Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:12][CH2:13][CH3:14])(=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[C:15]([O-])([O-])=[O:16].[K+].[K+].C[C:22]([CH3:24])=[O:23]>>[CH2:13]([O:12][C:1](=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([O:8][CH2:24][C:22]([O:16][CH3:15])=[O:23])=[C:4]([O:5][CH3:6])[CH:3]=1)[CH3:14]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Reactant: CC(C)=O
Agent: [K+]
Product: CCOC(=O)c1ccc(OCC(=O)OC)c(OC)c1
Yield: 70 %

Procedure:
To a mixture of Ethyl Vanillate (100 grams, 510 mmol), and anhydrous K2CO3 (300 grams, 2.17 mol) in anhydrous acetone (1000 mL) was added methyl chloro acetate (123.8 grams, 1.14 mmol) and refluxed for 8 hours. Acetone was distilled and water (1500 mL) was added. Crude 8 was filtered, dried, and recrystallized from a mixture of toluene:Hexane (1:5) to give pure 8 (95.7 grams, 70%) as a white powder. The melting point was found to be 72.7-74.3° C. The structure was confirmed by I.R and NMR. IHNMR (CDCl3) δ 1.40 (t, 3H, CH2CH3), 3.80 (s, 3H, Ester), 3.92 (s, 3H, OCH3), 4.38 (q, 2H, OCH2CH3), 4.88 (s, 2H, OCH2), 6.80 (d, 1H, Ar), 7.59 (d, 1H, Ar), 7.66 (dd, 1H, Ar).
Reaction SMILES: C([N:8]([CH2:23][C@H:24]([OH:33])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[C:17]([Cl:22])[C:18]([O:20][CH3:21])=[CH:19][C:11]=2[CH2:10]1)C1C=CC=CC=1.[H][H]>[Pd].ClC1C=CC=CC=1.CO>[ClH:22].[Cl:22][C:17]1[C:18]([O:20][CH3:21])=[CH:19][C:11]2[CH2:10][CH:9]([NH:8][CH2:23][CH:24]([OH:33])[CH2:25][O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:15][CH2:14][CH2:13][C:12]=2[CH:16]=1
Reactant: [H][H]
Reactant: COc1cc2c(cc1Cl)CCCC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)C2
Agent: [Pd]
Solvent: Clc1ccccc1
Solvent: CO
Product: COc1cc2c(cc1Cl)CCCC(NCC(O)COc1ccccc1)C2
Product: Cl
Yield: 124.8 %

Procedure:
A mixture of (2S)-1-[N-benzyl-N-(2-chloro-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl) amino]-3-phenoxy-2-propanol (172 mg) and 10% palladium on activated carbon (50% wet, 50 mg) in a mixture of chlorobenzene (2 ml) and methanol (2 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 2 hours. After filtration, the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol=20:1 to 10:1) and followed by treatment with 4N hydrogen chloride in ethyl acetate to give 1-(2-chloro-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino-3-phenoxy-2-propanol hydrochloride (95 mg).
