Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[N:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:6](=[O:20])[CH:5]=1)[NH2:3].[CH3:21]OC(OC)N(C)C>CN(C)C=O>[CH3:1][N:2]1[C:4]2[C:9](=[N:8][N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=3)[C:6](=[O:20])[CH:5]=2)[CH:21]=[N:3]1
Reactant: COC(OC)N(C)C
Reactant: CN(N)c1cnn(-c2cccc(C(F)(F)F)c2)c(=O)c1
Solvent: CN(C)C=O
Product: Cn1ncc2nn(-c3cccc(C(F)(F)F)c3)c(=O)cc21

Procedure:
In 225 ml. of absolute dimethylformamide (dried over molecular sieves) under a nitrogen atmosphere are dissolved 8.5 grams of 5-(1-methylhydrazino)-2-(3'-trifluoromethylphenyl)-3(2H)-pyridazinone. To this solution are added 7.1 grams of N,N-dimethylformamide dimethyl acetal and the solution is refluxed for 72 hours. The reaction is followed by thin layer chromatography The reaction mixture is then evaporated to dryness in vacuo and column chromatographed on silica gel, eluting with a mixture of benzene-chloroform (50/50), to obtain the crude title product which is then refined by preparative chromatography on a silica gel plate, eluting with chloroform to give crystalline title product, which is then washed with diethyl ether, m.p. 160°-163° C.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Li+].C(O)C.Cl>O>[N:32]1[CH:33]=[CH:34][CH:35]=[C:30]([C:27]2[CH:28]=[CH:29][C:24]([C:20]3[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]4[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:36])=[O:3])=[CH:14][CH:13]=4)[N:19]=3)=[CH:25][CH:26]=2)[CH:31]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4cccnc4)cc3)oc2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1oc(-c2ccc(-c3cccnc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1

Procedure:
To a 20 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-pyrid-3-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (0.268 mmoles), lithium hydroxide (0.535 mmoles, 0.268 mL of a 2N solution), and ethanol (5 mL). This solution was heated to reflux for 2 h. Distilled water was added to the mixture and the pH was adjusted to 3 using a 1N HCl solution. The organic layer was extracted with ethyl acetate, washed with brine, and concentrated in-vacuo. This crude oil was re-solvated in pure ethyl acetate and filtered over a pad of Celite. The filtrate was concentrated in-vacuo, and the crude oil was crystallized using acetonitrile. The crystals were collected and dried in-vacuo affording 2-(4-{2-[2-(4-pyrid-3-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) 8.91 (1H, m), 8.61 (1H, m), 8.08 (2H, m), 7.94 (1H, m), 7.64 (2H, d), 7.45 (1H, m), 7.38 (1H, m), 6.91 (2H, m), 6.78 (2H, m), 4.20 (2H, t), 3.00 (2H, t) 2.39 (3H, s), 1.54 (6H, s).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17][OH:18])[CH2:12]2)=[C:4](Cl)[N:3]=1.NC(N)=[S:22].C(=O)(O)[O-].[Na+]>O>[NH2:1][C:2]1[NH:3][C:4](=[S:22])[C:5]2[N:6]=[CH:7][N:8]([C@H:11]3[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17][OH:18])[CH2:12]3)[C:9]=2[N:10]=1
Reactant: Nc1nc(Cl)c2ncn([C@@H]3C[C@H](CO)[C@@H](O)C3)c2n1
Reactant: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1nc2c(ncn2[C@@H]2C[C@H](CO)[C@@H](O)C2)c(=S)[nH]1
Yield: 71.1 %

