Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=CCCCCCC.B1[CH:14]2[CH2:15][CH2:16][CH2:17][CH:10]1[CH2:11][CH2:12][CH2:13]2.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:26]([N:33]1[CH2:38][CH:37]([C:39]2[CH:44]=[CH:43][C:42](Br)=[CH:41][CH:40]=2)[O:36][CH2:35][CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:26]([N:33]1[CH2:34][CH2:35][O:36][CH:37]([C:39]2[CH:44]=[CH:43][C:42]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:10])=[CH:41][CH:40]=2)[CH2:38]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: B1C2CCCC1CCC2
Reactant: Brc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Solvent: C=CCCCCCC
Product: CCCCCCCCc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
To a solution of 1-octene (2.12 mL, 13.5 mmol) in THF (50 mL) was added 9-BBN (4.3 g, 17.6 mmol), at 0° C. The reaction mixture was allowed to warm to RT and stirred overnight. Subsequently, K3PO4 (7.6 g, 35.8 mmol) was added, followed, after 45 minutes, by 4-benzyl-6-(4-bromo-phenyl)-morpholine (3.0 g, 9 mmol), palladium(II) acetate (80 mg; 4 mol %), and dicyclohexyl-(2′,6′-dimethoxy-biphenyl-2-yl)-phosphane (296 mg; 8 mol %). The resulting mixture was heated under reflux for 2 hours. After cooling to RT the mixture was concentrated in vacuo, the residue dissolved in EtOAc, and washed with 5% aqueous NaHCO3 solution. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O:hexanes, 1:1) to afford 4-benzyl-2-(4-octyl-phenyl)-morpholine (2.58 g).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][C:23]#[N:24].O>CN(C)C=O>[C:23]([CH2:22][CH2:21][CH2:20][CH2:19][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])=[C:3]1[N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1)#[N:24]
Reactant: Cc1c(-n2ccnc2)[nH]c2ccccc12
Reactant: N#CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-n2ccnc2)n(CCCCC#N)c2ccccc12
Reaction time: 0.5 h

Procedure:
A solution of 3-methyl-2-(1-imidazolyl)-indole (2.0 g) in 12 ml of dimethylformamide is added to a suspension of 0.6 g of 50% sodium hydride (dispersion in mineral oil) in 6 ml of dimethylformamide at 0°. The mixture is stirred at 0° for 0.5 hour and is treated with a solution of 1.8 g of 5-bromovaleronitrile in 4 ml of dimethylformamide. This mixture is stirred at room temperature overnight and is poured into 125 ml of water. This is extracted with 2×50 ml of ethyl acetate, the extract is washed with water and dried over magnesium sulfate to give 1-(4-cyanobutyl)-3-methyl-2-(1-imidazolyl)-indole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.[CH3:13][C:14]1[CH:15]=[C:16]([CH3:31])[N:17]=[C:18]([NH:20][S:21]([C:24]2[CH:25]=[CH:26][C:27]([NH2:30])=[CH:28][CH:29]=2)(=[O:23])=[O:22])[N:19]=1.C(N(CC)CC)C.C(N=C=NC(C)C)(C)C>C(Cl)(Cl)Cl>[CH3:31][C:16]1[CH:15]=[C:14]([CH3:13])[N:19]=[C:18]([NH:20][S:21]([C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:10](=[O:12])[CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[CH:28][CH:29]=2)(=[O:23])=[O:22])[N:17]=1
Reactant: Cc1cc(C)nc(NS(=O)(=O)c2ccc(N)cc2)n1
Reactant: COc1ccccc1CC(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccccc1CC(=O)Nc1ccc(S(=O)(=O)Nc2nc(C)cc(C)n2)cc1
Yield: 40 %

Procedure:
