Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:12][C:13]([C@@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][N:16]2C(OC(C)(C)C)=O)=[O:14])[C:10]#[N:11])=[CH:4][CH:3]=1.[OH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O>>[C:10]([C@@H:9]([NH:12][C:13]([C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][NH:16]1)=[O:14])[CH2:8][C:5]1[CH:6]=[N:7][C:2]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[OH:28])=[CH:3][CH:4]=1)#[N:11]
Reactant: OB(O)c1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@H](C#N)Cc1ccc(Br)nc1
Product: N#C[C@H](Cc1ccc(-c2ccccc2O)nc1)NC(=O)[C@@H]1CCCCN1

Procedure:
Prepared by a process analogous to that described in Method 2 Example 2 using (S)-tert-butyl 2-((S)-2-(6-bromopyridin-3-yl)-1-cyanoethylcarbamoyl)piperidine-1-carboxylate and 2-hydroxyphenylboronic acid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:32][NH:33][O:34][CH3:35].C(N(CC)C(C)C)(C)C>C1COCC1.C(Cl)Cl>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([N:33]([O:34][CH3:35])[CH3:32])=[O:16])[CH2:6][CH2:5]2
Reactant: CNOC
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CON(C)C(=O)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 69 %

Procedure:
To a solution of 5.47 g 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (21.9 mmol) in 170 mL THF was added 3.92 g CDI (24.2 mmol) and stirred for 1.25 h at room temperature. To this was added a solution of 2.14 g N,O-dimethylhydroxylamine hydrochloride (21.97 mmol) and 8.2 g N,N-diisopropylethylamine in 50 mL CH2Cl2 dropwise over 1 h. The reaction was stirred overnight, concentrated, 250 mL CH2Cl2 added and washed sequentially with 100 mL 0.625 M HCl, 100 mL 1.0 M NaHCO3 and 100 mL saturated NaCl. The organics were dried over Na2SO4, concentrated and purified by flash chromatography yielding 4.43 g of 6-hydroxy-N-methoxy-N,2,5,7,8-pentamethylchroman-2-carboxamide as an off-white crystalline solid.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C[Al](C)C.C[O:10][C:11]([C:13]1[CH:18]=[N:17][C:16]([NH:19][CH2:20][C:21]2[C:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:23][O:24][C:25]=2[CH3:26])=[CH:15][N:14]=1)=O.O>O1CCOCC1>[CH:1]([NH:4][C:11]([C:13]1[CH:18]=[N:17][C:16]([NH:19][CH2:20][C:21]2[C:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:23][O:24][C:25]=2[CH3:26])=[CH:15][N:14]=1)=[O:10])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cnc(NCc2c(-c3ccccc3)noc2C)cn1
Reactant: CC(C)N
Agent: C[Al](C)C
Solvent: O
Solvent: C1COCCO1
Product: Cc1onc(-c2ccccc2)c1CNc1cnc(C(=O)NC(C)C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a solution of isopropylamine (0.69 mL, 8 mmol) in dioxane (5 mL) was added dropwise trimethylaluminum solution (2M solution in hexane, 4 mL, 8 mmol). After stirring for 1 h at room temperature a suspension of 5-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-pyrazine-2-carboxylic acid methyl ester (650 mg, 2 mmol) in dioxane (5 mL) was added. The reaction mixture was stirred at 90° C. for 90 min, cooled to room temperature and poured into water. Extraction with ethyl acetate and washing with saturated aqueous Seignette salt solution was followed by drying of the organic phase over sodium sulfate and evaporation which afforded an oil. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 20:80) afforded the title compound (600 mg, 85%) as a white solid MS: m/e=352.3 [M+H]+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:19](=O)[C@H:20]([O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)[CH3:21].[C:30](OCC)(=O)C.CCCCCC>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:19]([C@H:20]([O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)[CH3:21])=[CH2:30]
Reactant: C[C@@H](OC1CCCCO1)C(=O)c1ccc(F)cc1F
Reactant: CCOC(C)=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C(c1ccc(F)cc1F)[C@@H](C)OC1CCCCO1
Temperature: 8 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A mechanically stirred mixture of methyl triphenylphosphonium bromide (84.6 g, 0.237 moles) in 175 ml of dry tetrahydrofuran was cooled to 8° C. A solution of lithium bis (trimethylsilyl)amide (42.4 g, 0.253 moles) in 250 ml tetrahydrofuran was added to the above mixture at a rate so that the temperature of the mixture remained 23° C. After stirring for 1 hour at room temperature the contents were cooled to -70° C. and stirred for 1/2 hour. Added a solution of compound 4b, (2R)-2',4'-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (50 g, 0.185 moles) in 125 ml of tetrahydrofuran slowly to maintain the temperature of the mixture below -70° C. The resulting mixture was stirred at 7° C. for 60 hours. Added 33 ml of ethyl acetate to the above mixture followed by the addition of 2 L of hexane and allowed to stand for 15 minutes. The solid was removed by suction-filtration and washed thoroughly with 325 ml of hexane. The filtrate was washed with 1:1 mixture of methanol : water (2×650 ml) and brine (650 ml) and dried over MgSO4. The solvent was evaporated to give the title compound 5b as an oil (47.7 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:10][CH2:11][C:12](=[O:15])[NH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:17][CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21].CC1(C)CCOC1=O.Br.C(Cl)(=O)C(Cl)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(N(CC)CC)C.CO>[C:20]([C:19]([CH3:25])([CH3:24])[CH2:18][CH2:17][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[CH2:10][CH2:11][C:12](=[O:15])[NH:13][N:14]=2)=[CH:3][C:2]=1[Cl:1])([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C(C)(C)CCBr
Reactant: O=C1CCC(c2ccc(O)c(Cl)c2)=NN1
Agent: Br
Agent: CC1(C)CCOC1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)C(C)(C)CCOc1ccc(C2=NNC(=O)CC2)cc1Cl
Temperature: 100 °C
Yield: 74.8 %