Procedure:
(+)-(1S,2R,4R)-4-(2-Amino-6-chloro-9H-purin-9-yl)-2-(hydroxymethyl)cyclopentanol, (1.70 g, 6.00 mmol) and thiourea (456 mg, 6.00 mmol) were refluxed in water (15 mL) for 1.0 hour. The cooled solution was adjusted to pH5 with saturated aqueous sodium bicarbonate. The resulting precipitate was filtered, washed with water and dried to give title compound as white powder (1.20 g, 71%); m.p. 290-291° dec; mass spectrum (Cl, CH4) 282 (M+1); 1H-NMR (DMSO-d6)δ: 11.90 (br s, 1, NH), 8.03 (s, 1, H-8), 6.78 (br s, 2, NH2), 4.95-4.70 (m, overlapping d at 4.78, J=27 Hz, total 2, CHN and OH), 4.7-4.6 (m, 1, CH2OH), 4.1-4.0 (m, 1, CHOH), 3.6-3.4 (m, 2, CH2O), 2.4-2.2 (m, 1, CH), 2.2-1.9 (m, 3, methylene), 1.7-1.5 (m, 1, 1/2CH2); [α]20589 +6.43°, [α]20578 +6.71°, [α]20546 +7.43°, [α]20436 +8.43°, [α]20 365 +8.43° (c=0.70, 0.1N NaOH).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:9]=[CH:10][C:5]2=[CH:4][N:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:2]2[N:7]=[C:6]3[N:8]([CH:11]4[CH2:16][CH2:15][CH2:14][CH2:13][O:12]4)[N:9]=[CH:10][C:5]3=[CH:4][N:3]=2)[CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1
Reactant: Clc1ncc2cnn(C3CCCCO3)c2n1
Reactant: COc1cc(OC)cc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(OC)cc(-c2ncc3cnn(C4CCCCO4)c3n2)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (5.2 mmol), (3,5-dimethoxyphenyl)boronic acid (1.0 g, 5.7 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (0.3 g, 0.4 mmol) and potassium phosphate (2.2 g) in 1,4-dioxane (10 mL) and water (2 mL) in a reaction vial was degassed and sealed. The mixture was stirred at 100° C. for 3 h. After cooling, the reaction mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-35%) to afford the desired product. LCMS (M+H)+=341.1.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:26][CH2:27][CH:28]([OH:30])[CH3:29]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][S:26][CH2:27][CH:28]([OH:30])[CH3:29])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: CC(O)CS
Product: CC(O)CSCCCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 58 %

Procedure:
Following a procedure similar to that described in Example 1, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 1-mercapto-2-propanol as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a 58% yield.
Reaction SMILES: [F:1][C:2]1[C:3]([F:14])=[CH:4][C:5]2[O:9][C:8]([C:10]([NH2:12])=O)=[CH:7][C:6]=2[CH:13]=1.F[B-](F)(F)F.C([O+](CC)CC)C.C(=O)([O-])O.[Na+].[Cl-].[NH4+:33]>ClCCl.C(O)C.C(OCC)(=O)C>[F:1][C:2]1[C:3]([F:14])=[CH:4][C:5]2[O:9][C:8]([C:10]([NH2:33])=[NH:12])=[CH:7][C:6]=2[CH:13]=1
Reactant: [NH4+]
Reactant: NC(=O)c1cc2cc(F)c(F)cc2o1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CCO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N=C(N)c1cc2cc(F)c(F)cc2o1
Temperature: 25 °C
Reaction time: 64 h
Yield: 39.5 %

