Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[CH2:3][CH2:4][C@@H:5]([C:20](=[O:43])[NH:21][CH:22]1[C:28](=[O:29])[NH:27][C:26]2[C:30]([CH2:34][OH:35])=[CH:31][CH:32]=[CH:33][C:25]=2[C:24]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=2)=[N:23]1)[C@H:6]([CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:7]([O:9]C(C)(C)C)=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:45][C:2]([F:1])([F:44])[CH2:3][CH2:4][C@@H:5]([C:20](=[O:43])[NH:21][CH:22]1[C:28](=[O:29])[NH:27][C:26]2[C:30]([CH2:34][OH:35])=[CH:31][CH:32]=[CH:33][C:25]=2[C:24]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=2)=[N:23]1)[C@H:6]([CH2:14][CH2:15][C:16]([F:17])([F:18])[F:19])[C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)OC(=O)[C@@H](CCC(F)(F)F)[C@@H](CCC(F)(F)F)C(=O)NC1N=C(c2cccc(F)c2)c2cccc(CO)c2NC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2c(CO)cccc2C(c2cccc(F)c2)=NC1NC(=O)[C@H](CCC(F)(F)F)[C@H](CCC(F)(F)F)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.7 %

Procedure:
To a solution of Intermediate 37I (65 mg, 0.100 mmol) in DCM (2 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 3 h and then concentrated to dryness. The crude material was purified by preparative reversed-phase HPLC (aq. MeOH, containing 0.1% TFA). The desired fractions were combined and concentrated to dryness to afford Intermediate 37J (30 mg, 51%). HPLC: RT=2.680 min (CHROMOLITH® SpeedROD column 4 6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm), MS(ES): m/z=592.3 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8].Br[CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:17]1(=[O:26])[N:16]([CH2:15][CH2:14][NH:1][C:2]2[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=2[CH3:8])[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]12
Reactant: Cc1c(N)c(=O)n(C)c(=O)n1C
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(NCCN2C(=O)c3ccccc3C2=O)c(=O)n(C)c(=O)n1C

Procedure:
24.7 g. 5-Amino-1,3,6-trimethylpyrimidine-2,4(1H,3H)-dione, 44.5 g. N-(2-bromoethyl)-phthalimide and 30.2 g. potassium carbonate are stirred in 450 ml. acetonitrile for 4 days in an autoclave at 110° to 130° C. The inorganic salts are filtered off with suction and the filtrate is evaporated. The residue is purified over silica gel using ethyl acetate as elution agent. There are obtained 13.7 g. (27% of theory) of the desired product in the form of colorless crystals; m.p. 178°-180° C.
Reaction SMILES: C(O[C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][C:16]([OH:20])=[CH:17]2)=[CH:12][CH:11]=1)CCCCCCC>C1C2C(=CC=CC=2)C=CC=1O.C(Cl)(Cl)(Cl)Cl>[CH:11]1[CH:12]=[C:13]2[CH:14]=[CH:15][C:16]([OH:20])=[C:17]([C:17]3[C:18]4[C:13](=[CH:12][CH:11]=[CH:10][CH:19]=4)[CH:14]=[CH:15][C:16]=3[OH:20])[C:18]2=[CH:19][CH:10]=1
Reactant: CCCCCCCCOc1ccc2ccc(O)cc2c1
Agent: Oc1ccc2ccccc2c1
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Reaction time: 0.17 h
Yield: 99 %

