Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:9]([CH3:22])[CH:8]=2)=[O:4].O1CCOCC1.O.[OH-].[Li+].Cl>O>[CH2:15]([O:14][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[CH3:22])[NH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:13]2)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1cc2cc(OCc3ccccc3)c(C)cc2[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc2[nH]c(C(=O)O)cc2cc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
To a solution of 5-benzyloxy-6-methyl-1H-indole-2-carboxylic acid methyl ester (1.3 g) in a mixed solvent of 1,4-dioxane (40 mL) and water (20 mL) was added Lithium hydroxide mono hydrate (1.8 g) at room temperature and this mixture was stirred at 50° C. for 1 hour. After this reaction mixture was cooled to room temperature, 1 mol/L hydrochloric acid was added. This precipitated solid was collected by filtration, and washed with water, dried under reduced pressure to give the title compound (1.0 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:16])OC2C=CC=CC=2)=[CH:3][CH:2]=1.[NH2:17][C:18]1[CH:47]=[CH:46][C:21]([CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]([OH:45])([C:41]([F:44])([F:43])[F:42])[C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)[CH2:25][CH2:24]2)=[CH:20][C:19]=1[F:48]>O1CCOCC1>[F:48][C:19]1[CH:20]=[C:21]([CH2:22][CH:23]2[CH2:24][CH2:25][N:26]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([C:36]([OH:45])([C:41]([F:42])([F:43])[F:44])[C:37]([F:39])([F:40])[F:38])=[CH:34][CH:35]=3)[CH2:27][CH2:28]2)[CH:46]=[CH:47][C:18]=1[NH:17][C:8]([NH:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)=[O:16]
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Reactant: Nc1ccc(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Solvent: C1COCCO1
Product: O=C(Nc1ccncc1)Nc1ccc(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Temperature: 130 °C
Yield: 35.9 %

Procedure:
Phenyl pyridin-4-ylcarbamate (1.933 mmol, 0.414 g) was added to a stirred solution of 2-(4-((4-(4-amino-3-fluorobenzyl)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (1.292 mmol, 0.6 g) in dioxane (6 mL) and the mixture heated in a microwave for 10 minutes at 130° C. The mixture was washed with water (10 mL) and the organic phase dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting with 1% to 10% methanol/dichloromethane) to afford the title compound (271 mg). MS (ESI) m/z 585.3 [M+H]+
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].[C:10]1(=[O:17])[O:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][O:8][CH3:9])[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][OH:17]
Reactant: O=C1CCCCCO1
Reactant: COCCNCCOC
Solvent: Cc1ccccc1
Product: COCCN(CCOC)C(=O)CCCCCO
Temperature: 65 °C
Reaction time: 20 h
Yield: 108.5 %

Procedure:
A mixture of Bis(2-methoxyethyl)amine (11.85 g) and toluene (100 mL) was warmed to 65° C. under nitrogen. A solution of epsilon-Caprolactone (9.23 g) in toluene (35 mL) was added over several minutes. The mixture was stirred at this temperature until all the caprolactone was consumed, as determined by thin layer chromatography (silica gel plate), 4:1 ethanol/NH4OH). After 20 hours, an additional portion of bis(2-methoxyethyl)amine (3.1 g) was added and heating continued. After about 36 hours, all caprolactone had been consumed. The solvent was removed in vacuo on a rotary evaporator to afford the product as an oil (21.7 g).
Reaction SMILES: [C:1]([C:5]1[O:6][CH:7]=[C:8]([CH2:10]Cl)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[P:12]([O:19]CC)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15].C(OCC)(=O)C>C(OCC)(=O)C.C(O)C>[C:1]([C:5]1[O:6][CH:7]=[C:8]([CH2:10][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(CCl)co1
Reactant: CCOP(OCC)OCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1coc(C(C)(C)C)n1)OCC
Temperature: 160 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
A mixture of 2-tert-butyl-4-chloromethyl-1,3-oxazole (10.42 g) and triethyl phosphite (19.94 g) was stirred at 160° C. for 16 hrs. Excess triethyl phosphite was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v), ethyl acetate, then ethyl acetate-ethanol (10:1, v/v) to give diethyl [(2-tert-butyl-1,3-oxazol-4-yl)methyl]phosphonate as a colorless oil (16.51 g, yield 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][NH:9][S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.NN>[Ni].CO>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][NH:9][S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: CCS(=O)(=O)NCc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Agent: NN
Solvent: CO
Product: CCS(=O)(=O)NCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the residue of the product from step 1 (0.25 mmol) is added methanol (350 μL), hydrazine (33 μL), and Raney-Nickel (10 mg). The reaction mixture is shaken at room temperature for 16 hours, then filtered and the solution concentrated to yield ethanesulfonic acid 4-amino-benzylamide, which is used as such for the subsequent reaction.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[CH2:28][C:29]([NH:31][O:32]CC1C=CC=CC=1)=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[CH2:28][C:29]([NH:31][OH:32])=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCN(CC(=O)NOCc3ccccc3)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Solvent: CO
Product: COc1ccc(N2CCN(CC(=O)NO)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reaction time: 4 h
Yield: 56.3 %

