Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[CH:12]=[N:11][C:10]([S:13][CH2:14][CH2:15][CH2:16][O:17][C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=3)[C:21]#[N:22])=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])(O)(=O)=O.[Na+]>C1COCC1>[C:32]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:8]2[CH:12]=[N:11][C:10]([S:13][CH2:14][CH2:15][CH2:16][O:17][C:18]3[CH:19]=[C:20]([CH2:21][NH2:22])[CH:23]=[CH:24][CH:25]=3)=[N:9]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: N#Cc1cccc(OCCCSc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: NCc1cccc(OCCCSc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
A solution of 3-[(3-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]thio}propyl)oxy]benzonitrile obtained in Reference Example 6 (2.00 g, 3.98 mmol) in THF (15 mL) was added slowly to a suspension of lithium aluminum hydride (1.51 g, 39.8 mmol) in THF (45 mL) at room temperature, and the mixture was stirred at room temperature for 4 hr. Sodium hydrogensulfate 10 hydrate (5.13 g, 15.9 mmol) was added to the reaction mixture at 0° C., and mixture was stirred at room temperature for 30 min. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Toluene and ethanol were added to the residue, and the mixture was concentrated under reduced pressure to give the title compound as a pale-yellow oil (1.91 g, 95%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:6]#[N:7].[CH3:21][O:22][C:23]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][NH:35][CH3:36])=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]>>[C:6]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:3][CH2:2][N:35]([CH3:36])[CH2:34][CH2:33][C:30]1[CH:31]=[CH:32][C:23]([O:22][CH3:21])=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26])#[N:7]
Reactant: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Reactant: CNCCc1ccc(OC)c(C(=O)OC)c1
Product: COC(=O)c1cc(CCN(C)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)ccc1OC

Procedure:
Reaction of 1f with 2h produced 3ag. MS found M+H=483. The oxalate salt of 3ag was recrystallized from ethyl acetate; mp 76-81° C.
Reaction SMILES: C1(S([CH:10]2[CH:20]([C:21]3[CH:26]=[C:25]([Br:27])[CH:24]=[C:23]([CH3:28])[N:22]=3)[NH:19][C:12]3([CH2:16][CH2:15][N:14]([CH3:17])[C:13]3=[O:18])[CH2:11]2)(=O)=O)C=CC=CC=1.CC(C)([O-])C.[K+].C(O)(=O)C>C1COCC1>[Br:27][C:25]1[CH:24]=[C:23]([CH3:28])[N:22]=[C:21]([C:20]2[CH2:10][CH2:11][C:12]3([CH2:16][CH2:15][N:14]([CH3:17])[C:13]3=[O:18])[N:19]=2)[CH:26]=1
Reactant: Cc1cc(Br)cc(C2NC3(CCN(C)C3=O)CC2S(=O)(=O)c2ccccc2)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc(Br)cc(C2=NC3(CC2)CCN(C)C3=O)n1
Reaction time: 1.5 h

Procedure:
To a solution of 7-(benzenesulfonyl)-8-(4-bromo-6-methyl-2-pyridyl)-3-methyl-3,9-diazaspiro[4.4]nonan-4-one (which may be prepared as described in Description 12) in THF (20 mL) at 00° C. was added 1.7 M potassium tert-butoxide in THF (2.69 mL, 4.58 mmol) dropwise over 5 minutes. The reaction mixture was stirred at 00° C. for 1.5 hours. The reaction was quenched by the addition of acetic acid (0.26 mL, 4.58 mmol) and then the mixture was filtered, washed with dichloromethane and the filtrate concentrated at reduced pressure to give a brown gum. The product was purified by silica gel chromatography eluting with 40-100% ethyl acetate in iso-hexane to give racemic 2-(4-bromo-6-methyl-2-pyridyl)-7-methyl-1,7-diazaspiro[4.4]non-1-en-6-one a pale yellow solid (D13) (314 mg);
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)[CH:6]=[C:7]([O:12]C)[C:8]=1[CH:9]([CH3:11])[CH3:10].Cl.N1C=CC=CC=1>>[OH:22][C:19]1[CH:20]=[CH:21][C:16]([CH:15]=[CH:14][C:5]2[CH:6]=[C:7]([OH:12])[C:8]([CH:9]([CH3:10])[CH3:11])=[C:3]([OH:2])[CH:4]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(C=Cc2cc(OC)c(C(C)C)c(OC)c2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)c1c(O)cc(C=Cc2ccc(O)cc2)cc1O
Yield: 30 %

