Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([F:18])([F:17])[CH:14]([F:16])[F:15])=[CH:7][N:6]=1)=[O:4].[OH-].[Li+].Cl>C1COCC1.O>[F:18][C:13]([F:17])([CH:14]([F:16])[F:15])[CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCC(F)(F)C(F)F)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCC(F)(F)C(F)F)cn1
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
To a solution of 5-(2,2,3,3-tetrafluoro-propoxy)-pyridine-2-carboxylic acid methyl ester (2.6 g) in THF (20 ml) and water (15 ml) was added lithium hydoxide solution (1 M, 19.4 ml) and the reaction mixture was stirred at 22° C. for 30 min. The reaction mixture was neutralised by addition of aqueous HCl (1 N, 19.4 ml), the organic solvent was evaporated, the suspension obtained still containing water was filtered and the residue was dried to give 5-(2,2,3,3-tetrafluoro-propoxy)-pyridine-2-carboxylic acid (2.3 g) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][CH3:12])=[O:10].C(=O)(O)[O-].[Na+].[CH3:18][S:19][CH2:20]Cl.NC(N)=O>CC(C)=O>[CH3:12][N:11]([CH2:18][S:19][CH3:20])[C:9]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:10]
Reactant: CNC(=O)Nc1ccccc1F
Reactant: CSCCl
Agent: NC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CSCN(C)C(=O)Nc1ccccc1F
Reaction time: 2 h

Procedure:
To a stirred slurry of 16.8 g. (0.1 mol) of N-(2-fluorophenyl)-N'-methyl urea, dissolved in 500 ml. of acetone containing 9.24 g. (0.11 mol) of sodium bicarbonate was added 10.6 g. ((0.11 mol) of chloromethyl methyl sulfide. The resulting mixture was stirred for 2 hours at a gentle reflux. The precipitated solid was removed by filtration. The filtrate was evaporated to give a clear oil. Crystallization from benzene gave 7.1 g. of the original urea. The filtrate from this crystallization was evaporated and the residue crystallized from diethylether to give 3.4 g. of a crystalline solid product, melting point 81°-82°C. Analysis calculated for C10H13FN2OS: S, 14.03%; F, 8.32%. Found: S, 14.02%; F, 8.43%. The infrared spectrum showed strong adsorption at 3.0, 6.9, 7.3 and 13.0μ. The NMR spectra was consistent with the assigned structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[Si](C=[N+]=[N-])(C)(C)[CH3:14]>C1COCC1.CO>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)Cc1ccc(O)c(F)c1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(O)c(F)c1
Reaction time: 1 h
Yield: 64.6 %

Procedure:
2-(3-Fluoro-4-hydroxyphenyl)acetic acid (1.0 g, 5.88 mmol) was diluted with THF:MeOH (3:1) (10 mL) followed by the addition of TMSCHN2 (5.88 ml, 11.8 mmol). After stiffing for 1 hour, the reaction was quenched with 2N HCl and diluted with DCM. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified by silica gel chromatography, eluting with hexanes:ethyl acetate (2:1) to yield methyl 2-(3-fluoro-4-hydroxyphenyl)acetate (700 mg, 64.7% yield) as a clear oil.
Reaction SMILES: [CH:1]1([N:4]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][N:38]3[CH2:42][C@@H:41]([C:43]4[CH:54]=[CH:53][C:46]5[O:47][C:48]([CH3:52])([CH3:51])[O:49][CH2:50][C:45]=5[CH:44]=4)[O:40]C3=O)[CH:22]=2)(=[O:14])=[O:13])C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.C[Si](C)(C)[O-].[K+].P([O-])([O-])([O-])=O>C1COCC1>[CH:1]1([NH:4][S:12]([C:15]2[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][NH:38][CH2:42][C@@H:41]([C:43]4[CH:54]=[CH:53][C:46]5[O:47][C:48]([CH3:51])([CH3:52])[O:49][CH2:50][C:45]=5[CH:44]=4)[OH:40])[CH:22]=3)=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:13])=[O:14])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N(C1CC1)S(=O)(=O)c1ccccc1-c1cccc(COCCOCCCCCCN2C[C@@H](c3ccc4c(c3)COC(C)(C)O4)OC2=O)c1
Agent: C[Si](C)(C)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCOCc3cccc(-c4ccccc4S(=O)(=O)NC4CC4)c3)ccc2O1
Yield: 60.6 %

