 3.29-3.41 (m, 1H), 4.09-4.28 (m, 3H), 5.17 (d, J=3.54 Hz, 2H), 6.99 (dd, J=8.84, 2.27 Hz, 1H), 7.34 (d, J=8.84 Hz, 1H), 7.44 (d, J=2.27 Hz, 1H), 7.53 (t, J=6.25 Hz, 1H), 7.56-7.61 (m, 1H), 7.64-7.69 (m, 1H), 7.73 (s, 1H), 7.90 (d, J=8.34 Hz, 1H), 8.23 (td, J=7.86, 1.58 Hz, 1H), 8.66 (d, J=4.42 Hz, 1H).
Reaction SMILES: C[O-:2].[Na+].Cl[C:5]1[N:6]=[N:7][C:8]([S:11][C:12]2[O:13][C:14]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:15]=3[C:16]=2[CH3:17])=[CH:9][CH:10]=1>CO>[Cl:22][C:19]1[CH:20]=[CH:21][C:14]2[O:13][C:12]([S:11][C:8]3[CH:9]=[CH:10][C:5](=[O:2])[NH:6][N:7]=3)=[C:16]([CH3:17])[C:15]=2[CH:18]=1
Reactant: C[O-]
Reactant: Cc1c(Sc2ccc(Cl)nn2)oc2ccc(Cl)cc12
Agent: [Na+]
Solvent: CO
Product: Cc1c(Sc2ccc(=O)[nH]n2)oc2ccc(Cl)cc12

Procedure:
Sodium methoxide (299 mL, 1.31 mol, 5 equiv) was added to a slurry of 3-chloro-6-(5-chloro-3-methyl-benzofuran-2-ylsulfanyl)-pyridazine (the title compound of Example One) in methanol (500 mL, 6.1 vol). The resultant mixture was heated at 50° C. for five hours to provide, 3-(5-chloro-3-methyl-benzofuran-2-ylsulfanyl)-6-methoxy-pyridazine, which was not isolated. The reaction mixture was cooled to room temperature and concentrated hydrochloric acid (12N, 329 mL, 3.95 mol, 15 equiv) was added. The reaction mixture was heated at reflux for 15 hours and then cooled to room temperature. Water (400 mL) was added to the slurry and the mixture was cooled to 0° C. for 30 minutes. The solids were collected by filtration, dried under vacuum, and repulped in dichloromethane (600 mL, 8 vol) and isopropyl ether (150 mL, 2 vol) to afford the title compound of Example Two (71 g, 92%) as an off-white solid.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:30])[CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:10]1=[O:29].Cl>O.CO>[C:19]1([CH2:18][N:11]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:9]([CH2:8][CH2:7][C:6]([OH:30])=[O:5])[C:10]2=[O:29])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)CCn1c(=O)n(Cc2cccc3ccccc23)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCn1c(=O)n(Cc2cccc3ccccc23)c2ccccc21
Reaction time: 6 h
Yield: 98.2 %

Procedure:
Lithium hydroxide monohydrate (31 mg, 0.75 mmol) is dissolved in water (3.5 mL) and this solution is added into 3-(3-naphthalen-1-ylmethyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propionic acid methyl ester (180 mg, 0.5 mmol) in methanol (3.5 mL) at room temperature. The mixture is stirred for 6 hr and 1.0 M HCl aqueous solution (1.5 mL) is added along with water (25 mL). Then the mixture is extracted with EtOAc (3×50 mL) and the organic layers are combined, dried over MgSO4 and concentrated to give 170 mg of crude 3-(3-Naphthalen-1-ylmethyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propionic acid which is used in the following step without further purification.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[N:15]=[C:14]([NH:16][C@H:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH2:18][OH:19])[C:13]([N+:27]([O-])=O)=[CH:12][N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[C:30](O)(=O)C.C(N)=N>[Pd].CCO.CCOC(C)=O.CCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[N:15]=[C:14]4[C:13]([N:27]=[CH:30][N:16]4[C@H:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH2:18][OH:19])=[CH:12][N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1cnc(Nc2cc(C3CC3)[nH]n2)nc1N[C@@H](CO)c1ccc(F)cc1
Agent: [Pd]
Agent: N=CN
Solvent: CCOC(C)=O
Solvent: CCO
Product: OC[C@@H](c1ccc(F)cc1)n1cnc2cnc(Nc3cc(C4CC4)[nH]n3)nc21
Temperature: 70 °C
Yield: 61.3 %

Procedure:
To a 25 ml round bottom flask was added palladium on activated carbon (10%, 104 mg, 0.098 mmol) and stirring bar. The flask was sealed, evacuated and refilled with hydrogen using balloon. A solution of (2R)-2-({2-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-5-nitropyrimidin-4-yl}amino)-2-(4-fluorophenyl)ethanol (Method 1, 196 mg, 0.49 mmol) in EtOH/EtOAc (6 ml/1 ml) via syringe. The reaction mixture was stirred at room temperature for 19 hours and was filtered through paper. The filtrate was concentrated to give a pink solid. The solid was then dissolved in EtOH (4 ml) and to the mixture was added formamidine acetate (100 mg, 0.96 mmol). The reaction mixture was heated on heating block (70° C.) for 4 hours. Removal of solvent followed by flash chromatography on silica gel (10-15% MeOH in EtOAc) gave the desired product as a solid (114 mg, 61% for two steps). NMR: 0.63 (m, 2H), 0.93 (m, 2H), 1.86 (m, 1H), 4.04 (m, 1H), 4.38 (m, 1H), 5.34 (m, 1H), 5.70 (m, 1H), 6.20 (m, 1H), 7.18 (m, 2H), 7.45 (m, 2H), 8.45 (s, 1H), 8.73 (s, 1H), 9.48 (br s, 1H), 11.85 (br s, 1H).