Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([NH:11][C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[C:31]5[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=5)[N:25]([CH3:33])[N:24]=4)[N:21]=3)[N:16](COCC[Si](C)(C)C)[CH:15]=2)=[O:13])[CH3:10])=[CH:5][CH:4]=1)#[N:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@H:9]([NH:11][C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[C:31]5[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=5)[N:25]([CH3:33])[N:24]=4)[N:21]=3)[NH:16][CH:15]=2)=[O:13])[CH3:10])=[CH:7][CH:8]=1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1ccc(C#N)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.3 %

Procedure:
In a round-bottomed flask containing 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyanophenyl)-ethyl]-amide (32 mg, 0.056 mmol) dissolved in THF (1 ml) was added TBAF (1.0 M in THF, 1.0 ml, 1.0 mmol). The flask was backfilled with nitrogen then sealed and placed in an oil bath at 85° C. for 2 h. The reaction was cooled to room temperature, quenched with acetone (2 ml) and sat'd NaHCO3 (4 ml). The mixture was stirred for 1 h then diluted with water and extracted with EtOAc. Brine was added and the aqueous layer was extracted twice with EtOAc. The combined organics were washed with water and brine then dried over MgSO4, filtered and concentrated. The crude solid was purified by flash chromatography (4 g silicycle) with 0% to 7.5% MeOH in dichloromethane. The appropriate fractions were combined and concentrated to afford 4 mg (19%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-phenyl)-ethyl]-amide as a white solid. LC-MS (M+H)+=440; 1H NMR (300 MHz, DMSO-d6) δ: 12.97 (br. s., 1H), 9.17 (s, 1H), 8.33-8.69 (m, 3H), 7.85 (d, J=8.3 Hz, 2H), 7.64-7.78 (m, 3H), 7.08 (d, J=2.0 Hz, 1H), 5.39 (br. s., 1H), 4.20 (s, 3H), 1.70 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:9][Si:10]([O:13][CH2:14][CH3:15])([CH3:12])[CH3:11].[Cl-]>>[CH:1]1([NH:7][CH2:9][Si:10]([O:13][CH2:14][CH3:15])([CH3:12])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCO[Si](C)(C)CCl
Reactant: NC1CCCCC1
Agent: [Cl-]
Product: CCO[Si](C)(C)CNC1CCCCC1
Temperature: 30 °C
Yield: 61 %

Procedure:
In a 500 ml three-necked flask having a reflux condenser, KPG stirrer and thermometer, 176 g of commercial cyclohexylamine (water content ≦2%) were heated to 100° C., and 122 g of (chloromethyl)ethoxydimethylsilane were added over the course of 30 min with stirring. After the end of the addition, the mixture was stirred for two hours under reflux and cooled to 30° C., and the white precipitate formed was filtered using a pressure filter, and rinsed with cyclohexylamine. Filtrate and wash solutions were combined and were freed from excess cyclohexylamine under reduced pressure. The subsequent fractional distillation gave 105 g (yield 61%) of (N-cyclohexylaminomethyl)ethoxydimethylsilane having a chloride content of 600 ppm.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][CH2:20][CH3:21])[C:14]3=[O:22])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:23][C:24]1[N:29]=[CH:28][C:27]([CH:30]=[CH:31][C:32](O)=[O:33])=[CH:26][CH:25]=1>>[NH2:23][C:24]1[N:29]=[CH:28][C:27]([CH:30]=[CH:31][C:32]([N:16]2[CH2:17][CH2:18][N:13]([CH2:12][C:8]3[CH:7]=[C:6]4[C:11]([C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)=[CH:10][CH:9]=3)[C:14](=[O:22])[C@@H:15]2[CH2:19][CH2:20][CH3:21])=[O:33])=[CH:26][CH:25]=1
Reactant: CCCC1NCCN(Cc2ccc3c(N)ncnc3c2)C1=O
Reactant: Nc1ccc(C=CC(=O)O)cn1
Product: CCC[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)C=Cc1ccc(N)nc1

