Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]([CH3:15])([CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])[C:4]#[N:5].[C:17]1([Li])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH4-].[Na+].NC(C1C=CC=CC=1)C1(N(C)C)CCCC1>C(OCCCC)CCC.C1COCC1.CO>[NH2:5][CH:4]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:3]([N:2]([CH3:16])[CH3:1])([CH2:6][O:7][Si:8]([C:11]([CH3:12])([CH3:14])[CH3:13])([CH3:10])[CH3:9])[CH3:15]
Reactant: CN(C)C(C)(C#N)CO[Si](C)(C)C(C)(C)C
Reactant: [Li]c1ccccc1
Agent: CN(C)C1(C(N)c2ccccc2)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCCCOCCCC
Product: CN(C)C(C)(CO[Si](C)(C)C(C)(C)C)C(N)c1ccccc1
Yield: 33 %

Procedure:
The title compound (930 mg, 33%) was prepared from 2-(dimethylamino)-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-methylpropanenitrile D47 (2.1 g, 8.67 mmol), phenyl lithium (10.0 ml of a 1.8M solution in dibutyl ether, 18.0 mmol) in THF (30 ml) followed by sodium borohydride (830 mg, 26.0 mmol) in methanol (50 ml) in a similar manner to that described in D2. Chromatography (Biotage Horizon) to isolate the title compound was carried out using (i) 0 to 100% ethyl acetate/pentane, (ii) 100% ethyl acetate and (iii) 0 to 20% methanol/ethyl acetate. The product containing fractions were combined and evaporated. Mass spectrum (Electrospray LC/MS), API+: Found 323 (MH+), 306 (M−16). C18H34N2OSi requires 322. Ret. time 2.35-2.39 min. (broad peak).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:27])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].Cl.[CH2:29]([O:36][NH2:37])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[CH2:29]([O:36][NH:37][C:14](=[O:15])[CH2:13][CH:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[N:17]1[C:18](=[O:27])[C:19]2=[CH:26][CH:25]=[CH:24][CH:23]=[C:20]2[C:21]1=[O:22])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)ccc1OC
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NOCc2ccccc2)N2C(=O)c3ccccc3C2=O)ccc1OC
Yield: 93.8 %

Procedure:
N-Benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-phthalimidopropionamide was prepared by the procedure of Example 1 from 3-(3-ethoxy-4-methoxyphenyl)-3-phthalimido-propanoic acid (869 mg, 2.36 mmol), N,N′-carbonyldiimidazole (410 mg, 2.53 mmol) and O-benzylhydroxylamine hydrochloride (444 mg, 2.78 mmol) in tetrahydrofuran (6 mL) to afford N-benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-phthalimidopropionamide as a white solid (1.05 g, 94% yield): mp, 165.0-166.0° C.; 1H NMR (CDCl3) δ1.44 (t, J=7.0 Hz, 3H, CH3), 2.95 (dd, J=5.8, 14.0 Hz, 1H, CHH), 3.49 (t, J=12.1 Hz, 1H, CHH), 3.83 (s, 3H, CH3), 4.07 (q, J=7.0 Hz, 2H, CH2), 4.77 (br s, 2H, PhCH2), 5.83 (dd, J=6.0, 10.0 Hz, 1H, NCH), 6.79 (d, J=8.0 Hz, 1H, Ar), 7.06-7.09 (m, 2H, Ar), 7.25-7.85 (m, 5H, Ar), 7.66-7.71 & 7.74-7.79 (2 ms, 4H, Ar), 8.34 (br s, 1H, NH); 13C NMR (CDCl3) δ14.68, 35.66, 51.54, 55.88, 64.34, 78.13, 111.32, 12.52, 120.08, 123.29, 128.52, 128.67, 129.06, 131.26, 131.76, 133.98, 134.98, 148.31, 149.15, 167.38, 168.26. Anal. Calcd for C27H26N2O6: C, 68.34; H, 5.52; N, 5.90. Found: C, 68.36; H, 5.47; N, 5.74.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH2:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:20]1[C:21]2[CH:28]=[CH:27][NH:26][C:22]=2[N:23]=[CH:24][N:25]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:20]2[C:21]3[CH:28]=[CH:27][NH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Product: O=C(OCc1ccccc1)N1CCC(CNc2ncnc3[nH]ccc23)CC1

