Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4](C(OCC)=O)([CH2:19][CH2:20][CH2:21][C:22]([O:29]C(=O)C)([CH3:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=1)(=[O:3])[CH3:2].C(C(C(OCC)=O)(CC=CC(OC(=O)C)CCCCC)CCCC1C=CC(C(OCC)=O)=CC=1)(=O)C>>[C:1]([CH:4]([CH2:19][CH2:20][CH2:21][C:22]([OH:29])([CH3:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:17][CH:18]=1)(=[O:3])[CH3:2]
Reactant: CCCCCC(C)(CCCC(CCCc1ccc(C(=O)OCC)cc1)(C(C)=O)C(=O)OCC)OC(C)=O
Agent: CCCCCC(C=CCC(CCCc1ccc(C(=O)OCC)cc1)(C(C)=O)C(=O)OCC)OC(C)=O
Product: CCCCCC(C)(O)CCCC(CCCc1ccc(C(=O)O)cc1)C(C)=O

Procedure:
This compound is prepared by the method described in Example 3, Step C, except that an equivalent quantity of the product of Step B of the present example replaces ethyl 4-(4-acetyl-4-ethoxycarbonyl-8-acetoxytridec-6-en-1-yl)benzoate. The title compound is purified by column chromatography on silica gel with 4% methanol in chloroform as eluant and is obtained as a nearly colorless, viscous oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[CH2:14]([N:16]1[C:24]2[C:19](=[CH:20][C:21]([N+]([O-])=O)=[CH:22][CH:23]=2)[C:18]([CH3:28])=[N:17]1)[CH3:15].C([O-])=O.[NH4+]>CO.[Pd]>[CH2:14]([N:16]1[C:24]2[C:19](=[CH:20][C:21]([NH:11][CH2:10][CH2:9][C:6]3[CH:7]=[N:8][C:3]([C:2]([F:12])([F:1])[F:13])=[CH:4][CH:5]=3)=[CH:22][CH:23]=2)[C:18]([CH3:28])=[N:17]1)[CH3:15]
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Reactant: CCn1nc(C)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCn1nc(C)c2cc(NCCc3ccc(C(F)(F)F)nc3)ccc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
A solution of (6-trifluoromethyl-pyridin-3-yl)-acetonitrile (849 mg, 4.14 mmol, prepared as per example 47, step 1) and 1-ethyl-3-methyl-5-nitro-1H-indazole (700 mg, 3.76 mmol) in MeOH (10 mL) was treated with ammonium formate (5 eq.) and 10% Pd/C (140 mg) and stirred at 80° C. for 2 h. Filtration, concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 60:40) afforded the title compound (794 mg, 61%) as a light yellow oil. MS m/e: 349.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][NH:6][C:5](=[O:9])[N:4]=1.[C:10]([NH:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)(=[O:12])[CH3:11].N1C=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[N:7][N:6]([C:18]2[CH:19]=[C:14]([NH:13][C:10](=[O:12])[CH3:11])[CH:15]=[CH:16][CH:17]=2)[C:5](=[O:9])[N:4]=1
Reactant: COc1cn[nH]c(=O)n1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1cnn(-c2cccc(NC(C)=O)c2)c(=O)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
According to Scheme 6 Step 1: To a stirred solution of 5-methoxy-1,2,4-triazin-3(2H)-one (1 g, 7.9 mmol) in DMF (5 mL) were successively added the 3-acetamidophenylboronic acid (1.4 g, 7.9 mmol), copper(II) acetate (1.4 g, 7.9 mmol) and pyridine (1.2 g, 7.9 mmol). The mixture was stirred overnight at 60° C. The reaction mixture was quenched with a saturated sodium bicarbonate solution and extracted with ethyl acetate (×3). The combined organic layers were washed successively with water, brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography, 70 g column, CH2Cl2/MeOH 98/2 to afford (0.493 g, 24%) of N-(3-(5-methoxy-3-oxo-1,2,4-triazin-2(3H)-yl)phenyl)acetamide
Reaction SMILES: O[CH2:2][CH:3]([CH3:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:31][CH2:30][C:14]2([O:19][CH2:18][CH2:17][N:16]([C:20]([C:22]3[N:23]=[C:24]([CH:27]([CH3:29])[CH3:28])[S:25][CH:26]=3)=[O:21])[CH2:15]2)[CH2:13][CH2:12]1.C(Br)(Br)(Br)[Br:34].N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.O>[Br:34][CH2:2][CH:3]([CH3:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:31][CH2:30][C:14]2([O:19][CH2:18][CH2:17][N:16]([C:20]([C:22]3[N:23]=[C:24]([CH:27]([CH3:29])[CH3:28])[S:25][CH:26]=3)=[O:21])[CH2:15]2)[CH2:13][CH2:12]1
Reactant: CC(CO)CCCCCCCN1CCC2(CC1)CN(C(=O)c1csc(C(C)C)n1)CCO2
Reactant: BrC(Br)(Br)Br
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC(CBr)CCCCCCCN1CCC2(CC1)CN(C(=O)c1csc(C(C)C)n1)CCO2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(9-(9-Hydroxy-8-methylnonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone (example 283, step b) (100 mg), carbon tetrabromide (143 mg) and imidazole (30 mg) were dissolved in DCM (5 mL). The solution was cooled to 0° C. and a solution of triphenylphosphine (85 mg) in DCM (1 mL) was added dropwise. The reaction mixture was stirred at this temperature for 1 hour then at room temperature for 2 hours. A further amount of carbon tetrabromide (150 mg) was added, the mixture cooled to 0° C. and triphenylphosphine (114 mg) in DCM (1 mL) added dropwise. Stirred at room temperature for 1 hour then water was added and the phases separated. The organic phase was evaporated and the product purified by silica gel chromatography eluting with 0-10% methanol in DCM to afford the subtitled compound as an orange gum. Yield 0.088 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([NH:13][O:14][CH3:15])=[O:12])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][N:22]1[C:26]([CH3:27])=[C:25]([NH2:28])[CH:24]=[N:23]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1.C1COCC1>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([NH:13][O:14][CH3:15])=[O:12])=[CH:7][C:2]([NH:28][C:25]2[CH:24]=[N:23][N:22]([CH3:21])[C:26]=2[CH3:27])=[N:3][CH:4]=1
Reactant: Cc1c(N)cnn1C
Reactant: CONC(=O)c1ccccc1Nc1cc(Cl)ncc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CONC(=O)c1ccccc1Nc1cc(Nc2cnn(C)c2C)ncc1Cl
Temperature: 150 °C
Reaction time: 8 h
Yield: 7.3 %

