Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH2:19][CH2:20][NH:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:17]=1)[C:12]([OH:14])=O.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:61]([NH:64][CH2:65][CH2:66][C:67]#[N:68])([CH3:63])[CH3:62]>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:67]([CH2:66][CH2:65][N:64]([CH:61]([CH3:63])[CH3:62])[C:12](=[O:14])[C:11]1[CH:15]=[C:16]([O:18][CH2:19][CH2:20][NH:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:17]=[C:9]([CH3:8])[CH:10]=1)#[N:68]
Reactant: Cc1cc(OCCNc2ccncc2)cc(C(=O)O)c1
Reactant: CC(C)NCCC#N
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(OCCNc2ccncc2)cc(C(=O)N(CCC#N)C(C)C)c1
Reaction time: 24 h

Procedure:
A solution of 3-methyl-5-[2-(pyridin-4-ylamino)-ethoxy]-benzoic acid trifluoroacetate salt (0.026 g) in anhydrous DMF (2 ml) was treated at room temperature with 3-isopropylamino-propionitrile9 (0.017 g), PyBrop® (0.062 g) and DIPEA (0.025 ml). More PyBrop® was added after 2 days (0.072 g) and 7 days (0.065 g). More 3-isopropylamino-propionitrile was added after 2 days (0.03 ml), 4 days (0.1 ml) and 7 days (0.1 ml). After 24 h more, the mixture was evaporated to dryness under reduced pressure and the residue subjected to preparative hplc giving the title compound as a clear colourless gum (0.016 g).
Reaction SMILES: OS(O)(=O)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3:11].[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[NH:19][CH:18]=[C:17]2[CH2:25][C:26]#[N:27]>C1COCC1>[AlH3:11].[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:20]([NH:19][CH:18]=[C:17]2[CH2:25][CH2:26][NH2:27])=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1cc2[nH]cc(CC#N)c2cc1OC
Reactant: [Al+3]
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc2[nH]cc(CCN)c2cc1OC
Product: [AlH3]
Yield: 85.7 %

Procedure:
A solution of AlH3 in THF was prepared by dropwise addition of a solution of 0.52 ml (0.98 g, 10 mmol) of 100% H2SO4 in 4 ml of THF to a mixture of 0.76 g (20 mmol) of LiAlH4 and 20 ml of THF. Without removing the precipitated Li2SO4, a solution of 0.5 g (2.33 mmol) of 5,6-dimethoxy-3-indoleacetonitrile in 4 ml of THF was added over 30 min period. after stirring for another hour, the excess hydride was destroyed by the addition of small chips of ice. Most of the supernatant THF solution was decanted (setting aside most of the THF at this point greatly reduces emulsion formation in the subsequent extraction). The precipitated aluminum salts were treated with cold 20% NaOH, and the resulting cloudy solution was extracted with CHCl3. These extracts were combined with the THF solution, washed with NaCl solution, and dried over Na2SO4. The solvents were removed, and the residue was triturated with Et2-pentane. The crystalline product was washed with hot Et2O-Skelly B and dried, giving 0.44 g (83%) of pure 5,6-dimethoxytryptamine.
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH2:5]([O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:20][Sn]Cl>Cl>[ClH:20].[CH2:5]([O:12][C:13]1[CH:14]=[CH:15][C:16]([NH:17][NH2:1])=[CH:18][CH:19]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=N[O-]
Reactant: Cl[Sn]Cl
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Product: NNc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Yield: 95 %

Procedure:
A solution of sodium nitrite (3.8 g, 0.055 mol in 20 mL of H2O), is added dropwise to an ice cold stirring suspension of 4-benzyloxyaniline (13.0 g, 0.055 mol in 150 mL of concentrated HCl). The reaction mixture is stirred for 90 minutes at -8° to 10° C. A solution of SnCl2 ·2H2O (32.0 g, 0142 mol in 50 mL concentrated HCl) is added and stirred for i hour at 0° C. The reaction mixture is removed from the ice bath and is stirred at room temperature for 20 hours. The mixture is then filtered and washed with water to give 13.0 g (95% yield) of product, m.p. 182°-185° C.
Reaction SMILES: [C:1](#[N:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][C:12]1[NH:16][N:15]=[C:14]([NH2:17])[CH:13]=1.[CH3:18][S:19]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:21])=[O:20]>>[CH3:11][C:12]1[NH:16][N:15]=[C:14]([NH:17][C:3]2[CH:2]=[C:1]([N:25]3[CH2:26][CH2:27][N:22]([S:19]([CH3:18])(=[O:21])=[O:20])[CH2:23][CH2:24]3)[N:10]=[C:1]([CH:2]=[CH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:10]=2)[CH:13]=1
Reactant: N#CC=Cc1ccccc1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: Cc1cc(N)n[nH]1
Product: Cc1cc(Nc2cc(N3CCN(S(C)(=O)=O)CC3)nc(C=Cc3ccccc3)n2)n[nH]1