Procedure:
EXAMPLE 87 was prepared from 4-aminomethyl-piperidine-1-carboxylic acid benzyl ester and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (4-chloro-7H-pyrrolo[2,3-d]pyrimidine was prepared according to U. Lupke, F. Seela, Chem. Ber., 112:3832–3839(1979): MS (m+1)=366.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[OH:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:19][C:11]1[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=1[Cl:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(Cl)c(OCc2ccccc2)c1
Yield: 98.7 %

Procedure:
Benzyl bromide (0.6 mL, 5.04 mmol) was added dropwise to a mixture of 2-chloro-5-nitro-phenol (800 mg, 4.61 mmol) and potassium carbonate (1.27 g, 9.22 mmol) in acetone (20 mL) at room temperature and heated at reflux for 2 h. Inorganic salts were filtered off and washed with acetone (20 mL). The combined filtrate and washings were concentrated in vacuo, the resulting residue then being dissolved in ethyl acetate (25 mL) and washed successively with water (2×20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to yield 2-benzyloxy-1-chloro-4-nitro-benzene (1.20 g, 99%) as a cream solid.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH3:6])=O.C[O-:8].[Na+].[CH:10]([OH:13])([CH3:12])[CH3:11]>>[CH3:6][O:5][CH2:3][C:2]([O:13][CH:10]([CH3:12])[CH3:11])=[O:8]
Reactant: C[O-]
Reactant: COC(=O)CCl
Reactant: CC(C)O
Agent: [Na+]
Product: COCC(=O)OC(C)C
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 74 %

Procedure:
434.1 g (4.0 mol) of methyl chloroacetate are initially introduced and stirred at 25° C. 756.3 g (4.2 mol) of 30% strength sodium methoxide solution are added dropwise in the course of 2.5 h such that a reaction temperature of 65° C. is not exceeded. After the addition, stirring is continued at reflux temperature for a further 3 h. 436.0 g of methanol are then removed from the reaction mixture by distillation. 480.8 g (8 mol) of isopropanol are added to the residue and the mixture is heated under reflux. In the course of this, methanol is removed via a 0.5 m long Multifil column at a reflux ratio of approximately 1:1 (244.4 g of distillate). After 6.5 h, the conversion of the methyl methoxyacetate to the isopropyl methoxyacetate is >98%. After cooling, the reaction mixture is concentrated to dryness on a rotary evaporator at a maximum bath temperature of 120° C. and a pressure of <15 mbar. A residue of 274.3 g and a distillate of 668.0 g are obtained. The distillate is fractionated through a 0.5 m long Multifil column. Isopropyl methoxyacetate is obtained as the main fraction (390.6 g, yield 74%) with a purity of >99%, a chlorine content of 10 ppm and a water content of <0.05%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([Cl:13])=[CH:11][NH:10][CH:9]=1.[C:14](N1C=CN=C1)(=[O:16])[CH3:15]>CCOCC>[C:14]([N:10]1[CH:11]=[C:12]([Cl:13])[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:9]1)(=[O:16])[CH3:15]
Reactant: Clc1ccccc1-c1c[nH]cc1Cl
Reactant: CC(=O)n1ccnc1
Solvent: CCOCC
Product: CC(=O)n1cc(Cl)c(-c2ccccc2Cl)c1
Yield: 48 %