Procedure:
A mixture of 4.05 g (18.0 mmol) of 6-(3-chloro-4-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (prepared as described in Eur. Pat. application EP0 178,189), 4.52 g (21.6 mmol) of methyl 4-bromo-2,2-dimethylbutyrate (prepared by treatment of 2,2-dimethylbutyrolactone with gaseous HBr, conversion to the acid chloride with oxalyl chloride, and treatment with methanol and triethylamine), and 2.99 g (21.6 mmol) of anhydrous K2CO3 in 40 ml of DMF is heated at 100° C. for 4 hrs under N2. The DMF is removed under vacuum, the residue taken up in 300 ml of 50:50 water EtOAc, the organic phase washed with cold 5% NaOH (50 ml), then water (50 ml), and dried (MgSO4) The solvent is removed under vacuum to give an oily residue. The oil is crystallized by the addition of 50 ml of ethyl ether to give 4.75 g of 6-[4 -(3-carbomethoxy-3,3-dimethylpropyloxy)-3-chlorophenyl]-4,5-dihydro-3(2H)-pyridazinone as a white crystalline solid, m.p. 109°-110° C. Yield, 75%.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[OH-].[Na+]>CO>[CH:7]1([CH2:6][CH:5]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:4]([OH:21])=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title A compound, 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid ethyl ester (3.6 g, 12.3 mmol) is dissolved in 25 mL of methanol and aqueous NaOH (0.70 g, 17.5 mmol in 4 mL of water) is added and the mixture is stirred at RT overnight. The methanol is removed under reduced pressure and the residue is diluted with 100 mL of water and extracted with ether. The aqueous layer is then acidified with 1 N HCl (aq) and then extracted with ethyl acetate. The combined ethyl acetate layers are dried over anhydrous magnesium sulfate, filtered and reduced under vacuum to a crude orange oil. The crude oil is triturated with 100 mL of hexane/10-15 mL of ether to produce 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid as a solid: 1H NMR (400 MHz, CDCl3) δ 1.0-1.1 (m, 2H), 1.4-1.8 (m, 5H), 1.8-1.9 (m, 2H), 2.1-2.25 (m, 2H), 3.74 (t, 1H, J=7.8), 7.51 (d, 2H, J=8.8), 8.19 (d, 2H, J=8.8).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[C:5]([CH3:10])[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[N:3]=1.[N:20]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:1][C:2]1[C:6]([C:7]([N:28]2[CH2:29][CH2:30][CH:25]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:26][CH2:27]2)=[O:9])=[C:5]([CH3:10])[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[N:3]=1
Reactant: Cc1nn(-c2cccc([N+](=O)[O-])c2)c(C)c1C(=O)O
Reactant: C1CCN(C2CCNCC2)C1
Product: Cc1nn(-c2cccc([N+](=O)[O-])c2)c(C)c1C(=O)N1CCC(N2CCCC2)CC1
Yield: 93 %