Procedure:
A stirred mixture of 1,1-dimethylethyl cyclopropyl{[3′-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)-1,1′-biphenyl-2-yl]sulfonyl}carbamate (260 mg) and potassium trimethylsilanolate (420 mg) in THF (10 ml) was heated under reflux for 2 h. The mixture was cooled to 20°, poured into phosphate buffer solution (pH6.5, 50 ml) and extracted with EtOAc (3×30 ml). The combined organic extracts were washed with water (50 ml), dried (MgSO4) and the solvent evaporated in vacuo to give a residue which was purified by Biotage. Elution with dichloromethane-ethanol-ammonia (100:8:1) gave the title compound (132 mg). LCMS RT=3.06 min, ES+ve 653 (MH)+.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH:16]=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(O[C:21](=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])C>C(O)(=O)C.C1C=CC=CC=1.[Zn]>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][N:26]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]3=[O:27])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCCCN
Reactant: O=CC1c2ccccc2CCc2ccccc21
Agent: [Zn]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: O=C1CCCCN1CC1c2ccccc2CCc2ccccc21

Procedure:
By subjecting a mixture of 10,11-dihydro-5H-dibenzo-[a,d]cycloheptene-5-carboxaldehyde (2.2 g), described in Example 168, and 5-aminovaleric acid ethyl ester (1.45 g) and zinc dust (3.0 g) in 3.0 ml of acetic acid and 100 ml of benzene, to a two hour reflux, followed by removal of the excess zinc by filtration, addition of dilute sodium hydroxide solution to render the mixture alkaline and extraction with benzene affords the cyclic amide, N-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methyl]-2-piperidone, γmaxCHCl3 1650 cm-1, as an oil. Further treatment of this oil according to the conditions of the Bischler-Napieralski reaction described in Example 2, yields a product identical with the quaternary salt, 1,3,4,5,6,10,11,15b-octahydrobenzo[6,7]cyclohepta[1,2,3-de]pyrido[2,1-a]isoquinolinium chloride obtained in Example 2.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[C:8]=2[C:12]([F:15])([F:14])[F:13])[C:3]=1[C:18]([N:20]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:19]>C(O)=O.O>[CH2:32]([O:31][C:29]([N:20]([C:18]([C:3]1[C:4]2[C:9](=[C:8]([C:12]([F:13])([F:15])[F:14])[C:7]([O:16][CH3:17])=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[F:1])=[O:19])[CH2:21][C:22]([OH:24])=[O:23])=[O:30])[CH3:33]
Reactant: CCOC(=O)N(CC(=O)OC(C)(C)C)C(=O)c1c(F)ccc2c(C(F)(F)F)c(OC)ccc12
Solvent: O
Solvent: O=CO
Product: CCOC(=O)N(CC(=O)O)C(=O)c1c(F)ccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.2 %

Procedure:
A suspension of N-[[2-fluoro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-(ethoxycarbonyl)glycine, 1,1-dimethylethyl ester (2.40 g, 5.07 mmol) in formic acid (90 mL) was stirred at room temperature under a dry nitrogen atmosphere. After 10 minutes, dissolution occurred. After 11/2 hours, the reaction solution was diluted with water (1 L). The resultant suspension was stirred rapidly for 45 minutes, then filtered. The solid was washed with water (3×20 mL), air dried, and recrystallized from benzene:petroleum ether to provide the title compound as white needles (1.21 g, 57%), m.p. 135.5°-138° C.
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:15])(=[NH:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Br:16][C:17]1[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:18]=1[N:24]=[C:25]=[S:26]>C1C=CC=CC=1.CCCCCC>[Br:16][C:17]1[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:18]=1[NH:24][C:25]([NH:14][C:7](=[NH:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[S:26]
Reactant: CCCCCCC(=N)N
Reactant: S=C=Nc1ccc(Br)cc1Br
Agent: Cl
Agent: [Na]
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: CCCCCCC(=N)NC(=S)Nc1ccc(Br)cc1Br

