Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1.C(Cl)CCl.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2>ClCCl>[OH:9][C:8]1[CH:10]=[C:2]([CH:3]=[C:4]([OH:5])[C:6]=1[OH:7])[C:1]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:12]
Reactant: O=C(O)c1cc(O)c(O)c(O)c1
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(Nc1ccccc1-c1cc2ccccc2[nH]1)c1cc(O)c(O)c(O)c1

Procedure:
A 25-mL one-necked recovery flask equipped with a stirring bar and a septum was charged with gallic acid (176 mg; 1.03 mmol; 1.00 equiv). A clear, colorless solution was formed on addition of 5 mL of dichloromethane. Solid EDC (197 mg; 1.03 mmol; 1.00 equiv) and 2-(2-aminophenyl)indole (194 mg; 0.932 mmol; 0.904 equiv) were added sequentially as solids. The reaction was worked up after 24 h by extraction with 10 mL of NaHCO3 (satd aq). The organic layer was dried (anhydrous sodium sulfate), filtered and concentrated by rotary evaporation to yield a yellow oily paste. The crude was purified using DCM-MeOH (19:1) to yield a light yellow solid (230 mg; 68%).
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([CH2:31][OH:32])[CH:20]=[C:19]1[CH3:33])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].CC[O:36]CC>C(#N)C.I(O)(=O)(=O)=O.[O-2].[Cr+3].[O-2].[O-2].[Cr+3]>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[C@H:21]([C:31]([OH:36])=[O:32])[CH:20]=[C:19]1[CH3:33])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CCOCC
Agent: [Cr+3]
Agent: [O-2]
Agent: [O-][I+3]([O-])([O-])O
Solvent: CC#N
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of (2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-(hydroxymethyl)-4-methyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 18, 5 g, 10.34 mmol) in wet acetonitrile (60 mL) (0.75% by volume) at 0° C. was added dropwise the previously formed periodic acid/chromium oxide solution (60 mL, 3 eq). After 30 minutes the reaction was complete by LC/MS. The reaction mixture was diluted with ether and washed with 10% citric acid, saturated sodium bicarbonate and brine. The organics were dried over magnesium sulfate, filtered and concentrated to afford an orange foam (4.16 g, 81%).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].O=[C:7]1[CH:18]([C:19](OC)=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][C:8]21[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:4][C:3]1[N:5]=[C:19]([OH:20])[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[C:7]=2[N:2]=1
Reactant: N=C(N)N
Reactant: COC(=O)C1CCCCC2(CCCCC2)C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(O)c2c(n1)C1(CCCCC1)CCCC2
Temperature: 120 °C

Procedure:
A mixture of guanidine hydrochloride (430 mg, 4.5 mmol), the product from Example 16B (430 mg, 1.8 mmol), and potassium carbonate (623 mg, 4.5 mmol) in DMF (8 mL) was heated at 100° C. for 16 hours. Then, the temperature was raised to 120° C. for 2 hours. The mixture was cooled to ambient temperature and filtered through a layer of diatomaceous earth, then the filter pad was washed with a small amount of DMF. The filtrate was concentrated under reduced pressure, and the residue was chromatographed on silica gel (10:45:45 MeOH/CH2Cl2/EtOAc, eluant) to provide the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) ppm 10.62 (s, 1 H), 6.04 (s, 2 H), 2.57-2.64 (m, 2 H), 1.93-2.05 (m, 2 H), 1.60-1.71 (m, 4 H), 1.35-1.57 (m, 9 H), 1.15-1.28 (m, 1 H). MS (DCI+) m/z 248 (M+H).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8](Br)[CH2:9][CH2:10][CH3:11]>>[CH2:8]([N:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:9][CH2:10][CH3:11]
Reactant: C1CCCNCC1
Reactant: CCCCBr
Product: CCCCN1CCCCCC1

Procedure:
The first N-substitution of azepane was carried out using butyl bromide as an N-alkylating agent to form 1-butylazepane. An equimolar amount of butyl bromide was added dropwise to a solution of azepane in methanol keeping the temperature at 2° C. by an ice-water bath. The mixture was hydrolyzed with potassium carbonate, extracted with ether, and dried over Na2SO4. The solution was fractionally distilled at reduced pressure and the fraction with by 195° C. was collected. 1H-NMR (300 MHz, CDCl3) δ 0.90 (t, 3H), 1.28 (sextet, 2H), 1.42 (m, 2H), 1.60 (broad m, 8H), 2.42 (m, 2H), 2.60 (m, 4H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:11](=[O:33])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]1[S:25][C:26]([C:30]([NH2:32])=[O:31])=[C:27]([CH3:29])[N:28]=1)=[CH:14][CH:13]=2)(C)(C)C.[ClH:39]>C(OCC)(=O)C>[ClH:39].[NH2:7][CH2:8][C:9]1[N:10]([CH2:34][CH:35]([CH3:36])[CH3:37])[C:11](=[O:33])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]1[S:25][C:26]([C:30]([NH2:32])=[O:31])=[C:27]([CH3:29])[N:28]=1)=[CH:14][CH:13]=2
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C)c(C(N)=O)s3)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCOc1c(CN)n(CC(C)C)c(=O)c2ccc(-c3nc(C)c(C(N)=O)s3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
Tert-butyl{6-[5-(aminocarbonyl)-4-methyl-1,3-thiazol-2-yl]-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate (0.22 g, 0.4 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml). The solution was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give 2-[3-(aminomethyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-4-methyl-1,3-thiazole-5-carboxamide hydrochloride (0.18 g, 94.7%) as crystals.