Procedure:
The mixture of 4.35 g of 3-(2-chlorophenyl)-4-chloropyrol and 5.3 g of N-acetylimidazole was heated for 4 hours at 100° to 110° C. After cooling, the reaction mixture was dissolved in 200 ml of ether and the resulting ether solution was washed with successive, diluted hydrochloric acid and water. The ether solution was dried with anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residual crude product was purified by silicagel chromatography using mixed solvent of n-hexane and benzene (1:1) to obtain 2.5 g of the desired product (colorless crystal, m.p. 82°-84° C.).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[C:9](F)=[N:10][CH:11]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:13]=1.CN(C)C(=O)C.[CH3:32][C:33]1[N:34]=[CH:35][C:36]([NH:39][C:40]2[C:49]3[C:44](=[CH:45][CH:46]=[C:47]([OH:50])[CH:48]=3)[N:43]=[CH:42][N:41]=2)=[N:37][CH:38]=1>O>[Cl:7][C:8]1[C:9]([O:50][C:47]2[CH:48]=[C:49]3[C:44](=[CH:45][CH:46]=2)[N:43]=[CH:42][N:41]=[C:40]3[NH:39][C:36]2[CH:35]=[N:34][C:33]([CH3:32])=[CH:38][N:37]=2)=[N:10][CH:11]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:13]=1
Reactant: Cc1cnc(Nc2ncnc3ccc(O)cc23)cn1
Reactant: Fc1ncc(OCCCOC2CCCCO2)cc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cnc(Nc2ncnc3ccc(Oc4ncc(OCCCOC5CCCCO5)cc4Cl)cc23)cn1
Temperature: 180 °C
Reaction time: 14 h
Yield: 70.7 %

Procedure:
Potassium tert-butoxide (0.89 g, 7.90 mmol) and 3-chloro-2-fluoro-5-[3-(tetrahydro-2H-pyran-2-yloxy)propoxy]pyridine (2.52 g, 8.69 mmol) were added to an N,N-dimethylacetamide solution (2.5 ml) of 4-[(5-methylpyrazin-2-yl)amino]quinazolin-6-ol (1.0 g, 3.95 mmol), and stirred at 180° C. for 14 hours under a nitrogen atmosphere in a sealed tube. The reaction solution was cooled with ice, water was added, and extracted with chloroform/methanol (10:1). The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amine-type silica gel column chromatography (Moritex NH, hexane:ethyl acetate=3:1 to 3:2) to obtain 6-({3-chloro-5-[3-(tetrahydro-2H-pyran-2-yloxy)propoxy]pyridin-2-yl}oxy)-N-(5-methylpyrazin-2-yl)quinazoline-4-amine (1.46 g, yield: 71%) as an orange oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH3:9][O:10][CH2:11][CH2:12][CH2:13]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:13][CH2:12][CH2:11][O:10][CH3:9]
Reactant: Oc1ccccc1I
Reactant: COCCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCCOc1ccccc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
To a stirred solution of 2-iodophenol (3.00 g, 13.6 mmol), 3-methoxy-1-propanol (1.57 ml, 16.4 mmol) and triphenylphosphine (4.29 g, 16.4 mmol) in THF (15 ml) was added dropwise diisopropyl azodicarboxylate (3.22 ml, 16.4 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was quenched with water and extracted with EA. The organic layer was separated, dried over sodium sulfate, filtered, and evaporated under reduced pressure: The residue was purified by silica gel chromatography (EA/HEP 1:5). 4.00 g of the title compound were obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:12]([N:19]=[C:20]=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1C=CC=CC=1>O1CCCC1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:20](=[O:21])[NH:19][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCCN=C=O
Reactant: Oc1ccc2ncccc2c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)Oc1ccc2ncccc2c1
Temperature: 21 °C
Reaction time: 40 h