Procedure:
Following a procedure similar to that described in Example 1 but using 2.3 g. sodium in 300 ml. dry acetone, 16.5 g. heptanamidine hydrochloride, and 29.3 g. 2,4-dibromophenyl isothiocyanate (m.p. 68°-70° C.; prepared from 2,4-dibromoaniline) in 100 ml. dry acetone there was obtained 1-(2,4-dibromophenyl)-3-(heptanimidoyl)-2-thiourea, m.p. 86°-88° C. (from benzene-n-hexane); hydrochloride (14 g.), m.p. 164°-165° C. (from acetonitrile).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][C:14](Br)=[CH:15][C:16]([CH3:17])=[C:11]2[N:10]=[C:9]1[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([Cu])#[N:22].O.[C-]#N.[K+]>N1C=CC=CC=1.CCOC(C)=O>[CH2:1]([N:8]1[C:12]2=[N:13][C:14]([C:21]#[N:22])=[CH:15][C:16]([CH3:17])=[C:11]2[N:10]=[C:9]1[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[Cu]
Reactant: CCc1nc2c(C)cc(Br)nc2n1Cc1ccccc1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCc1nc2c(C)cc(C#N)nc2n1Cc1ccccc1
Temperature: 50 °C
Yield: 93.9 %

Procedure:
A mixture of 620 mg (1.8 mmol) of the product of Step D and CuCN (806 mg, 9.0 mmol) was heated in pyridine (4 mL) at reflux for 10 hours under nitrogen. The reaction was cooled, then water (50 mL), KCN (1.17 g), and EtOAc (20 mL) were added and the mixture was heated to 50° C. for 5 min. Cooling and extraction with EtOAc (2×50 mL) gave 467 mg of the title compound as a tan solid.
Reaction SMILES: [CH2:1]1[C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[NH:3][C:2]1=[O:14])[N:10]=[CH:9][CH:8]=[CH:7]3.[Br:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([Br:25])[C:23]=1[OH:24])[CH:19]=O.[ClH:26]>C(O)(=O)C>[ClH:26].[Br:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([Br:25])[C:23]=1[OH:24])[CH:19]=[C:1]1[C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[NH:3][C:2]1=[O:14])[N:10]=[CH:9][CH:8]=[CH:7]3
Reactant: O=Cc1cc(Br)c(O)c(Br)c1
Reactant: O=C1Cc2c(ccc3ncccc23)N1
Agent: Cl
Solvent: CC(=O)O
Product: O=C1Nc2ccc3ncccc3c2C1=Cc1cc(Br)c(O)c(Br)c1
Temperature: 115 °C
Reaction time: 8 h