Procedure:
A reaction flask described in example 9 was charged with a solution of catalyst 1c (12.2 mg, 0.02 mmol) in anhydrous CCl4 (1 mL). The solution was stirred for 10 min under an oxygen atmosphere and then treated with a solution of 7-octyloxy-2-naphthol (54 mg, 0.2 mmol) in anhydrous CCl4 (1 mL) under 0° C. The reaction mixture was stirred at 0° C. until the reaction was complete (monitored by TLC). The crude mixture was concentrated under reduced pressure, and purified by column chromatography (Ethyl acetate/Petroleum ether=⅓) to give (R)-BINOL 3j, Yield 99%. [α]D25=−153.8 (c=0.5 in EtOAc), 1HNMR (300 MHz, CDCl3) δ (ppm) 7.87 (d, J=9.0 Hz, 2H, 2×HC (5)), 7.78 (d, J=9.0 Hz, 2H, 2×HC (4)), 7.21 (d, J=9.0 Hz, 2H, 2×HC (3)), 7.03 (dd, J=9.0 Hz, 2.4 Hz, 2H, 2×HC (6)), 6.49 (d, J=2.1 Hz, 2H, 2×HC (8)), 5.07 (s, 2H, 2×OH), 3.67–3.77 (m, 4H, 4×OCH2), 1.59–1.66 (m, 4H, 4×OCH2CH2), 1.25–1.29 (m, 20H, 20×CH2), 0.86–0.90 (t, 6H, 6×CH3). e.e. 94%.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:30])=[C:6]([CH3:29])[C:7]2[O:11][C:10]([CH2:13][N:14]3[CH2:26][CH2:25][C:24]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[NH:17][C:16]=4[CH2:15]3)([CH3:12])[CH2:9][C:8]=2[C:27]=1[CH3:28])([O-])=O.Cl.[OH-].[Na+]>C(O)C>[NH2:1][C:4]1[C:5]([CH3:30])=[C:6]([CH3:29])[C:7]2[O:11][C:10]([CH2:13][N:14]3[CH2:26][CH2:25][C:24]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[NH:17][C:16]=4[CH2:15]3)([CH3:12])[CH2:9][C:8]=2[C:27]=1[CH3:28]
Reactant: Cc1c(C)c([N+](=O)[O-])c(C)c2c1OC(C)(CN1CCc3c([nH]c4ccccc34)C1)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCc3c([nH]c4ccccc34)C1)O2
Temperature: 0 °C
Yield: 77.5 %

Procedure:
1.49 g of (±)-2-(5-nitro-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-2-ylmethyl)-2,3,4,9-tetrahydro-1H-beta-carboline, 2.49 g of stannous chloride, 11 ml of hydrochloric acid and 25 ml of ethanol were added and, after heating at reflux for 6.5 hours, the mixture was poured into ice-water and an aqueous sodium hydroxide solution was added. The reaction solution was extracted with chloroform, washed with saturated saline and dried over anhydrous magnesium sulfate and, after the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (chloroform:methanol=100:3) to obtain 1.07 g of the objective product (melting point: 150-153° C.)
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][N:6]=[C:7]([C:10]1[C:11](=[O:26])[CH2:12][CH:13]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[CH2:14][C:15]=1[OH:16])[CH2:8][CH3:9])[CH3:4].[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O.O1CCCC1>[C:27]([O:26][C:11]1[CH2:12][CH:13]([C:17]2[C:18]([CH3:25])=[CH:19][C:20]([CH3:24])=[CH:21][C:22]=2[CH3:23])[CH2:14][C:15](=[O:16])[C:10]=1[C:7](=[N:6][O:5][CH2:3][CH3:4])[CH2:8][CH3:9])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCON=C(CC)C1=C(O)CC(c2c(C)cc(C)cc2C)CC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCON=C(CC)C1=C(OC(=O)c2ccccc2)CC(c2c(C)cc(C)cc2C)CC1=O
Yield: 67.4 %

Procedure:
A solution of sodium hydroxide (0.12 g) in water (0.7 ml) was added dropwise, with stirring, to a solution of 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-mesitylcyclohex-2-en-1-one (0.89 g) in tetrahydrofuran (9.5 ml). Benzoyl chloride (0.42 g) was added dropwise, with stirring and the mixture was stirred at room temperature for a period of 30 minutes. The solvent was removed by evaporation under reduced pressure and the residue was taken up in dichloromethane and water. The dichloromethane solution was separated, washed twice with water, dried, and the solvent evaporated under reduced pressure. The remaining oil was triturated with petroleum ether (b.p. 40°-60° C.) and the solid which formed was recrystallised from isopropanol to give 3-benzoyloxy-2-[1-(ethoxyimino)propyl]-5-mesitylcyclohex-2-en-1-one (0.79 g) as a solid m.p. 94°-95.5° C.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][C:5]1[C:6]([CH3:19])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[C:9]=1[CH3:10].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:19][C:6]1[C:5]([CH2:4][C:3]([OH:2])=[O:20])=[C:9]([CH3:10])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:23]([C:22]([F:21])([F:32])[F:33])=[CH:24][CH:25]=3)=[CH:14][CH:13]=2)[N:7]=1
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(N)cc2)c1C
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn(Cc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2)c(C)c1CC(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Coupling: To a solution of [1-(4-amino-benzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-acetic acid methyl ester (intermediate 1.1.3, 85 mg, 0.26 mmol) in dimethylformamide (1 mL) was added 4-(trifluoromethyl)benzoic acid (62 mg, 0.32 mmol), diisopropylethylamin (90 μL, 0.53 mmol) and TBTU (94 mg, 0.29 mmol). The reaction mixture was stirred for 18 h at room temperature. The reaction mixture was treated with aqueous K2CO3 solution (2 M, 0.15 mL) and filtered over Alox B, eluting with 10% methanol in dichloromethane. Saponification: The volatiles were removed under reduced pressure and the remaining residue was treated with aqueous NaOH solution (4 M, 0.2 mL). The mixture was purified via preparative reversed phase HPLC (gradient of methanol in water+0.1% NH3).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[C@@H:7]1[CH2:11][C@@H:10]([C:12]#[N:13])[CH2:9][N:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:21])[C@@H:7]1[CH2:11][C@H:10]([CH2:12][NH2:13])[CH2:9][N:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@H](C#N)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H](CN)CN1C(=O)OC(C)(C)C