Procedure:
A mixture of quinolin-6-ol (0.29 g., 2 mmol), heptyl isocyanate (0.39 ml, 2.4 mmol) and pyridine (2 ml) in dry tetrahydrofuran (10 ml) was stirred at room temperature (21° C.) for 40 hours, the reaction mixture was concentrated under vaccum and the residue was washed with water (2×5 ml) and crystallized with ether to give 1b; yield: 0.30 g. (52.4%).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH2:32]([NH2:35])[CH2:33][CH3:34].[BH4-].[Na+]>ClCCl.CO.C(O)(=O)C>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:35][CH2:32][CH2:33][CH3:34])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: CCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCNCc1cccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (20 mg, 0.046 mmol) in dichloromethane (0.7 mL) and methanol (0.7 mL) was added propylamine (22 uL, 0.27 mmol) and 1 drop of acetic acid. This mixture was stirred for 1 h at room temperature and then sodium borohydride (10 mg, 0.27 mmol) was added. The reaction was stirred overnight at ambient temperature, and the solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC (water/CH3CN, 0.1% TFA 10-90%) to give the title compound (22.1 mg, 99%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:22][O:23][C:24](=[O:31])[C@@H:25]([C:27]([SH:30])([CH3:29])[CH3:28])[NH2:26]>>[CH3:7][C:4]([CH3:5])([O:3][C:1]([NH:8][C@H:9]([C:18]([NH:26][C@@H:25]([C:24]([O:23][CH3:22])=[O:31])[C:27]([SH:30])([CH3:29])[CH3:28])=[O:20])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)=[O:2])[CH3:6]
Reactant: COC(=O)[C@H](N)C(C)(C)S
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](NC(=O)[C@H](Cc1ccc(F)cc1)NC(=O)OC(C)(C)C)C(C)(C)S

Procedure:
The title compound was synthesized by coupling Nα -Boc-(p-fluoro) phenylalanine (1.3 g, 40.0 mmol) to 8.2 g (41.0 mmol) of D-penicillamine methylester hydrochloride using the procedure described above in Example 19. The title compound was obtained as a white solid (14.8 g, 86.5%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[O:16][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.[N-:29]=[N+:30]=[N-:31].[Na+].Cl.[NH+]1C=CC=CC=1>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[O:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]2[NH:31][N:30]=[N:29][N:23]=2)=[CH:24][CH:25]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(COc2cccc(OCc3ccc4ccccc4n3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: c1cc(OCc2ccc(-c3nnn[nH]3)cc2)cc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C

Procedure:
A slurry of 2.0 g (5.48 mmol) of 4-(3-(2-quinolinylmethyloxy)phenoxymethyl)benzonitrile, 1.78 g (27.4 mmol) of sodium azide, and 3,16 g (27.4 mmol) of pyridinium hydrochloride in 12 ml of dry DMF is stirred under nitrogen at 100° C. for 20 hrs. The reaction mixture is then cooled to room temperature and concentrated. The residue is taken up on 100 ml of 1N aqueous NaOH and the solution extracted with ether. The aqueous layer is acidified to pH 6 with 1N aqueous HCl, and the precipitate collected, triturated with water, filtered and lyophilized to obtain 5-(4-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenyl)tetrazole (M.P. 91° C. dec.)
Reaction SMILES: Cl.CN(C)[C:4](=[CH:10][CH:11]=[C:12]([C:19]#[N:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C([OH:24])C>>[OH:24][C:4](=[CH:10][CH:11]=[C:12]([C:19]#[N:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCO
Reactant: CCOC(=O)C(=CC=C(C#N)c1ccccc1)N(C)C
Agent: Cl
Product: CCOC(=O)C(O)=CC=C(C#N)c1ccccc1
Temperature: 10 °C

