Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][O:14][C@@H:15]3[CH2:20][CH2:19][CH2:18][C@H:17]([O:21][CH2:22][C:23]4[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[C:24]=4[C:25]([O:27]C)=[O:26])[CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1.[OH-].[K+].Cl>CC(O)(C)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][O:14][C@@H:15]3[CH2:20][CH2:19][CH2:18][C@H:17]([O:21][CH2:22][C:23]4[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[C:24]=4[C:25]([OH:27])=[O:26])[CH2:16]3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(C)cccc1CO[C@H]1CCC[C@@H](OCc2coc(-c3ccc(F)cc3)n2)C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: Cc1cccc(CO[C@H]2CCC[C@@H](OCc3coc(-c4ccc(F)cc4)n3)C2)c1C(=O)O
Reaction time: 24 h

Procedure:
4.2 g (9.2 mmol) of 5b were dissolved in 120 ml of t-BuOH. 50 ml of 50% aq. KOH were added, and the mixture was then boiled at 100° C. for 24 hours. For work-up, the mixture was allowed to cool and then diluted with 100 ml of ethyl acetate. The aqueous phase was made slightly acidic by addition of 2 N aqueous HCl and extracted 2 more times with 100 ml of ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated, and the residue was purified by flash chromatography (methylene chloride/methanol/conc. ammonia, 30/5/1). This gave 6b as a white amorphous solid. TLC (methylene chloride/methanol/conc. ammonia, 30/5/1). Rf=0.3. Recrystallization from toluene. C25H26FNO5 (432.42) MS(ESI): 433 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]#[C:10][C:11]1[CH:12]=[N:13][C:14]([NH2:29])=[C:15]([O:17][CH:18]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[Cl:28])[CH3:19])[CH:16]=1)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[NH2:7][CH2:8][C:9]#[C:10][C:11]1[CH:16]=[C:15]([O:17][CH:18]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[Cl:28])[CH3:19])[C:14]([NH2:29])=[N:13][CH:12]=1
Reactant: CC(Oc1cc(C#CCNC(=O)OC(C)(C)C)cnc1N)c1c(Cl)ccc(F)c1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(Oc1cc(C#CCN)cnc1N)c1c(Cl)ccc(F)c1Cl
Yield: 93 %

Procedure:
The solution of (3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-carbamic acid tert-butyl ester in 25% TFA in dichloromethane was stirred for 2 hr, then washed by 2N NaOH, water twice, brine, dried over Na2SO4. After filtration and evaporation, 5-(3-amino-prop-1-ynyl)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine was obtained in 93% yield.
Reaction SMILES: [OH:1][C@@H:2]([CH3:21])[CH2:3][C@@H:4]([CH3:20])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].Cl>N1C=CC=CC=1>[C:22]([O:1][C@@H:2]([CH3:21])[CH2:3][C@@H:4]([CH3:20])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](O)C[C@@H](C)Oc1ccc(-c2ccc(C#N)cc2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)O[C@@H](C)C[C@@H](C)Oc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
2.81 g of the (R,S)-4-[4'-(3"-hydroxy-1"-methylbutoxy)phenyl]benzonitrile prepared in the above Example 1 was mixed with 5.10 g of acetic anhydride and 0.3 g of pyridine. The mixture was stirred at 100° C. for one hour. After cooling, the reaction mixture was carefully poured into 50 ml of 2N hydrochloric acid and extracted with diethyl ether. After washing with water, drying and desolvating, the obtained residue was purified by silica gel column chromatography with the use of a mixture of n-hexane and ethyl acetate (3:1) as a developing solvent. Thus 2.65 g of (R,S)-4-[4'-(3"-acetoxy-1"-methylbutoxy)phenyl]benzonitrile was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:20][CH3:21])[C:10](=[O:19])[NH:11][C:12]=2[C:16]([OH:18])=O)[C:7]1=[O:22].[CH2:27]([O:34][CH2:35][CH2:36][NH:37][CH2:38][CH2:39][CH2:40][CH2:41][O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:27]([O:34][CH2:35][CH2:36][N:37]([CH2:38][CH2:39][CH2:40][CH2:41][O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:44])[CH3:45])[C:16]([C:12]1[NH:11][C:10](=[O:19])[C:9]([O:20][CH3:21])=[C:8]2[C:13]=1[CH2:14][CH2:15][N:6]([CH2:5][C:4]1[CH:23]=[CH:24][C:25]([F:26])=[C:2]([Cl:1])[CH:3]=1)[C:7]2=[O:22])=[O:18])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCCNCCOCc1ccccc1
Reactant: COc1c2c(c(C(=O)O)[nH]c1=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1c2c(c(C(=O)N(CCCCO[Si](C)(C)C(C)(C)C)CCOCc3ccccc3)[nH]c1=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6(3-chloro-4-fluorobenzyl)-4-methoxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylic acid (0.19 g, 0.49 mmol), N-[2-(benzyloxy)-ethyl]-4-{[tert-butyl(dimethyl)silyl]oxy}butan-1-amine (0.19 g, 0.55 mmol), EDC (0.10 g, 0.55 mmol), HOAt (75 mg, 0.55 mmol) and diisopropylethylamine (0.35 mL, 1.99 mmol) in DMF (2 mL) was stirred at room temperature overnight. The product mixture was concentrated under vacuum. The residue was partitioned between methylene chloride and water. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford the title compound. This material was used in the following step without further purification.
Reaction SMILES: [ClH:1].[CH:2]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH2:9])=[NH:8])=O.[NH2:13][NH:14][C:15]([NH2:17])=[S:16]>CO.O.Cl>[ClH:1].[CH:2](=[N:13][NH:14][C:15]([NH2:17])=[S:16])[C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH2:9])=[NH:8]
Reactant: N=C(N)c1cccc(C=O)c1
Reactant: NNC(N)=S
Agent: Cl
Solvent: O
Solvent: CO
Product: N=C(N)c1cccc(C=NNC(N)=S)c1