Procedure:
A solution (4R)-1-(tert-butyloxycarbonyl)-4-cyano-L-proline tert-butyl ester (220 mg, 0.742 mmol) in 90% ethanol (11 mL) was hydrogenated in the presence of 10% palladium-on-charcoal (100 mg) at 450 psi for 18 hours. The catalyst was removed by filtration through Celite, the filter washed with methanol, and the combined filtrate and washings evaporated. Purification was achieved by flash silica gel chromatography eluting with 95:5:0.5 chloroform-methanol-ammonia; yield 164 mg (74%).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[N:18][C:19]=1[CH:20]([O:23]C)OC)[N:16]([C:25]([O:27]C1C=CC=CC=1)=O)[CH2:15][CH2:14][CH2:13]2)(C(C)(C)C)(C)C.[NH2:34][C:35]1[CH:42]=[C:41]([O:43][CH:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)[C:38]([C:39]#[N:40])=[CH:37][N:36]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH4+].[Cl-]>C1COCC1>[C:39]([C:38]1[C:41]([O:43][CH:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[CH:42][C:35]([NH:34][C:25]([N:16]2[C:17]3[C:12](=[CH:11][C:10]([CH2:9][OH:8])=[C:19]([CH:20]=[O:23])[N:18]=3)[CH2:13][CH2:14][CH2:15]2)=[O:27])=[N:36][CH:37]=1)#[N:40]
Reactant: N#Cc1cnc(N)cc1OC1CCOCC1
Reactant: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2C(=O)Oc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1cnc(NC(=O)N2CCCc3cc(CO)c(C=O)nc32)cc1OC1CCOCC1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
Phenyl 6-(((tert-butyldimethylsilyl)oxy)methyl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (intermediate 38, 40 mg, 0.085 mmol) and 6-amino-4-((tetrahydro-2H-pyran-4-yl)oxy)nicotinonitrile (intermediate 45B, 22.3 mg, 0.102 mmol) were dissolved in THF (1 ml) under argon. The resulting solution was cooled to −78° C. and treated slowly with LHMDS (1 M in THF, 0.186 ml, 0.186 mmol). The reaction mixture was stirred at −78° C. for 45 min and then slowly warmed up to room temperature. The reaction mixture was poured into NH4Cl sat. aq. and extracted twice with DCM. The organic phase was then dried over Na2SO4, filtered and evaporated. The crude material was purified by preparative supercritical fluid chromatography (SFC 1, NH2 column). The 6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(5-cyano-4-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide containing fractions were concentrated and then dissolved in THF (1 ml) and water (1 ml) and treated with conc. HCl (0.14 ml). The reaction mixture was stirred 16 h at room temperature. The reaction mixture was quenched with sat. aq. NaHCO3 and extracted with DCM (3×). The org layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude material was treated with a small quantity of DCM and then the product was precipitated by addition of heptane. The solid was collected by centrifugation and dried under vacuum to obtain the title compound as a white solid.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:36]=[CH:37][C:38]=1[CH2:39][O:40][Si](C(C)(C)C)(C)C)[O:13][CH2:14][C:15]1[S:19][C:18](/[C:20](/[CH2:34][CH3:35])=[CH:21]/[CH:22]=[CH:23]/[C:24]([C:30]([F:33])([F:32])[F:31])([OH:29])[C:25]([F:28])([F:27])[F:26])=[CH:17][CH:16]=1)(C(C)(C)C)(C)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:36]=[CH:37][C:38]=1[CH2:39][OH:40])[O:13][CH2:14][C:15]1[S:19][C:18](/[C:20](/[CH2:34][CH3:35])=[CH:21]/[CH:22]=[CH:23]/[C:24]([C:30]([F:33])([F:31])[F:32])([OH:29])[C:25]([F:26])([F:28])[F:27])=[CH:17][CH:16]=1
Reactant: CC/C(=C\C=C\C(O)(C(F)(F)F)C(F)(F)F)c1ccc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: CC/C(=C\C=C\C(O)(C(F)(F)F)C(F)(F)F)c1ccc(COc2ccc(CO)c(CO)c2)s1