Reaction SMILES: [F-].[K+].[C:3](F)([C:5]([F:31])([O:10][C:11]([F:30])([F:29])[C:12]([F:28])([O:17][C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[C:13]([F:16])([F:15])[F:14])[C:6]([F:9])([F:8])[F:7])=[O:4].F[C].[OH2:35]>COCCOCCOC>[C:20]([C:19]([C:18]([O:17][C:12]([C:11]([O:10][C:5]([C:3]([OH:4])=[O:35])([C:6]([F:7])([F:8])[F:9])[F:31])([F:30])[F:29])([C:13]([F:14])([F:16])[F:15])[F:28])([F:26])[F:27])([F:25])[F:24])([F:22])([F:23])[F:21]
Reactant: O
Reactant: O=C(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Agent: [C]F
Agent: [F-]
Agent: [K+]
Solvent: COCCOCCOC
Product: O=C(O)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Reaction time: 2.5 h

Procedure:
A suspension of 58.1 g (1.0 mol) of flame-dried KF in 1400 ml of dry diglyme was stirred at 25° while 333 g (0.67 mol) of hexafluoropropene oxide trimer was added rapidly. The two-phase system was stirred at 25° for 2 hr, during which time about half of the fluorocarbon layer slowly dissolved. The mixture was stirred at 5°-10° while 230 g (1.0 mol) of 1 was added. The mixture was stirred at 5°-10° for 2.5 hr, then overnight at 25°, and poured into 2 l. of H2O. The aqueous layer was extracted with 100 ml of CFCl2CF2Cl, and the combined organic layers washed with 2 l. of H2O, extracted with 100 ml of conc. H2SO4, clarified with CaSO4, filtered and distilled. Hydrolysis and bubbling were apparent in the water washed. Distillation afforded major fractions of 2 and 3, bp 55°-71° (20 mm) and 140 g of crude CF3CF2CF2OCF(CF3)CF2OCF(CF3)CO2H, bp mainly 101°-104° (20 mm). Redistillation of combined fractions of 2 and 3 gave 80 g of impure 3, bp 81°-86° (80 mm) and 33.0 g (8%) of 2, bp 94°-95° (80 mm).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]([NH:15][C@H:16]1[CH2:22][S:21][CH2:20][C@@H:19]([CH3:23])[N:18]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:17]1=[O:32])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].C(OC([C@@H](N[C@H]1CSC[C@@H](C)N(CC(OC(C)(C)C)=O)C1=O)CCC1C=CC=CC=1)=O)C>>[CH2:1]([O:3][C:4]([CH:6]([NH:15][C@H:16]1[CH2:22][S:21][CH2:20][C@@H:19]([CH3:23])[N:18]([CH2:24][C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[C:17]1=[O:32])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H](CCc1ccccc1)N[C@H]1CSC[C@@H](C)N(CC(=O)OC(C)(C)C)C1=O
Agent: CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1CSC[C@@H](C)N(CC(=O)OC(C)(C)C)C1=O
Product: CCOC(=O)C(CCc1ccccc1)N[C@H]1CSC[C@@H](C)N(CC(=O)OC(C)(C)C)C1=O

Procedure:
The procedure described in steps (a) to (h) of Example 1 was repeated, except that D-2-amino-1-propanol was used as the starting material. Two isomers (derived from the asymmetric carbon atom to which the phenethyl group is attached), that is t-butyl α-{6(R)-[1(R)-ethoxycarbonyl-3-phenylpropylamino]-3(R)-methyl-5-oxoperhydro-1,4-thiazepin-4-yl}acetate (isomer A) and t-butyl α-{6(R)-[1(S)-ethoxycarbonyl-3-phenylpropylamino]-3(R)-methyl-5-oxoperhydro-1,4-thiazepin-4-yl}acetate (isomer B) were obtained as oils.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9]([OH:11])=[O:10].[CH3:16]N(C)C=O>CO>[CH3:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9]([O:11][CH3:16])=[O:10]
Reactant: Cc1ccc(C(=O)O)cc1C