Procedure:
Example 71 was synthesized via Scheme 6 according to the general scheme provided above with the appropriate starting materials cinnamonitrile, 5-methyl-1H-pyrazole-3-amine, and 4-methylsulfonylpiperazine. Structure of the target was confirmed by 1H-NMR. The 1H-NMR is attached.
Reaction SMILES: O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[C:12]1([Li])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([Li])CCC.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[C:31](#[N:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1>[C:12]1([C:31]([NH2:38])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1ccccc1
Reactant: Brc1ccccc1
Reactant: [Li]c1ccccc1
Agent: [Ce+3]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Cerium chloride heptahydrate (15.0 g, 40 mmol) was dried and stirred with 80 mL of dry tetrahydrofuran as described in Example 1. To this was added by cannulation below -50° a solution of phenyllithium prepared by addition of 16 mL of 2.5M n-butyllithium in hexanes (40 mmol) to 6.28 g (40 mmol) of bromobenzene in 15 mL of tetrahydrofuran below -40°. The mixture was stirred in a dry ice-acetone bath for 30 minutes, and 1.34 g (13 mmol) of benzonitrile in 2 mL of tetrahydrofuran were added. The bath was removed and the mixture was stirred for 2 hours. Isolation as described in Example 1 gave 3.30 g (98%) of triphenylmethylamine, identical by infrared, 1H and 13C NMR spectroscopy with an authentic sample.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([N+:22]([O-])=O)[C:15]=2[C:25]#[N:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.NN>C(O)C.[Ni].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([NH2:22])[C:15]=2[C:25]#[N:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C#N)c([N+](=O)[O-])c1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(N)c(C#N)c(N2CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
To 370 mg (1.02 mmol) of 4-(2-cyano-5-methoxy-3-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester dissolved in 5 mL ethanol and 5 mL ethyl acetate was added a pipet of Raney nickel slurry in water followed by 64 μL (2 eq., 2.04 mmol) hydrazine. The mixture was stirred 30 minutes to completion, filtered through Celite and concentrated under reduced pressure to provide 300 mg of crude 4-(3-amino-2-cyano-5-methoxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12]S(O)(=O)=O.C1N2CN3CN(C2)CN1C3.Cl.[OH2:28]>>[CH:12]([C:11]1[CH:10]=[C:5]([CH:4]=[CH:3][C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7])=[O:28]
Reactant: O
Reactant: CS(=O)(=O)O
Reactant: COC(=O)c1ccc(O)cc1
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: COC(=O)c1ccc(O)c(C=O)c1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 31 %

Procedure:
To a mixture of methyl 4-hydroxybenzoate (20 g, 131 mmol) and methanesulfonic acid (80 mL), hexamethylenetetramine (20 g, 144 mmol) was added in small portions at room temperature. After stirring at 100° C. for 3.5 hours, concentrated hydrochloric acid (10 mL) and water (300 mL) were added. The reaction mixture was extracted twice with ethyl acetate and the organic phase was dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20-65:35) to give methyl 3-formyl-4-hydroxy-benzoate (7.24 g, 31%, mp 87.5-89.0° C.) as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][NH:7]1.Br[CH2:29][C:30](Br)=[O:31].[NH2:33][C@@H:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][C@@H:35]1[OH:43]>>[CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:29][C:30]([NH:33][C@@H:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][C@@H:35]1[OH:43])=[O:31]
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(OC)c(OC)c1OC)NCC2
Reactant: O=C(Br)CBr
Product: COc1cc2c(cc1OC)C(Cc1ccc(OC)c(OC)c1OC)N(CC(=O)N[C@@H]1c3ccccc3C[C@@H]1O)CC2