Procedure:
A mixture of 1.4 g (7.1 mmol) of 5,6-difluorobenzofuran-2-carboxamide and 1.62 g (8.5 mmol) of triethyloxonium tetrafluoroborate in 40 ml of anhydrous dichloromethane was stirred at room temperature over 64 hours. Subsequently, the mixture was poured into 70 ml of saturated sodium hydrogen carbonate solution, extracted twice with 100 ml of dichloro-methane each time and the combined organic phases were washed once with 70 ml of saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated in a vacuum. The brown solid obtained was dissolved in 30 ml of anhydrous ethanol, treated with 2 g of ammonium chloride and heated under reflux for 22 hours. The mixture was diluted with 90 ml of ethyl acetate and extracted three times with 50 ml of water each time. Subsequently, the combined aqueous phases were made basic with 3N sodium hydroxide solution and the solid was filtered off and washed with water. After drying there was obtained 0.55 g (40%) of 5,6-difluorobenzofuran-2-carboxamidine as a white solid with m.p. 178°.
Reaction SMILES: Cl.[CH:2]([N:5]1[C:14]2[C:9](=[C:10]([CH3:15])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([C:16]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:17])[C:6]1=[O:26])([CH3:4])[CH3:3].Br[CH:28]([CH3:36])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH:2]([N:5]1[C:14]2[C:9](=[C:10]([CH3:15])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([C:16]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:28]([CH3:36])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:22][CH2:21]2)=[O:17])[C:6]1=[O:26])([CH3:4])[CH3:3]
Reactant: Cc1cccc2c1cc(C(=O)NCC1CCNCC1)c(=O)n2C(C)C
Reactant: CC(Br)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cccc2c1cc(C(=O)NCC1CCN(C(C)C(=O)OC(C)(C)C)CC1)c(=O)n2C(C)C
Temperature: 70 °C
Reaction time: 23 h
Yield: 65 %

Procedure:
A mixture of 1-isopropyl-5-methyl-2-oxo-N-(piperidin-4-ylmethyl)-1,2-dihydroquinoline-3-carboxamide hydrochloride (467 mg, 0.98 mmol, step 4 in preparation 3), tert-butyl 2-bromopropanoate (0.24 mL, 1.47 mmol), and triethylamine (0.41 mL, 2.93 mmol) in tetrahydrofuran (30 mL) was stirred at 70° C. for 23 h. After cooling to room temperature, the mixture was poured onto saturated aqueous sodium hydrogen carbonate (100 mL), and the aqueous layer was extracted with dichloromethane (100 mL×2). The combined organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with ammonia/methanol/dichloromethane (0.1:1:30) to give 299 mg (65%) of the title compound as a yellow amorphous.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:14])=[CH:11][N:10]=2)[C:6]=1[O:7][CH3:8].[CH3:25][O:26][C:27]1[C:32]([O:33][CH3:34])=[C:31](B(O)O)[CH:30]=[CH:29][N:28]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:25][O:26][C:27]1[C:32]([O:33][CH3:34])=[C:31]([C:2]2[CH:3]=[N:4][N:5]([C:9]3[CH:24]=[CH:23][C:12]([C:13]([NH:15][CH2:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:14])=[CH:11][N:10]=3)[C:6]=2[O:7][CH3:8])[CH:30]=[CH:29][N:28]=1
Reactant: COc1c(Br)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Reactant: COc1nccc(B(O)O)c1OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: COc1nccc(-c2cnn(-c3ccc(C(=O)NCC4CCOCC4)cn3)c2OC)c1OC
Yield: 42.7 %