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]2[C:8]([N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]4[CH:32]=[C:31]5[C:26]([CH:27]=[CH:28][C:29](=[O:33])[NH:30]5)=[CH:25][CH:24]=4)[CH2:14][CH2:13]3)=[CH:9][CH:10]=[CH:11][C:4]1=2.[C:34](=[O:45])([O:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)[O:35][CH2:36][Cl:37].Cl>O1CCCC1>[ClH:37].[CH:39]1([O:38][C:34](=[O:45])[O:35][CH2:36][N:30]2[C:31]3[C:26](=[CH:25][CH:24]=[C:23]([O:22][CH2:21][CH2:20][CH2:19][CH2:18][N:15]4[CH2:14][CH2:13][N:12]([C:8]5[C:5]6[CH:6]=[CH:7][S:3][C:4]=6[CH:11]=[CH:10][CH:9]=5)[CH2:17][CH2:16]4)[CH:32]=3)[CH:27]=[CH:28][C:29]2=[O:33])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: O=C(OCCl)OC1CCCCC1
Reactant: O=c1ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCn1c(=O)ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21)OC1CCCCC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
Sodium hydride (55% oil) (0.962 g, 22.04 mmol) was suspended in tetrahydrofuran (THF) (200 ml), 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one (8.31 g, 19.17 mmol) was added and the mixture was stirred at 50° C. for 1 hr. The mixture was cooled to 0° C., chloromethyl cyclohexyl carbonate (4.80 g, 24.92 mmol) was added dropwise and the mixture was stirred at room temperature overnight. After cooling to 0° C., excess 2N hydrochloric acid was added to quench the reaction. The precipitated solid was collected by filtration and dried. In addition, the filtrate was extracted with ethyl acetate. The organic layer was concentrated and purified by moderate-pressure silica gel column chromatography (methylene chloride:methanol=100:0 to 20:1). Likewise, the solid was purified by moderate-pressure silica gel column chromatography. Concentration under reduced pressure gave the title compound (yield, 5.04 g, 42%) as a white solid.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][N:6]([C:8]3[CH:9]=[C:10]([NH:14][C:15]4[C:16]5[N:24]=[CH:23][S:22][C:17]=5[N:18]=[C:19](Cl)[N:20]=4)[CH:11]=[CH:12][CH:13]=3)[CH2:5]2)[CH2:3][O:2]1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=2)[C:36]([O:38][CH3:39])=[O:37])O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]1[C:4]2([CH2:7][N:6]([C:8]3[CH:9]=[C:10]([NH:14][C:15]4[C:16]5[N:24]=[CH:23][S:22][C:17]=5[N:18]=[C:19]([C:33]5[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=5)[C:36]([O:38][CH3:39])=[O:37])[N:20]=4)[CH:11]=[CH:12][CH:13]=3)[CH2:5]2)[CH2:3][O:2]1
Reactant: Clc1nc(Nc2cccc(N3CC4(COC4)C3)c2)c2ncsc2n1
Reactant: COC(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cccc(-c2nc(Nc3cccc(N4CC5(COC5)C4)c3)c3ncsc3n2)c1
Yield: 30.5 %

Procedure:
To a solution of N-(3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)-5-chlorothiazolo[5,4-d]pyrimidin-7-amine (160 mg, 0.5 mmol) and methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (145 mg, 0.55 mmol) in 9 mL of 1,4-dioxane and 1 mL of water was added Na2CO3 (159 mg, 1.5 mmol) followed by Pd(PPh3)4 (58 mg) under nitrogen with stirring. The mixture was refluxed for 15 hours under nitrogen. After cooled, the solvent was evaporated by rotary evaporation. The residue was poured into water and extracted with EtOAc (3×10 mL). The organic layer was washed with brine and dried over Na2SO4. After filtration and concentration, the residue was purified by column chromatography on silica gel eluting with (petroleum ether EtOAc=1:1) to give methyl 3-(7-(3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoate (70 mg, 30%). LC-MS: 460 [M+H]+, tR=1.74 min.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)=[O:4].[CH2:12]([C:14]1[NH:15][CH:16]=[CH:17][N:18]=1)[CH3:13]>O1CCOCC1>[Br:11][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][N:15]2[CH:16]=[CH:17][N:18]=[C:14]2[CH2:12][CH3:13])[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CBr)c1cccc(Br)c1
Reactant: CCc1ncc[nH]1
Solvent: C1COCCO1
Product: CCc1nccn1CC(=O)c1cccc(Br)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of 2-bromo-1-(3-bromophenyl)ethanone (120 mg, 0.432 mmol) in dioxane (2 mL) was added 2-ethylimidazole (83.0 mg, 0.864 mmol) and the reaction mixture was stirred for 1 h at 80° C. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography using MeOH:CH2Cl2 (6:94) as eluent to give the sub-title compound in 51% yield (65 mg, 0.22 mmol).
