Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C1(C)C=CC=CC=1.Cl>[CH3:23][S:24]([O:15][C:6]1[CH:7]=[CH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:26])=[O:25]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(OS(C)(=O)=O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
21.00 g (0.102 mol) of 2,4-di-tert-butylphenol and 11.84 g (0.117 mol) of triethylamine were dissolved in 200 mL of toluene followed by dropping in 12.24 g (0.107 mol) of methanesulfonyl chloride over the course of 30 minutes at 10° C. Following completion of dropping, the mixture was stirred for 2 hours at 25° C. and the 2,4-di-tert-butylphenol was confirmed to no longer be present. The reaction liquid was placed in 3% aqueous hydrochloric acid solution and following separation of the organic layer, was washed once with saturated aqueous NaHCO3 solution and twice with saturated brine followed by drying with MgSO4 and concentrating. The resulting crude crystals were purified by crystallization with n-heptane to obtain 25.8 g (yield: 90%) of 2,4-di-tert-butylphenyl methanesulfonate (white crystals, melting point: 63° C.).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1.C(C1C=C(B(O)O)C=CC=1)=O.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1>>[CH3:10][N:5]1[C:4]2[CH:11]=[CH:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:14][C:3]=2[C:2]([C:38]2[CH:37]=[CH:36][CH:35]=[C:34]([C:33]([F:44])([F:43])[F:32])[CH:39]=2)=[N:8][CH2:7][C:6]1=[O:9]
Reactant: CN1C(=O)CN=C(Cl)c2cc(-c3ccccc3)ccc21
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: O=Cc1cccc(B(O)O)c1
Product: CN1C(=O)CN=C(c2cccc(C(F)(F)F)c2)c2cc(-c3ccccc3)ccc21
Yield: 20 %

Procedure:
Prepared from 5-chloro-1-methyl-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one using the same method described for Example 9 and instead of using 3-formylbenzene boronic acid, we used 3-trifluoromethylphenyl boronic acid. The title compound (30 mg) was obtained as a beige solid, (yield=20%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[F:20][C:21]1[CH:22]=[C:23]([N:37]2[CH2:41][C@H:40]([CH2:42][NH:43][C:44](=[O:46])[CH3:45])[O:39][C:38]2=[O:47])[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1([OH:36])[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(N(CC)CC)C.C[Si](C)(C)Cl>CN1CCCC1=O>[C:44]([NH:43][CH2:42][C@@H:40]1[O:39][C:38](=[O:47])[N:37]([C:23]2[CH:24]=[CH:25][C:26]([O:27][CH2:28][C:29]3([OH:36])[CH2:35][CH2:34][CH2:33][N:32]([C:2]4[N:11]=[C:10]5[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]5[CH:12]5[CH2:14][CH2:13]5)=[CH:4][C:3]=4[F:19])[CH2:31][CH2:30]3)=[C:21]([F:20])[CH:22]=2)[CH2:41]1)(=[O:46])[CH3:45]
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(O)CCCNCC3)c(F)c2)C(=O)O1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(=O)NC[C@H]1CN(c2ccc(OCC3(O)CCCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)CC3)c(F)c2)C(=O)O1

Procedure:
In analogy to example 1 step 7 with 98 mg 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-[1,8]naphthyridine-3-carboxylic acid (MW: 282.66, 0.348 mmol), 138 mg N-{(5S)-3-[3-fluoro-4-(4-hydroxy-azepan-4-ylmethoxy)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (MW: 395.43, 0.348 mmol), 140 mg triethylamine (MW: 101.19, 1.39 mmol) and 113 mg trimethylchlorsilan (MW: 108.64, 1.04 mmol) in 1 ml N-methyl-pyrrolidin-2-one. Yield: 150 mg, 77%. MS: 642.7 (M+H)+, 640.7 (M+H)−, Method ESI+, ESI−.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[CH:11]=1.[N:12]1([C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C.C(O)CO>O>[N:4]1[C:3]([CH2:2][N:15]2[CH2:16][CH2:17][N:12]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH2:13][CH2:14]2)=[CH:11][N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=12
Reactant: NS(=O)(=O)c1ccc(N2CCNCC2)cc1
Reactant: ClCc1cn2ccccc2n1
Solvent: CCN(CC)CC
Solvent: O
Solvent: OCCO
Product: NS(=O)(=O)c1ccc(N2CCN(Cc3cn4ccccc4n3)CC2)cc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 62.5 %