Procedure:
A microwave tube was charged with 2-[(2,5-dichloro-4-pyridinyl)amino]-N-(methyloxy)benzamide (200 mg, 0.64 mmol), 1,5-dimethyl-1H-pyrazol-4-amine (142 mg, 1.28 mmol), cesium carbonate (626 mg, 1.92 mmol) and dioxane/THF (3:1 ml). The reaction mixture was degassed under nitrogen for 10 min and palladium (II) acetate (5.8 mg, 0.03 mmol) and BINAP (40 mg, 0.06 mmol) were added. The tube was sealed and the mixture was stirred in an oil bath at 150° C. overnight. The dark brown solution was filtered thru celite and evaporated. It was dissolved in MeOH and filtered thru an Acrodisc (Pall Corporation; www.pall.com) and further purified on preparative Agilent HPLC (5 to 95% water:acetonitrile with 0.1% formic acid). The dark brown oil residue was dissolved in DMF and water was slowly added. A tan precipitate crashed out and was filtered off and dried under vacuum at 40° C. for 2 hrs to afford the desired product (18 mg, 7.3%) as a tan solid. LC-MS [M+H]+=387.1, 389.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.91 (br. s., 1 H) 9.41 (br. s., 1 H) 7.85-7.98 (m, 2 H) 7.49-7.59 (m, 3 H) 7.42 (br. s., 1 H) 7.07-7.13 (m, 1 H) 6.50 (br. s., 1 H) 3.69 (d, J=10.36 Hz, 6 H) 2.11 (s, 3 H).
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:30])[C:15]2[C:16]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:17][NH:18][C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:10]([N+:31]([O-:33])=[O:32])[CH:9]=1.O=[Cr](=O)=O.C1C=CC=CN=1.C1C=CC=CN=1>C(Cl)Cl.[O-2].[Cr+6].[O-2].[O-2]>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:15]2[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:18][NH:17][C:16]=2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:30])=[C:10]([N+:31]([O-:33])=[O:32])[CH:9]=1
Reactant: CCOC(=O)c1n[nH]c(C(=O)OCC)c1C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: O=[Cr](=O)=O
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1n[nH]c(C(=O)OCC)c1C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 92.7 %