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1ccc(C)c(C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Thionyl chloride (80 ml; 2 equiv.) was added at room temperature to a solution of 3,4-dimethylbenzoic acid (35 g; 1 equiv.) and dimethylformamide (1 ml) in 227 ml of methanol. The resulting reaction mixture was stirred for 12 h at room temperature and then concentrated under reduced pressure. The resulting residue was taken up in dichloromethane and washed with 5% sodium carbonate solution. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The methyl 3,4-dimethylbenzoate so obtained (38.2 g) was used in the next stage without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(N(CC)CC)C.C(NC1C=CC(S([N:37]=[N+:38]=[N-])(=O)=O)=CC=1)(=O)C>C(#N)C>[N+:37](=[C:10]([C:9]([C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8])=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N-:38]
Reactant: CCOC(=O)CC(=O)c1c(F)cccc1F
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C(=[N+]=[N-])C(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl 3-(2,6-difluorophenyl)-3-oxopropanoate (12.3 g, 53.8 mmol) and triethylamine (22.5 mL, 0.161 mol, 3.0 equiv) were dissolved in acetonitrile (160 mL) and treated with 4-acetamidobenzenesulfonyl azide. The mixture was stirred for 18 hours at ambient temperature, concentrated in vacuo and the residue was purified by silica gel chromatography (eluting with chloroform), providing the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[C:4]([N:14]2[CH:18]=[CH:17][C:16]([CH3:19])=[N:15]2)[CH:3]=1.[NH2:20][C:21]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][C@H:34]([NH:38]C(OC(C)(C)C)=O)[C:35]([OH:37])=[O:36])=[CH:29][CH:28]=2)[CH:24]=[C:23](Cl)[N:22]=1.O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[NH2:38][C@@H:34]([CH2:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]2[CH:24]=[C:23]([O:13][C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[N:14]3[CH:18]=[CH:17][C:16]([CH3:19])=[N:15]3)[C:9]([F:12])([F:11])[F:10])[N:22]=[C:21]([NH2:20])[N:26]=2)=[CH:28][CH:29]=1)[C:35]([OH:37])=[O:36]
Reactant: Cc1ccn(-c2cc(Cl)ccc2C(O)C(F)(F)F)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(Cl)nc(N)n2)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(-c3ccc(C[C@H](N)C(=O)O)cc3)nc(N)n2)C(F)(F)F)n1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
1-[4-Chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-trifluoro-ethanol (0.120 g, 0.41 mmol), (S)-3-[4-(2-amino-6-chloro-pyrimidine-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid (0.176 g, 0.45 mmol), 1,4-dioxane (4 ml), and Cs2CO3 (0.533 g, 1.64 mmol) were combined in a 20 ml sealed tube, and the mixture was heated at 100° C. for 12 hours. The mixture was concentrated. To the residue, 10% methanol in DCM (50 ml) was added and the mixture was filtered. The filtrate was concentrated to give a crude product, which was taken in THF/3N HCl (30 ml/15 ml) and the resulting mixture was stirred at 40-45° C. for 12 hours. LCMS indicated the completion of reaction with desired product. The mixture was concentrated to give a crude product, which was dissolved in MeOH and H2O (1:1) and purified by preparative HPLC using MeOH/H2O/TFA as solvent system to give (S)-2-amino-3-[4-(2-amino-6-{1-[4-chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-trifluoro-ethoxy}-pyrimidine-4-yl)-phenyl]-propionic acid as a TFA salt. LCMS: M+1=547. 