Procedure:
A solution of 2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-benzyloxy-acetamide (Example 71) (30 mg, 0.0566 mmol) was dissolved in MeOH (10 mL), purged with a stream of nitrogen, treated with 20% Pd/C (100 mg, 50% water content), and hydrogenated under 40 psi pressure of hydrogen for 4 h. The crude reaction mixture was then purged with nitrogen, filtered, and evaporated. The crude product was then dissolved in chloroform (5 mL) and filtered through a nylon syringe filter to remove residual Pd/C. The organic solution was evaporated to afford product as a colorless foam (14 mg, 56%). LC/MS 5.03 min, [M+1]+ 440.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[Br:10][C:11]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][C:17]([Br:24])=[CH:18][CH:19]=3)[C:14]([CH2:29][CH2:30][CH2:31]Br)([CH2:25][CH2:26][CH2:27]Br)[C:13]=2[CH:12]=1>COCCOC>[Br:10][C:11]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][C:17]([Br:24])=[CH:18][CH:19]=3)[C:14]([CH2:25][CH2:26][CH2:27][O:8][CH2:7][CH:5]3[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]3)([CH2:29][CH2:30][CH2:31][O:8][CH2:7][CH:5]3[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]3)[C:13]=2[CH:12]=1
Reactant: CC1(C)OCC(CO)O1
Reactant: BrCCCC1(CCCBr)c2cc(Br)ccc2-c2ccc(Br)cc21
Solvent: COCCOC
Product: CC1(C)OCC(COCCCC2(CCCOCC3COC(C)(C)O3)c3cc(Br)ccc3-c3ccc(Br)cc32)O1
Reaction time: 0.33 h

Procedure:
Potassium terbutylate (3.0 g, 26.7 mmoles) are added, in an inert atmosphere, to a solution of solketal (3.5 g, 26.7 mmoles) in 50.0 ml of 1,2-dimethoxyethane. After 20 minutes, 5.0 g of 2,7-dibromo-9,9-bis(3′-bromopropyl)fluorene (5.0 g, 8.9 mmoles) dissolved in 15.0 ml of 1,2-dimethoxyethane are added.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.CO>O>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:13][CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Clc1cccc(N2CCN(CCCNC(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)c1
Agent: Cl
Solvent: O
Solvent: CO
Product: NCCCN1CCN(c2cccc(Cl)c2)CC1
Yield: 68 %

Procedure:
Gaseous hydrochloric acid is introduced for 10 min into a round bottom flask containing 11.2 g (22.6 mmol) of 3-[4-(3-chlorophenyl]piperazin-1-yl]-N-(triphenylmethyl)propanamine and 300 ml of methanol, while the mixture is cooled in a bath of iced water. The mixture is allowed to return to room temperature and is then heated under reflux for 5.5 h. The solution is reduced to half its volume and is allowed to cool. The solid which precipitates is filtered off, is treated with water and aqueous ammonia, the mixture is extracted with ethyl acetate, the organic phase is washed with water and is dried and the solvent is evaporated off. 3.9 g of light yellow oil are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]#[CH:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Li]CCCC.Cl[C:17]([O:19][CH3:20])=[O:18].C(=O)(O)[O-].[Na+]>C1COCC1.C(=O)=O.CC(C)=O.C(OCC)C>[CH3:20][O:19][C:17](=[O:18])[C:10]#[C:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=1
Reactant: C#Cc1cc(C)cc(C)c1
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C#Cc1cc(C)cc(C)c1
Reaction time: 1 h