Procedure:
The title compound is prepared as described in EXAMPLE 123, using 1-(4-aminoquinazoline-7-ylmethyl)-3-propyl-piperazine-2-one, EXAMPLE 78 and 3-(6-amino-pyridin-3-yl)-acrylic acid, EXAMPLE 36. 1H NMR (d6-DMSO, 300 MHz) δ9.73 (bs, 2H), 8.81 (s, 1H), 8.36 (m, 2H), 8.22 (m, 3H), 7.62 (d, 1H), 7.52 (m, 1H), 7.39 (m, 1H), 7.21 (m, 1H), 6.91 (d, 1H), 5.00 (m, 1H), 4.78 (m, 1H), 4.60 (m, 2H), 4.34 (m, 1H), 3.30 (m, 2H), 1.87 (m, 2H), 1.24 (m, 2H), 0.90 (m, 3H). MS (ion spray), m/z, 446, 448 (M+H), (Cl pattern).
Reaction SMILES: [C:1]1(=O)[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[SH:16]>CO>[CH:2]1[C:1]2[C:6]([S:16][C:11]3[C:10]([N:9]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:5][C:4](=[O:7])[CH:3]=1
Reactant: O=C1C=CC(=O)C=C1
Reactant: Nc1ccccc1S
Solvent: CO
Product: O=c1ccc2nc3ccccc3sc-2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
To a stirring suspension of 1.72 kg (16 mol) of p-benzoquinone in 13 liters MeOH at room temperature was added slowly a solution of 1.0 kg (8 mol) of 2-aminothiophenol in 600 ml MeOH over a period of 1 hour. The resulting red mixture was stirred at room temperature for another 2 hours and then the product 3H-phenothiaz-3-one was filtered off. This 3H-phenothiazin-3-one was washed thoroughly with methanol and dried to give 1.07 kg of 3H-phenothiazin-3-one (61.49% yield), m.p. 157°-159° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[C:16]([CH3:19])=[C:15]([CH3:20])[C:14]1=[O:21].[H][H]>C(OCC)(=O)C.[Pt]=O>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:11])[CH3:12])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[C@H:16]([CH3:19])[C@H:15]([CH3:20])[C:14]1=[O:21]
Reactant: [H][H]
Reactant: CC1=C(C)C(=O)N(c2cc(OC(C)C)c(Cl)cc2F)C1=O
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(N2C(=O)[C@@H](C)[C@@H](C)C2=O)c(F)cc1Cl
Reaction time: 5 h

Procedure:
A mixture of 9.4 g (0.03 mol) of N-(2-fluoro-4-chloro-5-isopropoxyphenyl)-2,3-dimethylmaleic acid imide and 500 mg of platinum oxide (PtO2) in 100 ml of ethyl acetate is hydrogenated with hydrogen at room temperature under normal pressure. After about 5 hours, when the absorption of hydrogen has ceased, the catalyst is filtered off and the filtrate is concentrated to dryness. 7.9 g (85% of the theoretical yield) of an almost colourless oil which is uniform in a thin-layer chromatogram are obtained as residue and crystallised from isopropyl ether. The cis-N-(2-fluoro-4-chloro-5-isopropoxyphenyl)-2,3-dimethyl-succinimide so obtained has a melting point of 101°-102°.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:9][C:10]1[N:14]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[Cl:26])[N:13]=[C:12]([CH:27]=[N:28][OH:29])[C:11]=1[S:30]([CH3:32])=[O:31].N1C=CN=C1.O>CN(C)C=O>[Si:1]([O:29][N:28]=[CH:27][C:12]1[C:11]([S:30]([CH3:32])=[O:31])=[C:10]([NH2:9])[N:14]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:25])([F:23])[F:24])=[CH:17][C:16]=2[Cl:26])[N:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CS(=O)c1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)c1c(C=NO[Si](C)(C)C(C)(C)C)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 50 °C
Reaction time: 18 h
Yield: 29.6 %

Procedure:
A solution of tert-butyldimethylsilyl chloride (0.8 g) in N,N-dimethylformamide (DMF) was added to a stirred solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde oxime (2.0 g) in (DMF), followed by dropwise addition of a solution of imidazole (0.72 g) in DMF during 7-minutes. The mixture was heated at 50° C. for 3.5-hours and then held at 20° C. for 18 hours. The mixture was diluted (water), extracted (methyl tert-butyl ether) and the organic phase washed in turn with NaHCO3 solution, 5% HCl solution and with NaHCO3 solution, dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography on silica gel to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde O-(tert-butyldimethylsilyl)oxime (0.76 g)as a light yellow solid m.p.150-154° C. Compound 21.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=S)[C:10]([C:19](OCC)=[O:20])=[CH:9]2)=[CH:3][CH:2]=1.[NH2:30][NH2:31]>C(O)C>[C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3=[N:30][NH:31][C:19](=[O:20])[C:10]3=[CH:9]2)=[CH:3][CH:2]=1
Reactant: NN
Reactant: CCOC(=O)c1cn(Cc2ccc(-c3ccccc3)cc2)c2ccccc2c1=S
Solvent: CCO
Product: O=c1[nH]nc2c3ccccc3n(Cc3ccc(-c4ccccc4)cc3)cc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 1-(biphenyl-4-ylmethyl)-4-thioxo-1,4-dihydroquinoline-3-carboxylate (0.43 g, 1.1 mmol) and hydrazine (38 μL, 1.1 mmol, 1 equiv) were combined in absolute ethanol (10 mL) and placed into a preheated oil bath at 75° C. for 1 hour. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 90:10; dichloromethane:methanol), providing the titled compound.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]2[C:26]([C:29]([O:31]CC)=O)=[N:27][O:28][C:23]2=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:43]([NH2:46])([CH3:45])[CH3:44]>>[Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]2[C:26]([C:29]([NH:46][CH:43]([CH3:45])[CH3:44])=[O:31])=[N:27][O:28][C:23]2=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N
Reactant: CCOC(=O)c1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc12
Product: CC(C)NC(=O)c1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc12