Procedure:
Combined 6-(4-bromo-5-methoxy-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide (60.0 mg, 0.152 mmol), (2,3-dimethoxypyridin-4-yl)boronic acid (41.7 mg, 0.228 mmol), PdCl2(dppf)-CH2Cl2 Adduct (6.20 mg, 7.59 μmol), and sodium bicarbonate (63.8 mg, 0.759 mmol) in dioxane (1139 μl) and water (380 μl) and heated in a microwave reactor for 60 minutes at 110° C. The reaction mixture was diluted with 150 mL EtOAc and washed with 1 N HCl. Organic layers were collected, dried with sodium sulfate, and concentrated to a residue which was purified on a 60 g silica gel column and eluted with hexanes and EtOAc to give 6-(4-(2,3-dimethoxypyridin-4-yl)-5-methoxy-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide (29.4 mg, 42.7%) as a yellow oil. MS m/z [M+H]+ 454.4.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[NH:10][C:9](=O)[CH2:8][N:7]2[CH2:12][CH2:13][CH2:14][C@@H:6]12)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[C@@H:5]1([CH2:3][OH:2])[NH:10][CH2:9][CH2:8][N:7]2[CH2:12][CH2:13][CH2:14][C@@H:6]12
Reactant: COC(=O)[C@@H]1NC(=O)CN2CCC[C@@H]12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OC[C@@H]1NCCN2CCC[C@@H]12
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of cis-methyl-3-oxooctahydropyrrolo[1,2-a]pyrazine-1-carboxylate (Prepared according literature procedure: Heterocycles, 52(3), 2000)(270 mg) in anhydrous THF (10 mL) under a Nitrogen atmosphere at 0° C., lithium aluminium hydride (1M in THF, 6.8 mL) was added dropwise. The resulting mixture was stirred at 0° C. for 1 hour, then allowed to reach rt and stirred at this temperature for 30 minutes. Water (260 microL), NaOH (1M solution, 260 microL) and water (780 microL) were then added to the solution and the formation of a white precipitate was observed. The suspension was filtered over a Gooch funnel. The organic filtrate was dried and concentrated in vacuo to give the desired compound (198 mg) as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])=[CH:4][CH:3]=1.[CH3:16]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].CI>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:16])=[CH:14][CH:15]=1
Reactant: Oc1ccccc1Cc1ccc(F)cc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: COc1ccccc1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
A mixture of 2-(4-fluorobenzyl)phenol (4.51 gm, 22.41 mmol), DMF (60 mL), potassium carbonate (7.78 gm, 56.02 mmol) and methyl iodine (1.67 mL, 26.81 mmol) was stirred at rt for 16 h. The reaction was poured into 150 mL ethyl acetate, filtered, washed 3× with 50 mL H20, 1× with 100 m]L brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford 2-(4-fluorobenzyl)anisole (4.27 gm, 88%); 1H NMR (200 MHz, DMSO-d6): δ 7.11(m, 7H), 3.88(s, 2H), 3.76(s, 3H); TLC conditions: Uniplate silica gel, 250 microns; methylene chloride-hexanes (1:1); Rf=0.64.
Reaction SMILES: Br[C:2]1[C:3]([NH:22][CH2:23][CH2:24][CH2:25][OH:26])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC.O>[OH:26][CH2:25][CH2:24][CH2:23][NH:22][C:3]1[C:2]([C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: OB(O)c1cccnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(NCCCO)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(NCCCO)c(-c2cccnc2)c1
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-6-((3-hydroxypropyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 161.1, 72 mg, 0.15 mmol), pyridin-3-ylboronic acid (18.6 mg, 0.15 mmol) and Na2CO3 (48 mg, 0.450 mmol) in a mixture of DME (3.2 mL), EtOH (0.43 mL) and water (0.64 mL) was flushed with argon for 5 min. Pd(PPh3)2Cl2 was added (5.3 mg, 0.0075 mmol) and the mixture subjected to MW irradiation at 125° C. for 20 min. The vial was cooled to RT and the RM was evaporated to dryness under reduced pressure to give a residue that was triturated with THF and filtered. The filtrate was evaporated to dryness under reduced pressure and the crude product was purified by preparative LC-MS. TFA was removed using a SPE PL-HCO3 (StratoSpheres™ VariPure IPE) cartridge to afford the title compound. UPLC-MS (Condition 8) tR=1.86 min, m/z=433.1 [M+H]+, m/z=431.1 [M−H]−.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:41][C:42]([N:44]([CH2:46][CH2:47][O:48][CH3:49])[CH3:45])=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:41][CH2:42][N:44]([CH2:46][CH2:47][O:48][CH3:49])[CH3:45])=[CH:36][CH:37]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: COCCN(C)C(=O)CCl
Product: CCN(Cc1ccc(OCCN(C)CCOC)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 10.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-chloro-N-(2-methoxyethyl)-N-methylacetamide (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.1 mg) was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C>Cl.C(O)C>[ClH:26].[ClH:26].[Cl:27][C:22]1[CH:21]=[C:20]([N:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:25]=[CH:24][C:23]=1[Cl:26]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N(c2ccccc2)c2ccc(Cl)c(Cl)c2)C1
Agent: Cl
Solvent: CCO
Product: Clc1ccc(N(c2ccccc2)[C@H]2CCNC2)cc1Cl
Yield: 272 %