Procedure:
In analogy to the procedure described in Example 18], 3,5-dimethyl-1-(3-nitro-phenyl)-1H-pyrazole-4-carboxylic acid and 4-pyrrolidine-1-yl-piperidine gave the tide compound in 93% yield as green foam. MS: 398.1 (MH+).
Reaction SMILES: [C:1]([CH:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:7]2[CH:16]=[C:17]([CH2:20][N:21]3[C:25]4=[N:26][C:27]([CH3:31])=[CH:28][C:29]([CH3:30])=[C:24]4[N:23]=[C:22]3[CH2:32][CH3:33])[CH:18]=[CH:19][C:6]1=2)[CH3:4])#[N:2].C[Si]([N:38]=[N+:39]=[N-:40])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:32]([C:22]1[N:21]([CH2:20][C:17]2[CH:18]=[CH:19][C:6]3[N:5]([CH:3]([C:1]4[NH:40][N:39]=[N:38][N:2]=4)[CH3:4])[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[CH2:9][CH2:8][C:7]=3[CH:16]=2)[C:25]2=[N:26][C:27]([CH3:31])=[CH:28][C:29]([CH3:30])=[C:24]2[N:23]=1)[CH3:33]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(c1)CCc1ccccc1N2C(C)C#N
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(c1)CCc1ccccc1N2C(C)c1nnn[nH]1
Temperature: 70 °C
Reaction time: 48 h
Yield: 62.2 %

Procedure:
5-(1-Cyanoethyl)-2-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-dihydro-5H-dibenzo[b,f]azepine (520 mg, 1.19 mmol) obtained in step 1 of Example 19 was dissolved in toluene (12 mL), and the solution was added with trimethylsilylazide (2.54 mL, 19.1 mmol) and dibutyltinoxide (177 mg, 0.71 mmol), followed by stirring at 70° C. for 2 days. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=25/1) to give the title compound (compound 22, 354 mg, 62%).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH3:13])=[O:11])(OCC)=O)C.[Li]CCCC.[CH3:19][C:20]([CH3:24])([CH3:23])[CH:21]=O.O>C1COCC1>[CH3:13][O:12][C:10](=[O:11])[CH:9]=[CH:19][C:20]([CH3:24])([CH3:23])[CH3:21]
Reactant: CCOP(=O)(CC(=O)OC)OCC
Reactant: CC(C)(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C=CC(C)(C)C
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
Methyl diethylphosphonoacetate (13.35 mL, 73.6 mmol, 1.05 eq.) was dissolved in THF (30 mL) and cooled to −78° C. in an acetone-dry ice bath. n-BuLi (1.6M in hexanes) (45.8 mL, 73.2 mmol, 1.05 eq.) was added slowly over 20 min. Trimethylacetaldehyde (6.0 g, 69.6 mmol, 1.0 eq.), was added to the reaction and allowed to stir at −78° C. for 20 minutes and warmed to room temperature and stirred overnight. Water (30 mL) was added to quench and extracted with ethyl ether (3×100 mL). The combined organics were washed with brine and dried over MgSO4, filtered and evaporated to provide 4,4-Dimethyl-pent-2-enoic acid methyl ester, a colorless liquid (8.52 g, 60.0 mmol, 86%) and was used directly in the next reaction. 1H NMR (CDCl3, 400 MHz) δ 0.89 (s, 9H), 3.64 (s, 3H), 5.64 (d, 1H, J=16.0 Hz), 6.88 (d, 1H, J=16.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.CCN(CC)CC.Br[CH2:17][CH:18]([O:21][CH3:22])[O:19][CH3:20].O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:17][CH:18]([O:21][CH3:22])[O:19][CH3:20])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: COC(CBr)OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC(CSc1ccc(Cl)cc1)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-chlorobenzenethiol (13 mmol) and Et3N (1.4 g, 13 mmol) in THF (25 mL) at room temperature was added 2-bromo-1,1-dimethoxyethane (2.36 g, 13 mmol) in THF (5 mL). After stirring at room temperature for 30 minutes, the reaction mixture was poured into water (200 mL) and extracted with diethyl ether (3×150 mL). The combined organic layer was dried over Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].CN(C)CCN(C)C.C([Li])(CC)C.[CH3:24][N:25]([CH2:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][CH:29]=1)[CH3:26].[Cl-].[NH4+]>C1COCC1>[CH3:26][N:25]([CH2:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]([OH:33])[CH2:1][N:2]([CH3:10])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[CH:30][CH:29]=1)[CH3:24]
Reactant: CN(C)Cc1ccc(C=O)cc1
Reactant: CN(C)C(=O)OC(C)(C)C
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(C(O)CN(C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
To a solution of tert-butyl dimethylcarbamate (350 mg, 2.4 mmol) and tetramethylethylenediamine (511 mg, 4.4 mmol) in THF (anhydrous, 10 mL) was added sec-butyllithium (1.4 M in cyclohexane, 2.2 mL, 3.1 mmol) at −78° C. The mixture was stirred at that temperature for 1 hour before 4-[(dimethylamino)methyl]benzaldehyde (J.Heterocycl.Chem.; 26; 1989; 1325-1330)(280 mg, 1.7 mmol) was introduced. The reaction mixture was stirred for 2 hours, warmed to room temperature and stirred for 1 hour. Saturated ammonium chloride aqueous solution (10 mL) was added to quench the reaction after the reaction mixture was cooled to −78° C. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with brine and dried over sodium sulfate and concentrated. The residue was purified with a silica gel column to give the title compound (0.40 g) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1>CO.[OH-].[Na+]>[O:21]=[C:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)[C:3]([OH:22])=[O:2]
Reactant: COC(=O)C(=O)c1ccc(OCC#Cc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCC#Cc2ccccc2)cc1
Yield: 82.5 %

