Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:6]2[O:7][CH2:8][CH2:9][O:10][C:5]=2[CH:4]=1.BrCC1CCCCO1.[O:21]=[C:22]1[C:30]2([C:34]3[CH:35]=[CH:36][C:37]([C:39]#[N:40])=[CH:38][C:33]=3[O:32][CH2:31]2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]1CC1C=CC=CN=1>>[O:7]1[C:6]2[CH:11]=[CH:12][C:3]([CH2:2][N:23]3[C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:30]4([C:34]5[CH:35]=[CH:36][C:37]([C:39]#[N:40])=[CH:38][C:33]=5[O:32][CH2:31]4)[C:22]3=[O:21])=[CH:4][C:5]=2[O:10][CH2:9][CH2:8]1
Reactant: N#Cc1ccc2c(c1)OCC21C(=O)N(Cc2ccccn2)c2ccccc21
Reactant: ClCc1ccc2c(c1)OCCO2
Agent: BrCC1CCCCO1
Product: N#Cc1ccc2c(c1)OCC21C(=O)N(Cc2ccc3c(c2)OCCO3)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 6-(chloromethyl)-2,3-dihydrobenzo[b][1,4]dioxine (Capilla, A. S. et al., Tetrahedron (2001), 57:8297) to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile was obtained (54%) as a colorless solid: mp 181-183° C. (dichloromethane/diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.29-7.16 (m, 1H), 7.15-6.97 (m, 3H), 6.89-6.75 (m, 5H), 5.04 (d, J=9.2 Hz, 1H), 4.94 (d, J=15.3 Hz, 1H), 4.80-4.67 (m, 2H), 4.25-4.19 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 176.2, 160.8, 143.8, 143.3, 142.2, 134.7, 131.3, 129.5, 128.5, 125.8, 124.4, 123.8, 123.7, 120.5, 118.5, 117.8, 116.3, 113.8, 113.3, 109.8, 80.2, 64.3 (2C), 57.8, 43.8.
Reaction SMILES: [C:1]1([C:6]2[C:14]3[C:9](=[C:10]([O:15][CH3:16])[N:11]=[CH:12][CH:13]=3)[N:8]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1.O>CO.[Pd]>[CH:1]1([C:6]2[C:14]3[C:9](=[C:10]([O:15][CH3:16])[N:11]=[CH:12][CH:13]=3)[N:8]([C:17]3[CH:18]=[CH:19][C:20]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:21][CH:22]=3)[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1nccc2c(C3=CCCC3)nn(-c3ccc(S(N)(=O)=O)cc3)c12
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COc1nccc2c(C3CCCC3)nn(-c3ccc(S(N)(=O)=O)cc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 135.6 %

Procedure:
To a solution of 4-(3-(cyclopent-1-en-1-yl)-7-methoxy-1H-pyrazolo[3,4-c]pyridin-1-yl)benzenesulfonamide (22 mg) in methanol (10 mL) was added 10% palladium/carbon (6.32 mg) containing water, and the mixture was stirred overnight under hydrogen atmosphere at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (30 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[CH3:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13](O)=[CH:12][CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CN(C)CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCN(C)C)cc1
Temperature: 22 °C
Reaction time: 8 h