Procedure:
This material was prepared from 1-(3,5-dimethoxy-4-i-propylphenyl)-2-(4-methoxyphenyl)ethene and pyridine hydrochloride in 30% yield in the same way as described in example 3. 1H NMR (DMSO-d6, ppm): δ 1.22 (d, J=7.0 Hz, 6H), 3.41 (m, 1H), 6.40 (s, 2H), 6.73 (d, J=6.3 Hz, 4H), 7.33 (s, 1H), 7.41 (s, 1H), 8.98 (s, 2H), 9.51 (s, 1H).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[Cl:22][C:23]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[CH:27][C:24]=1[C:25]#[N:26].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]1[N:26]=[C:25]([C:24]2[CH:27]=[CH:28][CH:29]=[C:30]([N+:31]([O-:33])=[O:32])[C:23]=2[Cl:22])[N:2]([CH3:1])[N:3]=1
Reactant: N#Cc1cccc([N+](=O)[O-])c1Cl
Reactant: CN(N=C(Cl)c1ccccc1Cl)S(=O)(=O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Cn1nc(-c2ccccc2Cl)nc1-c1cccc([N+](=O)[O-])c1Cl
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2-chlorobenzohydrazonoyl chloride (1.72 g), 2-chloro-3-nitrobenzonitrile (1.00 g), anhydrous aluminum chloride (0.70 g) and o-dichlorobenzene (20 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, the reaction mixture is dissolved in chloroform (100 ml), washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 1.12 g of desired compound (melting point: 124.0°-125.0° C.).
Reaction SMILES: [C:1]12([C:11](O)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br.[C:15]([O:19][C:20](=[O:30])[CH2:21][N:22]1[C:26]([CH3:27])=[C:25]([CH3:28])[S:24][C:23]1=[NH:29])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20](=[O:30])[CH2:21][N:22]1[C:26]([CH3:27])=[C:25]([CH3:28])[S:24][C:23]1=[N:29][C:11]([C:1]12[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2)=[O:12])([CH3:18])([CH3:16])[CH3:17]
Reactant: Cc1sc(=N)n(CC(=O)OC(C)(C)C)c1C
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Agent: Br
Product: Cc1sc(=NC(=O)C23CC4CC(CC(C4)C2)C3)n(CC(=O)OC(C)(C)C)c1C
Yield: 6.2 %