2-Methoxyphenylacetic acid (33 mg, 0.20 mmol) and sulfamethazine (55 mg, 0.20 mmol) were dissolved in 4 ml of chloroform. Triethylamine (70 μl, 0.55 mmol) and diisopropylcarbodiimide (50 μl, 0.20 mmol) were added to the reaction mixture. Solution was stirred and refluxed overnight. The reaction mixture was then evaporated to dryness, washed with water and purified on silica using gradient elution (chloroform to 2% methanol in chloroform) to obtain white crystals with the yield of 40%. 1H NMR (CDCl3, 500 MHz): 8.04 (2H, m), 7.54 (2H, m), 7.30 (2H, m), 6.98 (2H, m), 6.60 (1H, s), 3.95 (3H, s), 3.72 (2H, s), 2.33 (6H, s); MS (ESI+): m/z 449 (M+Na)+, 427 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]=[C:7]([C:14]([CH3:16])=O)[C:8]([O:10][CH2:11][CH2:12][CH3:13])=[O:9])=[CH:4][CH:3]=1.[CH3:19][NH:20]/[C:21](/[CH3:29])=[CH:22]\[C:23]([O:25][CH2:26][CH2:27][CH3:28])=[O:24]>CC(O)CC>[Br:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]2[C:22]([C:23]([O:25][CH2:26][CH2:27][CH3:28])=[O:24])=[C:21]([CH3:29])[N:20]([CH3:19])[C:14]([CH3:16])=[C:7]2[C:8]([O:10][CH2:11][CH2:12][CH3:13])=[O:9])=[CH:4][CH:3]=1
Reactant: CCCOC(=O)/C=C(/C)NC
Reactant: CCCOC(=O)C(=Cc1ccc(Br)cc1)C(C)=O
Solvent: CCC(C)O
Product: CCCOC(=O)C1=C(C)N(C)C(C)=C(C(=O)OCCC)C1c1ccc(Br)cc1

Procedure:
A solution of 6.22 g (0.02 mol) of propyl 2-(4-bromobenzylidene)acetoacetate and 3.14 g (0.02 mol) of propyl 3-methylamino-crotonate in 25 ml of 2-butanol is stirred under reflux for 10 hours. The mixture is then concentrated in vacuo, and the precipitate formed in the cold is filtered off with suction. After recrystallization from propanol, 5.32 g (59.1% of theory) of melting point 97°-99° C. are obtained.
Reaction SMILES: [C:1](O[K])(C)(C)C.[CH3:7][O:8][C:9]1[CH:10]=[N:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([CH:19]=O)[C:17]=2[N:18]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCOCC>[CH3:7][O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17](=[C:16]([CH:19]=[CH2:1])[CH:15]=[CH:14][CH:13]=2)[N:18]=1
Reactant: COc1cnc2cccc(C=O)c2n1
Reactant: CC(C)(C)O[K]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=Cc1cccc2ncc(OC)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A suspension of methyltriphenylphosphonium bromide (22.78 g) in THF (200 mL) was treated with tBuOK (7.15 g) and further stirred at rt for 1 h. The mixture was cooled to 0° C. and treated with a solution of 3-methoxy-5-quinoxalinecarboxaldehyde (10.0 g; prepared according to WO 2006/021448) in THF (100 mL). The mixture was further stirred at rt for 3 h, diluted with ether and washed with water and an aq. sat. NH4Cl solution. The org. phase was dried over MgSO4 and concentrated under reduced pressure. The residue was crystallized from ether and the crystals were filtered off. The mother liquor was purified by CC (Hex/EA 1:1), affording a light orange solid (8.70 g; 88% yield).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)=[CH:13][CH:12]=[C:11]2[CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[C:6]([CH3:32])[CH:5]=1)(=[O:3])[NH2:2].O.[OH-].[Li+]>C1COCC1.O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:17][CH:16]=3)=[CH:13][CH:12]=[C:11]2[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[C:6]([CH3:32])[CH:5]=1)(=[O:3])[NH2:2]
Reactant: CCOC(=O)CCc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(C(N)=O)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(N)=O)ccc1-n1c(CCC(=O)O)ccc1-c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a solution of ethyl 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(methylsulfonyl)phenyl)-1H-pyrrol-2-yl)propanoate (28C) (100 mg, 0.22 mmol) in THF/H2O (v/v=1/1, 1 mL) was added lithium hydroxide monohydrate (18 mg, 0.44 mmol) and stirred overnight at room temperature. THF was evaporated in vacuum and the resulting aqueous solution was acidified with 10% hydrochloric acid to pH=4.0. The resulting precipitate was separated by centrifuge, rinsed with distilled water and purified by prep-HPLC to afford 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(methylsulfonyl)phenyl)-1H-pyrrol-2-yl)propanoic acid (28D) as a light green solid (30 mg, 32%).