Procedure:
A mixture of 2-(chloromethyl)imidazo[1,2-a]pyridine (0.495 g), 4-(piperazin-1-yl) benzenesulfonamide (0.717 g), triethylamine (0.456 mL), and ethylene glycol (6 mL) is stirred at 80° C. for 1.5 h. After cooling, water is added and the resulting solid is collected and washed with water and toluene. Chromatography on silica gel using methanol/dichloromethane (6/94) yields 0.69 g of the title compound; mp 238-242° C.; IR (mineral oil) 1150, 1152, 1331, 1308, 1508 cm-1. 1H NMR (DMSOd6) δ2.61. 3.28, 3.66, 6.86, 7.02, 7.06, 7.20, 7.49, 7.61, 7.85, 8.50.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O-])=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1.Cl.CN(C)CCCN=C=NCC.[C:38]1([CH:44]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:45][CH2:46][NH2:47])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.Cl>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14](=[O:15])[NH:47][CH2:46][CH2:45][CH:44]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C(C(=O)[O-])C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1
Reactant: NCCC(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC1=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1

Procedure:
219 mg (0.61 mmol) of mono(2-cyanoethyl) 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, 138 mg (0.72 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 201 mg (0.95 mmol) of 3,3-diphenylpropylamine and 20 mg (0.16 mmol) of 4-dimethylaminopyridine were stirred in 10 ml of dichloromethane at room temperature overnight. 2 N hydrochloric acid was added to the reaction mixture. After the extraction with dichloromethane, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=1/1) to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:17](=[O:25])[C:16]3=[C:26]([S:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([O:36]C)[CH:31]=4)[CH:27]=[CH:28][N:15]3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.B(Br)(Br)Br>ClCCl>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:17](=[O:25])[C:16]3=[C:26]([S:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=4)[CH:27]=[CH:28][N:15]3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: COc1cccc(Sc2ccn3nc([C@H](C)Nc4ncnc(N)c4C#N)n(-c4ccccc4)c(=O)c23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nn2ccc(Sc3cccc(O)c3)c2c(=O)n1-c1ccccc1
Yield: 49 %

Procedure:
(S)-4-Amino-6-((1-(5-((3-methoxyphenyl)thio)-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (70 mg, 0.14 mmol) was treated with boron tribromide (1M in dichloromethane, 411 μl, 0.41 mmol) with dichloromethane as a solvent according to the method described in Example 23. The residue was purified by reverse phase using SP1® Purification System to give 33 mg (49% yield) as a solid. Purity 100%.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:27]=[CH:26][C:8]2[N:9]=[C:10]([NH:12][C:13]3[N:17]([CH3:18])[C:16]4[CH:19]=[CH:20][C:21]([C:23](O)=[O:24])=[CH:22][C:15]=4[N:14]=3)[S:11][C:7]=2[CH:6]=1)(=[O:4])=[O:3].[CH3:28][S:29][CH2:30][CH2:31][NH2:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:28][S:29][CH2:30][CH2:31][NH:32][C:23]([C:21]1[CH:20]=[CH:19][C:16]2[N:17]([CH3:18])[C:13]([NH:12][C:10]3[S:11][C:7]4[CH:6]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:27]=[CH:26][C:8]=4[N:9]=3)=[N:14][C:15]=2[CH:22]=1)=[O:24]
Reactant: CSCCN
Reactant: Cn1c(Nc2nc3ccc(S(C)(=O)=O)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CSCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(S(C)(=O)=O)cc3s1)n2C