Procedure:
1,3-Dihydro-pyrrolo[3,2-f]quinoline-2-one (552 mg, 3.00 mmol) was combined with 855 mg (3.05 mmol) of 3,5-dibromo-4-hydroxybenzaldehyde (TCl Chemicals) in 6 mL of glacial acetic acid with 1 mL of concentrated hydrochloric acid. The reaction was stirred at 115° C. for 8 hr, cooled and filtered, washing with ethyl acetate, to give 1.32 g of 1-(3,5-Dibromo-4-hydroxy-benzylidene)-1,3-dihydro-pyrrolo[3,2-f]quinolin-2-one hydrochloride as a brown solid which consisted of a 9/1 mixture of Z/E isomers. Mass spectrum (negative ion chemical ionization): m/z=443 (40%), 445 (100%), 447 (40%). 1H NMR (DMSO-d6): δ7.69 (d, J=8.8 Hz, 1H); 7.93 (dd, J=8.7, 4.9 Hz, 1H); 8.24 (d, J=8.8 Hz, 1H); 8.27 (s, 1H); 8.80 (s, 1H); 9.04 (d, J=4.7 Hz, 1H); 9.51 (d, J=8.6 Hz, 1H); 11.3 (s, 1H).
Reaction SMILES: C(=O)([O-])O.[Na+].Br[CH2:7][C:8]([NH:10][C:11]1[C:12]([S:22][CH:23]([CH3:25])[CH3:24])=[N:13][C:14]([CH3:21])=[CH:15][C:16]=1[S:17][CH:18]([CH3:20])[CH3:19])=[O:9].[SH:26][C:27]1[O:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1>C(#N)C>[O:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[S:26][CH2:7][C:8]([NH:10][C:11]1[C:12]([S:22][CH:23]([CH3:25])[CH3:24])=[N:13][C:14]([CH3:21])=[CH:15][C:16]=1[S:17][CH:18]([CH3:20])[CH3:19])=[O:9]
Reactant: Cc1cc(SC(C)C)c(NC(=O)CBr)c(SC(C)C)n1
Reactant: Sc1nc2ccccc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cc1cc(SC(C)C)c(NC(=O)CSc2nc3ccccc3o2)c(SC(C)C)n1
Temperature: 25 °C
Reaction time: 28 h
Yield: 44 %

Procedure:
This nitropyridine (1.08 g, 3.77 mmol) was dissolved in a mixed solvent of acetic acid (35 ml) and conc. hydrochloric acid (1.6 ml), and zinc (2.96 g, 45.25 mmol) was added thereto in small portions while being cooled with ice. After the mixture was stirred for 1 hour, the reaction mixture was filtered, and the filtrate was neutralized with an aqueous solution of sodium hydrogencarbonate, and extracted with chloroform. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting residue was purified through silica gel column chromatography (eluent—hexane:ethyl acetate=30:1→10:1) to obtain 774 mg (yield 80%) of 3-amino-2,4-bis(isopropylthio)-6-methylpyridine as a yellow oil. Triethylamine (336 mg, 3.32 mmol) was added to a THF (10 ml) solution of this aminopyridine (774 mg, 3.02 mmol), and bromoacetyl bromide (732 mg, 3.62 mmol) was then slowly added thereto dropwise while being cooled with ice, and the mixture was stirred for 17 hours. The reaction mixture was filtered, and the filtrate was concentrated. Then, the residue was purified through silica gel chromatography (eluent—hexane:ethyl acetate=10:1) to obtain 595 mg (yield 52%) of 2-bromo-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]acetamide as a colorless powdery crystal. sodium hydrogencarbonate (29 mg, 0.35 mmol) was added to an acetonitrile (5 ml) solution of this amide (132 mg, 0.35 mmol) and 2-mercaptobenzoxazole (53 mg, 0.35 mmol), and the mixture was stirred at room temperature for 28 hours. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through preparative thin-layer chromatography (eluent—hexane:benzen=6:1) to obtain 69 mg (yield 44%) of the desired compound as a colorless powdery crystal.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C:10](=[O:20])[C@H:11]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH2:12].CN1CCOCC1.[CH3:28][O:29][C:30]1[CH:56]=[CH:55][C:33]([CH2:34][S:35][CH:36]([CH2:52][CH2:53][CH3:54])[C:37]([NH:39][C@H:40]([C:49](O)=[O:50])[CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:38])=[CH:32][CH:31]=1.Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1>ClCCl.CO.ClCCl>[CH3:8][NH:9][C:10](=[O:20])[C@H:11]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:12][C:49](=[O:50])[C@H:40]([CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[NH:39][C:37](=[O:38])[CH:36]([S:35][CH2:34][C:33]1[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:56][CH:55]=1)[CH2:52][CH2:53][CH3:54]
Reactant: CCCC(SCc1ccc(OC)cc1)C(=O)N[C@@H](CCc1ccccc1)C(=O)O
Reactant: CNC(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCOCC1
Product: CCCC(SCc1ccc(OC)cc1)C(=O)N[C@@H](CCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)NC
Reaction time: 0.25 h