Reaction SMILES: [CH2:1]([CH:3]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:4][N:5]([SiH:14]([O:17][CH3:18])[O:15][CH3:16])[CH2:6][CH:7]([CH2:12][CH3:13])[CH2:8][CH2:9][CH2:10][CH3:11])[CH3:2].C([Mg]Cl)(C)C.C(C(CCCC)CNCC(CC)CCCC)C.[F:45][C:46]([F:57])([F:56])[CH2:47][CH2:48][Si](OC)(OC)OC>C1COCC1>[F:45][C:46]([F:57])([F:56])[CH2:47][CH2:48][Si:14]([N:5]([CH2:6][CH:7]([CH2:12][CH3:13])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH:3]([CH2:1][CH3:2])[CH2:19][CH2:20][CH2:21][CH3:22])([O:17][CH3:18])[O:15][CH3:16]
Reactant: CO[Si](CCC(F)(F)F)(OC)OC
Reactant: CCCCC(CC)CN(CC(CC)CCCC)[SiH](OC)OC
Agent: CC(C)[Mg]Cl
Agent: CCCCC(CC)CNCC(CC)CCCC
Solvent: C1CCOC1
Product: CCCCC(CC)CN(CC(CC)CCCC)[Si](CCC(F)(F)F)(OC)OC
Temperature: 15 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
3,3,3-Trifluoropropyl(bis(2-ethylhexyl)aminodimethoxysilane--A 500 mL round bottomed flask was charged with tetrahydrofuran (300 mL) and isopropylmagnesium chloride (25 mL of a 2.0 M solution in THF, 50 mmol). The contents were cooled to 15° C. Bis(2-ethylhexyl)amine (50 mmol) was added over fifteen minutes via pressure equalizing addition funnel. The cold bath was removed and the contents stirred for two hours. 3,3,3-Trifluoropropyltrimethoxysilane (45 mmol) was added via pressure equalizing addition funnel. The contents were brought to reflux (65-70° C.) for two hours, and reaction progress was monitored by GC. Isolation was accomplished by removing the THF via rotary evaporation, taking the residue up in ether (250 mL), filtration and ether removal via rotary evaporation. Purification was accomplished by distillation to provide 3,3,3-trifluoropropyl bis(2-ethylhexyl)aminodimethoxysilane (44 mmol; 98% yield). C21H44NO2SiF3 (mw=427.66) bp=200° C. at 1.4 mmHg; 1H NMR: (CDCl3) δ 3.5 (s, 6H), 2.6-2.4 (dd, 4H), 2.2-2.0 (m, 2H), 1.6-1.1 (m, 18H), 1.0-0.7 (m, 14H); 13C NMR: (CDCl3) δ 128 (quartet, J=275 Hz), 50.4, 48.5, 39.4, 36.9, 30.8, 29.1, 28.2 (quartet, J=30 Hz), 23.2, 14.2, 10.3, 3.2; MS: m/z (relative abundance) 328 (100), 230 (25.6), 155 (7.4), 109 (2.9).