Procedure:
Adamantane-1-carboxylic acid (2.2 g, 12 mmol) and the product of Example 82A (2.9 g, 10 mmol) were processed according to the method of Example 77B. Purification by column chromatography (SiO2, 20-35% ethyl acetate/hexanes gradient) afforded 0.25 g (63%) of the title compound. 1H NMR (CDCl3, 300 MHz) δ ppm 1.47 (s, 9H), 1.71-1.75 (m, 6H), 1.96-2.00 (m, 6H), 2.00-2.04 (m, 3H), 2.14 (s, 3H), 2.21 (s, 3H), 4.85-5.02 (m, 2H); MS (DCI/NH3) m/z 405 (M+H)+. Anal. Calculated for C22H32N2O3S: C, 65.31; H, 7.97; N, 6.92. Found: C, 65.38; H, 7.95; N, 6.84.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:7]=1)=[O:5])C.[OH-].[Na+].Cl.O>C(O)C>[N+:11]([C:10]1[C:6]([C:4]([OH:5])=[O:3])=[N:7][N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=1)([O-:13])=[O:12]
Reactant: CCOC(=O)c1nn(-c2ccccc2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1nn(-c2ccccc2)cc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
To a stirred suspension of 4-nitro-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester (240 mg, 0.92 mmol) at rt in ethanol (3 ml) under an argon atmosphere was added 1 N NaOH (1.8 ml). The mixture was stirred for 2 hrs. 3 N HCl was added until pH˜2 was reached. Upon addition of H2O (˜2 ml), the product precipitated out. It was collected by filtration, washed with H2O and dried. Off-white solid (184 mg, 86%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[NH:10][N:9]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[S:7]1)=[O:5])[CH3:2].[CH:15]1[C:27]2[CH:26]([CH2:28][O:29][C:30](=[O:39])[NH:31][CH:32]([C:36](Cl)=[O:37])[CH:33]([CH3:35])[CH3:34])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[N:10]([C:36](=[O:37])[CH:32]([NH:31][C:30]([O:29][CH2:28][CH:26]2[C:27]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:20]3[C:25]2=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:39])[CH:33]([CH3:35])[CH3:34])[N:9]=[C:8]([C:11]([CH3:13])([CH3:12])[CH3:14])[S:7]1)=[O:5])[CH3:2]
Reactant: CC(C)C(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Cl
Reactant: CCOC(=O)C1NN=C(C(C)(C)C)S1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1SC(C(C)(C)C)=NN1C(=O)C(NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reaction time: 16 h
Yield: 49.5 %

Procedure:
A stirred suspension of polyvinylpyridine (2.63 g, 25 mmol) in a solution of 5-tert-butyl-2,3-dihydro-[1,3,4]thiadiazole-2-carboxylic acid ethyl ester (36) (J. Med. Chem., 34, p. 439 (1991)), (2.16 g, 10 mmol) in dry toluene was treated with the dropwise addition of (1-chlorocarbonyl-2-methyl-propyl)-carbamic acid 9H-fluoren-9-ylmethyl ester (4.76 g, 12.1 mmol) in 20 mL of anhydrous toluene. After stirring for 16 hours, the suspension was filtered and the filtrate was washed with saturated sodium bicarbonate solution. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and evaporated to give a yellow oil. Purification by flash chromatography eluting with 9/1 hexane/ethyl acetate gave 2.66 g (49% yield) of the title compound (37) as a clear, viscous oil. 1H NMR (500 MHz, CD3OD) δ 0.89 (d, 1.5H), 0.93 (d, 1.5H), 1.00 (d, 1.5H), 1.06 (d, 1.5H), 1.22 (t, 3H), 1.28 (s, 9H), 2.12-2.22 (m, 0.5H), 2.32-2.42 (m, 0.5H), 4.18-4.28 (m, 2H), 4.31-4.45 (m, 2H), 4.96-5.01 (m, 0.5H), 5.02-5.10 (m, 0.5H), 5.52 (d, 0.5H), 5.61 (d, 0.5H), 6.10 (s, 0.5H), 6.13 (s, 0.5H), 7.27-7.34 (m, 2H), 7.35-7.42 (m, 2H), 7.56-7.64 (m, 2H), 7.73-7.78 (m, 2H).
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1[C:40]([OH:42])=O>>[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1[C:40]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:29])=[O:3])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:18])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:42]
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Reactant: O=C(O)c1ccc2ccccc2c1
Agent: Cl
Product: CN(C(=O)c1ccc2ccccc2c1)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) according to example 12 with 2-naphthoic acid followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(2-naphthoyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 520 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:18])[C:12]([CH3:17])([CH3:16])[CH2:13][CH:14]=[CH2:15])=[CH:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:5]2=[N:6][CH:7]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:16][C:12]([CH3:17])([CH2:13][CH:14]=[CH2:15])[C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:31]3[CH:32]=[C:33]([O:37][CH3:38])[C:34]([O:35][CH3:36])=[C:29]([O:28][CH3:27])[CH:30]=3)[N:3]=2)[N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:9]=1)=[O:18]
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: C=CCC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: C=CCC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cc(OC)c(OC)c(OC)c3)nc12
Yield: 72.1 %