Procedure:
In a manner similar to that of Example 6(l), by reaction of 200 mg of (3E,5E)-6-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-2-thienyl}-1,1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol with 700 μL (0.7 mmol) of 1.0 M tetrabutylammonium bromide, the desired product is obtained in the form of white crystals (m.p.=113-114° C.; m=70 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]3[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[O:10][C:8]3=[CH:9][C:4]=2[NH:3][C:2]1=[O:18].[OH-].[K+]>C(O)C>[O:1]1[C:5]2[CH:6]=[C:7]3[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[O:10][C:8]3=[CH:9][C:4]=2[NH:3][C:2]1=[O:18]
Reactant: CCOC(=O)c1cc2cc3oc(=O)[nH]c3cc2o1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2cc3oc(=O)[nH]c3cc2o1
Yield: 95.8 %

Procedure:
A stirred mixture of 1.0 g (4 mmol) of ethyl 3H-furo[2,3-f]benzoxazole-2-one-6-carboxylate, 100 ml of ethanol and 0.5 g of potassium hydroxide is refluxed for 1 h. The mixture is concentrated, the residue is dissolved in water and acidified with 20% aqueous sulfuric acid solution. The precipitated crystals are filtered off and washed with water to yield 0.84 g (95%) of the title compound. Mp.: 190-192° C. (water).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[F:27][C:28]1[CH:36]=[C:35]2[C:31]([CH2:32][CH2:33]/[C:34]/2=[CH:37]\[C:38]([NH2:40])=[O:39])=[CH:30][CH:29]=1>C(Cl)(Cl)(Cl)Cl.C1C=CC=CC=1>[Br:1][CH:33]1[CH2:32][C:31]2[C:35](=[CH:36][C:28]([F:27])=[CH:29][CH:30]=2)/[C:34]/1=[CH:37]/[C:38]([NH2:40])=[O:39]
Reactant: NC(=O)/C=C1\CCc2ccc(F)cc21
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: NC(=O)/C=C1/c2cc(F)ccc2CC1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 3.4 %

Procedure:
N-Bromosuccinimide (22.57 g, 126.8 mmoles, Aldrich) and benzoyl peroxide (1.89 g, 7.8 mmoles, Aldrich) were added to a suspension of (E)-2-(6-fluoro-1-indanylidene)acetamide (21.00 g, 109.8 mmoles) in carbon tetrachloride (400 mL) and benzene (400 mL). The mixture was refluxed under a calcium chloride drying tube while shining an infrared lamp on it for two hours, after which time an orange solution formed. The heat and light were removed, and the solution was stirred at ambient temperature for 18 hours. The mixture was filtered, and the solids were washed with ethyl acetate. The washings and filtrate were combined and evaporated in vacuo. The residue was dissolved in ethyl acetate (800 mL) and washed with water (3×200 mL) and brine (200 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The residue was chromatographed on silica gel eluting first with hexane: ethyl acetate (2:1) gradually increasing the polarity to hexane: ethyl acetate (1:1). The fractions containing the major spot were combined and evaporated in vacuo to give a yellow solid which was dried in a vacuum at 70° C. for 18 hours to give 1.022 g (3%) of (Z)-2-(2-bromo-6-fluoro-1-indanylidene)acetamide as a yellow solid, mp 162°-163° C. 1H-NMR (DMSO-d6): d7.19-7.85 (m, 5H), 6.46 (s, 1H), 6.32 (d, 1H, J=5.7 Hz), 3.64 (dd, 1H, J=5.6 Hz, 18.4 Hz) and 3.27 (d, 1H, J=18.5 Hz); steady-state nOe: irradiation at 6.46 d, observed 21% nOe at 7.39 d.
Reaction SMILES: [C:1](=[O:21])([O:7][C:8]1[C:12]2[CH:13]=[C:14]([CH:19]=[O:20])[C:15](F)=[C:16]([F:17])[C:11]=2[O:10][N:9]=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].CCN(C(C)C)C(C)C.[CH3:31][C@H:32]1[O:37][C@@H:36]([CH3:38])[CH2:35][NH:34][CH2:33]1>C(#N)C>[C:1](=[O:21])([O:7][CH:8]1[C:12]2[CH:13]=[C:14]([CH:19]=[O:20])[C:15]([N:34]3[CH2:33][C@H:32]([CH3:31])[O:37][C@H:36]([CH3:38])[CH2:35]3)=[C:16]([F:17])[C:11]=2[O:10][NH:9]1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)Oc1noc2c(F)c(F)c(C=O)cc12
Reactant: C[C@@H]1CNC[C@H](C)O1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(c2c(C=O)cc3c(c2F)ONC3OC(=O)OC(C)(C)C)C[C@H](C)O1
Temperature: 80 °C