1H-NMR (400 MHz, CD3OD): δ (ppm) 2.30 (s, 3H), 3.10-3.30 (m, 2H), 4.20 (t, 1H), 6.32 (d, 1H), 6.74 (s, 1H), 7.0 (q, 1H), 7.38 (d, 2H), 7.50 (m, 2H), 7.72 (m, 1H), 7.90 (m, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.C[O:8][C:9]([C:11]1[C:15]([NH:16][C:17]([C:19]2[C:24]([NH:25][C:26]3[CH:27]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:23][CH:22]=[C:21]([CH:32]3[CH2:34][CH2:33]3)[N:20]=2)=[O:18])=[CH:14][N:13]([CH3:35])[N:12]=1)=O>>[OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:9]([C:11]2[C:15]([NH:16][C:17]([C:19]3[C:24]([NH:25][C:26]4[CH:27]=[N:28][CH:29]=[N:30][CH:31]=4)=[CH:23][CH:22]=[C:21]([CH:32]4[CH2:34][CH2:33]4)[N:20]=3)=[O:18])=[CH:14][N:13]([CH3:35])[N:12]=2)=[O:8])[CH2:3]1
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: OC1CCNC1
Product: Cn1cc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)N2CCC(O)C2)n1
Yield: 15 %

Procedure:
According to the general method described in step 5 of example 27, reaction of 3-hydroxy-pyrrolidine with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (15%) as sticky yellow solid.
Reaction SMILES: Cl.Cl.[CH2:3]([N:10]1[CH2:17][CH:16]2[O:18][CH:12]([CH2:13][NH:14][CH2:15]2)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:19]([NH:23][C:24](=[O:29])[O:25][CH2:26][CH2:27]Br)([CH3:22])([CH3:21])[CH3:20].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:3]([N:10]1[CH2:17][CH:16]2[O:18][CH:12]([CH2:13][N:14]([CH2:27][CH2:26][O:25][C:24](=[O:29])[NH:23][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15]2)[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)NC(=O)OCCBr
Reactant: c1ccc(CN2CC3CNCC(C2)O3)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)NC(=O)OCCN1CC2CN(Cc3ccccc3)CC(C1)O2
Temperature: 70 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
A mixture of 3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane dihydrochloride (8 g, 0.0275 mol, 1.0 eq.; see WO 01/28992), 2-bromoethyl tert-butylcarbamate (9.23 g, 0.0412 g, 1.5 eq.) and fused K2CO3 (18.96 g, 0.1375 mol, 5.0 eq.) in dry acetonitrile (120 mL) was stirred at 70° C. overnight under a N2 atmosphere. The reaction mixture was cooled to RT, filtered and concentrated under reduced pressure. The resulting resiude was purified by column chromatography over silica gel (using 92:8 DCM:methanol as final eluent) to yield the sub-title compound (5 g, 43%).
Reaction SMILES: [Br-].[O:2]1[CH2:6][CH2:5][O:4][CH:3]1[CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].[F:30][C:31]1[CH:32]=[CH:33][C:34]([O:39][CH3:40])=[C:35]([CH:38]=1)[CH:36]=O.[Cl-].[NH4+]>C1COCC1>[F:30][C:31]1[CH:32]=[CH:33][C:34]([O:39][CH3:40])=[C:35]([CH:36]=[CH:8][CH:7]2[O:2][CH2:6][CH2:5][O:4][CH2:3]2)[CH:38]=1
Reactant: c1ccc([P+](CCC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccc(F)cc1C=O
Agent: [Br-]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C=CC1COCCO1
Temperature: 0 °C
Reaction time: 12 h
Yield: 110.4 %

Procedure:
To a suspension of 2-(1,3-dioxolan-2-yl)ethyltriphenylphosphonium bromide (5.0 g, 11.3 mmol) in THF (30 mL) under Ar was added NaH (60% in mineral oil, 0.48 g, 11.3 mmol). The reaction was heated to reflux for 1 h. The resulting orange colored suspension was cooled to 0° C. and 5-fluoro-2-methoxybenzaldehyde (1.54 g, 10.0 mmol) was added and the reaction was stirred for 12 h at room temperature. The mixture was poured to a separatory funnel containing ammonium chloride aqueous solution (sat. NH4Cl/H2O=1:1, v:v, 30 