Procedure:
1H NMR(CDCl3) δ7.12 (2H,s), 6.98 (1H,s), 3.00 (1H,s), 2.29 (6H, s). 1-(3,5-dimethylphenyl)acetylene (11.3 g, 86.3 mmol) in dry THF (80 mL) was cooled in dry ice/acetone bath under an argon atmosphere. The n-BuLi (1.6M in hexanes, 65 mL, 104 mmol) was added slowly, followed by methyl chloroformate (11.4 g, 9.4 mL, 121 mmol) addition. The reaction vessel was transferred to an ice/water bath and stirred for 1 h. Saturated sodium bicarbonate solution and ethyl ether were added to the reaction mixture. The organic layer was washed with saturated brine, dried (Na2SO4), and concentrated to give crude 3-(3,5-dimethylphenyl)propynoic acid methyl ester which was used for next step.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][C:3](=O)[CH2:2]1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:28]=1)[NH:25][CH:24]=[CH:23]2.C([SiH](CC)CC)C>ClCCl>[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:28]=1)[NH:25][CH:24]=[C:23]2[CH:3]1[CH2:4][CH2:5][S:1][CH2:2]1
Reactant: CCOC(=O)c1cc(Br)cc2cc[nH]c12
Reactant: O=C1CCSC1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)cc2c(C3CCSC3)c[nH]c12
Temperature: 0 °C
Yield: 46.9 %

Procedure:
Dihydro-3(2H)-thiophenone (0.381 g, 3.73 mmol) was dissolved in dichloromethane (50 ml) in an oven dried flask containing 3 Å molecular sieves and stirred under Argon at 0° C. TMS-OTf (0.826 g, 3.73 mmol, 0.67 mL) was added slowly to the mixture over 10 min. Ethyl 5-bromo-1H-indole-7-carboxylate (1 g, 3.73 mmol) was dissolved in DCM (6 mL) and added to the reaction via syringe pump over 2 hours, after which it was stirred for 30 min at 0° C. Triethylsilane (0.651 g, 0.89 ml, 5.59 mmol) was then added all at once and the reaction was stirred at room temperature for 18 hours. The reaction was then quenched with a saturated sodium bicarbonate solution (35 mL) and extracted with DCM (2×50 mL). The combined organics were washed with water (2×100 mL), brine, dried with MgSO4, and concentrated. The crude compound was purified on Combiflash silica column with 10% EA/Hexane to give 0.620 g (47%) of the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:10][C:9]2=[O:22])=[O:5])C.[OH-].[Na+]>C(O)C>[O:22]=[C:9]1[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][C:11]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:10]1
Reactant: CCOC(=O)c1ccc2[nH]c(-c3ccccc3)cc(=O)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2[nH]c(-c3ccccc3)cc(=O)c2c1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
Saponification proceeded with dissolving 26.5 g (0.1 mol) 4-oxo-2-phenyl-1,4-dihydro-quinoline-6-carboxylic acid ethyl ester in ethanol (100 mL), adding 10 eq. of 1N NaOH solution and stirring at 40° C. for 4 hr. The ethanol was evaporated, water was added and acidified, and the precipitate filtered. The white product was dried over P2O5 to give quantitative amounts of 4-oxo-2-phenyl-1,4-dihydro-quinoline-6-carboxylic acid.
Reaction SMILES: [CH3:1]/[CH:2]=[C:3](/[C:5]([O:7][C@@H:8]1[C@:16]23[C@H:20]([C@@:21]([C@:25]45[O:30][C@@:29]4([CH3:31])[C@H:28]4[C@:32]6([OH:38])[C@H:36]([O:37][C@@H:26]5[CH2:27]4)[O:35][CH:34]=[CH:33]6)([CH3:24])[C@H:22]([OH:23])[C@H:14]4[C@H:15]2[C@:11]([C:44]([O:46][CH3:47])=[O:45])([CH2:12][O:13]4)[C@H:10]([O:48][C:49]([CH3:51])=[O:50])[CH2:9]1)[C@@:19]([OH:43])([C:39]([O:41][CH3:42])=[O:40])[O:18][CH2:17]3)=[O:6])\[CH3:4].[H][H]>O.O.[Pt](=O)=O.C(OCC)(=O)C>[CH3:1]/[CH:2]=[C:3](/[C:5]([O:7][C@@H:8]1[C@:16]23[C@H:20]([C@@:21]([C@:25]45[O:30][C@@:29]4([CH3:31])[C@@H:28]4[C@:32]6([OH:38])[C@@H:36]([O:37][C@H:26]5[CH2:27]4)[O:35][CH2:34][CH2:33]6)([CH3:24])[C@H:22]([OH:23])[C@H:14]4[C@H:15]2[C@:11]([C:44]([O:46][CH3:47])=[O:45])([CH2:12][O:13]4)[C@H:10]([O:48][C:49]([CH3:51])=[O:50])[CH2:9]1)[C@@:19]([OH:43])([C:39]([O:41][CH3:42])=[O:40])[O:18][CH2:17]3)=[O:6])\[CH3:4]
Reactant: [H][H]
Reactant: C/C=C(\C)C(=O)O[C@H]1C[C@@H](OC(C)=O)[C@@]2(C(=O)OC)CO[C@H]3[C@@H](O)[C@@](C)([C@]45O[C@@]4(C)[C@@H]4C[C@H]5O[C@@H]5OC=C[C@@]54O)[C@H]4[C@]1(CO[C@]4(O)C(=O)OC)[C@@H]32
Agent: O=[Pt]=O
Solvent: O
Solvent: CCOC(C)=O
Product: C/C=C(\C)C(=O)O[C@H]1C[C@@H](OC(C)=O)[C@@]2(C(=O)OC)CO[C@H]3[C@@H](O)[C@@](C)([C@]45O[C@@]4(C)[C@H]4C[C@@H]5O[C@H]5OCC[C@@]54O)[C@H]4[C@]1(CO[C@]4(O)C(=O)OC)[C@@H]32
Reaction time: 1.25 h