Procedure:
2-(6-Methanesulfonyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (2-methylsulfanyl-ethyl)-amide (41 mg) was prepared by following General Procedure F using 2-(6-methanesulfonyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (80 mg), 2-methylthio-ethylamine (0.2 ml), HBTU (76 mg), and DIEA (0.2 ml). LCMS: m/z 477.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]2[CH:25](O)[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:33][CH3:34])[C:23]=3[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:18]2=[O:35])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:33][CH3:34])[C:23]=3[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:18]2=[O:35])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCOc1c(OC)ccc2c1C(O)N(CCc1ccc(OCc3ccccc3)cc1)C2=O
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCOc1c(OC)ccc2c1CN(CCc1ccc(OCc3ccccc3)cc1)C2=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.6 %

Procedure:
2-[2-(4-Benzyloxyphenyl)ethyl]-3-hydroxy-5-methoxy-4pentyloxy-2,3-dihydroisoindol-1-one (142 mg, 0.30 mmol, 1.0 eq) was dissolved in dichloromethane (3 ml), and triethylsilane (0.095 ml, 0.60 mmol, 2.0 eq) was added. The mixture was stirred for 10 minutes at room temperature. Trifluoroacetic acid was added thereto, and the mixture was further stirred for 4 hours. A saturated aqueous sodium hydrogencarbonate solution (30 ml) was added to this reaction mixture. The mire was extracted twice with ethyl acetate (30 ml). The organic layers were combined, then washed with saturated brine (60 ml) and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give 2-[2-(4-benzyloxyphenyl)ethyl]-5-methoxy-4-pentyloxy-2,3-dihydroisoindol-1-one (136 mg, 99.8%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[N:14]=[C:15]([C:24]([CH3:28])([CH3:27])[CH2:25][NH2:26])[NH:16][C:17]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH:7]=[CH:6]2.[C:29]([N:33]=[C:34]=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([NH:33][C:34]([NH:26][CH2:25][C:24]([C:15]1[NH:16][C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)[N:14]=1)([CH3:28])[CH3:27])=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)N=C=O
Reactant: COc1ccc2cc(-c3nc(C(C)(C)CN)[nH]c3-c3ccncc3)ccc2c1
Product: COc1ccc2cc(-c3nc(C(C)(C)CNC(=O)NC(C)(C)C)[nH]c3-c3ccncc3)ccc2c1
Yield: 39 %

Procedure:
The title compound (10 mg, 39%) was prepared starting from the product of Example 2 and tert-butyl isocyanate using the method described in Example 10; MS(ES) m/e 472 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.CCN(C(C)C)C(C)C>>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:19][CH2:20][N:21]([CH2:2][C:3]2[S:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:22][CH2:23]1
Reactant: ClCc1nc2cccnc2s1
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(N2CCN(Cc3nc4cccnc4s3)CC2)nc1

Procedure:
The product from Example 38A (150 mg, 0.81 mmol), 1-(2-pyridinyl)piperazine (160 mg, 0.98 mmol), and DIEA (280 μL, 1.6 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.80 (m, 4H) 3.55 (m, 4H) 4.04 (s, 2H) 6.63 (m, 1H) 6.81 (m, 1H) 7.53 (m, 2H) 8.11 (m, 1H) 8.33 (dd, J=8.14, 1.70 Hz, 1H) 8.59 (dd, J=4.58, 1.53 Hz, 1H); (ESI) m/z 312 (M+H)+.
Reaction SMILES: [Cl:1]CCl.[OH:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17].S(Cl)(Cl)=O.Cl>CN(C)C=O>[OH:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:8]([C:9]([Cl:1])=[O:10])=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17]
Reactant: ClCCl
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Cl)cc([N+](=O)[O-])c1O
Temperature: 40 °C