Procedure:
prepared by reaction of 1-(2,3,4-Trimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with (1R,2S)-1-amino-2-indanol
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH3:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([CH:26]=O)[CH:21]=1.O>O1CCCC1>[CH3:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22](/[CH:26]=[CH:9]/[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH:21]=1
Reactant: Cc1ccnc(C=O)c1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccnc(/C=C/C(=O)OC(C)(C)C)c1
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
A solution of tert-butyl diethylphosphonoacetate (6.2 g, 24 mmol) in tetrahydrofuran (20 ml) was added dropwise to a mixture of sodium hydride (60% in oil, 1.1 g, 26 mmol) and tetrahydrofuran (120 ml) at 0° C., and the mixture was stirred at the same temperature for 30 minutes. Successively, a solution of 4-methyl-2-pyridinecarbaldehyde (1.5 g, 12 mmol) in tetrahydrofuran (30 ml) was added dropwise to the mixture at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was combined with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was subjected to a silica gel column chromatography. The fractions eluted with ethylacetate-hexane (1:5, v/v) were collected and concentrated to give the titled compound (1.9 g, 70%).
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][C:12]([NH2:14])=[NH:13].[O-]CC.[Na+].C([O:21][C:22]([CH:24]1[CH2:28][CH2:27][CH2:26][C:25]1=O)=O)C>C(O)C>[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][C:12]1[NH:14][C:25]2[CH2:26][CH2:27][CH2:28][C:24]=2[C:22](=[O:21])[N:13]=1
Reactant: N=C(N)CCc1cccc(F)c1F
Reactant: CCOC(=O)C1CCCC1=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=c1nc(CCc2cccc(F)c2F)[nH]c2c1CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
To a solution of 3-(2,3-difluorophenyl)-propionamidine hydrochloride (Int. A3) (3.90 g, 17.7 mmol) in ethanol (80 ml) was added sodium ethoxide (1.44 g, 21.2 mmol) in portions and resulting slurry stirred at ambient temperature for 1 h. 2-Oxo-cyclopentanecarboxylic acid ethyl ester (3.09 ml, 21.2 mmol) was then added and the mixture refluxed for 2 days. Evaporation of the reaction mixture followed by chromatography (silica, dichloromethane-acetone) gave the title compound (2.76 g, 56%) as a cream solid. 1H-NMR (DMSO) δ 1.94 (2H, m), 2.59 (2H, t), 2.72 (2H, t), 2.82 (2H, t), 3.05 (2H, t), 7.07-7.29 (3H, m), 12.20 (1H, s); MS (APCI+) found (M+1)=277; C15H14F2N2O requires 276.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH2:9]([O:11][C:12](=[O:19])[CH:13]=[C:14]([NH2:18])[S:15][CH2:16][CH3:17])[CH3:10]>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[CH:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[CH:13]([C:12]([O:11][CH2:9][CH3:10])=[O:19])[C:14]([S:15][CH2:16][CH3:17])=[N:18][C:14]=1[NH2:18])=[O:19])[CH3:10]
Reactant: CCOC(=O)C=C(N)SCC
Reactant: O=Cc1ccncc1
Solvent: CCO
Product: CCOC(=O)C1=C(N)N=C(SCC)C(C(=O)OCC)C1c1ccncc1

Procedure:
Upon boiling a solution of 5.3 g of pyridine-4-aldehyde and 17.5 g of 3-amino-3-ethylmercaptoacrylic acid ethyl ester in 100 ml of ethanol for 5 hours, 2-amino-4-(4-pyridyl)-6-ethylmercapto-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 156°C is obtained.
Reaction SMILES: N(C(OC(C)C)=O)=NC([O:5][CH:6](C)[CH3:7])=O.[OH:15][C@H:16]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:43]=[N:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=2)=[CH:38][CH:37]=1)[C@H:17]([CH2:21][CH2:22][N:23]1[C:28](=[O:29])[C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[N:25]=[N:24]1)[C:18]([OH:20])=[O:19].C(P(CCCC)CCCC)CCC.C(O)(=O)C>O1CCCC1>[C:6]([O:15][C@H:16]([CH2:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]2[CH:43]=[N:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=2)=[CH:40][CH:41]=1)[C@H:17]([CH2:21][CH2:22][N:23]1[C:28](=[O:29])[C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[N:25]=[N:24]1)[C:18]([OH:20])=[O:19])(=[O:5])[CH3:7]
Reactant: COc1ccc(-c2ccc(CC[C@@H](O)[C@H](CCn3nnc4ccccc4c3=O)C(=O)O)cc2)cn1
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(CC[C@@H](OC(C)=O)[C@H](CCn3nnc4ccccc4c3=O)C(=O)O)cc2)cn1
Reaction time: 1 h
Yield: 73.5 %