Procedure:
40.8 mg. azadirachtin A (5.67×1031 5 mole) were dissolved in 4 ml. ethyl acetate and 20 mg. platinum dioxide dihydrate were added thereto. The mixture was stirred and hydrogen passed therethrough for 75 minutes, the course of the reaction being monitored by HPLC. After the disappearance of the azadirachtin A peak, the reaction was discontinued and the reaction mixture centrifuged. The supernatant solution was evaporated and purified on silicon dioxide thin layer chromatography plates using the elution agent chloroform/acetone (7:3 v/v); Rf 0.33. Yield: 28.2 mg. (69% of theory).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:16]=[C:17]([CH:46]=[CH:47][CH:48]=1)[CH2:18][N:19]1[C:23]2[CH:24]=[C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][N:31]=3)[CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[C@H:37]1[CH2:42][CH2:41][CH2:40][CH2:39][C@H:38]1[C:43]([OH:45])=[O:44]>>[CH3:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][O:28][C:25]2[CH:26]=[CH:27][C:22]3[N:21]=[C:20]([C@H:37]4[CH2:42][CH2:41][CH2:40][CH2:39][C@H:38]4[C:43]([OH:45])=[O:44])[N:19]([CH2:18][C:17]4[CH:46]=[C:47]([C:6]5[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=5)[CH:48]=[CH:15][CH:16]=4)[C:23]=3[CH:24]=2)=[N:31][CH:32]=1
Reactant: Cc1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4cccc(Br)c4)c3c2)nc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: Cc1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4cccc(-c5ccc(C(F)(F)F)cc5)c4)c3c2)nc1