Procedure:
A mixture of impure 1-[2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-pent-4-en-1-one (0.900 g, “2.05 mmol), 3,4,5-trimethoxyphenyl boronic acid (0.479 g, 2.26 mmol), potassium carbonate (0.850 g, 6.15 mmol) and Pd(dppf)Cl2.CH2Cl2 (0.171 g, 0.21 mmol) in 15 mL of 1,4-dioxane and 4 mL of water was stirred at 120° C. in a microwave for 1 h. The resulting mixture was partitioned between 300 mL of ethyl acetate and 200 mL of water. The organic layer was dried over MgSO4, filtered and concentrated to a residue. Column chromatography (0→35% EtOAc/hexanes) afforded 0.777 g (29% for three steps from 2-bromo-5H-pyrrolo[2,3-b]pyrazine) of 2,2-dimethyl-1-[2-(3,4,5-trimethoxy-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-pent-4-en-1-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=O.N1CCCCC1.C(O)=O.[CH3:23][C:24](=[O:29])[CH2:25][C:26](=[O:28])[CH3:27]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:25]([C:24](=[O:29])[CH3:23])[C:26](=[O:28])[CH3:27])[CH:7]=[CH:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)c1ccc(C=O)cc1Cl
Reactant: CC(=O)CC(C)=O
Solvent: O=CO
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(=O)C(=Cc1ccc(S(C)(=O)=O)c(Cl)c1)C(C)=O
Temperature: 20 °C

Procedure:
To a solution containing 1.42 g 3-chloro-4-methylsulfonylbenzaldehyde, 0.05 ml piperidine and 0.02 ml formic acid in 20 ml DMF was added 1.50 ml 2,4-pentanedione with stirring at 20° C. The solution was stirred overnight at 20° C. and poured into water. The oily residue was separated and crystallized from ethanol, yield 0.24 g (10%), mp. 140-142° C. 1H-NMR (DMSO-d6, 400 MHz): 2.28 (s, 3 H, CH3), 2.50 (s, 3 H, CH3), 3.40 (s, 3 H, CH3), 7.60 (m, 1 H, Ar), 7.80 (m, 1 H, Ar), 7.77 (s, 1 H, CH), 8.1 (m, 1 H, Ar).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][C:16]#[N:17])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si](C)(C)N[Si](C)(C)C.[Li]>O1CCCC1.[Cl-].[NH4+]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:16]#[N:17])[CH2:3][CH:2]=[CH:1][CH2:5]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(CC#N)cc1OC1CCCC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Product: COc1ccc(C2(C#N)CC=CC2)cc1OC1CCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 124.5 %