Procedure:
3(S)-[(3,4-dichlorophenyl)phenylamino]pyrrolidine-1-carboxylic acid tert-butyl ester (0.13 g) was dissolved in 1 N hydrochloric acid-ethanol and heated under reflux for one hour. The reaction solution was concentrated to dryness to thereby obtain 0.11 g of brown amorphous solid 3(S)-(3,4-dichlorophenyl)phenylpyrrolidin-3-ylamine hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]([CH3:16])[CH2:11][C:12]([O:14]C)=[O:13])[C:6]=2[CH:17]=1>Cl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]([CH3:16])[CH2:11][C:12]([OH:14])=[O:13])[C:6]=2[CH:17]=1
Reactant: COC(=O)CC(C)n1cnc2ccc(N)cc21
Agent: Cl
Product: CC(CC(=O)O)n1cnc2ccc(N)cc21

Procedure:
A solution of methyl 3-(6-amino-1H-benzimidazol-1-yl)butanoate (78 mg, 334 μmol) in hydrochloric acid (5 mL of a 5N solution) was stirred at room temperature for 163 hours. The solution was then evaporated in vacuo to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=1.53 min, MH+ 220].
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([N:9]3[CH2:36][CH2:35][C:12]4[N:13]=[C:14]([C:24]5[C:32]([CH3:33])=[CH:31][CH:30]=[C:29]6[C:25]=5[C:26]([CH3:34])=[N:27][NH:28]6)[N:15]=[C:16]([N:17]5[CH2:20][CH:19]([O:21][CH2:22][CH3:23])[CH2:18]5)[C:11]=4[CH2:10]3)[N:6]([CH3:37])[N:5]=2)[CH2:3][CH2:2]1.[Cl:38]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:38][C:8]1[C:4]([CH:1]2[CH2:2][CH2:3]2)=[N:5][N:6]([CH3:37])[C:7]=1[N:9]1[CH2:36][CH2:35][C:12]2[N:13]=[C:14]([C:24]3[C:32]([CH3:33])=[CH:31][CH:30]=[C:29]4[C:25]=3[C:26]([CH3:34])=[N:27][NH:28]4)[N:15]=[C:16]([N:17]3[CH2:18][CH:19]([O:21][CH2:22][CH3:23])[CH2:20]3)[C:11]=2[CH2:10]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC1CN(c2nc(-c3c(C)ccc4[nH]nc(C)c34)nc3c2CN(c2cc(C4CC4)nn2C)CC3)C1
Solvent: ClCCl
Product: CCOC1CN(c2nc(-c3c(C)ccc4[nH]nc(C)c34)nc3c2CN(c2c(Cl)c(C4CC4)nn2C)CC3)C1
Reaction time: 0.5 h

