Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:12]([CH2:24][C:25]([OH:27])=[O:26])[CH2:13][CH2:14][N:15]([CH2:20][C:21]([OH:23])=O)[CH2:16][C:17]([OH:19])=[O:18])[CH2:2][N:3]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][C:5]([OH:7])=O>C(Cl)(Cl)Cl>[CH2:20]1[N:15]([CH2:14][CH2:13][N:12]([CH2:24][C:25]([OH:27])=[O:26])[CH2:1][CH2:2][N:3]2[CH2:8][C:9](=[O:10])[O:11][C:5](=[O:7])[CH2:4]2)[CH2:16][C:17](=[O:19])[O:18][C:21]1=[O:23]
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CCN(CC(=O)O)CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=C(O)CN(CCN1CC(=O)OC(=O)C1)CCN1CC(=O)OC(=O)C1
Reaction time: 0.02 h

Procedure:
A 0.1 mg/ml solution of DTPA anhydride in dry chloroform was prepared and an aliquot containing the desired quantity of DTPA was added to a reaction vessel. The chloroform was removed by evaporation with nitrogen gas at room temperature. A pH 7.0 solution of antibody (approximately 0.5 mg) in 0.05M bicarbonate buffer was added to said reaction vessel to produce a 7:1 molar ratio of anhydride to protein. The solution was incubated with shaking for one minute and the coupled antibody was recovered by passage over a Sephadex G-50 column.
Reaction SMILES: C([O:3][C:4](=O)[C@H:5]([O:7][C:8]1[CH:13]=[C:12]([NH:14][S:15]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)(=[O:17])=[O:16])[N:11]=[C:10]([S:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=2[F:32])[N:9]=1)[CH3:6])C.[BH4-].[Li+]>C1COCC1>[F:32][C:26]1[C:27]([F:31])=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][S:23][C:10]1[N:11]=[C:12]([NH:14][S:15]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)(=[O:16])=[O:17])[CH:13]=[C:8]([O:7][C@H:5]([CH3:6])[CH2:4][OH:3])[N:9]=1
Reactant: CCOC(=O)[C@@H](C)Oc1cc(NS(=O)(=O)c2nccs2)nc(SCc2cccc(F)c2F)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](CO)Oc1cc(NS(=O)(=O)c2nccs2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-[[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(2-thiazolylsulfonyl)amino]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester (the product from step ii) (0.11 g) in THF (3 mL) was added lithium borohydride (2 M solution in THF, 0.23 mL) and the mixture was mixture was stirred at ambient temperature for 20 h. The reaction mixture was cooled to 0° C., quenched with 0.5M HCl solution and the aqueous was extracted with EtOAc (×2). The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel using MeOH/DCM (99:1 to 98:2 gradient) as eluent to give the title compound as a white solid. Yield: 15 mg
Reaction SMILES: [O:1]=[C:2]1[C:6]2=[CH:7][N:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:18][CH:17]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]2=[N:4][N:3]1[CH2:27][C:28]([O:30]CC)=[O:29].[OH-].[Li+].Cl>O1CCOCC1.ClCCl>[O:1]=[C:2]1[C:6]2=[CH:7][N:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:18][CH:17]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]2=[N:4][N:3]1[CH2:27][C:28]([OH:30])=[O:29]
Reactant: CCOC(=O)Cn1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(O)Cn1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Reaction time: 18 h