Procedure:
Starting material: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-7-chloro-6-((2R,6S)-2,6-dimethylmorpholino)isoxazolo[4,5-b]pyridine-3-carboxylate (Intermediate 211) and isopropylamine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].[N-:16]=[N+]=[N-].[Na+]>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([OH:11])[CH:10]([NH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(N)C(O)C1
Temperature: 60 °C

Procedure:
6-Oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (12.1 g, 65.3 mmol) was dissolved in a 8:1 methanol/water mixture (108 mL). Ammonium chloride (15 g) and sodium azide (21.4 g, 329 mmol) was added and the mixture was heated at 60° C. overnight. After dilution with ether (500 mL), the mixture was washed with saturated aqueous NaHCO3 (200 mL) and brine (200 mL), dried with MgSO4 and evaporated under vacuum. The crude product was dissolved in methanol (200 mL). 10% Palladium on activated carbon (1.5 g) was added and the mixture was stirred at ambient temperature under a hydrogen atmosphere until TLC analysis showed the disappearance of the starting material. The mixture was filtered through a pad of Celite and evaporated to dryness under vacuum. The product was purified by flash chromatography on silica gel. Eluent: 5% methanol in ethyl acetate to 20% methanol, 3% triethylamine in ethyl acetate. Yield: 4.3 g 3-amino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester as yellowish solid.
Reaction SMILES: [Si]([O:8][C@H:9]([C:62]1[CH:67]=[CH:66][C:65]([F:68])=[CH:64][CH:63]=1)[CH2:10][S:11][C@H:12]1[C:15](=[O:16])[N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:19][CH:18]=2)[C@@H:13]1[C:31]1[CH:61]=[CH:60][C:34]([O:35][CH2:36][C:37]([NH:39][CH2:40][C:41]([NH:43][C@@H:44]([C:57]([OH:59])=[O:58])[CH2:45][CH2:46][CH2:47][CH2:48][NH:49]C(OC(C)(C)C)=O)=[O:42])=[O:38])=[CH:33][CH:32]=1)(C(C)(C)C)(C)C.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[Ce+4].[N+]([O-])(O)=O.O>CC#N>[F:68][C:65]1[CH:66]=[CH:67][C:62]([C@@H:9]([OH:8])[CH2:10][S:11][C@H:12]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[C:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:21][CH:22]=3)[C@@H:13]2[C:31]2[CH:32]=[CH:33][C:34]([O:35][CH2:36][C:37]([NH:39][CH2:40][C:41]([NH:43][C@@H:44]([C:57]([OH:59])=[O:58])[CH2:45][CH2:46][CH2:47][CH2:48][NH2:49])=[O:42])=[O:38])=[CH:60][CH:61]=2)=[CH:63][CH:64]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(F)cc3)C(=O)N2c2ccc(C#CCNS(C)(=O)=O)cc2)cc1)C(=O)O
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: O
Solvent: CC#N
Solvent: O=[N+]([O-])O
Product: CS(=O)(=O)NCC#Cc1ccc(N2C(=O)[C@H](SC[C@H](O)c3ccc(F)cc3)[C@H]2c2ccc(OCC(=O)NCC(=O)N[C@H](CCCCN)C(=O)O)cc2)cc1
Temperature: 45 °C