Reaction SMILES: [CH:1]1([N:4]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:5](=[O:19])[C:6]2[CH:11]=[CH:10][C:9]([C@@:12]([OH:18])([CH3:17])[C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.C(O[C:29]1(O[Si](C)(C)C)[CH2:31][CH2:30]1)C.CC(O)=O.[BH3-]C#N.[Na+]>CO.CCOC(C)=O>[CH:1]1([N:4]([CH:20]2[CH2:21][CH2:22][N:23]([CH:29]3[CH2:31][CH2:30]3)[CH2:24][CH2:25]2)[C:5](=[O:19])[C:6]2[CH:11]=[CH:10][C:9]([C@@:12]([OH:18])([CH3:17])[C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=2)[CH2:2][CH2:3]1
Reactant: C[C@](O)(c1ccc(C(=O)N(C2CCNCC2)C2CC2)cc1)C(F)(F)F
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: C[C@](O)(c1ccc(C(=O)N(C2CC2)C2CCN(C3CC3)CC2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of (S)-N-cyclopropyl-N-(piperidin-4-yl)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide prepared above in step c in Example 1 (120 mg, 0.337 mmol, 1.0 equiv.), (1-ethoxycyclopropoxy)trimethylsilane (404 μL, 2.02 mmol, 6.0 equiv.) and AcOH (193 μL, 3.37 mmol, 10 equiv.) in MeOH (2.0 mL) was treated with NaBH3CN (95 mg, 1.52 mmol, 4.5 equiv.). After being stirred for 48 h at 25° C. and being refluxed for additional 24 h, the reaction was diluted (EtOAc) and washed (1×1 N aqueous NaOH, and 1× brine). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by flash chromatography (SiO2, 0-7% MeOH/CH2Cl2, gradient elution) gave the title compound as a pale yellow solid: 1H NMR (CDCl3, 500 MHz) δ 7.55 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H), 4.22-4.13 (m, 1H), 3.12 (d, J=11.5 Hz, 2H), 2.96 (s, br, 1H), 2.54-2.50 (m, 1H), 2.39-2.22 (m, 2H), 2.12-1.99 (m, 2H), 1.88-1.82 (m, 2H), 1.74 (s, 3H), 1.61-1.57 (m, 1H), 0.88-0.85 (m, 2H), 0.55-0.41 (m, 6H); MS(ESI) 398 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.[NH2:21][C:22]([CH2:29][CH3:30])([CH2:27][CH3:28])[C:23]([NH:25][CH3:26])=[O:24]>>[CH2:27]([C:22]([NH:21][C:12]([C:10]1[CH:9]=[CH:8][C:7]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:23](=[O:24])[NH:25][CH3:26])[CH2:29][CH3:30])[CH3:28]
Reactant: O=C(O)c1ccc(C2CCOCC2)c(OCC2CC2)n1
Reactant: CCC(N)(CC)C(=O)NC
Product: CCC(CC)(NC(=O)c1ccc(C2CCOCC2)c(OCC2CC2)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid (Example 9 f) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70 b) as starting materials, MS (EI): m/e=404.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17]Cl)[C:12]=2[CH2:19][CH3:20])[CH:3]=1.[CH3:21][NH2:22].[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27]>C(O)C.CO>[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:22][CH3:21])[C:12]=2[CH2:19][CH3:20])[CH:3]=1
Reactant: CN
Reactant: CCc1c(CCl)cccc1Oc1cc(Cl)ccc1C#N
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CO
Product: CCc1c(CNC)cccc1Oc1cc(Cl)ccc1C#N
Temperature: 25 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
To a solution of 4-chloro-2-(3-chloromethyl-2-ethyl-phenoxy)-benzonitrile (0.39 g, 1.3 mmol) in ethanol (20 mL) was added methylamine (33% in ethanol, 5.0 mL, 40 mmol), and the reaction mixture stirred for 24 h at ambient temperature. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and a solution of fumaric acid (148 mg, 1.3 mmol) in methanol (5 mL) was added. After the solvent was removed in vacuo, the residue was triturated with diethyl ether overnight, collected by filtration, and dried to give 4-chloro-2-(2-ethyl-3-methylaminomethyl-phenoxy)-benzonitrile fumarate (455 mg, 86%) as a white solid.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:36]1([C:42](Cl)=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[N:36]1([C:42]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]4[O:17][C:18]5[C:23]([C:24](=[O:26])[CH:25]=4)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=5[N:29]4[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]4)=[O:15])=[CH:11][CH:12]=3)[CH2:2][CH2:3]2)=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCNCC4)cc3)cc(=O)c2c1
Product: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCN(C(=O)N5CCOCC5)CC4)cc3)cc(=O)c2c1

Procedure:
This compound was prepared from 6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (Example 43) and commercially available morpholine-4-carbonyl chloride (Aldrich) via the parallel synthesis described above.