Procedure:
Ethyl (3-oxo-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-3,5-dihydro-2H-pyrazol[4,3-c]quinolin-2-yl)acetate (Example 524, 10 mg, 0.023 mmol) was suspended in dioxane (2 mL), treated with an lithium hydroxide (22 μL, 1 N aqueous, 0.023 mmol, 1.05 equiv) and stirred vigorously for 18 hours. The mixture was diluted with dichloromethane until homogeneous (2 mL) and stirred for an additional 6 hours. The mixture was treated with hydrochloric acid (1 drop from 9″ pipette, 12 N aqueous) and concentrated in vacuo, providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 9.06 (1H, s), 8.44 (1H, d, J=2.7 Hz), 8.15 (1H, d, J=7.9 Hz), 7.81 (2H, d, J=8.8 Hz), 7.74 (1H, d, J=8.5 Hz), 7.71 (1H, d, J=1.3 Hz), 7.58 (1H, t, 7.8 Hz), 7.50 (1H, t, J=7.3 Hz), 7.43 (2H, d, J=8.5 Hz), 7.14 (1H, hr s), 6.52 (1H, m), 5.74 (2H, s), 4.59 (2H, s) ppm; high resolution mass spectrometry (ES+) m/z 400.1412 [(M+H)+; calculated for C22H18N5O3: 400.1404].
Reaction SMILES: [CH3:1][N:2]1[C:12]2[C:7](=[CH:8][C:9]([OH:13])=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:3]1=[O:4].[OH-].[K+].[I-].[Na+].[CH3:18][N:19]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl.[Na+].[Cl-]>CS(C)=O>[CH3:1][N:2]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:23][CH2:22][CH2:21][C:20]([N:19]([CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)[CH3:18])=[O:25])=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:3]1=[O:4]
Reactant: CN(C(=O)CCCCl)C1CCCCC1
Reactant: CN1C(=O)CCc2cc(O)ccc21
Agent: [Cl-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1C(=O)CCc2cc(OCCCC(=O)N(C)C3CCCCC3)ccc21
Reaction time: 4.5 h

Procedure:
3.4 Grams of 1-methyl-6-hydroxy-3,4-dihydrocarbostyril, 0.9 g of potassium hydroxide, 3.2 g of sodium iodide and 5.0 g of N-methyl-N-(4-chlorobutyryl)-cyclohexylamine are added to 50 ml of dimethylsulfoxide and agitated at 70° to 80° C. for 4.5 hours. After the reaction, the reaction solution is poured into 400 ml of saturated NaCl solution and the precipitated crystals are filtered out and washed with water. The resultant crude crystals are recrystallized from ligroin to obtain 3.1 g of 1-methyl-6-[3-(N-cyclohexyl-N-methylaminocarbonyl)propoxy]-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with melting point of 104.5°-106.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](OS(C(F)(F)F)(=O)=O)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.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>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:25]3[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][C:26]=3[Cl:28])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: O=c1cc(OS(=O)(=O)C(F)(F)F)c2ccc(Br)cc2o1
Reactant: OB(O)c1ccc(Cl)cc1Cl
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: C1CCOC1
Product: O=c1cc(-c2ccc(Cl)cc2Cl)c2ccc(Br)cc2o1
Temperature: 70 °C
Yield: 67.9 %

Procedure:
To a solution of the triflate from Step 1 (712 mg, 1.91 mmol) in 15 ml THF was added 2,4-dichlorophenyl boronic acid (400 mg, 2.10 mmol), (Ph3P)4Pd (110 mg, 0.095 mmol) and aqueous Na2CO3 (1.91 mL, 3.82 mmol). The mixture was heated at 70° C. for 2 h, cooled and partitioned between aqueous NH4Cl and EtOAc (50 mL each). The layers were separated and the aqueous phase was extracted with EtOAc (3×25 mL). The combined organic layers were dried over anhydrous MgSO4. The solvent was evaporated and the residue chromatographed on silica gel (hexane:EtOAc 9:1) to give 480 mg (68%) of the title compound.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[F:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](=[NH:19])[O:17][CH3:18])=[CH:14][CH:13]=1.Cl.[CH3:23][O:24][C:25](=[O:30])[CH:26](CO)N>C(Cl)Cl>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]2[O:17][CH2:18][CH:26]([C:25]([O:24][CH3:23])=[O:30])[N:19]=2)=[CH:20][CH:21]=1
Reactant: COC(=N)c1ccc(F)cc1
Reactant: COC(=O)C(N)CO
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1COC(c2ccc(F)cc2)=N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.7 %