Procedure:
Pyridine (481.6 g, 6.08 moles) was added dropwise over 35 minutes to a mechanically stirred suspension of chromium (VI) oxide (304.56 g, 3.05 moles) (WARNING: adding pyridine to chromium (VI) oxide is an extremely dangerous procedure and, therefore, chromium (VI) oxide should preferably be added to pyridine) and methylene chloride (6 L) under N2. The reaction as stirred for 40 minutes after pyridine addition was completed and then a solution of diethyl 4-[(4-chloro-2-nitrophenyl)hydroxymethyl]-1H-pyrazole-3,5-dicarboxylate (202.5 g, 0.507 mole) in methylene chloride (1.3 L) was added dropwise over 0.5 hours at room temperature. Stirring at room temperature was continued overnight. CELITE™ (205 g) and additional Collins reagent [chromium (VI) oxide (50g, 0.5 mole) and pyridine (120.3 g, 1.52 moles; methylene chloride (1 L)] were added and the reaction mixture was stirred for 4 days. The reaction mixture was filtered. The filter cake was washed with methylene chloride (3 L) and filtered. The filtrate and wash liquors were combined and concentrated under water aspirator vacuum. The residue was dissolved in ethyl acetate (2 L) and this solution was filtered through a short column of silica gel (3 L). The filtrate was concentrated under water aspirator vacuum. The solid residue was dissolved in warm toluene (800 mL) and then hexane (800 mL) was added with stirring. The mixture was allowed to cool to room temperature and was then filtered. The filter cake was washed with hexane (2×500 mL), and dried under vacuum at 50° C. to give the title compound as a white powder (186.08 g, 93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][Br:9])=[CH:5][CH:4]=1.[N+:12]([O-])([OH:14])=[O:13]>FC(F)(F)C(O)=O>[Br:9][CH2:8][CH2:7][C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CCBr)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Into a 500 mL pear flask was charged 4-methoxyphenethyl bromide (0.727 ml, 4.65 mmol) in trifluoroacetic acid (9.30 ml). The solution was cooled to 0° C. In a 50 mL Erlenmeyer flask was added nitric acid (0.231 ml, 4.65 mmol) and trifluoroacetic acid (2.0 mL). The nitric acid solution was added to the reaction dropwise via syringe. The reaction was stirred at room temperature for 2 hours. The solvent was removed on a rotovap and the residue taken up into ethyl acetate. The reaction was washed with 1N HCl, saturated aqueous sodium bicarbonate, and brine, dried over MgSO4, filtered and concentrated onto silica gel. The reaction was purified by flash chromatography (10% ethyl acetate:hexanes for 20 minutes, then to 50% ethyl acetate:hexanes over 20 minutes) to provide the title compound. MS (DCI) m/e 277 (M+NH4).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:12]([OH:15])[CH2:13]Cl)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CC(O)C>[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@H:12]1[O:15][CH2:13]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CO1