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:18])[S:17][C:13]=2[C:12]([C@@H:19]([OH:46])[CH2:20][N:21](CC2C=CC=CC=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH:47]([OH:49])=[O:48]>[Pd]>[CH:47]([OH:49])=[O:48].[OH:8][C:9]1[C:14]2[NH:15][C:16](=[O:18])[S:17][C:13]=2[C:12]([C@@H:19]([OH:46])[CH2:20][NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:11][CH:10]=1
Reactant: O=c1[nH]c2c(OCc3ccccc3)ccc([C@@H](O)CN(CCCCCCOCCCCc3ccccc3)Cc3ccccc3)c2s1
Agent: [Pd]
Solvent: O=CO
Product: O=c1[nH]c2c(O)ccc([C@@H](O)CNCCCCCCOCCCCc3ccccc3)c2s1
Reaction time: 8 h

Procedure:
4-(Benzyloxy)-7-((1R)-2-{benzyl[6-(4-phenylbutoxy)hexyl]amino}-1-hydroxyethyl)-1,3-benzothiazol-2(3H)-one (7.4 mg) was dissolved in 98% formic acid (0.5 ml)and palladium black catalyst (4 mg) added. After stirring for 8 h, the catalyst was removed by filtration through celite and the filtrate evaporated in vacuo. The residue was purified on mass directed autoprep, to give the title compound (0.51 mg). LCMS RT=2.95 min. ES+ve 459 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[C:5]([NH2:8])=[N:6][CH:7]=1.CC([O-])=O.[K+].[Li+].[Cl-].[CH3:17][Si:18]([CH3:23])([CH3:22])[C:19]#[C:20][CH3:21]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:20]([CH3:21])=[C:19]([Si:18]([CH3:23])([CH3:22])[CH3:17])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)cc1I
Reactant: CC#C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c([Si](C)(C)C)[nH]c2ncc(Br)cc12
Temperature: 90 °C

Procedure:
To a solution of 5-bromo-3-iodopyridin-2-amine (B-5-2) (30 g, 0.1 mol) in DMF (600 mL) were added KOAc (29.4 g, 0.3 mol) and LiCl (4.25 g, 0.1 mol). After the mixture was degassed under N2 for 3 times, Pd(OAc)2 (2.24 g, 0.01 mol) was added, and the mixture was degassed again. Then trimethyl-prop-1-ynyl-silane (56 g, 0.5 mol) was added. The resulting mixture was heated to 80-100° C. for 2 days. TLC (EtOAc: Petroleum ether=1:5) showed that the reaction was complete. Excess DMF was removed under reduced pressure. The residue was dissolved in EtOAc (500 mL), washed with saturated aqueous NaCl, dried over Na2SO4 and concentrated to give crude product, which was purified via a silica gel column chromatography (100-200) (Petroleum ether, then EtOAc:Petroleum ether=1:10) to give 5-bromo-3-methyl-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridine (B-5-3) (not pure, 5 g, 17.7%) as a brown oil.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:16]3[C:15]4[CH2:17][NH:18][CH2:19][CH2:20][C:14]=4[NH:13][C:12]=3[N:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.C(N(CC)CC)C>ClCCCl>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:18]2[CH2:19][CH2:20][C:14]3[NH:13][C:12]4[N:11]=[CH:10][CH:9]=[C:8]([NH:7][C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[C:16]=4[C:15]=3[CH2:17]2)=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: c1ccc(Nc2ccnc3[nH]c4c(c23)CNCC4)cc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(c1ccc(F)cc1)N1CCc2[nH]c3nccc(Nc4ccccc4)c3c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
Phenyl-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (25 mg, 0.09 mmol), 4-fluorobenzoyl chloride (18 mg, 0.11 mmol), and triethylamine (0.04 mL, 0.28 mmol) were dissolved in 1,2-dichloroethane (2.0 mL), and stirred overnight at room temperature. The reaction mixture was added directly to a Biotage column. The crude product was purified via Biotage eluting with CH2Cl2/MeOH (9/1, v/v) to provide 7 (33 mg, 90% yield) as a tan solid. LC-MS (M+H=388, obsd.=388).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH2:10][CH2:11][OH:12])=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:3]=1.[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[O:9][CH2:10][CH2:11][O:12][C:6]=2[N:7]=1
Reactant: OCCOc1c(Cl)nc(Cl)nc1N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1nc2c(c(N3CCOCC3)n1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a solution of 2-(2,4-dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-ethanol (145 mg, 0.49 mmol) in THF (5 mL) was added sodium hydride (59 mg, 1.50 mmol, 60% dispersion in mineral oil) and the resulting mixture stirred at RT for 30 minutes. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo affording 2-Chloro-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine as a white solid (114 mg, 90%). LCMS: RT=2.62 min, [M+H]+=258/260.