Procedure:
N,N-diisopropylethylamine (11 mL, 63.3 mmol) was added dropwise to a solution of methyl 4-fluorobenzimidate hydrochloride (10 g, 52.74 mmol) and DL-serine methyl ester HCl salt (9.9 g, 63.63 mmol) in dry CH2Cl2 (200 mL) at 0° C. The reaction mixture was stirred at room temperature for 24 h and then concentrated under reduced pressure. The reaction mixture was diluted with CH2Cl2 and the organic layer was washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to get methyl 2-(4-fluorophenyl)-4,5-dihydrooxazole-4-carboxylate (9.5 g, yield 81%) as an orange liquid. 1H NMR (300 MHz, CDCl3) δ 8.02-7.97 (m, 2H), 7.13-7.07 (t, J=8.7 Hz, 2H), 4.98-4.92 (m, 1H), 4.73-4.57 (m, 2H), 3.83 (s, 3H). MS (ESI) m/z: Calculated for C11H10FNO3: 223.06. found: 223.8 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:53]=[CH:52][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:44][C:45]([O:47]C(C)(C)C)=[O:46])[C:24](=[O:43])[C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:42])[CH2:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=4)=[CH:27][CH:26]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)(C(F)(F)F)=O>>[CH2:1]([O:8][C:9]1[CH:53]=[CH:52][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:44][C:45]([OH:47])=[O:46])[C:24](=[O:43])[C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:42])[CH2:33][C:34]4[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=4)=[CH:27][CH:26]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)OC(C)(C)C)C(=O)c3ccc(NC(=O)Cc4ccc(OC)cc4)cc3)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)O)C(=O)c3ccc(NC(=O)Cc4ccc(OC)cc4)cc3)cc2)cc1
Reaction time: 1 h
Yield: 23 %

Procedure:
Prepared using General Procedure 8: To crude 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-5 (70 mg) was added TFA (1 mL). After stirring for 1 h, the solvent was concentrated and the product was purified by preparative HPLC to provide 19 mg (23%) of 2-(N-(4-((4-(heptyloxy)benzoyl)oxy)benzyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido)acetic acid 1. LCMS-ESI (m/z) calculated for C39H42N2O8: 667; found 666 [M−H]−, tR=9.51 min (Method 4). 1H NMR (400 MHz, DMSO) δ 12.80 (s, 1H), 10.31 (s, 1H), 8.16-7.97 (m, 2H), 7.69-7.58 (d, J=8.5 Hz, 2H), 7.48-7.27 (m, 4H), 7.28-7.19 (d, J=8.1 Hz, 4H), 7.15-7.05 (m, 2H), 6.93-6.82 (d, J=8.1 Hz, 2H), 4.74-4.51 (d, J=35.4 Hz, 2H), 4.15-3.80 (m, 4H), 3.71 (s, 3H), 3.66 (s, 2H), 1.84-1.66 (m, 2H), 1.48-1.19 (m, 8H), 0.93-0.80 (t, J=6.6 Hz, 3H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][S:13]([O-:15])=[O:14].[Na+]>CS(C)=O>[CH3:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=[C:2]([S:13]([CH3:12])(=[O:15])=[O:14])[N:7]=1
Reactant: CS(=O)[O-]
Reactant: Cc1nc(Br)ccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1nc(S(C)(=O)=O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.3 %

Procedure:
A mixture of 6-bromo-2-methyl-3-nitropyridine (100 g, 461 mmol) and sodium methanesulfinate (47.0 g, 461 mmol) in DMSO (300 mL) was stirred at room temperature for 1.5 h. The reaction mixture was poured into ice-water (1 L) and stirred until all the ice had melted. The ice-cold solution was filtered, and a dark purple solid was collected. The solid collected was dissolved in ethyl acetate (1 L). The solution was treated with activated charcoal, filtered through Celite™. The Celite™ cake was washed with ethyl acetate, and the filtrate was collected. The solvent was evaporated from the filtrate under reduced pressure to give the title compound (87.0 g, 87%) as a yellow solid. Exact mass calculated for C7H8N2O4S: 216.0. Found: LCMS m/z=217.2 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH2:13][CH3:14]>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:12][CH2:13][CH3:14])[N:5]=1)([O-:3])=[O:2]
Reactant: CCCBr
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCn1ccc([N+](=O)[O-])n1
Yield: 66.6 %