Procedure:
2-Propanol (12.9 ml) and aqueous 6.08 mol/l sodium hydroxide solution (2.94 g) were added to a solution containing (2R, 3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane obtained in Example 17 {(2R, 3S) content of 2.79 g; (2S, 3S) content of 83.9 mg}, for agitation at 4° C. for 15 hours. The resulting solution was analyzed by HPLC, which indicates that the objective (2R, 3S) compound was at 94.0% (HPLC area ratio). After the reaction was quenched by the addition of aqueous 4.4% citric acid solution (20.9 g), the reaction solution was cooled from 25° C. to −10° C. over 2.3 hours; then, the seed crystal was added, followed by addition of water (19.2 ml) for overnight agitation, to crystallize (2R, 3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane. By filtration of the resulting slurry, the crystal of the objective (2R, 3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane was obtained {(2R, 3S) yield: 2.4 g (96.2%)}. The dried crystal was then analyzed by HPLC. (2R, 3S): (2S, 3S)=97.9:2.1. Additionally, the purity of (2R, 3S) was at 95.4% (HPLC area ratio).
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[OH:25][CH2:26][CH:27]([CH2:29]O)[OH:28]>>[CH3:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:24][CH2:29][CH:27]([OH:28])[CH2:26][OH:25])=[O:23]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: OCC(O)CO
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO

Procedure:
The preferred source of monoglycerides for use in the esterification process of the present invention is at least about 90%, preferably at least about 95%, and most preferably at least about 98%, pure monobehenin. This preferred monoglyceride can be obtained by hydrolysis of substantially completely hydrogenated (i.e., I.V. about 10 or less) high erucic acid rapeseed oil, solventless fractionation of the resulting fatty acid mixture to provide a behenic fatty acid-enriched fraction, and then esterification of glycerol with this behenic acid-enriched fraction to provide a crude mixture of monoglycerides. This crude monoglyceride mixture can be subsequently purified by molecular distillation, solvent (e.g., ethyl alcohol) crystallization, liquid/liquid extraction or adsorption on a weak acid ion exchange resin to yield a source of monoglycerides having the desired purity monobehenin.
Reaction SMILES: C[C@H](NC)C(N[C@H:6]([C:13]([N:15]1[C@H:19]([C:20]([NH:22][C:23]2[C:28]([C:29]3N=CC=CN=3)=[CH:27][CH:26]=[CH:25][CH:24]=2)=O)C[CH2:17][CH2:16]1)=O)[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=O.C[C@@H]1[C@@H](C(N[C:46]2[C:51](C3N=CC=CN=3)=[CH:50][CH:49]=[CH:48][CH:47]=2)=O)N(C([C@@H](NC([C@@H](NC)C)=O)C2CCCCC2)=O)CC1.[CH3:74][C:75]([O:77][CH2:78][C@H:79]([C@H:103]([OH:114])[CH2:104][C@@H:105]([O:110][C:111]([CH3:113])=[O:112])[C:106]([OH:109])([CH3:108])[CH3:107])[C@@H:80]1[C@@:84]2([CH3:101])[CH2:85][CH2:86][C:87]3[C@@:92]4([CH3:100])[CH2:93][CH2:94][C@H:95]([OH:99])[C:96]([CH3:98])([CH3:97])[C@@H:91]4[CH2:90][CH2:89][C:88]=3[C@:83]2([CH3:102])[CH2:82][CH2:81]1)=[O:76]>>[CH3:74][C:75]([O:77][CH2:78][C@H:79]([C@H:103]([OH:114])[CH2:104][C@@H:105]([O:110][C:111]([CH3:113])=[O:112])[C:106]([OH:109])([CH3:108])[CH3:107])[C@@H:80]1[C@@:84]2([CH3:101])[CH2:85][CH2:86][C:87]3[C@@:92]4([CH3:100])[CH2:93][CH2:94][C@H:95]([OH:99])[C:96]([CH3:97])([CH3:98])[C@@H:91]4[CH2:90][CH2:89][C:88]=3[C@:83]2([CH3:102])[CH2:82][CH2:81]1)=[O:76].[CH2:26]1[CH2:25][CH2:24][CH:23]([N:22]2[CH2:17][CH2:16][N:15]([CH:13]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:19][CH2:20]2)[CH2:28][CH2:29][CH2:27]1
Reactant: CN[C@@H](C)C(=O)N[C@H](C(=O)N1CC[C@H](C)[C@H]1C(=O)Nc1ccccc1-c1ncccn1)C1CCCCC1
Reactant: CN[C@@H](C)C(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1-c1ncccn1)C1CCCCC1
Agent: CC(=O)OC[C@H]([C@H](O)C[C@@H](OC(C)=O)C(C)(C)O)[C@H]1CC[C@@]2(C)C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Product: c1ccc(CC(c2ccccc2)N2CCN(C3CCCCCC3)CC2)cc1