Procedure:
Combine (L)-phenylalanine N-methyl amide trifluoroacetic acid salt (0.22 g, 0.75 mmol) and N-methylmorpholine (0.09 mL, 0.83 mmol) in dichloromethane (5 mL). After 15 minutes, add 2-(4-methoxybenzylthio)-pentanoyl-(L)-homophenylalanine (0.18 g, 0.45 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.086 g, 0.45 mmol) and hydroxybenzotriazole (0.060 g, 0.45 mmol). After 18 hours, partition the reaction mixture between ethyl acetate and an aqueous 5% sulfuric acid solution. Separate the layers, extract the organic layer with a saturated sodium bicarbonate solution and then brine. Dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 4% methanol/dichloromethane to give the title compound.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[CH:27]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>CN(C=O)C.C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:32][C:28]3[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: Nc1cccnc1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3cccnc3)nc12
Temperature: 140 °C
Yield: 28.5 %

Procedure:
A mixture of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 351 mol), pyridin-3-amine (49.5 mg, 526 mol), BINAP (10.9 mg, 17.5 mol), palladium (II) acetate (19.7 mg, 87.7 mol) and sodium tert-butoxide (84.3 mg, 877 mol) in DMF (1 mL) and toluene (500 μL) was heated in a microwave at 140° C. for 20 min. The reaction mixture was diluted with water then extracted into ethyl acetate (3×). The combined organic extracts were washed with brine then dried over magnesium sulfate. Purification by chromatography (silica, 30-70% ethyl acetate in hexanes) gave N-tert-butyl-2-(pyridin-3-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (44 mg, 99.9 mol, 28.5%) as a yellow solid. MS (EI/CI) m/z: 311.1 [M+H].
Reaction SMILES: BrC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)(=O)=O)=CC=1.[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>CS(C)=O.C(=O)(O)[O-].[Na+]>[CH3:26][C:21]1[CH:20]=[CH:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14][C@H:13]([CH2:12][N:41]4[CH2:40][CH2:39][N:38]([C:29]5[CH:30]=[CH:31][C:32]6[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=6)[CH:28]=5)[CH2:43][CH2:42]4)[O:27][C:17]3=2)[N:22]=1
Reactant: c1ccc2cc(N3CCNCC3)ccc2c1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CN1CCN(c2ccc4ccccc4c2)CC1)O3
Temperature: 50 °C
Yield: 69.8 %

Procedure:
A mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-bromobenzenesulfonate (2.73 g, 6.06 mmol) and 1-naphthalen-2-yl-piperazine (3.86 g, 18.2 mmol) in anhydrous dimethylsulfoxide (60 mL) was heated at 50° C. overnight. The cooled reaction was diluted with saturated aqueous sodium bicarbonate (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography on silica gel (2/2/95 methanol/ammonium hydroxide/methylene chloride) did not provide clean product. Re-chromatography on silica gel (90/5/5 ethyl acetate/hexane/triethylamine) afforded 1.80 g (69%) of the title compound as a beige solid: mg 134–137° C.; MS (ES) m/z426 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:15])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:12](=O)[CH3:13])[CH:8]=[C:9]([CH3:11])[CH:10]=1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[F:1][CH:2]([F:15])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]([NH:22][S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH3:13])[CH:8]=[C:9]([CH3:11])[CH:10]=1
Reactant: CC(=O)c1cc(C)cc(OCC(F)F)c1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(OCC(F)F)cc(C(C)N[S@](=O)C(C)(C)C)c1
Yield: 77 %