Procedure:
A mixture of alpha-oxo-4-[(3-phenyl-2-propynyl)oxy]benzeneacetic acid methyl ester (0.7 g) in methanol (10 mL) and 0.SN sodium hydroxide (8 mL) was treated as in Example 19. Extraction provided solids which were crystallized from diethyl ether-hexane to give 0.55 g of colorless alpha-oxo-4-[(3-phenyl-2-propynyl)oxy]benzeneacetic acid, mp 97°-99° C.
Reaction SMILES: [CH:1]([NH:14][S:15]([CH2:18][CH2:19][CH2:20]Cl)(=[O:17])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(N(CC)CC)C>CN(C)C=O>[C:25]([O:24][C:22]([N:29]1[CH2:34][CH2:33][N:32]([CH2:20][CH2:19][CH2:18][S:15](=[O:17])(=[O:16])[NH:14][CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:31][CH2:30]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(CCCCl)NC(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(CCCS(=O)(=O)NC(c2ccccc2)c2ccccc2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
In a three-neck round bottom flask equipped with argon inlet was charged with anhydrous dimethylformamide and 3-chloro-propane-1-sulfonic acid benzhydryl-amide (893 mg, 2.76 mmol). 1-Boc-piperazine (771 mg, 4.14 mmol, Aldrich) was added, followed by triethylamine (0.77 mL, 5.52 mmol). The mixture was stirred at 60° C. overnight. It was then heated at 120° C. for 10 min and at 180° C. for 15 min using the microwave synthesizer. Upon cooling, the reaction mixture was concentrated, and the residue was diluted with ethyl acetate. The organic layer was washed with water, brine, and concentrated. Purification of the crude residue by flash column chromatography gave 4-[3-(benzhydryl-sulfamoyl)-propyl]-piperazine-1-carboxylic acid tert-butyl ester as yellow oil (688 mg).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([C:23](O)=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][C:12]=2[C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)=[O:9])[NH:6][CH:7]=1)#[N:2].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CCOC(C)=O>[C:26]1([C:12]2[CH:13]=[C:14]([C:17]3([CH2:23][OH:24])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[CH:15]=[CH:16][C:11]=2[NH:10][C:8]([C:5]2[NH:6][CH:7]=[C:3]([C:1]#[N:2])[N:4]=2)=[O:9])[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3(C(=O)O)CCOCC3)cc2C2=CCCCC2)n1
Agent: CCOC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3(CO)CCOCC3)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
To a mixture of 4-{4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-tetrahydro-pyran-4-carboxylic acid (as prepared in Example 18, step (d), 20.0 mg, 0.0476 mmol) and triethylamine (Et3N) (7.3 μL, 0.052 mmol) in 1 mL of THF at 0° C. was added ClCO2Et (3.6 mg, 0.038 mmol). The mixture was stirred at RT for 0.5 h and NaBH4 (5.4 mg, 0.14 mmol) was added. After stirring at RT for 16 h, the mixture was treated with 30 mL of EtOAc and 10 ml of 10% citric acid. The aqueous layer was separated and extracted with EtOAc (10 mL). The combined organic layers were washed with saturated NaHCO3 aqueous solution (10 mL), H2O (10 mL) and brine (10 mL). After drying over Na2SO4 and concentrating in vacuo, the residue was purified by silica gel chromatography (1-2% MeOH/DCM) to afford the title compound (14 mg, 70%) as a white solid. 1H-NMR (1:5 CD3OD/CDCl3; 400 MHz): δ 8.24 (d, 1H, J=8.6 Hz), 7.72 (s, 1H), 7.26 (dd, 1H, J=8.6, 2.3 Hz), 7.14 (d, 1H, J=2.3 Hz), 5.84 (m, 1H), 3.82 (m, 2H), 3.57 (s, 2H), 3.54-3.60 (m, 2H), 2.27 (m, 4H), 2.14 (m, 2H), 1.95 (m, 2H), 1.82 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C23H26N4O3, 407.2 (M+H). found 407.1.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].[CH2:9]([NH2:13])[CH:10]([CH3:12])[CH3:11]>>[CH2:9]([NH:13][C:4](=[O:6])[CH2:3][C:1]#[N:2])[CH:10]([CH3:12])[CH3:11]
Reactant: CCOC(=O)CC#N
Reactant: CC(C)CN
Product: CC(C)CNC(=O)CC#N
Reaction time: 2 h