Procedure:
Dispersion 3 containing comparison solvents CS-2 and CS-3 and comparison stabilizer CST-1 has a high number of crystals. Use of the solvent of the invention with CST-1 reduces the number of crystals, as in Dispersion 4, but further improvement is achieved through the use of the solvent of the invention S-1 combined with stabilizer of the invention ST-1 as in Dispersions 5, 6, 7, and 9. The use of solvent S-3 with ST-1 and IC-7 also provided a dispersion with low crystals, as in Dispersion 10. The combination of the coupler of the invention and the solvent of the invention also provided a low crystal dispersion, as in Dispersion 9.
Reaction SMILES: [CH2:1]1[O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6][CH2:5][CH2:4][O:3][CH2:2]1.FC(F)(F)[C:22](O)=[O:23]>>[CH2:1]1[O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][C:12]2[CH:11]=[C:10]([CH:22]=[O:23])[CH:9]=[CH:8][C:7]=2[O:6][CH2:5][CH2:4][O:3][CH2:2]1
Reactant: O=C(O)C(F)(F)F
Reactant: c1ccc2c(c1)OCCOCCOCCOCCO2
Product: O=Cc1ccc2c(c1)OCCOCCOCCOCCO2

Procedure:
A solution of hexamethylenetretramine (1.87 mmol, 0.27 g) in trifluoroacetic acid (1.4 cm3) was added to benzo 15-crown-5 ether (1.87 mmol, 0.5 g) under nitrogen; the mixture was heated to reflux for 12 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([CH3:25])[C:12]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=1)([OH:17])[C:13]([F:16])([F:15])[F:14])[C:5](O)=[O:6].[CH2:26]([O:28][C:29]([C:31]1[N:32]=[C:33]([NH2:36])[O:34][CH:35]=1)=[O:30])[CH3:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH2:26]([O:28][C:29]([C:31]1[N:32]=[C:33]([NH:36][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][C:10]([CH:11]([CH3:25])[C:12]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=3)([OH:17])[C:13]([F:14])([F:15])[F:16])=[C:2]([Cl:1])[CH:3]=2)[O:34][CH:35]=1)=[O:30])[CH3:27]
Reactant: CC(c1ccc(C(=O)O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: CCOC(=O)c1coc(N)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CCOC(=O)c1coc(NC(=O)c2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)n1

Procedure:
In analogy to Example 26, step 4, 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-benzoic acid (Example 26, step 3), was reacted with 2-aminooxazol-4-carboxylic acid ethylester and HBTU at r.t. 17 h to give the title compound as a white solid. MS (m/e)=532.3 [M+H+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[C:4]([F:15])[C:3]=1[F:16].[CH3:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O)(=[O:20])=[O:19].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>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]>[F:16][C:3]1[C:4]([F:15])=[C:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH:6]=[CH:7][C:2]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([CH3:17])(=[O:20])=[O:19]
Reactant: Nc1cnc(-c2ccc(Br)c(F)c2F)cn1
Reactant: CS(=O)(=O)c1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1F
Temperature: 25 °C
Yield: 40 %