Procedure:
2-(3-Cyclopentyloxy-4-methoxyphenyl)ethane nitrile (4.0 g) was dissolved in tetrahydrofuran (75 ml) under argon atmosphere, and a tetrahydrofuran solution (40.4 ml) of 1.0 M lithium hexamethyldisilazane was added dropwise thereto at −78° C., followed by stirring at −78° C. for 1 hour. The reaction mixture was diluted with a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The extract was washed with water and saturated saline in this order, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to thereby obtain the title compound (3.05 g) having the following physical properties.
Reaction SMILES: C([O:5][C:6](=[O:45])[C:7]([O:10]/[N:11]=[C:12](/[C:32]1[N:33]=[C:34]([NH:37]C(OC(C)(C)C)=O)[S:35][CH:36]=1)\[C:13]([NH:15][C@H:16]1[C@@H:19]([CH2:20][N:21]2[CH2:25][CH2:24][NH:23][C:22]2=[O:26])[N:18]([S:27]([OH:30])(=[O:29])=[O:28])[C:17]1=[O:31])=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:37][C:34]1[S:35][CH:36]=[C:32](/[C:12](=[N:11]/[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:45])=[O:5])/[C:13](=[O:14])[NH:15][C@H:16]2[C@@H:19]([CH2:20][N:21]3[CH2:25][CH2:24][NH:23][C:22]3=[O:26])[N:18]([S:27]([OH:30])(=[O:29])=[O:28])[C:17]2=[O:31])[N:33]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2CN2CCNC2=O)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1CN1CCNC1=O)c1csc(N)n1)C(=O)O
Yield: 6.3 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (3S,4R)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-oxo-4-((2-oxoimidazolidin-1-yl)methyl)azetidine-1-sulfonic acid (99 mg, 0.147 mmol), DCM (1.47 mL) and TFA (566 μl, 7.35 mmol). The crude residue purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min), affording the title compound (4.8 mg) as a white powder. LCMS: Rt=0.31 min, m/z=520.0 (M+1) Method 2m_acidic; 1H NMR (500 MHz, DMSO-d6) δ 9.25 (dd, J=9.0, 5.0 Hz, 1H), 6.83 (s, 1H), 5.21 (dd, J=9.0, 5.8 Hz, 1H), 4.06-4.00 (m, 1H), 3.65 (dd, J=14.5, 4.7 Hz, 1H), 3.33-3.30 (m, 1H assumed; obscured by water), 3.25 (dd, J=14.5, 6.9 Hz, 2H assumed; obscured by water), 3.17 (ddd, J=16.7, 8.6, 6.7 Hz, 2H), 1.43 (s, 3H), 1.42 (s, 3H).
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)([O-:14])=[O:13].[Cl-].[Li+].C(N(C(C)C)CC)(C)C.C(OC(C)C)(C)C>O1CCCC1.[Hg]>[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][CH:3]([C:2](=[O:1])[CH2:9][CH2:10][CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCCC(=O)CC(=O)OCC
Agent: [Cl-]
Agent: [Hg]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: CCCC(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)OCC
Temperature: 25 °C
Yield: 73.5 %

Procedure:
127.7 g of ethyl 3-oxohexanoate are dissolved in 700 ml of tetrahydrofuran. 174.5 g of 4-nitrobenzyl bromide and 35 g of lithium chloride are added and the mixture is stirred at room temperature. 286 ml of diisopropylethylamine are then introduced dropwise, which causes a slight exothermic effect. The mixture is then stirred for 3 hours at room temperature and thereafter for 10 hours under reflux. The solvents are evaporated off under vacuum and the residue is taken up with water and then extracted with chloroform. The organic phase is separated after settling has taken place and then washed with dilute hydrochloric acid solution, dried over magnesium sulphate and evaporated under vacuum. The oily residue obtained is taken up with isopropyl ether and the crystals formed are filtered off. The mother liquors are concentrated under vacuum and the residue is heated to 130° C. at 20 mmol mercury in order to remove the residual starting materials. 174 g of ethyl 2-(4-nitrobenzyl)-3-oxohexanoate are thereby obtained in the form of an oil, which is used without further purification for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([N+:12]([O-])=O)[CH:6]=[CH:7][CH:8]=2)[CH:3]=1>O.[Fe]>[NH2:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[C:2]([Br:1])[CH:11]=[CH:10]2
Reactant: O=[N+]([O-])c1cccc2ccc(Br)cc12
Agent: [Fe]
Solvent: O
Product: Nc1cccc2ccc(Br)cc12
Yield: 62 %