Procedure:
To a solution of 6-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3,5-dimethyl-1H-indazol-4-yl)-4-(3-ethoxyazetidin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (30 mg, 0.060 mmol) in DCM (2 mL) was added N-chlorosuccinimide (9.64 mg, 0.072 mmol) at room temperature. The mixture was stirred for 30 min then concentrated. The residue was purified by reverse phase HPLC (C18, 10-100% acetonitrile-H2O with 0.1% NH4OH) to give 6-(4-chloro-3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3,5-dimethyl-1H-indazol-4-yl)-4-(3-ethoxyazetidin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.43 (d, J=8.46 Hz, 1H), 7.30 (d, J=8.59 Hz, 1H), 4.49 (dd, J=6.63, 9.41 Hz, 2H), 4.35-4.45 (m, 3H), 4.14 (dd, J=4.04, 10.36 Hz, 2H), 3.66 (s, 3H), 3.46-3.55 (m, 4H), 2.89 (t, J=5.68 Hz, 2H), 2.27 (s, 3H), 2.04 (s, 3H), 1.81-1.88 (m, 1H), 1.19 (t, J=7.01 Hz, 3H), 0.76-0.93 (m, 4H); MS (ESI+) m/z 533.4 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:14](Cl)(=O)=O)[CH:11]=2)[O:6][CH2:5]1)#[N:2].CC1N=C(C2C=CC(C(F)(F)F)=CC=2)SC=1CSC1C=C2C(=CC=1)OCC(CC#N)C2>>[SH:14][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[O:6][CH2:5][CH:4]([CH2:3][C:1]#[N:2])[CH2:13]2
Reactant: N#CCC1COc2ccc(S(=O)(=O)Cl)cc2C1
Agent: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CSc1ccc2c(c1)CC(CC#N)CO2
Product: N#CCC1COc2ccc(S)cc2C1

Procedure:
Compound 18E was prepared according to the method of example 1C utilizing compound 18D. Compound 18E was prepared in 35% yield. MS: 204 (M−1)+. Preparation of 6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-chroman-3-yl-acetonitrile (Compound 18F)
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[C:25]([F:26])=[C:24]([F:27])[CH:23]=[CH:22][C:21]=1B(O)O>>[CH3:16][C:7]1[C:6]2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:23]3[CH:22]=[CH:21][C:20]([F:19])=[C:25]([F:26])[C:24]=3[F:27])[C:10]=2[N:9]2[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]=12
Reactant: OB(O)c1ccc(F)c(F)c1F
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(F)c(F)c4F)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, white solid (17 mg, 19%), MS (ISP) m/z=356.5 [(M+H)+], mp 238° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 2,3,4-trifluoro-phenylboronic acid (57.2 mg, 0.325 mmol).
Reaction SMILES: Br.[O:2]=[C:3]1[CH:7]=[C:6]([C@@H:8]2[CH2:13][CH2:12][N:11](C(OC)=O)[C@@H:10]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[CH2:9]2)[O:5][NH:4]1>>[F:28][C:25]([F:26])([F:27])[C:22]1[CH:21]=[CH:20][C:19]([CH2:18][C@H:10]2[CH2:9][C@H:8]([C:6]3[O:5][NH:4][C:3](=[O:2])[CH:7]=3)[CH2:13][CH2:12][NH:11]2)=[CH:24][CH:23]=1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(C(F)(F)F)cc1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@@H](Cc3ccc(C(F)(F)F)cc3)C2)o[nH]1
Reaction time: 8 h
Yield: 64 %

Procedure:
Hydrogen bromide (33% in acetic acid, 5 mL) was added to a reaction flask containing (2R,4R)-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (87 mg, 0.23 mmol). The reaction was stirred vigorously overnight. The solvent was evaporated. Purification using PrepLC (pH=11, small column, sample dissolved in MeOH, gradient 5-45, 20 min) yielded 5-((2R,4R)-2-(4-(trifluoromethyl)benzyl)piperidin-4-yl)isoxazol-3(2H)-one (48 mg, 65%). 1H NMR (600 MHz, cd3od) δ 1.74-1.80 (m, 1H), 1.99-2.13 (m, 3H), 2.94 (dd, 1H), 2.98-3.05 (m, 2H), 3.19-3.26 (m, 2H), 3.36-3.42 (m, 1H), 5.50 (s, 1H), 7.42 (d, 2H), 7.62 (d, 2H). HRMS Calcd for [C16H17F3N2O2+H]+: 327.1320. Found: 327.1289.