Procedure:
To an ice-water cooled solution of 2-dimethylamino-ethanol (305.0 mg, 3.0 mmol), 4-hydroxy-benzoic acid methyl ester (456.3 mg, 3.0 mmol), and triphenylphosphine (1.59 g, 6.0 mmol) in THF (4 mL) is added DEAD (40% solution in toluene, 2.75 mL, 6.0 mmol) dropwise. After stirred at 22° C. overnight, the reaction mixture is passed through a SGX column, washed with methanol, and eluded with 2M ammonia in methanol. Removal of the solvent gives a crude product, which is used in the next step without purification.
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[OH:12][CH2:13]/[CH:14]=[C:15](/[CH2:17][CH2:18]/[CH:19]=[C:20](/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])\[CH3:21])\[CH3:16]>ClCCl>[CH3:26][C:25]([CH3:27])=[CH:24][CH2:23][CH2:22]/[C:20](/[CH3:21])=[CH:19]/[CH2:18][CH2:17]/[C:15](/[CH3:16])=[CH:14]/[CH:13]=[O:12]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a stirred solution of 15 g of PCC in 250 mL of dichloromethane was added 10 g of (E,E)-farnesol (1). The reaction mixture was stirred at room temperature overnight and filtered through a 55-cm (height) by 5-cm (diameter) column of silica gel. The eluate was dried over MgSO4, and the solvent was removed by rotary evaporation to give a greenish-yellow oil. The crude farnesal was purified by column chromatography (silica gel/chloroform) to yield 7.25 g of product 2, predominantly the (E,E)-isomer. 1H NMR δ (ppm) 10.0 (d, CHO), 5.9 (d, CH2C(CH3)═CHCO), 5.1 (t, CH3C(CH3)═CH and CH2C(CH3)═CH), 2.3 (m, CH2C(CH3)═CH—CO), 2.5 (m, CH2C(CH3)═CHCH2CH2), 2.2 (s, CH3C═CH—CO), 2.0 (m, CH3C(CH3)═CHCH2CH2), 1.6-1.7 (all s, CH3C(CH3)═CHCH2CH2CCH3).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH2:10]([O:17][C@@H:18]1[C@:22]([CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([CH:23]([F:25])[F:24])[O:21][C@@H:20]([N:35]2[CH:40]=[CH:39][C:38](=[O:41])[NH:37][C:36]2=[O:42])[C@H:19]1O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([O:17][C@@H:18]1[C@:22]([CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([CH:23]([F:25])[F:24])[O:21][C@@H:20]([N:35]2[CH:40]=[CH:39][C:38](=[O:41])[NH:37][C:36]2=[O:42])[C@@H:19]1[F:7])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=c1ccn([C@@H]2O[C@@](COCc3ccccc3)(C(F)F)[C@@H](OCc3ccccc3)[C@@H]2O)c(=O)[nH]1
Solvent: C1CCOC1
Product: O=c1ccn([C@@H]2O[C@@](COCc3ccccc3)(C(F)F)[C@@H](OCc3ccccc3)[C@H]2F)c(=O)[nH]1
Temperature: 60 °C
Reaction time: 16 h
Yield: 46.5 %

Procedure:
Diethylaminosulfur trifluoride (7.6 g, 47.4 mmol) was added to a suspension of compound 34 (1.5 g, 3.16 mmol) in dry THF (150 mL). The mixture was stirred at 60° C. for 16 h and then cooled to room temperature. The mixture was quenched by the addition of saturated aqueous NaHCO3 solution and then extracted with ethyl acetate. The organic phase was washed with brine, dried (Na2SO4) and evaporated to dryness under reduced pressure. Purification by silica gel chromatography [petroleum ether:ethyl acetate (4:1)] afforded 39 as a brown solid (700 mg, 46%). LC-MS (M+H)+=477.4
Reaction SMILES: [Br:1][C:2]([Br:14])=[CH:3][C:4]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[CH:8]=[CH:7][C:5]=1[NH2:6].Br[CH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]([Br:14])=[CH:3][C:4]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[CH:8]=[CH:7][C:5]=1[NH:6][CH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: CCOc1ccc(N)c(C=C(Br)Br)c1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(NCc2cccc(C(=O)OC)c2)c(C=C(Br)Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
A suspension of 2-(2,2-dibromovinyl)-4-ethoxyaniline (240 mg), methyl 3-(bromomethyl)benzoate (180 mg) and potassium carbonate (124 mg) in N,N-dimethylformamide (2 mL) was stirred overnight at room temperature. Water was added to the reaction mixture and this resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (258 mg).
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19]([OH:21])=O)=[CH:14][CH:13]=[CH:12]3)[CH:3]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27]>C(Cl)Cl.CO>[F:22][C:23]([F:31])([F:32])[C:24]1[CH:25]=[C:26]([NH:27][C:19]([C:15]2[C:16]3[C:11](=[CH:10][C:9]([CH2:8][C:4]4[CH:3]=[C:2]([OH:1])[N:7]=[CH:6][N:5]=4)=[CH:18][CH:17]=3)[CH:12]=[CH:13][CH:14]=2)=[O:21])[CH:28]=[CH:29][CH:30]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1cccc2cc(Cc3cc(O)ncn3)ccc12
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc2cc(Cc3cc(O)ncn3)ccc12