mL). The organics were extracted with EtOAc (3×80 mL) and the combined organic layers were washed with brine (60 mL) and dried over Na2SO4. The solvent was removed in vacuo and product was purified by flash column chromatography (Rf=0.15, EtOAc/Hexane, 7:93, v:v) to result in the product (2.63 g, 66%) as a mixture of cis and trans (cis:trans=4:1): 1H NMR (the major isomer): (CDCl3, 500 MHz): δ 7.08 (dd, J=3.1, 8.7 Hz, 1 H), 6.93 (dt, J=3.1, 8.7 Hz, 1 H), 6.78 (dd, J=4.3, 8.7 Hz, 1 H), 6.63 (d, J=11.9 Hz, 1 H), 5.83 (td, J=7.3 Hz, 11.9 Hz, 1 H), 4.99 (t, J=4.6 Hz, 1 H), 4.02-3.99 (m, 2 H), 3.90-3.87 (m, 2 H), 3.80 (s, 3 H), 2.64-2.62 (m, 2 H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:25]=[C:24]([C:26]#[N:27])[C:23]4[N:28]=[CH:29][N:30]([CH3:31])[C:22]=4[CH:21]=3)=[CH:16][C:15]=2[C:32]([F:35])([F:34])[F:33])[CH2:7][CH2:6]1)=[O:4].[CH:36]([N:39]([CH:42]([CH3:44])C)CC)([CH3:38])C.N1CCCC1>CO>[CH3:31][N:30]1[C:22]2[CH:21]=[C:20]([C:17]3[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][CH:8]4[CH2:7][CH2:6][N:5]([C:3](=[O:4])[CH2:2][N:39]5[CH2:36][CH2:38][CH2:44][CH2:42]5)[CH2:10][CH2:9]4)=[C:15]([C:32]([F:34])([F:33])[F:35])[CH:16]=3)[N:25]=[C:24]([C:26]#[N:27])[C:23]=2[N:28]=[CH:29]1
Reactant: Cn1cnc2c(C#N)nc(-c3ccc(OCCC4CCN(C(=O)CCl)CC4)c(C(F)(F)F)c3)cc21
Reactant: CCN(C(C)C)C(C)C
Solvent: C1CCNC1
Solvent: CO
Product: Cn1cnc2c(C#N)nc(-c3ccc(OCCC4CCN(C(=O)CN5CCCC5)CC4)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A mixture of 6-(4-(2-(1-(2-chloroacetyl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (25 mg), diisopropylethylamine (82 μL), and pyrrolidine (21 μL) in MeOH (1 ml) was stirred for 36 hours at room temperature. The mixture was purified by prep HPLC (acidic) to give the expected product (14 mg). 1H NMR (CD3OD) δ: 8.42 (s, 1H), 8.24-8.35 (m, 3H), 7.27 (d, 1H), 4.50 (d, 1H), 4.23 (t, 2H), 3.91-4.07 (m, 4H), 3.22-3.61 (m, 6H), 3.05 (t, 1H), 2.64 (t, 1H), 1.76-2.02 (m, 9H), 1.10-1.30 (m, 2H). MS m/z 541 (M+H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=N[CH:7]=1.F[C:12]1C(B(O)O)=CC=CN=1.C(=O)([O-])[O-].[Na+].[Na+].CCO>O1CCOCC1.O.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>[NH:8]1[C:5]2[CH:12]=[CH:7][CH:2]=[N:3][C:4]=2[CH:10]=[CH:9]1
Reactant: Brc1cnc2[nH]ccc2n1
Reactant: OB(O)c1cccnc1F
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: C1COCCO1
Solvent: O
Solvent: CCO
Product: c1cnc2cc[nH]c2c1
Temperature: 140 °C
Yield: 137.7 %

Procedure:
To a 25 mL microwave vial was added 2-bromo-5H-pyrrolo[2,3-b]pyrazine (0.5 g, 2.52 mmol), 2-fluoropyridin-3-ylboronic acid (600 mg, 4.26 mmol) and sodium carbonate (803 mg, 7.57 mmol) in dioxane (10.0 ml), water (5.00 ml), and EtOH (2.5 ml). The reaction mixture was bubbled through with argon for 10 mins. Pd(PPh3)4 (292 mg, 0.252 mmol). The reaction was bubbled through with argon for 5 mins. The vial was capped and heated in the microwave at 140° C. for 15 min. The reaction mixture was diluted with EtOAc and water. The combined organics were separated, dried (MgSO4), filtered and concentrated. The crude residue dissolved in DCM and treated with silica. The solvent was evaporated and the crude absorbed in silica was purified by SiO2 chromatography eluting with EtOAc/hexane gradient (0% to 60%) to afford 410 mg (76%) of pyrrolopyridine as a light yellow solid. MS m/z (ES): 215 (M+H)+.