Procedure:
In a reactor 68 kg dichloromethane, 20 kg 5-nitro-vanillic acid of example 1b, 76 gram of N,N-dimethylformamide and 13.4 kg (8 L) thionyl chloride, was charged at 20.2° C. The mixture was heated to 40° C. until all the starting material dissolved and the evolution of HCl and SO2 stopped. When all the starting material was consumed 5-10 L dichloromethane was distilled off at normal pressure at 40° C. then the mixture was cooled to 20-25° C. and the distillation was continued until dry under vacuum at 40° C. The evaporation residue was dissolved in 36 kg dry THF. The THF solution was used in Example 4d.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([O:35][CH3:36])=[O:34])[CH:28]=2)[C:7]2[C:12]([C:13]=1[CH2:14][CH2:15]OS(C1C=CC(C)=CC=1)(=O)=O)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].[C:37]([O-:40])(=[S:39])[CH3:38].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([O:35][CH3:36])=[O:34])[CH:28]=2)[C:7]2[C:12]([C:13]=1[CH2:14][CH2:15][S:39][C:37](=[O:40])[CH3:38])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)c1cccc(-n2c(C(=O)OC)c(CCOS(=O)(=O)c3ccc(C)cc3)c3ccccc32)c1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(-n2c(C(=O)OC)c(CCSC(C)=O)c3ccccc32)c1
Yield: 106.5 %

Procedure:
A solution of 1-(3-methoxycarbonyl-phenyl)-3-[2-(toluene-4-sulfonyloxy)-ethyl]-1H-indole-2-carboxylic acid methyl ester (0.37 g, 0.73 mmol) and potassium thioacetate (0.092 g, 0.8 mmol) in DMF (5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with saturated NaHCO3, dried over Na2SO4, and concentrated to give 0.32 g of 3-(2-acetylsulfanyl-ethyl)-1-(3-methoxycarbonyl-phenyl)-1H-indole-2-carboxylic acid methyl ester as a yellow oil (100% crude yield): 1H NMR (CDCl3, 300 MHz) δ 2.36 (s, 3H), 3.20 (q, J=6.87 Hz, 2H), 3.40 (q, J=6.87 Hz, 2H), 3.74 (s, 3H), 3.91 (s, 3H), 7.01 (d, J=7.82 Hz, 1H), 7.20–7.31 (m, 3H), 7.44 (d, J=8.02 Hz, 1H), 7.48–7.52 (m, 1H), 7.59(t, J=7.82 Hz, 1H), 7.88 (d, J=7.82 Hz, 1H), 7.97(t, J=1.53 Hz, 1H); 8.13 (dt, J=7.82, 1.34 Hz, 1H).
Reaction SMILES: [CH2:1]([S:19][CH2:20][CH2:21][CH2:22]Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]CCCCCC.[NH:24]([CH2:28][CH2:29][OH:30])[CH2:25][CH2:26][OH:27].C(O)C1C=CC=CC=1.[OH-].[Na+]>>[CH2:1]([S:19][CH2:20][CH2:21][CH2:22][N:24]([CH2:28][CH2:29][OH:30])[CH2:25][CH2:26][OH:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCCCCCCCSCCCCl
Reactant: OCCNCCO
Agent: [Na+]
Agent: [OH-]
Solvent: OCc1ccccc1
Product: CCCCCCCCCCCCSCCCN(CCO)CCO