Reaction SMILES: [Na].[C:2]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)#[N:3].C(O)(=O)C.N[C:15]1[CH:16]=[C:17]([CH:22]([CH3:26])[C:23]([OH:25])=[O:24])[CH:18]=[CH:19][C:20]=1[OH:21]>CO.O>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:2]2[O:21][C:20]3[CH:19]=[CH:18][C:17]([CH:22]([CH3:26])[C:23]([OH:25])=[O:24])=[CH:16][C:15]=3[N:3]=2)[CH:5]=1
Reactant: N#Cc1cccnc1
Reactant: CC(C(=O)O)c1ccc(O)c(N)c1
Agent: [Na]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc2oc(-c3cccnc3)nc2c1

Procedure:
Sodium (0.115 g.) was dissolved carefully in methanol (45 ml.) and 3-cyanopyridine (5.2 g.) was added. Next day, acetic acid (0.3 g.) was added followed by 2-(3-amino-4-hydroxyphenyl)propionic acid (9.05 g.). The stirred mixture was heated under reflux for 5 hours. The solid dissolved completely during this time. An equal volume of water was added to the hot solution. On cooling, cream crystals separated which were filtered off and re-crystallised from dimethylformamide-ethanol to yield the desired acid, m.p. 197°-200°C.
Reaction SMILES: ClCCl.[NH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[N:11][C:12]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=3)=[C:18]([CH2:37][CH2:38][CH2:39][CH3:40])[N:17]=[C:16]2[CH3:41])=[N:13][CH:14]=1.N1C=CC=CC=1.[C:48](Cl)(=[O:50])[CH3:49]>O>[CH2:37]([C:18]1[N:17]=[C:16]([CH3:41])[N:15]([C:12]2[N:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][NH:4][C:48](=[O:50])[CH3:49])=[CH:10][N:11]=2)[C:20](=[O:21])[C:19]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]#[N:36])=[CH:25][CH:24]=1)[CH2:38][CH2:39][CH3:40]
Reactant: CC(=O)Cl
Reactant: CCCCc1nc(C)n(-c2ncc(OCCCN)cn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CCCCc1nc(C)n(-c2ncc(OCCCNC(C)=O)cn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
Process 3: To the dichloromethane (1 mL) solution of the crude product of 4′-{{1-[5-(3-aminopropoxy)pyrimidin-2-yl]-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl}biphenyl-2-carbonitrile (45 mg), pyridine (9.7 mg, 0.123 mmol) and acetyl chloride (8.3 mg, 0.106 mmol) were added and stirred at room temperature overnight. The reaction mixture was added water, and extracted with ethyl acetate. The organic layer was combined, washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain N-{3-{2-{4-butyl-5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxopyrimidin-1 (6H)-yl}pyrimidin-5-yl oxy}propyl}acetamide (35 mg) as a crude product.