Procedure:
N-({4-[(2R,3R)-3-{[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-fluorophenyl)ethyl]thio}-1-(4-{3-[(methylsulfonyl)amino]prop-1-yn-1-yl}phenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-N6-(tert-butoxycarbonyl)-D-lysine (Method 2) (21.9, 0.022 mmol) was dissolved in MeCN (1.5 ml). Cerium(4+) tetranitrate-nitric acid (1:2) diammoniate (25.1 mg, 0.046 mmol) and water (50 μl) were added. The reaction mixture was heated at 45° C. for 6 h and 30 minutes and it was allowed to stand at room temperature over the weekend. The solution was purified with preparative HPLC on a C8 column, UV 235/285 nm. A gradient from 10 to 90% MeCN in 0.1M NH4OAc buffer was used as eluent. Most of the MeCN was removed under reduced pressure and the residue was lyophilised to give the title compound as a yellow solid. H-NMR (500 MHz, DMSO-d6): 1.13-1.66 (m, 6H), 2.64-2.71 (m, 2H), 2.90-2.96 (m, 2H), 2.97 (s, 3H), 3.62-3.80 (m, 3H), 4.00 (s, 2H), 4.34 (d, 1H), 4.53 (s, 2H), 4.72 (t, 1H), 5.09 (d, 1H), 6.99 (d, 2H), 7.07-7.13 (m, 2H), 7.20 (d, 2H), 7.32-7.40 (m, 6H), 7.46 (b, 1H), 8.42 (t, 1H). M/z: 782.58 (M−1) and 784.42 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[Cl:11][C:4]1[CH:3]=[C:2]([C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]=12
Reactant: Clc1cc(Cl)c2c(n1)CCC2
Reactant: OB(O)c1ccc(Cl)cc1
Product: Clc1ccc(-c2cc(Cl)c3c(n2)CCC3)cc1
Yield: 72.3 %

Procedure:
Following General Procedure F, 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.350 g, 1.86 mmol) was reacted with (4-chlorophenyl)boronic acid (0.378 g, 2.42 mmol) to afford the title compound (0.355 g, 78%). MW=264.15. 1H NMR (CD3OD, 300 MHz) δ 7.96-7.83 (m, 2H), 7.61 (d, J=4.6 Hz, 1H), 7.51-7.39 (m, 2H), 3.13-2.99 (m, 4H), 2.25-2.14 (m, 2H); APCI MS m/z 264 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:21]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)O)n(C)n1
Reactant: C1COCCN1
Product: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)N2CCOCC2)n(C)n1
Yield: 25 %

Procedure:
As described for example 122, 5-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2-methyl-2H-pyrazole-3-carboxylic acid was converted, using morpholine instead of isopropylamine, to the title compound (8.3 mg, 25%) which was obtained as a white solid. MS: m/e=397.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Cc1cccnc1Br
Product: Cc1ccc(-c2ncccc2C)cc1
Yield: 75.4 %

Procedure:
4-methylphenylboronic acid (20.0 g, 0.147 mol) was reacted with 2-bromo-3-methylpyridine (21.1 g, 0.123 mol) under standard Suzuki coupling condition. A small amount of unreacted 2-bromo-3-methylpyridine was removed via vacuum distillation. Purification via flash silica gel chromatography with a 1/99 to 7.5/92.5 EtOAc/hexane solvent gradient yielded 17.0 g of 2-(4-methylphenyl)-3-methylpyridine as a colorless liquid.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14])(=O)C.C=CCCCC.C(O)(=[O:27])CCCC=C>Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[C:5]([OH:4])(=[O:27])[CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: C=CCCCC(=O)O
Reactant: CCCCC=CCCCCOC(C)=O
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: C=CCCCC
Product: CCCCC=CCCCC(=O)O

Procedure:
FIG. 6 shows an alternative synthesis of 5-decenyl acetate, in which 1-hexene is reacted with 5-hexenoic acid in the presence of Grubbs' catalyst to produce 5-decenoic acid that can be recrystallized, reduced to an alcohol, and acetylated to yield a greater than 90% E-5-decenyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[CH3:12])[CH:10]=1)[N:7](C)[N:6]=[CH:5]2.F[C:36](F)(F)C(O)=O.C(Cl)Cl>>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:13][CH2:14][C:15]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH3:12])[C:8]2[C:4](=[CH:5][N:6]([CH3:36])[N:7]=2)[CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cnn(C)c12
Solvent: ClCCl
Product: CC(OCC1(c2ccccc2)CCNCC1)c1cc(Cl)cc2cn(C)nc12