Procedure:
Prepared from 6-(6-hydroxy-pyrimidin-4-ylmethyl)-naphthalene-1-carboxylic acid (Step 3.8) and 3-trifluoromethyl-aniline analogously to Ex. 3: MS: [M+1]+=424; TLC (CH2Cl2/MeOH 9:1): Rf=0.26.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[Br:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[NH:25][CH2:24][CH2:23]2>>[Br:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[N:25]([C:2]1[C:3](=[O:15])[N:4]([C@H:9]([CH:12]3[CH2:14][CH2:13]3)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1)[CH2:24][CH2:23]2
Reactant: COc1cc(Br)c2c(c1)CCN2
Reactant: CC[C@@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Agent: Cl
Product: CC[C@@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(OC)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 7-bromo-5-methoxyindoline hydrochloride as the starting materials. mp 138–140° C.; 1H NMR (300 MHz, CDCl3): δ 6.94 (s, 1 H), 6.89 (d, J=2.2 Hz, 1 H), 6.76 (d, J=2.2 Hz, 1 H), 4.34–4.24 (m, 2 H), 4.10–4.01 (m, 1 H), 3.76 (s, 3 H), 3.09 (t, J=7.9 Hz, 2 H), 1.94–1.74 (m, 2 H), 1.06–0.98 (m, 1 H), 0.95–0.86 (m, 3 H), 0.79–0.72 (m, 1 H), 0.54–0.44 (m, 2 H), 0.35–0.22 (m, 1 H); HRMS (ESI) calcd for C19H22N3O2BrCl (M+H)+: 438.0584; found m/z 438.0605.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14]C)=[O:12])=[CH:5]2>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]([C:11]([O:13][CH3:14])=[O:12])[CH2:5]2
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Solvent: CO
Product: COC(=O)C1Cc2cc(F)ccc2N1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.9 %

Procedure:
To a suspension of 5-fluoro-1H-indole-2-carboxylic acid, ethyl ester (0.121 mole) in methanol (600 ml) was added Mg (0.36 mole). The mixture was in a 3-neck round bottom flask under argon at room temperature. The temperature of the reaction was monitored closely. After about 10 minutes, the mixture began to bubble, slowly at first and then more vigorously. The reaction temperature was maintained between 15 and 25° C. with intermittent applications of an ice bath. After 30 minutes, the bubbling had slowed. The mixture was allowed to stir at room temperature for three days. The mixture was partitioned between 600 ml of chloroform and 500 ml of saturated NH4Cl solution. The organic layer was dried over MgSO4 and concentrated to a brown oil. The oil was dissolved in ether and extracted with 3N HCl. The aqueous layer was washed with ether, basified with 3N NaOH, and extracted with chloroform. The extract was dried over MgSO4 and concentrated, yielding 13.91 g of methyl 5-fluoro-2,3-dihydro-1H-indole-2-carboxylate (intermediate 16).
Reaction SMILES: [OH-].[Li+].[C:3]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]CC)=[O:24])=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)[C@H:9]([NH:28][C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:8][C@@H:7]1[CH3:35])(=[O:5])[CH3:4]>CO>[C:3]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)[C@H:9]([NH:28][C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:8][C@@H:7]1[CH3:35])(=[O:5])[CH3:4]
Reactant: CCOC(=O)Cc1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N1c2ccc(-c3ccc(CC(=O)O)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 78 %