Procedure:
To a suspension of iron powder (1.66 g) in 25 ml water and 25% HCL (1.7 ml) was added 2-bromo-8-nitro-naphthalene (2.15 g, 8.5 mmol) and the reaction mixture was refluxed for 2 hours. The aqueous phase was extracted with ethyl acetate to give the crude product. Chromatography on silica gel (hexane/ethyl acetate 1/9 to 2/3) afforded 1.17 g (62%) of the product as brown oil. MS: m/e=222.2 (M+).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:4](=[CH:5][C:6]([F:24])=[C:7]([Cl:23])[CH:8]=2)[N:3]=1.Cl.[F:26][C:27]1([F:31])[CH2:30][NH:29][CH2:28]1>C(N(CC)CC)C>[Cl:23][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[F:24])[N:3]=[C:2]([N:29]1[CH2:30][C:27]([F:31])([F:26])[CH2:28]1)[C:11]([C:12]1[N:13]=[N:14][NH:15][N:16]=1)=[C:10]2[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: FC1(F)CNC1
Reactant: Fc1cc2nc(Cl)c(-c3nnn[nH]3)c(-c3ccccc3)c2cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: Fc1cc2nc(N3CC(F)(F)C3)c(-c3nn[nH]n3)c(-c3ccccc3)c2cc1Cl

Procedure:
The title compound was prepared in analogy to example 102 step C from 2,6-dichloro-7-fluoro-4-phenyl-3-(1H-tetrazol-5-yl)-quinoline (prepared as described in example 107 step B), 3,3-difluoroazetidine hydrochloride and triethylamine. Light brown solid. MS (ESI): 417.4 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27]>>[OH:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][S:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=2)(=[O:28])=[O:27])=[CH:4][CH:5]=1
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: NCc1ccc(CO)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(NCc1ccc(CO)cc1)c1ccccn1
Yield: 85 %

Procedure:
Using the above procedure J: Reaction of (4-aminomethyl-phenyl)-methanol (255 mg, 1.86 mmol, N,N-diisopropylethylamine (294 μL, 1.69 mmol), and pyridine-2-sulfonyl chloride (300 mg, 1.69 mmol) for 10 minutes at room temperature gave the title compound (400 mg, 85%) white solid. 1H NMR (300 MHz, CDCl3) δ 4.26 (br s, 2H), 4.66 (br s, 2H), 5.28 (br s, 1H), 7.23-7.30 (m, 4H), 7.49-7.51 (m, 1H), 7.90-7.92 (m, 1H), 7.99 (d, 1H, J=4.8 Hz), 8.68 (d, 1H, J=4.5 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].S([CH2:21][N+:22]#[C-:23])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]1[O:6][CH:23]=[N:22][CH:21]=1
Reactant: COc1ccccc1C=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccccc1-c1cnco1
Yield: 70.4 %

Procedure:
A mixture of 2-methoxybenzaldehyde (10.0 g, 73.4 mmol), tosylmethylisocyanide (14.34 g, 73.4 mmol) and potassium carbonate (10.14 g, 73.4 mmol) in 220 ml methanol is heated at reflux for 6 hours. The solvent is removed under reduced pressure and the residue poured into ice-water (800 ml). The precipitate is collected by filtration, washed with water, and dried in vacuo to give 9.05 g of 5-(2-methoxyphenyl)oxazole (70%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:30])[N:5]([C@@H:13]([C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:6]2=[O:12].I[Si](C)(C)C>C(Cl)Cl.[Cl-].[Na+].O>[NH2:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:30])[N:5]([C@@H:13]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=1)[CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:6]2=[O:12]
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2C(=O)c3ccc(O)c(N)c3C2=O)ccc1OC
Agent: C[Si](C)(C)I
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2C(=O)c3ccc(O)c(N)c3C2=O)ccc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of (S)-4-amino-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-5-hydroxy-isoindole-1,3-dione (1 mmol) in anhydrous CH2Cl2 (20 mL), is added iodotrimethylsilane (6 mmol). The mixture is stirred at room temperature for 24 hours. This mixture is diluted with brine (20 mL) and is extracted with CH2Cl2 (2×30 mL). The extracts are combined, and the solvent is removed in vacuo to give crude (S)-4-amino-2-[1-(3-ethoxy-4-hydroxy-phenyl)-2-methanesulfonyl-ethyl]-5-hydroxy-isoindole-1,3-dione. The product is purified by column chromatography.