Procedure:
To an ice cooled and stirred solution of tert-butyl 6,7-difluoro-5-formyl-1,2-benzisoxazol-3-yl carbonate (Intermediate 531, 3.0 g, 10.0 mmol) in anhydrous acetonitrile was added DIPEA (2.56 g, 20.0 mmol) followed by cis 2,6-dimethylmorpholine (1.27 g, 11.0 mmol) and the mixture heated at 80° C. for 12 hours. It was cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate, washed with water followed by brine and then dried over anhydrous sodium sulfate. It was filtered and the filtrate evaporated under reduced pressure. The residue was purified on a silica gel column using a gradient of ethyl acetate in pet.ether to give product as a solid. Yield: 2.9 g (74%).
Reaction SMILES: [F:1][C:2]1[C:3](I)=[CH:4][C:5](=[O:21])[N:6]([CH2:8][CH2:9][C@@:10]([CH3:20])([S:16]([CH3:19])(=[O:18])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:51]=[CH:50][C:34]([O:35][CH2:36][C@H:37]3[CH2:42][CH2:41][C@H:40]([O:43][CH:44]4[CH2:49][CH2:48][CH2:47][CH2:46][O:45]4)[CH2:39][CH2:38]3)=[CH:33][CH:32]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CC1CCCO1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[C:3]([C:31]2[CH:51]=[CH:50][C:34]([O:35][CH2:36][C@H:37]3[CH2:38][CH2:39][C@H:40]([O:43][CH:44]4[CH2:49][CH2:48][CH2:47][CH2:46][O:45]4)[CH2:41][CH2:42]3)=[CH:33][CH:32]=2)=[CH:4][C:5](=[O:21])[N:6]([CH2:8][CH2:9][C@@:10]([CH3:20])([S:16]([CH3:19])(=[O:18])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=1
Reactant: CCOC(=O)[C@@](C)(CCn1cc(F)c(I)cc1=O)S(C)(=O)=O
Reactant: CC1(C)OB(c2ccc(OC[C@H]3CC[C@H](OC4CCCCO4)CC3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CC1CCCO1
Solvent: O
Product: CCOC(=O)[C@@](C)(CCn1cc(F)c(-c2ccc(OC[C@H]3CC[C@H](OC4CCCCO4)CC3)cc2)cc1=O)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Pd(dppf)Cl2 (350 mg, 0.431 mmol) was added to a solution of ethyl (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate (1.6 g, 3.6 mmol), 2-[(trans-4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}cyclohexyl)oxy]tetrahydro-2H-pyran (1.9 g, 4.49 mmol), and potassium phosphate tribasic (2.9 g, 10.8 mmol) in 2-methyl tetrahydrofuran/water (5:1, 240 mL). The reaction mixture was heated to 80° C. and stirred at this temperature for 16 h. The reaction was allowed to cool to rt, and water (50 mL) was added. The mixture was extracted with EtOAc (3×150 mL). The combined organic phases were dried (Na2SO4), filtered, and concentrated under reduced pressure to afford the title compound as a light tan solid (1.4 g, 64%). MS (LCMS) m/z 608.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([O:22][CH3:23])=[N:20][C:19](Br)=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cu](C#N)[C:26]#[N:27]>CS(C)=O.[OH-].[NH4+].O.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([O:22][CH3:23])=[N:20][C:19]([C:26]#[N:27])=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1nc(Br)cnc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: N#C[Cu]C#N
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1nc(C#N)cnc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To 4-[(5-bromo-3-methoxy-pyrazin-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 0.00125 mol) in DMSO (10 mL), under nitrogen, was added copper cyanide (0.565 g, 0.00625 mol) and the mixture heated to 150° C. for 1.5 h. The reaction mixture was cooled to rt, diluted with a mixture of 20% ammonium hydroxide in water (50 mL) and dichloromethane (50 mL) and allowed to stir for 1 h. The organic layer was removed, dried over sodium sulfate, filtered and concentrated to an oil. The oil was chromatographed on silica using a gradient of 20–40% ethyl acetate/hexane to give the title compound as a foam. M.S.(M+1): 348.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[C:11]4[O:19][CH2:18][CH2:17][O:16][C:12]4=[CH:13][CH:14]=3)[C:9](=[O:20])[O:8]2)[CH2:4][CH2:3]1.ClC(OC(Cl)C)=O>ClCCCl>[CH2:18]1[CH2:17][O:16][C:12]2[C:11](=[C:10]3[C:15](=[CH:14][CH:13]=2)[C:5]2([CH2:6][CH2:7][NH:2][CH2:3][CH2:4]2)[O:8][C:9]3=[O:20])[O:19]1
Reactant: CN1CCC2(CC1)OC(=O)c1c2ccc2c1OCCO2
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: O=C1OC2(CCNCC2)c2ccc3c(c21)OCCO3
Yield: 42.7 %