Procedure:
1N aqueous hydrochloric acid solution (87 cc) is added in the course of 3 minutes to a solution, maintained under reflux, of ethyl 2-dimethylamino-5-cyano-5-phenyl-2,4-pentadienoate (21.3 g) in ethanol (27 cc). The mixture is cooled to a temperature of approximately 10° C. and the precipitate obtained is filtered off, washed with ethanol (15 cc) and dried. Ethyl 2-hydroxy-5-cyano-5-phenyl-2,4-pentadienoate (12.1 g), m.p. 189° C., is thereby obtained.
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:23]([N:25]([C@@H:27]([C@@H:60]([CH3:63])[CH2:61][CH3:62])[C@H:28]([O:58][CH3:59])[CH2:29][C:30]([N:32]3[CH2:36][CH2:35][CH2:34][C@H:33]3[C@H:37]([O:56][CH3:57])[C@@H:38]([CH3:55])[C:39](=[O:54])[NH:40][C@H:41]([C:49]3[S:50][CH:51]=[CH:52][N:53]=3)[CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:31])[CH3:26])=[O:24])[CH:20]([CH3:22])[CH3:21])=O)C3C(=CC=CC=3)C=2C=CC=1>O1CCCC1.C(NCC)C>[CH3:59][O:58][C@@H:28]([C@@H:27]([N:25]([CH3:26])[C:23](=[O:24])[C@H:19]([CH:20]([CH3:22])[CH3:21])[NH2:18])[C@@H:60]([CH3:63])[CH2:61][CH3:62])[CH2:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[C@H:37]([O:56][CH3:57])[C@@H:38]([CH3:55])[C:39](=[O:54])[NH:40][C@H:41]([C:49]1[S:50][CH:51]=[CH:52][N:53]=1)[CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:31]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: C1CCOC1
Solvent: CCNCC
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](N)C(C)C
Yield: 79 %

Procedure:
According to general procedure A, from #85 (5.00 g, 5.68 mmol, 1 eq.) in tetrahydrofuran (10 mL, 0.56 M) and diethylamine (3 mL) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0% to 10% methanol in dichloromethane) to give #86 (2.952 g, 79%) as a solid. LC-MS: m/z 658.5 [M+H+], 680.5 [M+Na+] retention time=0.66 minute; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [8.64 (br d, J=8.4 Hz) and 8.90 (br d, J=8.8 Hz), total 1H], [7.77 (d, J=3.3 Hz) and 7.80 (d, J=3.3 Hz), total 1H], [7.63 (d, J=3.3 Hz) and 7.66 (d, J=3.3 Hz), total 1H], 7.12-7.31 (m, 5H), [5.39 (ddd, J=11.2, 8.4, 4.2 Hz) and 5.54 (ddd, J=11.9, 8.9, 4.0 Hz), total 1H], 3.15, 3.19, 3.20 and 3.26 (4 s, total 6H), 2.86 and 2.98 (2 br s, total 3H), [1.06 (d, J=6.6 Hz) and 1.11 (d, J=6.6 Hz), total 3H].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[N:32][CH:33]=4)=[C:14]([C:16]#[C:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[H-].[Na+].[C:44]([O:48][C:49]([CH2:51]C(OC(C)(C)C)=O)=[O:50])([CH3:47])([CH3:46])[CH3:45].O>CN(C=O)C>[C:37]([O:36][C:35]([N:34]([C:31]1[CH:30]=[CH:29][C:28]([C:13]2[N:9]3[N:10]=[CH:11][CH:12]=[C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[C:8]3=[N:15][C:14]=2[C:16]#[C:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)=[CH:33][N:32]=1)[CH2:51][C:49]([O:48][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:50])=[O:41])([CH3:38])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound 38a (1.0 g, 1.7 mmol) in DMF (20 mL), was added sodium hydride (60%, 0.11 g, 2.7 mmol) in portions at 0° C. The resulting mixture was stirred at rt for 30 min, and treated with tert-butyl 2-(tert-butoxycarbonyl)acetate (0.53 g, 2.7 mmol). The resulting mixture was stirred at rt for 4 h, and treated with water (100 mL). The solids formed were collected by filtration, washed with Et2O (2×50 mL), and further purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether (2:1)) to obtain compound 38b as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C37H39N7O5: 662.3 (M+H). found: 662.2.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-])=O)[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]#[C:12][CH2:13][N:14]1[CH2:17][CH:16]([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:15]1.[NH4+].[Cl-]>[Fe]>[NH2:31][C:29]1[CH:28]=[CH:27][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[C:11]#[C:12][CH2:13][N:14]2[CH2:15][CH:16]([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:17]2)=[C:2]([F:1])[CH:30]=1
Reactant: CC(C)(C)OC(=O)NCC1CN(CC#Cc2cnccc2Oc2ccc([N+](=O)[O-])cc2F)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)NCC1CN(CC#Cc2cnccc2Oc2ccc(N)cc2F)C1