Procedure:
Lithium hydroxide (4N in water, 1 mL, 4.00 mmol) was added to a solution of ethyl {4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]phenyl}acetate (for a preparation see Intermediate 100) (32.6 mg, 0.072 mmol) in methanol (3 mL). The resulting mixture was stirred under nitrogen at room temperature for 12 h then most of the solvent was removed in vacuo. The residue was partitioned between AcOEt (30 mL) and water (15 mL) and the layers were separated. The aqueous phase was extracted with AcOEt (15 mL). The combined organic phases were washed with brine (20 mL), dried over MgSO4 and concentrated in vacuo. Purification of the residue by MDAP (modifier: formic acid) gave {4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]phenyl}acetic acid (23.8 mg, 0.056 mmol, 78%) as a white solid.
Reaction SMILES: C(OC([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[C:13]=2[CH2:12]1)=O)C1C=CC=CC=1.[ClH:35]>CO.O1CCOCC1.[Pd]>[ClH:35].[F:34][C:31]([F:32])([F:33])[C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]3[CH2:22][CH2:23][NH:11][CH2:12][C:13]2=3)=[CH:26][CH:27]=1
Reactant: O=C(OCc1ccccc1)N1CCc2c(n(Cc3ccc(C(F)(F)F)cc3)c3ccccc23)C1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: FC(F)(F)c1ccc(Cn2c3c(c4ccccc42)CCNC3)cc1
Reaction time: 6 h
Yield: 92 %

Procedure:
To a solution of 2-benzyloxycarbonyl-9-{[4-(trifluoromethyl)phenyl]methyl}-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole (8.73 g, 18.81 mmole) in methanol (50 mL), dioxane (50 mL) and HCl (19 mL, 1M in dioxane) at RT in a Parr hydrogenation flask was added 10% Pd/C (0.5 g). The reaction mixture was shaken under 45 psi of H2 for 6 hr. The suspension was filtered through celite®, and the filter pad was washed with methanol. The filtrate was concentrated on the rotavap, and the residue was dried under high vacuum to afford the titled compound (6.33 g, 92%) as a white solid: MS (ES) m/e 331 (M+H−HCl)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:12]([N:19]1[CH2:28][CH2:27][C:26]2[C:25](Cl)=[N:24][CH:23]=[N:22][C:21]=2[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C.CCCCCC>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:25]2[C:26]3[CH2:27][CH2:28][N:19]([CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:20][C:21]=3[N:22]=[CH:23][N:24]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: Clc1ncnc2c1CCN(Cc1ccccc1)C2
Solvent: CC#N
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(Nc2ncnc3c2CCN(Cc2ccccc2)C3)cc1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
A mixture of 4-tert-butylbenzenamine (0.312 mL, 1.98 mmol) and 7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (0.467 g, 1.80 mmol), prepared as described in Example 1.B. in acetonitile (2 mL) was heated in a sealed tube at 170° C. in a microwave (Emrys Optimizer model, Personal Chemistry) for five min. Upon cooling to room temperature, a precipitate formed. The mixture was diluted with hexane (5 mL) and the precipitate was collected by filtration to give 0.576 g of the title compound as a tan solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:11]=[C:10]([OH:12])[N:9]=[C:8]([O:13][CH3:14])[N:7]=1>CC(O)=O>[OH:5][C:6]1[C:11]([N+:1]([O-:4])=[O:2])=[C:10]([OH:12])[N:9]=[C:8]([O:13][CH3:14])[N:7]=1
Reactant: O=[N+]([O-])O
Reactant: COc1nc(O)cc(O)n1
Solvent: CC(=O)O
Product: COc1nc(O)c([N+](=O)[O-])c(O)n1
Yield: 68 %

