Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH:15]([C:17]2[C:18]([O:29][CH3:30])=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)[OH:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][C:9]1[C:14]([C:15]([C:17]2[C:18]([O:29][CH3:30])=[C:19]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:20]=[CH:21][CH:22]=2)=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(-c2ccccc2)cccc1C(O)c1cccc(-c2ccccc2)c1OCc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1c(C(=O)c2cccc(-c3ccccc3)c2OCc2ccccc2)cccc1-c1ccccc1
Yield: 62 %

Procedure:
A solution of crude 3 (3.46 mmol) in dichloromethane (60 mL) was treated with manganese dioxide (85%, 5.3 g, 15 equiv) and this suspension was stirred at reflux overnight. The solids were filtered out and washed with ethyl acetate. The solvent was removed in a rotary evaporator and the residue was chromatographed on silica (85 g) with 2% ethyl acetate in heptane (5 L). Pure 4 (0.48 g) as well as slightly impure 4 (1.01 g) were isolated (total yield 91%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:9][CH:10]=O)=[CH:4][CH:3]=1.[C:19]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21]C)=[O:20]>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:9]/[CH:10]=[CH:23]/[C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=CC=O)c2ccc(C)cc2)cc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(C(=C/C=C/C(=O)O)c2ccc(C)cc2)cc1
Yield: 67.4 %

Procedure:
In the manner described in Example 99, 3,3-bis(4-methylphenyl) -2-propenal (9.45 g) was reacted with (carbomethoxymethylene)triphenylphosphorane (15.3 g) in carbon tetrachloride (95 ml) for 3 days at room temperature. The solvent was removed under reduced pressure and the residue was stirred at reflux in mixture of methanol (40 mL) and 2N NaOH for 45 minutes. The cooled solution was diluted with water (300 ml), extracted with dichloromethane (3×100 mL) to remove non-acidic material, and then acidified with 6N HCI (50 ML) and extracted with dichloromethane. The dried (MgSO4) extracts were evaporated and the crude product was crystallized from 2-propanol to afford 7.5 g of (E)-5,5-bis(4-methylphenyl)-2,4-pentadienoic acid, mp 224.5°-226.5° C.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[Na].[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([OH:25])(=O)=[O:23])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl.CN(C)C=O>[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([Cl:4])(=[O:25])=[O:23])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=S(=O)(O)c1ccc(OCc2ccccc2)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Reaction time: 18 h
Yield: 89 %

Procedure:
A solution of 55 ml (639 mmol) of oxalyl chloride in 250 ml of dichloromethane is added dropwise to a solution of 61 g (213 mmol) of the sodium salt of 4-benzyloxybenzenesulfonic acid in 200 ml of dimethylformamide, while maintaining the temperature between −20° C. and −10° C. After addition, the reaction medium is slowly brought back to ambient temperature and then stirred for 18 h, poured onto ice and extracted with ethyl acetate. The organic phase is washed with water and with a saturated aqueous solution of sodium chloride and concentrated under vacuum. 54 g (89%) of 4-benzyloxybenzenesulfonyl chloride are obtained in the form of a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].CCN(C(C)C)C(C)C.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>C1COCC1>[Cl:13][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:26]([CH:23]2[CH2:25][CH2:24]2)=[O:27])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C(Cl)C1CC1
Reactant: COC(=O)c1cc(CN)ccc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(CNC(=O)C2CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a solution of methyl 5-(aminomethyl)-2-chlorobenzoate (15.0 g, 75 mmol) in dry THF (150 mL) was added DIPEA (15 mL) under nitrogen atmosphere. Cyclopropanecarbonyl chloride was added to the reaction mixture at 10° C. and (11.81 g, 113 mmol). The reaction mixture was stirred at RT for 5-6 h. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was washed with dilute HCl, followed with sodium bicarbonate solution and concentrated to afford 10.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.69 (m, 4H), 1.59 (m, 1H), 3.86 (s, 3H), 4.29 (d, J=6.0 Hz, 2H), 7.43 (d, J=6.6 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.67 (s, 1H), 8.64 (br s, 1H); MS (m/z): 268.16 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([N:34]1[N:38]=[N:37][C:36]([CH3:39])=[N:35]1)[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6].C(SCC(OC)CNS(CCC[I:67])(=O)=O)CCCCCCCCCCCCCCC>>[I:67][CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([N:34]1[N:38]=[N:37][C:36]([CH3:39])=[N:35]1)[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)n1nnc(C)n1
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCI)n1nnc(C)n1