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[N:18]2[C:19]3[C:24]([NH:25][C:26](=[O:27])[C:17]2=[CH:16][N:15]=1)=[CH:23][C:22]([C:28]([N:30]1[CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31]1)=[O:29])=[C:21]([CH3:39])[CH:20]=3)(C(C)(C)C)(C)C.Cl>CO>[CH2:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:38][N:30]1[C:28]([C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[CH3:39])[N:18]1[C:14]([C@@H:10]3[CH2:11][CH2:12][CH2:13][C@@H:9]3[OH:8])=[N:15][CH:16]=[C:17]1[C:26](=[O:27])[NH:25]2)=[O:29]
Reactant: Cc1cc2c(cc1C(=O)N1Cc3ccccc3C1)[nH]c(=O)c1cnc([C@@H]3CCC[C@@H]3O[Si](C)(C)C(C)(C)C)n12
Agent: Cl
Solvent: CO
Product: Cc1cc2c(cc1C(=O)N1Cc3ccccc3C1)[nH]c(=O)c1cnc([C@@H]3CCC[C@@H]3O)n12
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
To a mixture of 560 mg of 1-[cis-2-{[tert-butyl(dimethyl)silyl]oxy}cyclopentyl]-7-(1,3-dihydro-2H-isoindol-2-ylcarbonyl)-8-methylimidazo[1,5-a]quinoxalin-4(5H)-one and 20.0 mL of methanol was added 0.2 mL of concentrated hydrochloric acid, followed by stirring at room temperature overnight. The reaction liquid was concentrated under reduced pressure, and then, the residue was dissolved in water. A saturated aqueous sodium hydrogen carbonate solution was added thereto to adjust the pH to about 5, followed by extraction with a mixed solvent of chloroform/methanol=4/1, the organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=97/3-90/10) to give a powder from 2-propanol, thereby obtaining 333 mg of 7-(1,3-dihydro-2H-isoindol-2-ylcarbonyl)-1-[cis-2-hydroxycyclopentyl]-8-methylimidazo[1,5-a]quinoxalin-4(5H)-one as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:20]([C@H:21]4[CH2:25][CH2:24][O:23][CH2:22]4)[N:19]=[CH:18][C:17]=3[C:26]([O:28]CC)=O)=[C:12]([N+:31]([O-])=O)[CH:11]=2)[C:6]([CH3:34])=[CH:5][N:4]=1.[Cl-].[NH4+]>C(O)C>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([C:10]2[CH:15]=[CH:14][C:13]3[C:16]4[N:20]([C@H:21]5[CH2:25][CH2:24][O:23][CH2:22]5)[N:19]=[CH:18][C:17]=4[C:26](=[O:28])[NH:31][C:12]=3[CH:11]=2)[C:6]([CH3:34])=[CH:5][N:4]=1
Reactant: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1ccc(-c2c(C)cnc(OC)c2C)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: COc1ncc(C)c(-c2ccc3c(c2)[nH]c(=O)c2cnn([C@H]4CCOC4)c23)c1C
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 84.7 %

Procedure:
Ethyl 5-[4-(2-methoxy-3,5-dimethylpyridin-4-yl)-2-nitrophenyl]-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate (1.1 g) was suspended in ethanol (13 mL) Iron powder (280 mg) and a saturated aqueous ammonium chloride solution (3 mL) were added to the solution, and the mixture was stirred at 100° C. for 3.5 hours. The reaction mixture was cooled to room temperature and then filtered through Celite™. The filtrate was partitioned by adding ethyl acetate (100 mL) and water (50 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in acetic acid (2 mL), followed by stirring at 50° C. After four hours, the reaction mixture was cooled to mom temperature, and water (20 mL) was added. The precipitated solid was collected by filtration. 1-propanol (10 ml) and water (1.5 mL) were added to the resulting solid which was dissolved with heating under reflux. The solution was cooled with ice water. After one hour, the precipitated solid was collected by filtration and washed with MTBE (5 mL) to give the title compound (780 mg).