Procedure:
To glacial HOAc (860 mL) was added red fuming HNO3 (300 mL) with cooling and stirring, at such a rate that the temperature was kept below 20° C. This stirred mixture was cooled in an ice bath and the foregoing material prepared in Example 134 (200 g, 78% pure, 1.1 mol) was added in portions over a period of 1 hr such that the temperature was maintained between 18°-20° C. The reaction was then stirred overnight. The precipitate which formed was filtered off and washed with HOAc (50 mL). This solid was then slurried with ice-H2O (400 mL), filtered off and dried to constant weight in vacuo at 60° C. to yield 141 g (0.75 mol, 68% yield) of the title compound; nmr (d6 -DMSO) d: 3.95 (s); mass spectrum showed m/e 187 (M+). A separate synthesis gave an analytical sample.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1.Br[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1
Reactant: Cc1cc(C)nc(-n2c(C)ccc2C)c1
Reactant: BrCCCc1ccccc1
Product: Cc1cc(CCCCc2ccccc2)nc(-n2c(C)ccc2C)c1

Procedure:
By analogy to Example 53, Step B, the anion of 4,6-dimethyl-2-(2,5-dimethylpyrrol-1-yl)pyridine was alkylated with 1-bromo-3-phenylpropane to give 4-methyl-2-(2,5-dimethylpyrrol-1-yl)-6-(4-phenylbutyl)pyridine.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][Si](C(C)(C)C)(C)C)[C:4]=1[C:5]([O:7][CH3:8])=[O:6].[C:21](=O)(O)[O-:22].[Na+]>CO>[OH:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:3]([CH2:2][O:22][CH3:21])[C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(CBr)cccc1O[Si](C)(C)C(C)(C)C
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COCc1cccc(O)c1C(=O)OC

Procedure:
A solution of methyl 2-bromomethyl-6-(tert-butyldimethylsilyloxy)benzoate (Intermediate 12, 4.26 g) in methanol (63 mL) was stirred and heated at reflux overnight. After cooling, the mixture was basified by addition of solid sodium bicarbonate and then evaporated to dryness. The residue was triturated with DCM and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-25% to give methyl 2-hydroxy-6-methoxymethylbenzoate (1.46 g) as a white crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]([NH:21][C:22]3[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=3[C:24]([NH2:26])=[O:25])=O)[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:13][CH2:14][N:15]([CH2:18][C:19]3[NH:26][C:24](=[O:25])[C:23]4[C:22](=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:21]=3)[CH2:16][CH2:17]2)(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)N2CCN(CC(=O)Nc3ccccc3C(N)=O)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)N2CCN(Cc3nc4ccccc4c(=O)[nH]3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2-{2-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-acetylamino}-benzamide (432 mg, 1 mmol), 1N sodium hydroxide solution (5 mL) and 1,4-dioxane (5 mL) was stirred a room temperature for 1 day. The reaction mixture was concentrated to approximately half the volume and then neutralized with 1N HCl solution. The product precipitated and was collected by filtration as a white solid (306 mg, 74%). 1H NMR (400 MHz, CDCl3) δ 8.26 (dd, J=8.0, 1.3 Hz, 1H), 7.79 (t, J=8.4 Hz, 1H), 7.73 (dt, J=9.5, 2.5 Hz, 2H), 7.68 (d, J=7.7 Hz, 1H), 7.51 (t, J=8.1 Hz, 1H), 7.08 (dt, J=9.5, 2.4 Hz, 2H), 3.94 (s, 3H), 3.65 (s, 2H), 3.11 (m, 4H), 2.75 (t, J=4.9 Hz, 4H); HPLC ret. time 2.59 min, 10-99% CH3CN, 5 min run; ESI-MS m/z 415.3 (M+1)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][C:4](=O)[CH2:5][C:6]([O:8]CC)=[O:7].[N:13]([C:16]1[CH:26]=[CH:25][C:19]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)=[N+:14]=[N-:15].[O-]CC.[Na+].O>C(O)C>[CH2:23]([NH:22][C:20]([C:19]1[CH:25]=[CH:26][C:16]([N:13]2[C:4]([CH2:3][CH:2]([CH3:1])[CH3:12])=[C:5]([C:6]([OH:8])=[O:7])[N:15]=[N:14]2)=[CH:17][CH:18]=1)=[O:21])[CH3:24]
Reactant: CCOC(=O)CC(=O)CC(C)C
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CC(C)C)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 91.8 %