Procedure:
The title compound was prepared by the reduction of tert-butyl (1-(3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-ynyl)azetidin-3-yl)methylcarbamate (30 mg, 0.66 mmol) in the same manner as in Step E of Example 35 using Fe powder (50 mg, 0.091 mmol) and NH4Cl (96 mg, 1.82 mmol). The product was used in subsequent reactions without any purification. MS(ESI+): m/z 371.24 (100), [(M-C4H9)]+; m/z 427.27 (25), (M+H)+.
Reaction SMILES: Cl([O-])=O.[Na+].[OH2:5].O.P([O-])(O)(O)=O.[Na+].[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[CH2:22][CH:23]([CH3:25])[CH3:24])[CH:17]=[O:18]>O.C(O)(C)(C)C>[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[CH2:22][CH:23]([CH3:25])[CH3:24])[C:17]([OH:5])=[O:18]
Reactant: CC(C)Cc1ccc(C=O)cc1Cl
Reactant: O
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Product: CC(C)Cc1ccc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of sodium chlorite (80% assay, 1.06 g, 0.0094 mol) and sodium dihydrogenphosphate dihydrate (3.33 g, 0.0213 mol) in demineralized water (10 mL) is added in two equal lots (one hr interval) to a solution of 3-chloro-4-isobutylbenzaldehyde (0.7 g, 0.0036 mol) in tert-butanol (10 mL) at room temperature. After completion of addition, stirring at room temperature is continued for 4 hrs. It is then extracted in ethyl acetate (2×30 mL). Combined organic layer is dried over sodium sulfate and concentrated under reduced pressure to give 3-chloro-4-isobutylbenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([OH:23])=[O:22])[CH2:9]2)=[CH:4][CH:3]=1.CO.[CH3:26]C1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:26][O:22][C:21]([C:10]1[CH2:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[N:11]=1)=[O:23]
Reactant: O=C(O)C1=NN(c2ccc(Cl)cc2Cl)C(c2ccc(Cl)cc2)C1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C1=NN(c2ccc(Cl)cc2Cl)C(c2ccc(Cl)cc2)C1
Temperature: 80 °C
Reaction time: 24 h
Yield: 498.2 %

Procedure:
A mixture of 5-(4-chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid (78.0 g, 0.21 mol), methanol 150 mL, p-TsOH.H2O (0.042 mol) in toluene (350 mL) was stirred for 24 hours at 80° C. The reaction mixture was cooled to room temperature and the solvent was concentrated in vacuo. The residue was taken up in EtOAc (300 mL) and subsequently washed with sat. aq. NH4Cl and water and dried. The solvent was removed in vacuo to yield the title compound (80.27 g, 99%) white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[C:12]1([C:18]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=O)=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)C>CO>[C:12]1([C:18]2[C:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:1][C:2]3[C:3](=[CH:4][CH:5]=[CH:6][C:7]=3[NH2:8])[N:9]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cccc([N+](=O)[O-])c1N
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: Nc1cccc2nc(-c3ccccc3)c(-c3ccccc3)nc12

Procedure:
1.53 g (10 mmol) of 2,3-diaminonitrobenzene and 2.00 g (9.6 mmol) of benzil were placed in four-necked flask, to which 30 g of a solvent of acetic acid and methanol at a mixing ratio of 1:1 was added for dissolution. Subsequently, the mixture was reacted at a reaction temperature of 70° C. for 2 hours. After the reaction, the solvent was removed and the resulting product was extracted with a silica gel column (ethyl acetate:hexane=1:1).