Procedure:
3-(3-Chloropropylsulfonylamino)-2-(5-methyl-2H-tetrazol-2-yl)-1-octadecylcarbamoyloxypropane IIIh3 is allowed to react and worked up by the same procedure as described in (5). m.p. 53.5°-54° C. The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C@H:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:5]2[C:14]([CH3:21])=[C:15]([NH2:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=1>C(OCC)(=O)C.CCCCCC>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([NH:20][C:15]2[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]3[O:3][C:2]([CH3:22])([CH3:1])[C@H:6]([C:7]4[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=4)[C:5]=3[C:14]=2[CH3:21])=[O:33])=[CH:27][CH:26]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: Cc1ccc([C@@H]2c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(CC(=O)Nc2c(C)c(C)c3c(c2C)[C@@H](c2ccc(C)cc2)C(C)(C)O3)cc1
Yield: 74 %

Procedure:
Using (+)-(3R)-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 134 and -4-methoxyphenylacetic acid, the title compound was synthesized in the same manner as in Reference Example 359. Yield 74%. Melting point: 186-188° C. (ethyl acetate-hexane).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[N:3]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[C:14]=1[CH:21]1[O:25][CH2:24][CH2:23][O:22]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[N:3]=2)=[C:15]([F:20])[C:14]=1[CH:21]1[O:22][CH2:23][CH2:24][O:25]1
Reactant: COc1nc(Cl)ccc1C#N
Reactant: Oc1ccc(Br)c(C2OCCO2)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(Oc2ccc(Br)c(C3OCCO3)c2F)ccc1C#N
Yield: 85 %

Procedure:
A solution of 6-chloro-2-methoxynicotinonitrile (1.16 g, 6.88 mmol), 4-bromo-3-(1,3-dioxolan-2-yl)-2-fluorophenol (1.81 g, 6.88 mmol), potassium carbonate (1.14 g, 8.26 mmol), and N,N-dimethylformamide (35 mL) was stirred at 80° C. overnight. Water was added and the solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure and the residue was purified by silica gel column using Combiflash to give 6-(4-bromo-3-(1,3-dioxolan-2-yl)-2-fluorophenoxy)-2-methoxynicotinonitrile (2.31 g, 85% yield).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([N:13]([CH3:17])[C:14](=[O:16])[O-:15])[CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)=[N+]=[N-]>CCOC(C)=O.[Pd]>[NH2:1][CH2:4][C@@H:5]([N:13]([CH3:17])[C:14](=[O:16])[O:15][C:7]([CH3:12])([CH3:8])[CH3:6])[CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][O:9][CH2:8]1
Reactant: CN(C(=O)[O-])[C@H](CN=[N+]=[N-])C[C@H]1CCCOC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(C(=O)OC(C)(C)C)[C@H](CN)C[C@H]1CCCOC1
Yield: 91 %

Procedure:
Hydrogenation of (S)-1-azido-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-yl(methyl)carbamate (62 mg, 0.51 mmol) was carried out in EtOAc (20 mL), 10% Pd/C (15 mg) under 40 psi of H2 for 2 h. After filtration 52 mg of tert-butyl (S)-1-amino-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-ylcarbamate was obtained, yield 91%. MS ESI+ve m/z 273 (M+H).
Reaction SMILES: [CH:1]1([Si:6]([O:11][CH3:12])([O:9][CH3:10])[O:7][CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:13]1(O)[CH2:17]C[CH2:15][CH2:14]1.C[Si](C)(C)Cl>C[O-].[Na+]>[CH:10]1([O:9][Si:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)([O:11][CH3:12])[O:7][CH3:8])[CH2:15][CH2:14][CH2:13][CH2:17]1
Reactant: OC1CCCC1
Reactant: CO[Si](OC)(OC)C1CCCC1
Agent: C[O-]
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Product: CO[Si](OC)(OC1CCCC1)C1CCCC1
Yield: 85.1 %