Procedure:
The title compound was prepared using similar methods to those in Example 144 using (4-(trifluoromethyl)phenyl)boronic acid and racemic cis-2-{1-(3-bromobenzyl)-6-[(5-methylpyridin-2-yl)methoxy]-1H-benzimidazol-2-yl}cyclohexanecarboxylic acid. MS (ESI): mass calcd. for C35H32F3N3O3, 599.24; m/z found, 600.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.32 (d, J=2.0 Hz, 1H), 7.68 (d, J=8.1 Hz, 2H), 7.62 (d, J=8.8 Hz, 1H), 7.57 (d, J=8.1 Hz, 2H), 7.54 (d, J=7.8 Hz, 1H), 7.45 (dd, J=8.1, 2.2 Hz, 1H), 7.43-7.38 (m, 2H), 7.35 (d, J=8.0 Hz, 1H), 7.04 (dd, J=8.8, 2.3 Hz, 1H), 6.97 (d, J=7.8 Hz, 1H), 6.82 (d, J=2.3 Hz, 1H), 5.36 (s, 2H), 5.14 (s, 2H), 3.25-3.09 (m, 1H), 3.09-2.97 (m, 1H), 2.65-2.53 (m, 1H), 2.28 (s, 3H), 1.87-1.71 (m, 3H), 1.70-1.58 (m, 2H), 1.51-1.31 (m, 2H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C@@H:9]2[NH:13][C@@:12]([CH2:15][OH:16])([CH3:14])[CH2:11][CH2:10]2)[CH:6]=[N:7][CH:8]=1.Cl[C:18]1[CH:23]=[CH:22][N:21]2[N:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:20]2[N:19]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[F:2][C:3]1[CH:4]=[C:5]([C@@H:9]2[N:13]([C:18]3[CH:23]=[CH:22][N:21]4[N:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:20]4[N:19]=3)[C@@:12]([CH2:15][OH:16])([CH3:14])[CH2:11][CH2:10]2)[CH:6]=[N:7][CH:8]=1
Reactant: C[C@@]1(CO)CC[C@H](c2cncc(F)c2)N1
Reactant: CCOC(=O)c1cnn2ccc(Cl)nc12
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn2ccc(N3[C@@H](c4cncc(F)c4)CC[C@@]3(C)CO)nc12
Temperature: 190 °C
Yield: 25.2 %

Procedure:
A sealed reaction vessel was charged with ((2S,5R)-5-(5-fluoropyridin-3-yl)-2-methylpyrrolidin-2-yl)methanol hydrochloride (0.135 g, 0.547 mmol), ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (Preparation B, 0.136 g, 0.602 mmol), DIEA (0.124 mL, 0.711 mmol) and isopropyl alcohol (1 mL). The vessel was sealed and the mixture was heated at 190° C. for 48 hours. The reaction was cooled to ambient temperature and concentrated. The residue was purified by reverse phase column chromatography (0-50% acetonitrile/water) to afford ethyl 5-((2S,5R)-5-(5-fluoropyridin-3-yl)-2-(hydroxymethyl)-2-methylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (55 mg, 25% yield) as a viscous clear oil. MS (apci) m/z=400.1 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH:9][CH2:10][CH3:11])[CH3:8].[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1.Cl>O.C1COCC1>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:9]([CH2:10][CH3:11])[CH2:7][CH3:8])=[CH:15][CH:14]=1
Reactant: CCNCC
Reactant: BrCc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)Cc1ccc(Br)cc1
Yield: 74 %