Procedure:
(±)-tert-Butyl 4-((1-(5-chloro-1-methyl-1H-indazol-7-yl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate (27 mg, 0.06 mmol) was treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvent was evaporated to afford 18 mg (79%) as a clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.86 (s, 1H), 7.54 (d, J=1.8 Hz, 1H), 7.28-7.32 (m, 4H), 7.19-7.23 (m, 1H), 7.10 (d, J=1.8 Hz, 1H), 4.74 (q, J=6.4 Hz, 1H), 3.97 (s, 3H), 3.36 (d, J=9.2 Hz, 1H), 3.23 (d, J=9.2 Hz, 1H), 2.87-2.89 (m, 2H), 2.70-2.76 (m, 2H), 2.13-2.16 (m, 2H), 1.83-1.90 (m, 2H), 1.44 (d, J=6.4 Hz, 3H); 13C-NMR (126 MHz, CDCl3) δ ppm 144.1, 136.3, 132.5, 128.4, 128.3, 127.2, 126.8, 126.2, 126.1, 125.2, 119.4, 78.2, 42.7, 41.8, 39.9, 33.6, 33.4, 23.4. Mass spec.: 384.17 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:29])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.Cl>C(OCC)C.[BH4-].[Zn+2].[BH4-]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Zn+2]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(F)cc1
Reaction time: 2 h

Procedure:
While stirring zinc chloride (4.70 g, 34.5 mmol) in diethyl ether (80 ml), sodium borohydride (2.61 g, 68.9 mmol) was added as it was at room temperature and the mixture was stirred as it was for 2 hrs. The insoluble material of the mixture was removed by filtration and washed with diethyl ether to give a solution of zinc borohydride in diethyl ether. To the obtained solution was added a solution of ethyl 3-(4-fluorophenyl)-3-oxo-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate (7.176 g, 17.24 mmol) in diethyl ether (30 ml) at room temperature and the mixture was stirred as it was at room temperature for 2 hrs. Dilute hydrochloric acid was added to the solution by small portions to decompose excess zinc borohydride and the mixture was extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1−3/1) to give the objective substance.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:21]([OH:22])[C@:20]([CH3:24])([OH:23])[C@@H:19]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[O:18][C@H:10]1[O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:41]([O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:42]>C(Cl)Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:21]([O:22][C:41]([O:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:42])[C@:20]([CH3:24])([OH:23])[C@@H:19]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[O:18][C@H:10]1[O:11][CH2:12][CH2:13][Si:14]([CH3:16])([CH3:15])[CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](OCC[Si](C)(C)C)[C@H](OCc2ccccc2)[C@@H](O)[C@]1(C)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](OCC[Si](C)(C)C)[C@H](OCc2ccccc2)[C@@H](OC(=O)Oc2ccccc2)[C@]1(C)O
Reaction time: 0.33 h
Yield: 100 %

Procedure:
Compound 5.09 (4.0 g, 8.0 mmol) was dissolved in CH2Cl2 (80 mL) and pyridine (2.6 mL, 32 mmol) then chilled to 0° C. Phenyl chloroformate (1.1 mL, 8.8 mmol) was added and the reaction was stirred for 20 min then quenched with 20 mL MeOH and concentrated in vacuo. The residue was dissolved in CH2Cl2 then washed with H2O and brine. The organic layer was concentrated in vacuo and the residue was purified by silica gel chromatography (10% EtOAc/petroleum ether) to afford the title compound (5.0 g, 8.0 mmol, 100%). 1H NMR (500 MHz, CDCl3): δ ppm 7.36-7.25 (m, 7H, PhH), 7.22 (t, J=7.3 Hz, 1H, PhH), 7.10 (d, J=8.8 Hz, 2H, PhH), 4.97 (d, J=10.3 Hz, 1H, H-3), 4.95, 4.67 (ABq, J=11.2 Hz, OCH2Ph1H each,), 4.53 (d, J=7.8 Hz, 1H, H-1), 4.04-3.96 (m, 1H, OCHHCH2SiMe3), 3.89 (d, J=7.3 Hz, 2H, H-6), 3.64 (s, 1H, OH), 3.63-3.58 (m, 1H, OCHHCH2SiMe3), 3.54 (t, J=7.1 Hz, 1H, H-5), 3.38 (dd, J=10.3, 7.8 Hz, 1H, H-2), 1.36 (s, 3H, Me), 1.04 (t, J=8.8 Hz, 2H, OCH2CH2SiMe3), 0.91 (s, 9H, SiCMe3), 0.13, 0.12 (s, 3H each, SiMe2), 0.04 (s, 9H, SiMe3); 13C NMR (125 MHz, CDCl3): δ ppm 153.72, 151.34, 138.51, 129.43, 128.44, 127.66, 127.64, 125.97, 121.18, 103.63, 83.26, 79.14, 75.22, 74.80, 73.57, 68.06, 62.56, 25.94, 18.69, 18.26, 16.13, −1.29, −5.38, −5.55; HRMS calcd for C32H54NO8Si2 [M+NH4]+: 618.3044. found 618.9056.