Procedure:
In a 50 ml three-neck flask provided with a magnetic stirrer and a reflux condenser were charged 5.0 g (0.0262 mole) of cyclopentyl trimethoxysilane, 22.5 g (0.262 mole) of cyclopentyl alcohol and 18.6 mg (0.34 m mole) of sodium methoxide, which were then reacted with each other at room temperature for 2 hours under stirring. Then, trimethylchlorosilane was added to neutralize the alkali. Then, 5.4 g (0.0223 mole) of cyclopentyloxy cyclopentyl dimethoxysilane were obtained by vacuum distillation. Its structure was confirmed as in Example 1. The yield was 85%.
Reaction SMILES: CC1C=C(CC([O-])=O)C=C(C(C)(C)C)C=1O.[CH2:17]([OH:41])[CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][OH:40].CC1C=C(CC(OC)=O)C=C(C(C)(C)C)C=1O.[C:59]([C:63]1[CH:64]=[C:65]([CH2:74][CH2:75][C:76]([O:78]C)=[O:77])[CH:66]=[C:67]([C:70]([CH3:73])([CH3:72])[CH3:71])[C:68]=1[OH:69])([CH3:62])([CH3:61])[CH3:60]>>[CH2:39]([OH:40])[CH2:38][O:37][CH2:36][CH2:35][O:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][OH:41].[C:59]([C:63]1[CH:64]=[C:65]([CH2:74][CH2:75][C:76]([O-:78])=[O:77])[CH:66]=[C:67]([C:70]([CH3:71])([CH3:72])[CH3:73])[C:68]=1[OH:69])([CH3:62])([CH3:60])[CH3:61]
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: COC(=O)Cc1cc(C)c(O)c(C(C)(C)C)c1
Agent: Cc1cc(CC(=O)[O-])cc(C(C)(C)C)c1O
Agent: OCCOCCOCCOCCOCCOCCOCCOCCO
Product: CC(C)(C)c1cc(CCC(=O)[O-])cc(C(C)(C)C)c1O

Procedure:
In a similar fashion, nonobutyleneglycol (3-methyl-5-t-butyl-4-hydroxyphenyl)acetate can be prepared by substituting an equivalent amount of nonobutyleneglycol for octaethyleneglycol and substituting an equivalent amount of methyl (3-methyl-5-t-butyl-4-hydroxyphenyl)acetate for methyl 3-(3',5'-di-t-butyl-4'-hydroxyphenyl)propionate in the above procedure.
Reaction SMILES: [NH:1]=[C:2]1[N:6]([C:7]2[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=2[CH:14]([CH3:16])[CH3:15])[C:5](=[O:17])[CH2:4][S:3]1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:20].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.ClCCl>[CH:14]([C:8]1[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:7]=1[N:6]1[C:5](=[O:17])[CH2:4][S:3]/[C:2]/1=[N:1]\[C:19](=[O:20])[O:21][C:22]1[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=1)([CH3:15])[CH3:16]
Reactant: Cc1ccc(C(C)C)c(N2C(=N)SCC2=O)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: ClCCl
Product: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.9 %