Procedure:
Into a 500 ml round-bottomed flask were added 150 ml THF, 5 ml water, 2.2 g potassium carbonate, 6 ml diethyl amine, and 5 g p-bromobenzyl bromide. The resultant mixture was refluxed for 12 h. The mixture was then cooled to room temperature, into which 6 ml concentrated HCl was added, followed by the addition of 150 ml water. The mixture was extracted with 100 ml diethyl ether for three times. The diethyl ether solution was dried with anhydrous magnesium sulfate over night and then the magnesium sulfate was removed by filtration. Diethyl ether was evaporated and the raw product was purified by a silica gel column using hexane/chloroform mixture (1:1 by volume) as the eluent. (p-bromobenzyl)diethyl amine (BBDA) was obtained in 74% yield (3.6 g).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)O1.Cl[C:18]1[N:19]=[N:20][CH:21]=[CH:22][CH:23]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[N:19]1[CH:18]=[CH:23][CH:22]=[C:21]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[N:20]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Clc1cccnn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1ccc(-c2cccnn2)cn1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
To a sealed flask were added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine 145-1 (1.54 g, 7 mmol), 3-chloropyridazine 145-2 (0.8 g, 7 mmol), Pd(PPh3)4 (500 mg, 0.7 mmol), toluene (50 mL), ethanol (12 mL) and 2M Na2CO3 (11 mL). The reaction mixture was bubbled with nitrogen for 2 minutes and stirred at 90° C. for 10 hours. After cooled to room temperature, the solvents were evaporated and the residue was redissolved in dichloromethane (200 ml) and treated with 1M HCl aqueous solution (50 mL). The two layers were separated and the aqueous layer was treated with 10% NaOH aqueous solution to adjust the pH to around 13. The resulting solution was evaporated and the remaining solid was exacted with ethyl acetate (100 mL×3). The combined organic phases were concentrated to give 5-(pyridazin-3-yl)pyridin-2-amine 145-3 as dark brown solid. MS m/z 173.1 (M+1).
Reaction SMILES: [CH2:1]([C:8]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:27])[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[C:16]([N:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:19][CH2:20][CH3:21])[N:15]=[C:14](Cl)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36](=[O:39])([O-])[O-:37].[Na+].[Na+]>C(O)CCC.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl>[C:31]([O:30][C:29]([NH:28][C:8]([CH3:27])([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[C:16]([N:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:19][CH2:20][CH3:21])[N:15]=[C:14]([C:36]([O:37][CH2:8][CH2:1][CH2:2][CH3:3])=[O:39])[CH:13]=1)=[O:35])([CH3:34])([CH3:33])[CH3:32]
Reactant: CCCN(c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(Cl)n1)S(C)(=O)=O
Reactant: O=C([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Na+]
Solvent: CCCCO
Solvent: N#Cc1ccccc1
Product: CCCCOC(=O)c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(N(CCC)S(C)(=O)=O)n1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A suspension of tert-butyl [1-benzyl-2-({2-chloro-6-[(methylsulfonyl)(propyl)amino]pyridin-4-yl}methoxy)-1-methylethyl]carbamate (115 mg, 0.22 mmol, intermediate VI), sodium carbonate (70 mg, 0.66 mmol), PdCl2(PhCN)2 (2 mg, 0.004 mmol), 4A sieves and 1-[2-(dicyclohexylphasphanyl)ferrocenyl]ethyldicyclohexylphosphane (11 mg, 0.017 mmol, STREM) in n-butanol (2 ml, degassed with Argon), was purged with CO and stirred at 100° C. for 16 h under 1 atm of CO. The reaction mixture was diluted with dichloromethane, washed with water and brine, dried over sodium sulfate, concentrated in vacuo, azeothroped with toluene, and purified by flash chromatography (silica, 0-35% EtOAc/hexanes) to provide butyl 4-({2-[(tert-butoxycarbonyl)amino]-2-methyl-3-phenylpropoxy}methyl)-6-[(methylsulfonyl)(propyl)amino]pyridine-2-carboxylate as a yellow oil which was dissolved in 1:1 THF:MeOH (1.6 mL) and treated with aq LiOH (0.38 mL, 0.38 mmol, 1N) for 2 h at rt. The reaction mixture was acidified to pH 3-4 with 1N HCl, extracted with dichloromethane, dried over sodium sulfate, concentrated in vacuo, azeothroped with toluene to give 4-({2-[(tert-butoxycarbonyl)amino]-2-methyl-3-phenylpropoxy}methyl)-6-[(methylsulfonyl)(propyl)amino]pyridine-2-carboxylic acid as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.71 (s, 1H), 7.34-7.13 (m, 5H), 4.67 (s, 2H), 4.49 (s, 1H), 3.93 (t, J=7.6 Hz, 2H), 3.72 (A of AB, d, J=9.2 Hz, 1H), 3.62 (B of AB, d, J=9.2 Hz, 1H), 3.17 (A of AB, d, J=13.6 Hz, 1H), 3.05 (s, 3H), 2.90 (13 of AB, d, J=13.6 Hz, 1H), 1.70-1.55 (m, 2H), 1.46 (s, 9H), 1.27 (s, 3H), 0.96 (t, J=7.6 Hz, 3H).