Procedure:
3-Nitro-1H-pyrazole (prepared as in Example 15, 100 mg, 0.89 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL) and a 60% dispersion of sodium hydride in mineral oil (37 mg, 0.93 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture stirred for an additional 10 min, the 1-bromo-propane (91 μL, 1.00 mmol) was added. The mixture continued to stir under nitrogen for 16 h. The solution was diluted with ethyl acetate (50 mL), washed with water (2×20 mL), saturated aqueous brine solution (2×20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 25% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded 3-nitro-1-propyl-1H-pyrazole (92 mg, 67%) as a yellow oil: H1-NMR (400 MHz, CDCl3) δ 0.89 (3H, t, J=7.6 Hz), 1.90 (2H, sextet, J=7.2 Hz), 6.82 (1H, d, J=2.8 Hz), 7.44 (1H, d, J=2.4 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[N:4][CH:3]=1.N(C1C2CCCCC=2C(C#N)=CC=1)=C=O.[OH:29][C@H:30]1[C@@H:37]2[N:33]([C:34](=[O:51])N(C3C4CCCCC=4C(C#N)=CC=3)[C:36]2=[O:38])[CH2:32][CH2:31]1>>[OH:29][C@H:30]1[C@@H:37]2[N:33]([C:34](=[O:51])[N:1]([C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]([C:12]#[N:13])=[N:4][CH:3]=3)[C:36]2=[O:38])[CH2:32][CH2:31]1
Reactant: N#Cc1ncc(N)c2ccccc12
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1CCCC2
Agent: N#Cc1ccc(N=C=O)c2c1CCCC2
Product: N#Cc1ncc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2ccccc12

Procedure:
The title compound was synthesized from compound 13D by procedures analogous to those described in Experiment 2E to 2F. HPLC: 97.6% at 1.54 min (retention time) (Conditions: YMC S5 C-18 (4.6×50 mm); Eluted with 0% to 100% B; 4 min gradient; (A=90% H2O-10% MeCN-0.1% TFA and B=10% H2O-90% MeCN-0.1% TFA); Flow rate at 4 mL/min. UV detection at 220 nm). LC/MS m/z 309 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:17])([CH3:16])[O:6][C@@H:7]1[CH2:11][N:10]([CH2:12][C:13]#[CH:14])[C:9](=[O:15])[CH2:8]1)([CH3:4])[CH3:3].N1CCCC1.C=O.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C(O)(=O)C.O1CCOCC1>[CH3:4][C:2]([Si:5]([CH3:17])([CH3:16])[O:6][C@@H:7]1[CH2:11][N:10]([CH2:12][C:13]#[C:14][CH2:30][N:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[C:9](=[O:15])[CH2:8]1)([CH3:1])[CH3:3]
Reactant: C1CCNCC1
Reactant: C#CCN1C[C@@H](O[Si](C)(C)C(C)(C)C)CC1=O
Agent: C=O
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: C1CCNC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC(=O)N(CC#CCN2CCCC2)C1

Procedure:
A mixture of 1.5 g of (S)-4-[[(1,1-dimethylethyl)dimethylsily]oxy]-1-(2-propynyl)-2-pyrrolidinone, 20 ml of dioxane, 0.66 ml of pyrrolidine, 0.32 g of paraformaldehyde, 3.0 ml of acetic acid and 42 mg of cuprous chloride was reacted as described in Example 1 with the substitution of dimethylamine for piperidine. The residue was purified by chromatography (alumina), o giving 290 mg of the desired product as a pale yellow oil, [α]D26 =+4° (dichloromethane).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:34])[NH:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH3:33])[CH3:32])=[CH:26][CH:25]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:35]([O:37]C)=[O:36])#[N:2].[OH-].[Na+]>CO>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20](=[O:34])[NH:21][CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([CH2:30][N:31]([CH3:33])[CH3:32])=[CH:28][CH:29]=3)=[CH:18][CH:19]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:35]([OH:37])=[O:36])#[N:2]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(CN(C)C)cc4)cc3)c(C#N)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)Cc1ccc(CCNC(=O)c2ccc(Oc3cc4c(cc3C#N)C(C(=O)O)CCO4)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.8 %