Procedure:
A round-bottomed flask was charged with 2-imino-3-(2-isopropyl-5-methylphenyl)thiazolidin-4-one (CA49) (1.30 g, 5.23 mmol), 4-Nitrophenyl chloroformate (1.06 g, 5.23 mmol) and cesium carbonate (1.71 g, 5.23 mmol) were dissolved in acetonitrile (13 mL). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction was diluted with dichloromethane and adsorbed onto silica gel. Purification by flash column chromatography using 0-100% ethyl acetate/hexanes as eluent provided the title compound as a dark red solid (1.88 g, 86%): 1H NMR (400 MHz, CDCl3) δ 8.31-8.18 (m, 2H), 7.39-7.27 (m, 4H), 6.92-6.83 (m, 1H), 4.14-4.00 (m, 2H), 2.61 (p, J=6.9 Hz, 1H), 2.36 (d, J=0.7 Hz, 3H), 1.30-1.10 (m, 6H); ESIMS m/z 414 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[C:31]([F:32])=[CH:30][C:5]([CH2:6][C@H:7]2[C@H:15]3[C@@H:11]([N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=4)[C:13](=[O:16])[O:14]3)[CH2:10][S:9](=[O:29])(=[O:28])[CH2:8]2)=[CH:4][C:3]=1[CH2:33][CH3:34].CCN(C(C)C)C(C)C.[Cl:44][CH2:45][C:46](Cl)=[O:47].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:24]([C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:12]1[C@@H:11]2[C@H:15]([C@H:7]([CH2:6][C:5]3[CH:30]=[C:31]([F:32])[C:2]([NH:1][C:46](=[O:47])[CH2:45][Cl:44])=[C:3]([CH2:33][CH3:34])[CH:4]=3)[CH2:8][S:9](=[O:28])(=[O:29])[CH2:10]2)[O:14][C:13]1=[O:16])([CH3:26])([CH3:27])[CH3:25]
Reactant: O=C(Cl)CCl
Reactant: CCc1cc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc(F)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc(F)c1NC(=O)CCl
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a solution of (3aR,7S,7aS)-7-(4-amino-3-ethyl-5-fluoro-benzyl)-3-(3-tert-butyl-benzyl)-5,5-dioxo-hexahydro-1-oxa-5lambda*6*-thia-3-aza-inden-2-one (0.245 g, 0.5 mmol) and DIPEA (0.52 mL, 3 mmol) in CH2Cl2 was slowly added a solution of 2-chloroacetylchloride (0.226 g, 2.0 mmol) dissolved in CH2Cl2 (2 mL) at 0-5° C. After stirring for 1 h at 0-5° C. the reaction mixture was poured onto cold saturated NaHCO3 solution and extracted with CH2Cl2. Combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated. The crude product was dissolved in MeOH, stirred for 0.5 h at 25° C., and evaporated again. The title compound was obtained after chromatographic purification (Combi Flash, 12 g silica gel, hexane-EtOAc) as a light yellow solid: TLC (toluene-EtOAc 1:1) Rf=0.44; UPLC RtD=1.799 min; ESIMS [M+NH4]+=582; 1H NMR (600 MHz, DMSO-d6): δ 9.70 (s, 1H), 7.39 (s, 1H), 7.32 (d, 1H), 7.27 (t, 1H), 7.13 (d, 1H), 6.98 (d, 1H), 6.95 (s, 1H), 4.42 (d, 1H), 4.28 (s, 2H), 4.21 (d, 1H), 4.19 (t, 1H), 3.72 (m, 2H), 3.48 (t, 1H), 3.14 (dd, 1H), 2.98 (m, 2H), 2.55 (m, 4H), 1.26 (s, 9H), 1.08 (t, 3H).
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[C:12]3[CH:13]=[CH:14][S:15][C:16]=3[CH2:17][C:10]=2[C:9]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[N:8]1.Cl>CO>[S:15]1[CH:14]=[CH:13][C:12]2[C:11]3[NH:7][N:8]=[C:9]([C:18]4[CH:19]=[CH:20][C:21]([C:24]5[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=5)=[CH:22][CH:23]=4)[C:10]=3[CH2:17][C:16]1=2
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(-c3ccc(C#N)cc3)cc2)c2c1-c1ccsc1C2
Agent: Cl
Solvent: CO
Product: N#Cc1ccc(-c2ccc(-c3n[nH]c4c3Cc3sccc3-4)cc2)cc1
Temperature: 100 °C
Yield: 84 %