Reaction SMILES: [C:1]([Si:5]([C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[O:6][CH:7]1[C:11]([C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:26][SiH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])([C:12]([O:14][N:15]2C(=O)C3C(=CC=CC=3)[CH2:16]2)=O)[O:10][CH:9]([N:44]2[CH:49]=[CH:48][C:47](=[O:50])[NH:46][C:45]2=[O:51])[CH:8]1[O:52]C(=O)C)([CH3:4])([CH3:3])[CH3:2].CNN.CO.C=O>ClCCl>[C:1]([Si:5]([C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)([C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[O:6][CH:7]1[C:11]([C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:26][SiH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])([CH2:12][O:14][N:15]=[CH2:16])[O:10][CH:9]([N:44]2[CH:49]=[CH:48][C:47](=[O:50])[NH:46][C:45]2=[O:51])[CH:8]1[OH:52])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)OC1C(n2ccc(=O)[nH]c2=O)OC(C(=O)ON2Cc3ccccc3C2=O)(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)C1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: C=O
Agent: CNN
Solvent: CO
Solvent: ClCCl
Product: C=NOCC1(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)OC(n2ccc(=O)[nH]c2=O)C(O)C1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
This transformation is performed smoothly in high yield using published procedures (Bhat, B., et. al., J. Org. Chem. 1996, 61, 8186-8199). Generally, a portion of Compound 16 is dissolved in dichloromethane and cooled to −10° C. To this solution is added methylhydrazine (2.5 eq.). After 1-2 hours of stirring at 0° C., the mixture is diluted with dichloromethane, washed with water and brine, dried with anhydrous Na2SO4, filtered, and evaporated. The resulting residue is immediately redissolved in a 1:1 mixture of ethyl acetate:methanol, and treated with 20% (w/w) aqueous formaldehyde (1.1 eq.). After an hour at room temperature, the mixture is concentrated then purified by silica gel chromatography to give Compound 17.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[O:8])=[O:5])[CH3:2].[OH:9][C:10]1[N:14]=[C:13]([O:15][CH2:16][CH3:17])[S:12][N:11]=1.C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:3][C:4]([NH:6][C:7]([N:11]1[C:10](=[O:9])[N:14]=[C:13]([O:15][CH2:16][CH3:17])[S:12]1)=[O:8])=[O:5])[CH3:2]
Reactant: CCOc1nc(O)ns1
Reactant: CCOC(=O)N=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)NC(=O)n1sc(OCC)nc1=O
Temperature: 20 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
23 g of ethoxycarbonyl isocyanate were added dropwise to a solution of 14.6 g of 3-hydroxy-5-ethoxy-1,2,4-thiadiazole in 140 ml of tetrahydrofuran containing 1 ml of triethylamine and the mixture was stirred for 11/2 hours at 20° C and was filtered. The filtrate was concentrated to dryness and the residue was empasted with isopropyl ether and vacuum filtered. The product was crystallized from ethyl acetate to obtain 18 g of 2-(N-ethoxycarbonylcarbamoyl)-5-ethoxy-1,2,4-thiadiazole-3-one melting at 119° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16](=[O:32])[CH2:17][C@@H:18]([NH2:31])[C:19]([NH:21][C@H:22]([C:27](=[O:30])[NH:28][CH3:29])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CO[CH:35]1[CH:39]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:38][CH:37](OC)O1.FC(F)(F)C(O)=O.O>ClCCCl>[CH2:8]([O:15][C:16](=[O:32])[CH2:17][C@@H:18]([N:31]1[CH:37]=[CH:38][C:39]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:35]1)[C:19]([NH:21][C@H:22]([C:27](=[O:30])[NH:28][CH3:29])[C:23]([CH3:25])([CH3:26])[CH3:24])=[O:20])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC1CC(c2ccccc2)C(OC)O1
Reactant: CNC(=O)[C@@H](NC(=O)[C@H](N)CC(=O)OCc1ccccc1)C(C)(C)C
Solvent: ClCCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccccc2)c1)C(C)(C)C