Procedure:
Ethyl cyanoacetate (113 g., 1.0 mole) and isobutylamine (73 g., 1.0 mole) were refluxed with stirring for 2 hours to give N-isobutyl cyanoacetamide.
Reaction SMILES: C([C:3]([C:11](=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])([CH2:7][C:8]([O-:10])=[O:9])C([O-])=O)C.[OH-].[Na+].CCOCC>O>[O:17]=[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][CH2:7][C:8]([OH:10])=[O:9]
Reactant: CCCCCC(=O)C(CC)(CC(=O)[O-])C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCCCCC(=O)CCC(=O)O

Procedure:
The part (a) ester (1.0 g, 3.7 mmol) was treated with a solution of NaOH (1.5 g, 37.5 mmol) in water (15 ml). The heterogeneous mixture was heated under gentle reflux for 9 hours. After cooling, ether (20 ml) was added. The layers were separated. The aqueous layer was washed with ether (10 ml) and then acidified to pH 2 using concentrated HCl. The product was extracted into ether (3×20 ml). The ether extracts were washed with saturated NaCl solution, dried (MgSO4), and freed of solvent in vacuo leaving an oil which gradually solidified (345 mg). This was crystallized from petroleum ether to give title acid (189.9 mg, 30%) as colorless needles, m.p. 64°-66° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][NH:8][C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH:16][NH2:17])[C:10]=2[F:18])[N:6]=1.[CH:19]1([CH2:24][C@H:25]([CH2:29][N:30]([CH:38]=[O:39])[O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[C:26](O)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][NH:8][C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH:16][NH:17][C:26](=[O:27])[C@H:25]([CH2:24][CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH2:29][N:30]([O:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[CH:38]=[O:39])[C:10]=2[F:18])[N:6]=1
Reactant: Cc1nc(NN)c(F)c(NCc2csc(N)n2)n1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: Cc1nc(NCc2csc(N)n2)c(F)c(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.1 %

Procedure:
6-{[(2-Amino-1,3-thiazol-4-yl)methyl]amino}-5-fluoro-4-hydrazino-2-methylpyrimidine (125 mg, 0.44 mmol), (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (130 mg, 0.44 mmol), and HOAt (65 mg, 0.48 mmol) were dissolved in 4 mL of DMF. NMM (0.15 mL, 1.32 mmol) was added, followed by EDC (96 mg, 0.48 mmol). After stirring overnight at room temperature, the reaction mixture was purified by RP-HPLC to provide [(2R)-3-[2-(6-{[(2-amino-1,3-thiazol-4-yl)methyl]amino}-5-fluoro-2-methyl-4-pyrimidinyl)hydrazino]-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (114 mg, 46%). LCMS: (M+H)+: 565.3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[C:9]1(=O)[O:14][C:12](=[O:13])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:1]2[C:12](=[O:13])[C:11]3[C:10](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]2=[O:14])[CH:7]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1ccnc(N)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccnc(N2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Yield: 55.8 %

Procedure:
To a mixture of 2-Amino-4-methylpyridine (21.6 g, 0.2 mol) and phthalic anhydride (29.6 g, 0.2 mol) in toluene (160 ml), was added triethylamine (2.8 ml, 0.02 mol). The mixture was refluxed for 5 hr. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was suspended in acetic anhydride (250 ml). The mixture was then heated to reflux for 4 hr until the solid dissolves completely. After cooling to room temperature, white precipitate was collected by filtration and washed with acetic anhydride and hexane, and dried in high vacuo to give 26.6 g (56%) of 2-(4-methyl-pyridin-2-yl)-isoindole-1,3-dione as a white solid. 1H NMR (200 MHz, CDCl3) δ 2.45 (3H, s), 7.18 (1H, d, J=5.0 Hz), 7.25 (1H, s), 7.76-7.99 (4H, m), 8.53 (1H, d, J=5.0 Hz). m/z (EI) 238 (M+).