Procedure:
Diisopropyl azodicarboxylate (63 mg) was added to a solution of compound (100 mg) obtained from Example 1A above, tri-n-butylphosphine (93 mg) and acetic acid (1 ml) in dry tetrahydrofuran (3 ml) at 0° C. Reaction mixture was stirred for 1 hour and concentrated. Residue was taken in ethyl acetate and washed with water and brine. Organic layer was concentrated to get oily residue which was purified on preparative thin layer chromatography (2 mm thickness) using 10% methanol in dichloromethane to get the title compound (80 mg) (formed probably by esterfication of acetic acid (used in large excess) and not due to Mitsunobu reaction). Mass (m/z): 517.06 (M++1); 1HNMR: δ 8.37 (m, 2H), 8.15 (d, 1H, J=8 Hz), 7.97-7.93 (m, 1H), 7.82-7.80 (m, 1H), 7.41 (d, 2H, J=8 Hz), 7.20 (d, 2H, J=8 Hz), 6.83 (d, 1H, J=8 Hz), 5.28-5.27 (m, 1H), 4.56-4.58 (m, 2H), 4.01 (s, 3H), 2.85-2.80 (m, 1H), 2.55-2.75 (m, 2H), 2.31-2.29 (m, 2H), 2.25-2.10 (m, 2H), 2.063 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:9](Cl)=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]#[N:5].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.O>CN(C)C=O>[Cl:1][C:2]1[C:9]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c([N+](=O)[O-])ccc(Cl)c1Cl
Reactant: C1CCNC1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c([N+](=O)[O-])ccc(N2CCCC2)c1Cl
Yield: 88.2 %

Procedure:
13.0 g of 2,3-dichloro-6-nitrobenzonitrile was dissolved in 50 ml of dimethylformamide, and 11.0 g of pyrrolidine was added to the solution, followed by stirring while externally cooling because of heat generation. After continuing the stirring for 30 minutes, the reaction mixture was poured into water. The precipitate thus formed was filtered, washed with water and then with methanol to obtain 13.3 g of 2-chloro-6-nitro-3-pyrrolidinobenzonitrile (melting point: 170°-173° C.).
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([OH:15])=[O:14])[CH2:5]1)#[N:2].[CH3:16][CH2:17][CH2:18]CCCC=CCCC.IC(C)C>C(#N)C.C(OCC)C>[C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([O:15][CH:17]([CH3:18])[CH3:16])=[O:14])[CH2:5]1)#[N:2]
Reactant: CC1(C)O[C@H](CC#N)C[C@H](CC(=O)O)O1
Reactant: CCCC=CCCCCCC
Solvent: CC(C)I
Solvent: CC#N
Solvent: CCOCC
Product: CC(C)OC(=O)C[C@H]1C[C@@H](CC#N)OC(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (±)-cis-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid, 0.6 g (3 mmol), in acetonitrile, 2 mL, is added 1,8-diazabicyclo5.4.0]-undec-7-ene (DBU), 0.45 mL (3 mmol), and 2-iodopropane, 0.33 mL (3.3 mmol). The solution is stirred overnight at room temperature, diluted with diethyl ether, washed with brine, and dried (magnesium sulfate). Flash chromatography provides 0.55 g of (±)-cis-1-methylethyl 6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane4-acetate.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:24])=[C:5]([C:25]([NH:27][CH2:28][C:29]([CH3:36])([CH3:35])[C:30]([O:32]CC)=[O:31])=[O:26])[N:4]=1)#[N:2].O.CCOC(C)=O.Cl>CO.[OH-].[Na+]>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:24])=[C:5]([C:25]([NH:27][CH2:28][C:29]([CH3:36])([CH3:35])[C:30]([OH:32])=[O:31])=[O:26])[N:4]=1)#[N:2]
Reactant: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3cccc4ccccc34)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(Oc3cccc4ccccc34)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Ethyl 3-(1-cyano-4-hydroxy-7-(naphthalen-1-yloxy)isoquinoline-3-carboxamido)-2,2-dimethylpropanoate (16 mg, 0.03 mmol) was dissolved in MeOH (4 mL) and 2 N NaOH (4 mL). After stirring for 5 hours at room temperature, H2O (15 mL) and EtOAc (15 mL) were added. To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-30% MeOH/CH2Cl2) to give the title compound in 13 mg. MS: (−) m/z 454.03 (M−1).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[CH3:18][C:19](=[N:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38](=[N:43][O:44][CH3:45])[C:39](OC)=[O:40])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1.ClCCl>CO>[CH3:18][C:19](=[N:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38](=[N:43][O:44][CH3:45])[CH:39]=[O:40])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[CH:21]=1
Reactant: CON=C(C(=O)OC)c1ccccc1ON=C(C)c1cccc(C(F)(F)F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CON=C(C=O)c1ccccc1ON=C(C)c1cccc(C(F)(F)F)c1
Reaction time: 3 h
Yield: 49.1 %