Procedure:
Ethyl 5-methyl-3-oxohexanoate (1.20 g, 6.99 mmol, 1.4 eq.) obtained in Example 93a) and 4-azido-N-ethylbenzamide (1.00 g, 4.99 mmol) were dissolved in ethanol (20 ml), sodium ethoxide (491 mg, 6.49 mmol, 1.3 eq.) was added, and the mixture was stirred at room temperature for 30 min and at 60° C. for 18 hr. Water (20 ml) was added to the reaction mixture, and ethanol was evaporated. The residue was diluted with 2% aqueous sodium carbonate solution (25 ml), and the mixture was washed with ethyl acetate-hexane (2:1, 45 ml). The organic layer was extracted with 1% aqueous sodium carbonate solution (15 ml). The aqueous layers were combined, washed with ethyl acetate-hexane (1:1, 30 ml), acidified (pH<3) with 6N hydrochloric acid and extracted with ethyl acetate (40 ml and 30 ml). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, and ethyl acetate was added. The precipitate was collected by filtration, washed with ethyl acetate and diethyl ether and dried to give the title compound as a white powder (1.45 g, 4.58 mmol, 91.7%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:9]1[C:10]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]([CH:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:23][CH:22]=3)[CH:17]=2)=[N:11][C:12](Br)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:55][C:56]([C:60]1[CH:65]=[C:64](B2OC(C)(C)C(C)(C)O2)[CH:63]=[CH:62][N:61]=1)([CH3:59])[C:57]#[N:58]>C1(C)C=CC=CC=1.O>[C:1]([O:5][C:6]([N:8]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:9]1[C:10]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]([CH:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:23][CH:22]=3)[CH:17]=2)=[N:11][C:12]([C:64]2[CH:63]=[CH:62][N:61]=[C:60]([C:56]([C:57]#[N:58])([CH3:59])[CH3:55])[CH:65]=2)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1cc(-c2ccc(CN(C(=O)OC(C)(C)C)C3CCOCC3)cc2)no1
Reactant: CC(C)(C#N)c1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(-c2ccnc(C(C)(C)C#N)c2)nc1-c1cc(-c2ccc(CN(C(=O)OC(C)(C)C)C3CCOCC3)cc2)no1
Temperature: 70 °C
Yield: 68.1 %

Procedure:
A mixture of tert-butyl N-[[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-bromo-pyrazin-2-yl]isoxazol-3-yl]phenyl]methyl]-N-tetrahydropyran-4-yl-carbamate (110.0 g, 151 mmol), K2CO3 (41.6 g, 301 mmol), and 2-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]propanenitrile (41.0 g, 151 mmol) in toluene (770 mL) and water (220 mL) is stirred and degassed with N2 for 30 min. at 20° C. The catalyst Pd(dtbpf)Cl2 (1.96 g, 3.01 mmol) is added and the mixture is degassed for an additional 10 min. The mixture is heated at 70° C. until the reaction is complete. The mixture is cooled to ambient temperature, diluted with water (220 mL), and filtered through a bed of Celite. The organic phase is concentrated to remove most of the solvent. The concentrate is diluted with i-PrOH (550 mL). The resultant suspension is stirred for at least 1 h and then the solid is collected by filtration to afford a tan powder. The solid is dissolved in toluene (990 mL) and stirred with Biotage MP-TMT resin (18.6 g) for 2 h at ambient temperature. The resin is removed by filtration. The filtrate is concentrated then diluted with i-PrOH (550 mL) and then re-concentrated. Add i-PrOH (550 mL) and stir for 1 h at ambient temperature. Cool the suspension to 5° C. and collect the solid by filtration then dry to afford tert-butyl N-[[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-[2-(1-cyano-1-methyl-ethyl)-4-pyridyl]pyrazin-2-yl]isoxazol-3-yl]phenyl]methyl]-N-tetrahydropyran-4-yl-carbamate (Compound I-1) (81.9 g; 68%, yield, 98.7 area % purity by HPLC) as a cream-colored powder.