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@H:18]3[CH2:23][CH2:22][CH2:21][C:20]([F:25])([F:24])[C@@H:19]3[NH:26][C:27]([C:29]3[S:30][C:31]([CH2:43][CH3:44])=[C:32]([C:34]4[N:38]5[N:39]=[CH:40][CH:41]=[CH:42][C:37]5=[N:36][CH:35]=4)[CH:33]=3)=[O:28])C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[NH2:17][C@@H:18]1[C@@H:19]([NH:26][C:27]([C:29]2[S:30][C:31]([CH2:43][CH3:44])=[C:32]([C:34]3[N:38]4[N:39]=[CH:40][CH:41]=[CH:42][C:37]4=[N:36][CH:35]=3)[CH:33]=2)=[O:28])[C:20]([F:25])([F:24])[CH2:21][CH2:22][CH2:23]1
Reactant: CCc1sc(C(=O)N[C@@H]2[C@@H](NC(=O)OCC3c4ccccc4-c4ccccc43)CCCC2(F)F)cc1-c1cnc2cccnn12
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CCc1sc(C(=O)N[C@@H]2[C@@H](N)CCCC2(F)F)cc1-c1cnc2cccnn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
9H-Fluoren-9-ylmethyl[(1S,2R)-2-({[5-ethyl-4-(imidazo[1,2-b]pyridazin-3-yl)thiophen-2-yl]carbonyl}amino)-3,3-difluorocyclohexyl]carbamate (168 mg, 0.268 mmol) was dissolved in DMF (2.68 mL) and piperidine added (0.265 mL, 2.68 mmol). The solution was stirred at room temperature for 2 h. The solution was then subjected to prep HPLC for purification. The compound was neutralized by taking the fractions and adding an aqueous saturated sodium bicarbonate solution and extracting three times with dichloromethane. The combined organics were dried with magnesium sulfate, filtered, and concentrated to afford the title compound as a yellow solid. 1H NMR (500 MHz, CD3SOCD3) δ 8.61 (d, 1H); 8.41 (d, 1H); 8.21 (d, 1H); 8.19 (s, 1H); 7.95 (s, 1H); 7.29 (dd, 1H); 4.07 (m, 1H); 2.86 (m, 1H); 2.85 (q, 2H); 2.07 (m, 1H); 1.88 (m, 1H); 1.86 (m, 1H); 1.70 (m, 1H); 1.36 (m, 2H); 1.21 (t, 3H). LRMS (APCI) calc'd for (C19H21F2N5OS) [MA-1]+, 406.1. found 406.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]=[C:6]([CH:12]=O)[C:5]2=[O:14].[NH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[NH2:16].[OH-].[K+].Cl>C(O)(C)C.C(Cl)Cl.O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([OH:8])=[C:4]([C:5]([C:6]2[CH:12]=[N:16][N:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:7]=2)=[O:14])[CH:3]=1
Reactant: NNc1ccccn1
Reactant: O=Cc1coc2ccc(Br)cc2c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)O
Product: O=C(c1cnn(-c2ccccn2)c1)c1cc(Br)ccc1O
Reaction time: 0.25 h
Yield: 99.5 %

Procedure:
To a suspension of 6-bromo-3-formylchromone (253 mg) in isopropanol (3 mL) and CH2Cl2 (2 mL) was added 2-hydrazinopyridine (109 mg), and the mixture was stirred for 15 min to form a yellow slurry. The slurry was added KOH (0.25 g) in water (0.25 mL), and the reaction was heated to reflux for 1 h. The reaction mixture was diluted with water, added 3% HCl until pH<1 and extracted with CH2Cl2 (2×). The extract was washed with water and brine, dried (MgSO4) and concentrated to give 342 mg orange foam, which was purified by flash chromatography (SiO2, EA:Hep, 1:1) to give 53 mg (15%) yellow solid: LC/MS (an10p8): Rt 5.0 min, m/z 343.5 [M+H]+; 1H NMR (CDCl3): δ 6.98 (d, J=8.9 Hz, 1H), 7.31 (ddd, J=7.3, 4.9, 0.9 Hz, 1H), 7.60 (dd, J=8.9, 2.5 Hz, 1H), 7.87-7.93 (m, 1H), 8.03 (d, J=2.4 Hz, 1H), 8.04-8.09 (m, 1H), 8.02 (s, 1H), 8.47-8.51 (m, 1H), 9.13 (s, 1H), 11.94 (s, 1H); 13C NMR (CDCl3): δ 110.9, 113.3, 120.8, 121.6, 122.8, 123.1, 130.5, 133.5, 138.9, 139.3, 143.3, 148.7, 161.9, 191.4.