Procedure:
A mixture of 3-octadecylthiopropyl chloride (3.53 g., 0.01 mole), diethanolamine (2.1 g., 0.02 mole) and benzyl alcohol (5 ml.) is heated under reflux for one-half hour, then treated with an ethanolic solution of sodium hydroxide (0.4 g., 0.01 mole) and refluxed for five more minutes. The mixture is cooled, filtered, and the ethanol removed by evaporation. The benzyl alcohol is then removed by distillation in vacuo and the residue chromatographed on silica using first ether then methanol as eluants. The desired product is contained in the methanol eluate. It is isolated by evaporation of the solvent, m.p. 53°-54° C. Its hydrochloride salt melts at 65°-66° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([C:9](=[O:20])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)=[CH:5]OCC.C([O-])(=O)C.[Na+].Cl.[NH2:28]O>C(O)C>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[N:28][O:20][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)=[O:21]
Reactant: NO
Reactant: CCOC=C(C(=O)OC)C(=O)c1cccc(C(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1cnoc1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A mixture of methyl-2-(3'-trifluoromethylbenzoyl)-3-ethoxypropenoate (8.55 g.; 0.028 mol.) in 60 ml. of ethanol and anhydrous sodium acetate (2.5 g.; 0.03 mol.) was treated with hydroxylamine hydrochloride (2.1 g.; 0.03 mol.). The mixture was heated at reflux for 2 hours, cooled to 25° C., and then poured onto 50 g. of ice. The resulting liquid was extracted five times with 40 ml. of methylene chloride. The organic layer was washed with water, sodium bicarbonate, water, dried over sodium sulfate, filtered and concentrated to yield methyl-5-(3'-trifluoromethylphenyl)-4-isoxazolecarboxylate as an orange oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[N:11]3[N:12]=[C:13]([O:20][CH2:21][C:22]4[N:23](COCC[Si](C)(C)C)[N:24]=[CH:25][N:26]=4)[C:14]4[C:19]([C:10]3=[N:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:3]=1.Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[N:11]3[N:12]=[C:13]([O:20][CH2:21][C:22]4[N:26]=[CH:25][NH:24][N:23]=4)[C:14]4[C:19]([C:10]3=[N:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:3]=1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4ncnn4COCC[Si](C)(C)C)nn23)no1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4nc[nH]n4)nn23)no1
Temperature: 60 °C
Yield: 16.1 %

Procedure:
To a solution of 3-(5-methylisoxazol-3-yl)-6-[2-{[2-(trimethylsilyl)ethoxy]methyl}-1,2,4-triazolyl]methyloxy-1,2,4-triazolo-[3,4-a]phthalazine (1.20 g, 2.5 mmol) in ethanol (20 ml) was added 2N hydrochloric acid (40 ml) at room temperature. The mixture was heated at 60° C. for 5 h, saturated potassium carbonate solution wad added and the solvent evaporated in vacuo. The solid was triturated with ethanol, filtered and the filtrate evaporated in vacuo. The residue was flash chromatographed on silica gel, eluting with 4% methanol/dichloromethane, to give the title-product (140 mg, 16%), mp 260-262° C.; 1H NMR (360 MHz, d6-DMSO) δ 2.56 (3H, s, me), 5.75 (2H, s, CH2), 7.24 (1H, s, Ar—H), 8.00 (1H, t, J=8.1 Hz, Ar—H), 8.14 (1H, t, J=7.7 Hz, Ar—H), 8.26 (1H, d, J=8.0 Hz, Ar—H), 8.60 (1H, br s, NH), 8.65 (1H, d, J=7.4 Hz, Ar—H); MS (ES+) m/e 349 [MH]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18](I)[N:17]=1)=[O:14].CC1(C)C(C)(C)OB(C2CCN(C(OC(C)(C)C)=O)CC=2)O1.[O:45]1[CH2:50][CH:49]=[C:48](B2OC(C)(C)C(C)(C)O2)[CH2:47][CH2:46]1>>[O:45]1[CH2:46][CH:47]=[C:48]([C:18]2[N:17]=[C:16]([NH:15][C:13]([NH:12][C:7]3[C:6]4[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=4)[N:10]=[CH:9][CH:8]=3)=[O:14])[CH:21]=[CH:20][CH:19]=2)[CH2:49][CH2:50]1
Reactant: O=C(Nc1cccc(I)n1)Nc1ccnc2c(F)cccc12
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: O=C(Nc1cccc(C2=CCOCC2)n1)Nc1ccnc2c(F)cccc12