Procedure:
Into a 25 ml round bottom flask fitted with a nitrogen inlet, condenser, and a magnetic stirring bar were placed 1′-methyl-(4,5-ethylenedioxy)spiro(isobenzofuran-1(3H),4′-piperidin)-3-one (501 mg, 1.82 mmol) and 5.5 ml of 1,2-dichloroethane. The mixture was cooled to 0° before 1-chloroethyl chloroformate (0.8 ml, 7.28 mmol) was added slowly via a syringe. The mixture was then heated to reflux for 72 hours. The mixture was concentrated in vacuo and the residue taken up in 5.5 ml of methanol. This mixture was heated to reflux for 3 hours before concentration. This residue was diluted with water and made basic with concentrated ammonium hydroxide. The aqueous mixture was extracted with ethyl acetate. The organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was taken up in 2% methanol:ammonium hydroxide and chromatographed (100:10:1 methylene chloride:methanol:ammonium hydroxide) to give 203 mg of title product (43%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[O:36][CH3:37])[C:9]1[N:14]=[C:13]2[N:15]([CH2:21][CH3:22])[C:16]([C:18]([OH:20])=O)=[CH:17][C:12]2=[C:11]2[N:23]([CH3:26])[CH:24]=[N:25][C:10]=12)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH:39]1([NH:42][CH:43]2[CH2:45][CH2:44]2)[CH2:41][CH2:40]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C.CN(C1C=CN=CC=1)C>[CH:39]1([N:42]([CH:43]2[CH2:45][CH2:44]2)[C:18]([C:16]2[N:15]([CH2:21][CH3:22])[C:13]3=[N:14][C:9]([N:8]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=4[O:36][CH3:37])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[C:10]4[N:25]=[CH:24][N:23]([CH3:26])[C:11]4=[C:12]3[CH:17]=2)=[O:20])[CH2:41][CH2:40]1
Reactant: CCn1c(C(=O)O)cc2c3c(ncn3C)c(N(Cc3ccc(OC)cc3OC)C(=O)OC(C)(C)C)nc21
Reactant: C1CC1NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N(Cc3ccc(OC)cc3OC)C(=O)OC(C)(C)C)nc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.8 %

Procedure:
To a mixture of 4-(tert-butoxycarbonyl(2,4-dimethoxybenzyl)amino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxylic acid (example 1H, 0.89 g, 1.747 mmol) in acetonitrile (17.47 mL) was added dicyclopropylamine hydrochloride (0.303 g, 2.271 mmol), N-methylmorpholine (0.499 mL, 4.54 mmol), DMAP (0.021 g, 0.175 mmol), and HATU (0.797 g, 2.096 mmol). The reaction mixture was stirred at rt 5 h and heated to 50° C. for 45 min. The reaction was cooled to room temperature. Acetonitrile was removed in vacuo and the residue was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude solid was purified by flash chromatography using an Isco 80 g column eluting with 1-4% MeOH/CH2Cl2 to yield tert-butyl 7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(2,4-dimethoxybenzyl)carbamate (0.8 g, 78% yield) as an off-white solid.