Procedure:
To a stirred solution of methyl 6-cyano-7-(4-(4-((dimethylamino)methyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate (83 mg, 0.16 mmol) in methanol (1 mL) at ambient temperature was added a 2M solution of sodium hydroxide (0.40 mL, 0.80 mmol). After stirring at ambient temperature for 1 hour the solution was concentrated, and the residual solid was redissolved in water (5 mL). The pH was adjusted to 4.5 to precipitate the product, and chloroform (5 mL) was added. After stirring the multiphase mixture for a few minutes, the product separated as a thick oil on the side of the flask. The chloroform/water mixture was decanted away and the residue dried under vacuum to afford 6-cyano-7-(4-(4-((dimethylamino)methyl)phenethylcarbamoyl) phenoxy)chroman-4-carboxylic acid as a light yellow glass (23 mg, 28% yield). MS (apci) m/z=500.1 (M+H).
Reaction SMILES: Cl[CH2:2][C@H:3]([CH3:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Br:12].[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[Br:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C@@H:3]([CH3:13])[CH2:2][N:28]1[CH2:29][CH2:30][CH:25]([C:21]2[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1
Reactant: C[C@@H](CCl)COc1ccccc1Br
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](C)COc3ccccc3Br)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 2-bromophenyl (2R)-3-chloro-2-methylpropyl ether and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 473.0 (M+H)+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]([CH3:23])[C:13](=[O:22])[S:14][C:15]=3[CH:16]([OH:21])[C:17]([O:19][CH3:20])=[O:18])=[CH:10][C:5]=2[CH:4]=[CH:3][CH2:2]1>ClCCl.C(Br)(C)(C)C.[Ag]=O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]([CH3:23])[C:13](=[O:22])[S:14][C:15]=3[CH:16]([O:21][C:5]([CH3:10])([CH3:6])[CH3:4])[C:17]([O:19][CH3:20])=[O:18])=[CH:10][C:5]=2[CH:4]=[CH:3][CH2:2]1
Reactant: COC(=O)C(O)c1sc(=O)n(C)c1-c1ccc2c(c1)C=CCO2
Agent: O=[Ag]
Agent: CC(C)(C)Br
Solvent: ClCCl
Product: COC(=O)C(OC(C)(C)C)c1sc(=O)n(C)c1-c1ccc2c(c1)C=CCO2
Yield: 58.4 %

Procedure:
At room temperature, a solution of methyl (4-1-benzopyran-6-yl-3-methyl-2-oxo-2,3-dihydro-thiazol-5-yl)-hydroxy-acetate (33d) (84 mg, 0.25 mmol) and silver oxide (580 mg, 2.5 mmol) in dichloromethane (500 μL) and tert-butyl bromide (5 mL) was stirred for 8 hours. The mixture was then filtered and concentrated. The crude product was purified by flash chromatography on silica gel (dichloromethane/ethyl acetate 90/10) to afford the desired product (33e) as a white solid (29 mg, 0.073 mmol, 29%).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:12]([Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:11]=[CH:10][N:9]([Si](C)(C)C)[CH:8]=1.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:21][N:22]([CH3:26])[C:23]([N:9]1[CH:10]=[CH:11][C@H:12]([Si:13]([CH3:16])([CH3:15])[CH3:14])[C:7]([CH:3]2[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])=[CH:8]1)=[O:24]
Reactant: CN1CCCC1C1=CN([Si](C)(C)C)C=CC1[Si](C)(C)C
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)C(=O)N1C=C[C@H]([Si](C)(C)C)C(C2CCCN2C)=C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59 %