Procedure:
The title compound was prepared as described in example 27 step 2, substituting 1-(6-bromo-quinolin-4-yl)-3-(6-trifluoromethyl-pyridin-2-yl)-urea by 1-(8-fluoroquinolin-4-yl)-3-(6-iodopyridin-2-yl)urea (example 47, step 1) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate by 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].O1CCCC1.O[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([C@:29]1([CH3:35])[CH2:33][O:32][C:31](=[O:34])[NH:30]1)[CH:23]=[CH:22]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[CH3:35][C@@:29]1([C:24]2[CH:23]=[CH:22][C:21]3[C:26](=[CH:27][CH:28]=[C:19]([O:12][CH:9]4[CH2:8][CH2:7][CH:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10]4)[CH:20]=3)[CH:25]=2)[CH2:33][O:32][C:31](=[O:34])[NH:30]1
Reactant: CCCCCC1CCC(O)CC1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCCC1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1

Procedure:
In a 40 mL vial, 4-Pentyl-cyclohexanol (1144.4 mg, 0.0067202 mol) was diluted with tetrahydrofuran (30.0 mL, 0.370 mol, Acros) and subsequently (R)-4-(6-hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one (1.4924 g, 0.0061350 mol) and triphenylphosphine (2105.5 mg, 0.0080275 mol) were added and the mixture was stirred. Diethyl Azodicarboxylate in toluene (2.6 mL, 0.0086326 mol, Aldrich) was added, and the mixture was then stirred at room temperature for 38 h. The reaction mixture was evaporated to dryness and chromatographed 0-100% EtOAc/Hexanes (adsorbed onto silica gel). Isolated was 0.6142 g (18%) in approx 70% purity, the remainder being reduced DEAD reagent.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[CH2:14][NH:15][C:16]([C:18]1[C:19]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=2)=[N:20][CH:21]=[CH:22][CH:23]=1)=[O:17])[O:5][C@H:6]([CH3:10])[C:7](O)=[O:8].O1C2C=CC(OC3C(C(NCC4C=CC(O[C@H](C)C(O)=O)=CC=4F)=O)=CC=C[N:44]=3)=CC=2OC1>>[C:7]([C@H:6]([O:5][C:4]1[CH:11]=[CH:12][C:13]([CH2:14][NH:15][C:16](=[O:17])[C:18]2[CH:23]=[CH:22][CH:21]=[N:20][C:19]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=2)=[C:2]([F:1])[CH:3]=1)[CH3:10])(=[O:8])[NH2:44]
Reactant: C[C@@H](Oc1ccc(CNC(=O)c2cccnc2Oc2cccc(C#N)c2)c(F)c1)C(=O)O
Reactant: C[C@@H](Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1)C(=O)O
Product: C[C@@H](Oc1ccc(CNC(=O)c2cccnc2Oc2cccc(C#N)c2)c(F)c1)C(N)=O

Procedure:
The compound of Formula (5.5.17) was prepared in a manner analogous to that described in Example 14, substituting (R)-2-[3-fluoro-4-({[2-(3-cyano-phenoxy)-pyridine-3-carbonyl]-amino}-methyl)-phenoxy]-propionic acid for the corresponding (R)-2-[4-({[2-(benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-propionic acid material.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][C:6]=1[C:15]([F:18])([F:17])[F:16])(=[O:3])[CH3:2].[N+:19]([O-])([OH:21])=[O:20]>C(O)(=O)C>[C:12]([NH:11][C:8]1[CH:7]=[C:6]([C:15]([F:16])([F:17])[F:18])[C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])(=[O:14])[CH3:13]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(NC(C)=O)c(C(F)(F)F)c1
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(C(F)(F)F)c(NC(C)=O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 12 h

Procedure:
91.5 g (0.3 mol) of 1,4-bisacetylamino-2-trifluoromethylbenzene (prepared according to B.) are initially introduced into 300 ml of glacial acetic acid, and a mixture of 25 g of glacial acetic acid and 20 g of nitric acid (density 1.5) is added dropwise at 50° C. in the course of 60 minutes. The mixture is subsequently stirred at the same temperature for 12 hours and then poured onto 2.5 kg of ice. The product which has precipitated is filtered off with suction, washed with water and dried.