Procedure:
1M diisobutylaluminum hydride/toluene solution (11 ml, 16.5 mmol) was added dropwise to a mixture of methyl 2-[(α-methyl-3-trifluoromethylbenzylidene)aminooxy]-α-methoxyiminophenylacetate (4.83 g, 11.8 mmol) and dichloromethane (47 ml) at −65° C. or lower over 4 minutes, and the mixture was stirred at −78° C. to room temperature for 3 hours. Methanol (7 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The precipitated insoluble materials were removed, and the remaining mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-[(α-methyl-3-trifluoromethylbenzylidene)aminooxy]-α-methoxyiminophenylacetaldehyde (2.11 g, 47.3%) as a colorless
Reaction SMILES: [NH2:1][C@H:2]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=1)[CH2:3][CH2:4][C:5]([CH3:12])([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[O:21]=[C:22]1[NH:30][C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[C@:23]21[CH2:44][C:33]1[CH:34]=[C:35]3[C:40](=[CH:41][C:32]=1[CH2:31]2)[N:39]=[CH:38][C:37]([CH:42]=O)=[CH:36]3.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl.C(=O)(O)[O-].[Na+]>[F:20][C:15]1[CH:14]=[C:13]([C@@H:2]([NH:1][CH2:42][C:37]2[CH:38]=[N:39][C:40]3[C:35]([CH:36]=2)=[CH:34][C:33]2[CH2:44][C@:23]4([CH2:31][C:32]=2[CH:41]=3)[C:24]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[NH:30][C:22]4=[O:21])[CH2:3][CH2:4][C:5]([CH3:11])([CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:18]=[C:17]([F:19])[CH:16]=1
Reactant: CCOC(=O)C(C)(C)CC[C@H](N)c1cc(F)cc(F)c1
Reactant: O=Cc1cnc2cc3c(cc2c1)C[C@@]1(C3)C(=O)Nc2ncccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)CC[C@H](NCc1cnc2cc3c(cc2c1)C[C@@]1(C3)C(=O)Nc2ncccc21)c1cc(F)cc(F)c1
Reaction time: 0.17 h

Procedure:
To a stirred solution of ethyl (5S)-5-amino-5-(3,5-difluorophenyl)-2,2-dimethylpentanoate from Step A (˜82.0 mg, 0.289 mmol) and (7S)-2′-oxo-1′, 2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-3-carbaldehyde (91.0 mg, Intermediate 1) in dry chloroform (3 mL) was added HOAc (35 μL, 0.606 mmol). After 10 minutes, sodium triacetoxyborohydride (129 mg, 0.606 mmol) was added. After 80 minutes of stifling, the reaction mixture was diluted with DCM (30 mL) and saturated sodium bicarbonate (20 mL). The layers were separated and the aqueous layer was extracted once with DCM (20 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue. This residue was applied to a silica gel column for purification, eluting with a gradient of CH2Cl2:MeOH—99:1 to 93:7. Clean product-containing fractions were pooled and concentrated in vacuo to give the title compound, which still contained about 30% of the methyl ester. MS: m/z=585 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([F:8])[C:5]([OH:9])=[CH:4][CH:3]=1.CS(O[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([F:8])[C:5]([O:9][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: CC(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reactant: Oc1ccc(Br)nc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N1CCC(COc2ccc(Br)nc2F)CC1
Yield: 67.5 %

Procedure:
1-Methylethyl 4-{[(6-bromo-2-fluoro-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (0.238 g, 68%) was prepared as a white solid from 6-bromo-2-fluoro-3-pyridinol (0.18 g, 0.94 mmol), 1-methylethyl 4-{[(methylsulfonyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 131, Step 4, 0.38 g, 1.22 mmol) and K2CO3 (0.26 g, 1.88 mmol) in DMF (10 mL) in a manner similar to Example 131, Step 5. The crude product was purified by flash chromatography on an ISCO silica gel column using 0 to 35% EtOAc/hexanes. 1H NMR (400 MHz, CDCl3): δ 7.27 (d, 1H, J=8.3 Hz), 7.20-7.10 (m, 1H), 4.91 (septet, 1H, J=6.2 Hz), 4.30-4.10 (m, 2H), 3.85 (d, 2H, J=6.3 Hz), 2.85-2.70 (m, 2H), 2.10-1.95 (m, 1H), 1.90-1.75 (m, 2H), 1.45-1.20 (m, 8H); LRMS (ESI), m/z 375/377 (M+H).