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:49])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[CH2:33][CH2:34]C=C)[CH:22]4[CH2:24][CH2:23]4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:37])[C:12]=2[C@H:38]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[BH4-].[Na+]>C(Cl)Cl.O>[C:45]([O:44][C@@H:38]([C:12]1[C:13]([CH3:37])=[N:14][C:15]2=[CH:19][C:18]3=[N:17][N:16]2[C:11]=1[N:8]1[CH2:7][CH2:6][C:5]([CH3:49])([O:4][CH2:1][CH2:2][CH2:3][CH2:34][CH2:33][C:27]2[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=2[CH2:25][N:21]([CH:22]2[CH2:23][CH2:24]2)[CH2:20]3)[CH2:10][CH2:9]1)[C:39]([O:41][CH2:42][CH3:43])=[O:40])([CH3:46])([CH3:48])[CH3:47]
Reactant: C=CCCc1cc(F)ccc1CN(Cc1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N3CCC(C)(OCC=C)CC3)n2n1)C1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCCCc1cc(F)ccc1CN(C1CC1)C3
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
A mixture of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((2-(but-3-en-1-yl)-4-fluorobenzyl)(cyclopropyl)amino)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (45 mg, 0.067 mmol) and Grubb's II catalyst (5.65 mg, 6.66 μmol) in DCM (45 mL) was refluxed for 2 h. It was then concentrated and the residue was dissolved in MeOH (2 mL). NaBH4 (2.52 mg, 0.067 mmol) was added and the reaction mixture was stirred at rt for 1 h. It was then diluted with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil. It was then purified by biotage, eluting with 25% EtOac/hexane to obtain ethyl (2S)-2-(tert-butoxy)-2-{11-cyclopropyl-16-fluoro-4,25-dimethyl-24-oxa-1,5,7,8,11-pentaazapentacyclo[23.2.2.16,9.02,7.013,18]triaconta-2,4,6(30),8,13(18),14,16-heptaen-3-yl}acetate (35 mg, 0.054 mmol, 81% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.14 (dd, J=8.4, 6.1 Hz, 1H), 6.90 (dd, J=10.3, 2.8 Hz, 1H), 6.77 (td, J=8.4, 2.8 Hz, 1H), 6.48 (s, 1H), 6.10 (s, 1H), 4.58-4.48 (m, 1H), 4.28-4.21 (m, 1H), 4.18-4.12 (m, 1H), 4.04 (d, J=1.0 Hz, 2H), 3.96-3.83 (m, 2H), 3.62 (d, J=13.8 Hz, 1H), 3.44-3.33 (m, 2H), 3.06-2.98 (m, 1H), 2.90-2.72 (m, 3H), 2.68-2.60 (m, 3H), 2.03-1.85 (m, 3H), 1.79-1.62 (m, 8H), 1.30-1.21 (m, 19H). LCMS (M+1)=650.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+]>C1COCC1>[OH:10][CH2:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=1
Reactant: COc1cccc(C=O)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(CO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To 6-methoxy-pyridine-2-carbaldehyde (J. Org. Chem. 1990, 55, 69-73) (11.0 g, 80.3 mmol) in wet THF (200 mL) add portion wise with stirring sodium borohydride (3.0 g, 79 mmol) and continue stirring for 1 h at ambient temperature. Add brine, extract the reaction mixture twice with EtOAc, dry the organic layer over anhydrous Na2SO4 and concentrate in vacuo. Pass the residue