Procedure:
The title compound is prepared in 77% yield (0.85 g, colorless oil) from 1-(3-(2,2-difluoroethoxy)-5-methylphenyl)ethanone (1.06 g, 3.04 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15]2[C:5]([C:6]([OH:29])=[C:7]([C:18]([NH:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:19])[C:8](=[O:17])[C:9]32[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:4][C:3]=1[O:30][CH3:31]>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:16]=[C:15]2[C:5]([C:6]([OH:29])=[C:7]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[C:8](=[O:17])[C:9]32[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:4][C:3]=1[O:30][CH3:31]
Reactant: COc1cc2c(cc1Br)C1(CCOCC1)C(=O)C(C(=O)NCC(=O)OC(C)(C)C)=C2O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1Br)C1(CCOCC1)C(=O)C(C(=O)NCC(=O)O)=C2O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
A mixture of 1,1-dimethylethyl N-((7-bromo-4-hydroxy-6-(methyloxy)-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-yl)carbonyl)glycinate (0.27 g, 0.54 mmol) in 3 mL TFA was stirred at room temperature for 30 minutes, M+1=440/442. The mixture was concentrated and triturated in ether (20 mL). The solid was filtered, washed with 10 mL ether and dried under high vacuum to give 0.22 g of the product as a white solid. MS m/e=440/442 (M+H)+. Calculated for C18H18BrNO7 439.03/441.02.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3](=[O:25])[CH2:4][C@@H:5]([NH:14]C(=O)OCC1C=CC=CC=1)[CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>Br.C(O)(=O)C>[NH2:14][C@@H:5]([CH2:6][S:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:4][C:3]([N:2]([CH3:1])[CH3:26])=[O:25]
Reactant: CN(C)C(=O)C[C@H](CSc1ccccc1)NC(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: CN(C)C(=O)C[C@@H](N)CSc1ccccc1

Procedure:
A suspension of EXAMPLE 1B (10.60 g) in 50 mL 30% HBr/acetic acid was stirred at room temperature overnight. The resulting homogeneous reaction mixture was concentrated, diluted with water (200 mL) and 5% HCl (100 mL), and washed with diethyl ether (3×). The aqueous phase was adjusted to pH ˜8-9 with solid Na2CO3 and extracted with dichloromethane (5×). The combined organic phases were dried (MgSO4), filtered, and concentrated to give the desired product.
Reaction SMILES: Cl[Si](C)(C)C.[O:6]=[C:7]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:8]1.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>[Zn].C1COCC1>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][C:7]1([OH:6])[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[C@H:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:8]1)[CH3:32]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1
Reaction time: 0.25 h
Yield: 73 %

Procedure:
Zinc dust (1.05 g, 16 mmol, 1.6 eq.) in a flask was heated with a heat gun two times. Dry THF (10 mL) and chlorotrimethylsilane (0.405 mL, 3.2 mmol, 0.32 eq.) were added to this flask. The suspension was stirred for 15 min at room temp., heated to reflux, and then removed from the heat. (S)-di-tert-butyl 4-oxopyrrolidine-1,2-dicarboxylate (2.85 g, 10 mmol, 1 eq.) and ethyl 2-bromoacetate (1.77 mL, 16 mmol, 1.6 eq.) were combined with dry THF (10 mL), and added slowly to the Zinc suspension at a rate that at which a gentle reflux was observed. The reaction was refluxed for 2 hrs and monitored by TLC. Upon completion, the reaction was concentrated. Chromatography using hexanes and ethyl acetate gave 2.64 g (7.3 mmol) of (2S)-di-tert-butyl 4-(2-ethoxy-2-oxoethyl)-4-hydroxypyrrolidine-1,2-dicarboxylate (A1) as a 4:1 (2S,4S:2S,4R) mixture of the diastereomers. 1H NMR (300 MHz, DMSO) 4.97 (m, 1H), 4.14-4.01 (m, 3H), 3.48-3.33 (m, 2H), 2.56 (m, 2H), 2.35-2.19 (m, 1H), 2.03 (dd, 1H), 1.40-1.35 (m, 18H), 1.18 (t, 3H).