Procedure:
Nitrogen sparged DMSO (0.73 ml) was added to a mixture of 5-(4-bromo-2,3-difluorophenyl)pyrazin-2-amine (50 mg, 0.18 mmol), (2-(methylsulfonyl)phenyl)boronic acid (35 mg, 0.18 mmol), K2CO3 (73 mg, 0.532 mmol) and PdCl2(dppf).CH2Cl2 (13 mg, 0.018 mmol) and heated at 80° Celsius for 2.5 hours. The mixture was cooled to rt and partitioned between sat. NaHCO3 and EtOAc. The organic layer was isolated, dried over MgSO4, and concentrated to dryness. Purification by FCC afforded the title compound (26 mg, 41%). MS (ESI): mass calcd. for C17H13F2N3O2S, 361.07; m/z found, 362.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.44-8.41 (m, 1H), 8.14 (dd, J=7.9, 1.4, 1H), 8.04 (d, J=1.5, 1H), 7.84 (m, 1H), 7.78 (m, 1H), 7.75-7.66 (m, 1H), 7.53 (dd, J=7.5, 1.3, 1H), 7.30 (dd, J=11.6, 4.9, 1H), 6.85 (s, 2H), 3.06 (s, 3H).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[OH:18])[CH:14]([C:19]([OH:21])=[O:20])[CH2:13][CH2:12]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][C:22](=[O:24])[CH3:23])[CH:14]([C:19]([OH:21])=[O:20])[CH2:13][CH2:12]2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(c1ccccc1)c1cc2c(cc1O)C(C(=O)O)CC2
Product: CC(=O)Oc1cc2c(cc1C(=O)c1ccccc1)CCC2C(=O)O

Procedure:
Dry ammonia is passed into a solution of 27 g of crude 5-benzoyl-6-acetoxy-indane-1-carboxylic acid chloride in 200 ml of anhydrous benzene at a temperature of 15°-20° C, with exclusion of moisture, until saturation is reached. The reaction solution is then evaporated to dryness in vacuo and the evaporation residue is partitioned between 200 ml of water and 3 times 200 ml of methylene chloride. The organic phases are washed until neutral, dried over sodium sulphate and evaporated in vacuo. Fractional crystallisation of the evaporation residue from hot dimethylformamide-water gives 5-benzoyl-6-hydroxy-indane-1-carboxylic acid amide of melting point 205°-207° C. The starting material can be obtained as follows. A solution of 20 g of 5-benzoyl-6-hydroxy-indane-1-carboxylic acid in 200 ml of acetic anhydride is heated to the reflux temperature for 4 hours. It is then evaporated to dryness in vacuo, 50 ml of toluene are added to the evaporation residue and the mixture is evaporated to dryness. This procedure is repeated twice more. The crude 5-benzoyl-6-acetoxy-indane-1-carboxylic acid thus obtained is used directly for further conversion.
Reaction SMILES: [NH2:1][C:2](=O)[C@@H:3]([NH:25][C:26]([C:28]1([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:27])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17](=[O:19])[N:16]([CH2:20][CH2:21][O:22][CH3:23])[C:15]=3[CH:24]=2)=[CH:7][CH:6]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>ClCCl>[C:2]([C@@H:3]([NH:25][C:26]([C:28]1([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1)=[O:27])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17](=[O:19])[N:16]([CH2:20][CH2:21][O:22][CH3:23])[C:15]=3[CH:24]=2)=[CH:9][CH:10]=1)#[N:1]
Reactant: COCCn1c(=O)oc2ccc(-c3ccc(C[C@H](NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)C(N)=O)cc3)cc21
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: ClCCl
Product: COCCn1c(=O)oc2ccc(-c3ccc(C[C@@H](C#N)NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)cc3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.8 %

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(4-(3-(2-methoxyethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 24, step (ii), 162 mg) in dichloromethane (8 mL) was treated with Burgess' reagent (133 mg) and the mixture was stirred at room temperature for 18 h. The solvent was partially evaporated and the mixture was purified by chromatography on silica eluting with 1:1 ethyl acetate/isohexane as eluent to yield a white solid (141 mg).