Reaction time: 20 h
Yield: 36.7 %

Procedure:
A solution of crude 3(R)-amino-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]-succinamic acid benzyl ester trifluoroacetate salt (2.33 mmol), 2,5-dimethoxy-3-phenyl-tetrahydrofuran (583 mg, 2.80 mmol), trifluoroacetic acid (216 μL, 2.80 mmol), and water (50 μL, 2.8 mmol) in 1,2-dichloroethane (1 mL) was heated at 70° C. After 20 hours, the mixture was allowed to cool and concentrated in vacuo to give a brown oil, which was purified via flash column chromatography with 0.5% HOAc/35% EtOAc/hex as eluant to afford 407 mg (37%) of N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)-3(R)-(3-phenyl-1H-pyrrol-1-yl)succinamic acid benzyl ester as a yellow foam. 1H NMR: a 7.52-7.44 (m, 2H), 7.38-7.15 (m, 3H), 7.04 (dd, 1H, J=1.8, 1.8 Hz), 6.78 (t, 1H, J=2.5 Hz), 6.56 (dd, 1H, J=1.6, 2.5 Hz), 6.42 (d, 1H, J=9.0 hz), 5.95 (bd, J=4.0 Hz), 5.18-5.04 (m, 3H), 4.30 (d, 1H, J=9.0 Hz), 3.38 (dd, 1H, J=5.9, 16.8 Hz), 3.10 (dd, 1H, J=8.4, 16.8 hz), 2.72 (d, 3H, J=5.0 Hz), 0.93 (s, 9H). IR: 3301, 2960, 1736, 1645, 1542, 1166, 752, 695 cm-. HRFABMS: Calculated for C28H33N3O4Cs (M+Cs+): 608.1525. Found: 608.1549. Anal. Calculated for C28H33N3O4.0.2H2O: C, 70.18; H 7.03; N, 8.77. Found: C, 70.45; H, 6.99; N, 8.84.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH2:6][N:7]([CH3:9])[CH3:8].[CH2:13]([Li])[CH2:14]CC.ICC.C(OCC)C>C1COCC1>[CH2:13]([C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[CH:10][C:5]=1[CH2:6][N:7]([CH3:9])[CH3:8])[CH3:14]
Reactant: [Li]CCCC
Reactant: COc1cccc(CN(C)C)c1
Solvent: C1CCOC1
Solvent: CCI
Solvent: CCOCC
Product: CCc1c(CN(C)C)cccc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
(3-Methoxybenzyl)dimethylamine (2.03 mL, 2.00 g, 12.1 mmol) was dissolved in anhydrous THF (20 mL) under nitrogen and cooled to 0° C. with an ice-water bath. Butyllithium (2.5M in hexanes, 5.3 mL, 13.3 mmol) was added dropwise via syringe over 10 min (temperature kept below 5 C.). After stirring at 0° C. for 2 h, iodoethane (1.1 mL, 2.1 g, 13.8 mmol) was added dropwise via syringe over 25 min (temperature kept below 5° C.). The reaction mixture was allowed to reach ambient temperature. After 4 h, the reaction contents were transferred with diethyl ether and adsorbed onto silica gel (3.8 g) upon removal of the solvent in vacuo. Chromatography gave (2-ethyl-3-methoxybenzyl)dimethylamine (1.30 g, 56%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]4=[O:23])=[CH:13][CH:12]=3)[C:6](=[O:24])[C:5]=2[N:4]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[N:3]=1.[Li+].[Cl-].Cl.C1C[O:39][CH2:38][CH2:37]1>>[C:38]([C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]4=[O:23])=[CH:13][CH:12]=3)[C:6](=[O:24])[C:5]=2[N:4]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[N:3]=1)(=[O:39])[CH3:37]
Reactant: COc1ccc(-n2nc(Br)c3c2C(=O)N(c2ccc(-n4ccccc4=O)cc2)CC3)cc1
Reactant: C1CCOC1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Product: COc1ccc(-n2nc(C(C)=O)c3c2C(=O)N(c2ccc(-n4ccccc4=O)cc2)CC3)cc1
Temperature: 25 °C

Procedure:
To 3-bromo-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one (0.11 g, 0.22 mmol) was added THF (25 mL), 1-(ethoxyvinyl)tributyltin (0.078 mL, 0.23 mmol), and LiCl (27 mg, 0.65 mmol) and the mixture was degassed with N2 for 15 min. Tetrakistriphenylphosphine Palladium(0) (12 mg, 0.01 mmol) was added and the reaction was heated to reflux 24 h. The reaction was cooled to rt and treated with 1N HCl for 24 h. After extraction with EtOAc and drying (MgSO4), the product was purified by silica gel (mixed with KF) chromatography using 0-3% MeOH in CH2Cl2 and by HPLC to afford 6 mg (6%); High Resolution Mass Spec (M+H)+ for C26H23N4O4 455.1713.