Procedure:
4′-[4-(2-Trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl]-biphenyl-4-carbonitrile (0.23 g, 0.5 mmol) was dissolved in MeOH and treated with concentrated HCl (0.15 mL, 5 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding 4′-(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-biphenyl-4-carbonitrile (0.14 g, 0.42 mmol) as brown solid in 83% yield.
Reaction SMILES: C1(CCCN)C=CC=CC=1.[CH2:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH2:13][N:12]1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:32][CH:31]([C:33](O)=[O:34])[CH2:30]2)=[CH:25][CH:24]=1)=[O:21].C1C2C(=CC=CC=2)CN1C([NH:47][C:48]1C=C[C:51]([C:52]([OH:54])=O)=[CH:50][CH:49]=1)=O>>[O:54]1[CH2:52][CH2:51][CH2:50][CH:49]1[CH2:48][NH:47][C:33]([CH:31]1[CH2:30][N:29]([C:26]2[CH:27]=[CH:28][C:23]([NH:22][C:20]([N:12]3[CH2:11][C:19]4[CH:18]=[CH:17][N:16]=[CH:15][C:14]=4[CH2:13]3)=[O:21])=[CH:24][CH:25]=2)[CH2:32]1)=[O:34]
Reactant: O=C(O)C1CN(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)C1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Agent: NCCCc1ccccc1
Product: O=C(NCC1CCCO1)C1CN(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)C1

Procedure:
The title compound was prepared as described in Example 1C, substituting (tetrahydrofuran-2-yl)methanamine for 3-phenylpropan-1-amine and 1-(4-(2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carboxamido)phenyl)azetidine-3-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.59 (s, 1H), 8.49 (d, J=5.0 Hz, 1H), 8.13 (s, 1H), 8.05 (t, J=5.8 Hz, 1H), 7.42 (d, J=5.1 Hz, 1H), 7.35-7.27 (m, 2H), 6.41-6.34 (m, 2H), 4.79-4.73 (m, 4H), 3.94-3.68 (m, 6H), 3.68-3.55 (m, 1H), 3.54-3.39 (m, 1H), 3.20-3.07 (m, 2H), 1.93-1.71 (m, 3H), 1.55-1.41 (m, 1H); MS (ESI(+)) m/e 422 (M+H)+.
Reaction SMILES: C([O:8][C:9]([C@@H:11]([NH:16][C:17](=[O:48])[C@@H:18]([C@H:40]1[C:44](=[O:45])[O:43][C:42]([CH3:47])([CH3:46])[O:41]1)[CH2:19]/[CH:20]=[CH:21]/[CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)=[CH:27][CH:26]=1)[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])C1C=CC=CC=1>C(O)C.[Pd]>[C:9]([C@@H:11]([NH:16][C:17](=[O:48])[C@@H:18]([C@H:40]1[C:44](=[O:45])[O:43][C:42]([CH3:47])([CH3:46])[O:41]1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)=[CH:27][CH:26]=1)[C:12]([CH3:15])([CH3:14])[CH3:13])([OH:10])=[O:8]
Reactant: COc1cccc(-c2ccc(CCC/C=C/C[C@@H](C(=O)N[C@H](C(=O)OCc3ccccc3)C(C)(C)C)[C@@H]3OC(C)(C)OC3=O)cc2C)c1
Agent: [Pd]
Solvent: CCO
Product: COc1cccc(-c2ccc(CCCCCC[C@@H](C(=O)N[C@H](C(=O)O)C(C)(C)C)[C@@H]3OC(C)(C)OC3=O)cc2C)c1
Yield: 77.7 %

Procedure:
A solution of (2R, 4E)-N-{(1S)-1-[(benzyloxy)carbonyl]-2,2-dimethylpropyl}-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-5-[(3′-methoxy-2-methylbiphen-4-yl)propyl]pent-4-enamide (534 mg, 0.87 mmol) in ethanol (75 mL) was hydrogenated over 10% palladium on charcoal (50 mg) at 3 bar and 20° C. for 5.75 h. The mixture was filtered through Arbocel filter aid, concentrated under reduced pressure and azeotroped with ethyl acetate to give (2R)-N-[(1s)-1-(carboxy)-2,2-dimethylpropyl]-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-5-[(3′-methoxy-2-methylbiphen-4-yl)propyl]pentanamide (384 mg, 61%), as a white solid, which was used for Examples 30 and 31 without purification.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[NH:14][C:15](=[O:24])[C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23])(=O)[CH3:2].Cl.[NH2:26][OH:27].C(=O)(O)[O-].[Na+].O>C(O)C>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=1[C:15]([NH:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[N:6]=[CH:5][C:4]([C:1](=[N:26][OH:27])[CH3:2])=[CH:13]2)=[O:24]
Reactant: NO
Reactant: CC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=NO)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1
Yield: 75.3 %