Procedure:
To a stirred solution of 3-(1-methylpyrrolidin-2-yl)-1,4-bis-trimethylsilanyl-1,4-dihydropyridine i (0.2 mL, 1.36 mmol) in CH2Cl2 (6 mL) under Ar was added dropwise dimethylcarbamyl chloride (0.19 mL, 2.04 mmol). The reaction mixture was stirred at RT for 1 day. It was then poured into a saturated solution of NaHCO3 (3 mL). The aqueous phase was extracted with CH2Cl2 (5 times). The combined organic layers were washed with water and brine and dried over MgSO4. Evaporation of the solvent under reduced pressure afforded 0.49 g of crude material that was purified by RPLC (silica gel, 5% EtOAc/hex) to give 59% (0.2506 g) of 3-(1-methylpyrrolidin-2-yl)-4-trimethylsilanyl-4H-pyridine-1-carboxylic acid dimethylamide iii as a clear oil. IR (thin film, neat, NaCl): 3363, 2924, 2348, 1657, 1449, 1377 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.65 (d, 1H, J=6.9 Hz), 6.35 (s 1H), 4.83-4.78 (m, 1 H), 3.14-3.09 (m, 1 H), 2.88 (s, 6 H), 2.80-1.25 (m, 13 H), 0.085 (s, 6 H); 13C NMR (100 MHz, CDCl3): δ 149.29, 147.15, 128.04, 124.49, 120.09, 106.29, 68.23, 57.35, 41.47, 38.53, 33.04, 30.34, 29.91, 22.37, 0.63, −2.00. HRMS Calcd for C16H29N3OSi: 308.2157 [M+H]+. Found: 308.2157 [M+H]+. [α]25D −15.17 (CH2Cl2, c=0.145).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH2:15][CH3:16])=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[O:17]=[C:18]1[NH:27][C:26]2[N:25]=[C:24]([O:28][CH2:29][CH2:30][CH2:31][CH:32]=O)[CH:23]=[CH:22][C:21]=2[CH:20]=[CH:19]1>>[Cl:2][C:3]1[C:4]([CH2:15][CH3:16])=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:24]3[N:25]=[C:26]4[C:21]([CH:20]=[CH:19][C:18](=[O:17])[NH:27]4)=[CH:22][CH:23]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCc1c(Cl)cccc1N1CCNCC1
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Agent: Cl
Product: CCc1c(Cl)cccc1N1CCN(CCCCOc2ccc3ccc(=O)[nH]c3n2)CC1

Procedure:
In a manner similar to that of other examples above, 1-(3-chloro-2-ethyl-phenyl)-piperazine hydrochloride was coupled by reductive amination to 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 441.2 (Exact Mass: 440.20).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22]([C:24]2[C:29]([NH:30][C:31](=[O:41])[C:32]3[CH:37]=[CH:36][C:35]([S:38][CH3:39])=[CH:34][C:33]=3O)=[CH:28][CH:27]=[CH:26][N:25]=2)=[O:23])=[N:19][CH:20]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22]([C:24]2[C:29]([NH:30][C:31](=[O:41])[C:32]3[CH:33]=[CH:34][C:35]([S:38][CH3:39])=[CH:36][C:37]=3[O:13][CH2:12][CH:10]3[CH2:11][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]3)=[CH:28][CH:27]=[CH:26][N:25]=2)=[O:23])=[N:19][CH:20]=1
Reactant: CSc1ccc(C(=O)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(O)c1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Product: CSc1ccc(C(=O)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(OCC2CN(C(=O)OC(C)(C)C)C2)c1
Yield: 78 %

Procedure:
Using a procedure analogous to Example 38-D, 1-t-butoxycarbonyl-3-hydroxymethylazetidine and N-(5-chloro-pyridin-2-yl)-3-[2-hydroxy-4-(methylthio)benzoylamino]-pyridine-2-carboxamide gave the title compound as a white solid (1.1 g, 78%).
Reaction SMILES: [CH:1]1([CH2:5][NH:6][C@H:7]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]2)[CH2:4][CH2:3][CH2:2]1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:1]1([CH2:5][N:6]([C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=2[C:20]([F:19])([F:30])[F:31])[C@H:7]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NCC2CCC2)C1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](N(CC2CCC2)C(=O)c2ccccc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 104.2 %

Procedure:
tert-butyl (3S)-3-[(cyclobutylmethyl)amino]pyrrolidine-1-carboxylate (0.80 g, 3.15 mmol) in toluene (10 ml) was treated with 2-(trifluoromethyl)benzoyl chloride (0.55 ml, 3.78 mmol) and triethylamine (0.88 ml, 6.3 mmol). The solution was stirred for 18 hours at room temperature and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel using a gradient of pentane:ethylacetate (4:1 by volume) changing to pentane:ethylacetate (1:1 by volume) to afford the title compound as a colorless oil (1.40 g, crude) which is used directly in the next step.