through a small plug of silica gel eluting with hexane/EtOAc (3:1) to provide the desired intermediate as a clear liquid (9.0 g, 81%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]([CH3:29])([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[C:19]#[C:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:8])[CH3:5]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:30])[C:4]([CH3:5])([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:8])[CH3:29]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1C#CCCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1CCCCc1ccccc1
Reaction time: 6 h
Yield: 95 %

Procedure:
50 mg of 2-methyl-2-{[1-(4-phenyl-but-1-ynyl)-naphthalene-2-carbonyl]-amino}-propionic acid methyl ester were dissolved in 5 ml methanol, and after addition of 10 mg of Pd/C (10%) hydrogenated for 6 h. The reaction was then filtrated and the filtrate was concentrated to yield 48 mg of 2-methyl-2-{[1-(4-phenyl-butyl)-naphthalene-2-carbonyl]-amino}-propionic acid methyl ester.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][C@@H:10]([CH3:15])[C@@H:9]1[C:16]([OH:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:23][CH2:24]O>>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][C@@H:10]([CH3:15])[C@@H:9]1[C:16]([O:18][CH2:23][CH3:24])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1OCC(=O)N(Cc2ccccc2)[C@H]1C(=O)O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@H]1[C@H](C)OCC(=O)N1Cc1ccccc1
Temperature: 20 °C
Reaction time: 72 h
Yield: 61.4 %

Procedure:
A round-bottomed flask equipped with a magnetic stirrer was added (2S,3R)-4-benzyl-2-methyl-5-oxomorpholine-3-carboxylic acid (1 g, 4.01 mmol), EtOH (20 ml), thionyl chloride (1.155 ml, 16.05 mmol). The reaction was stirred at 20° C. for 72 hours. Concentrate in vacuo to afford a crude oil. The oil was purified by silica gel column chromatography (eluting with 20% EtOAc in Hexanes using the Moritex SI-60 size 60—half column). The resultant fractions were collected and concentrated in-vacuo to afford (2S,3R)-ethyl 4-benzyl-2-methyl-5-oxomorpholine-3-carboxylate (683 mg, 2.46 mmol, 61.4% yield) as a white solid. MS [M+H] found 278.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@H:4](/[CH:5]=[C:6]2/[C:7](=[O:11])[O:8][CH2:9][CH2:10]/2)[C@H:3]1[C:12]([OH:14])=[O:13].[CH:16](NC(=NC(C)C)OC(C)C)([CH3:18])[CH3:17]>C(O)C>[CH3:1][C:2]1([CH3:15])[C@H:4](/[CH:5]=[C:6]2/[C:7](=[O:11])[O:8][CH2:9][CH2:10]/2)[C@H:3]1[C:12]([O:14][CH:16]([CH3:18])[CH3:17])=[O:13]
Reactant: CC(C)N=C(NC(C)C)OC(C)C
Reactant: CC1(C)[C@H](/C=C2\CCOC2=O)[C@H]1C(=O)O
Solvent: CCO
Product: CC(C)OC(=O)[C@@H]1[C@@H](/C=C2\CCOC2=O)C1(C)C

Procedure:
Using the procedure of Example 17, 4 g of (1R,trans) 2,2-dimethyl-3-[(E) (dihydro-2-oxo-3(2H)-furanylidene)-methyl]-cyclopropane-1-carboxylic acid and 5 ml of isopropyl N,N'-diisopropylcarbamimidate were reacted to obtain 3.5 g of isopropyl (1R,trans) 2,2-dimethyl-3-[(E) (dihydro-2-oxo-3-(2H)-furanylidene)-methyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+38.5°±1.5° (c=1% in ethanol).