Procedure:
A mixture of 3-acetyl-8-(2,6-dichlorobenzoylamino)quinoline (399 mg), hydroxylamine hydrochloride (232 mg) and sodium bicarbonate (467 mg) in ethanol was refluxed for 5 hours. The mixture was poured into water and extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from ethanol to give 8-(2,6-dichlorobenzoylamino)-3-(1-hydroxyiminoethyl)quinoline (313 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([CH2:17][CH2:18][CH3:19])=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.C([Li])CCC.C(Cl)(Cl)(Cl)[Cl:26]>O1CCCC1>[Cl:26][C:16]1[N:11]2[N:10]=[C:9]([CH2:17][CH2:18][CH3:19])[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=3)=[C:12]2[CH:13]=[CH:14][CH:15]=1
Reactant: CCCc1nn2ccccc2c1-c1ccnc(F)c1
Reactant: ClC(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCc1nn2c(Cl)cccc2c1-c1ccnc(F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A solution of 3-(2-fluoropyridin-4-yl)-2-propylpyrazolo[1,5-a]pyridine (109 mg, 0.42 mmol) in tetrahydrofuran (5 mL) was cooled to −78° C. Butyllithium (0.4 mL, 1.6 M in hexane, 0.64 mmol) was added dropwise and the resultant solution was stirred at −78° C. for 45 minutes. Carbon tetrachloride (0.3 mL) was added and the mixture was stirred at −78° C. for 30 minutes and then quenched byt the addition of methanol while cold. Upon warming to room temperature water and ether were added and the layers separated. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate. Filtration and concentration followed flash chromatography on silica gel (4:1 to 2:1 hexane-ethyl acetate) provided 7-chloro-3-(2-fluoropyridin-4-yl)-2-propylpyrazolo[1,5-a]pyridine (77 mg, 63%) as an orange solid. 1H NMR (CDCl3) δ 8.33 (d, 1H), 7.58 (d, 1H), 7.30 (m, 1H), 7.22 (t, 1H), 7.02–6.98 (m, 2H), 2.99 (t (m, 2H), 1.01 (t, 3H); 19F NMR (CDCl3) δ −68.11; MS m/z 290 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:22])(=O)=O.[CH3:24][O:25][C:26]1[N:31]=[C:30]([CH:32]=O)[CH:29]=[CH:28][CH:27]=1>>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:22]=[C:32]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([O:25][CH3:24])[N:31]=3)[N:9]=[C:4]2[CH:3]=1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Nc1cc(Br)cc(N)n1
Reactant: COc1cccc(C=O)n1
Product: COc1cccc(-c2nc3cc(Br)cc(N)n3n2)n1

Procedure:
The title compound, MS m/e (%): 320 (M+, 100), was prepared in accordance with the general method of example 63 from 4-bromo-pyridine-2,6-diamine, O-mesitylene-sulfonyl-hydroxylamine, and 6-methoxy-pyridine-2-carbaldehyde. The purification was performed with reversed phase HPLC eluting with an acetonitrile/water gradient.
Reaction SMILES: Br[CH:2]1[C:10](=O)[C:6]2=[N:7][O:8][N:9]=[C:5]2[CH2:4][CH2:3]1.[NH2:12][C:13]([NH2:15])=[S:14]>C(O)C>[N:7]1[O:8][N:9]=[C:5]2[CH2:4][CH2:3][C:2]3[S:14][C:13]([NH2:15])=[N:12][C:10]=3[C:6]=12
Reactant: NC(N)=S
Reactant: O=C1c2nonc2CCC1Br
Solvent: CCO
Product: Nc1nc2c(s1)CCc1nonc1-2
Temperature: 60 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution commercially available 5-bromo-6,7-dihydro-5H-benzo[1,2,5]oxadiazol-4-one (1.1 g, 5.1 mmol) in absolute ethanol (60 mL) was added thiourea. The mixture was stirred at 60° C. overnight and then concentrated. The residue was triturated in hexanes and then collected by filtration to afford 1.3 g (90%) of the title compound MS (ESI+) m/z 195 (M+H)+.