Procedure:
A solution of 1.84 g (~0.01 mol) of crude 3-formylbenzamidine hydrochloride (prepared analogously to Example 1b) in 10 ml of methanol is added dropwise to a solution of 0.91 g (0.01 mol) of thiosemicarbazide in 5 ml of water and 10 ml of 2N hydrochloric acid. This mixture is heated under reflux for 1 hour, cooled, filtered and concentrated to dryness by evaporation. The residue is recrystallised from methanol; m.p. 210° (with decomposition). The product contains 0.5 mol of water.
Reaction SMILES: [Br-].[O:2]1[CH2:7][CH2:6][CH2:5][O:4][CH:3]1[CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CC(C)([O-])C.[K+].[F:40][C:41]1[CH:42]=[C:43]([CH:52]2[CH2:57][CH2:56][C:55](=O)[CH2:54][CH2:53]2)[CH:44]=[CH:45][C:46]=1[O:47][C:48]([F:51])([F:50])[F:49]>CCOCC>[O:4]1[CH2:5][CH2:6][CH2:7][O:2][CH:3]1[CH2:8][CH:9]=[C:55]1[CH2:54][CH2:53][CH:52]([C:43]2[CH:44]=[CH:45][C:46]([O:47][C:48]([F:49])([F:51])[F:50])=[C:41]([F:40])[CH:42]=2)[CH2:57][CH2:56]1
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCC(c2ccc(OC(F)(F)F)c(F)c2)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Fc1cc(C2CCC(=CCC3OCCCO3)CC2)ccc1OC(F)(F)F
Reaction time: 1 h

Procedure:
Into a three-necked flask equipped with a dropping funnel, a three-way cook and a thermometer was placed 2-(1,3-dioxan-2-yl)ethyltriphenylphosphonium bromide (9.1 g, 20 mmols), followed by adding tetrahydrofuran (100 ml), suspending, stirring under ice cooling till the liquid temperature reached 10° C. The resulting reaction mixture was added potassium t-butoxide (2.2 g, 20 mmols) followed by elevating the temperature up to room temperature under ice cooling for one hour, stirring for one hour, dropwise adding a tetrahydrofuran (50 ml) solution of 4-(3-fluoro-4-trifluoromethoxyphenyl)cyclohexanone (5.5 g, 20 mmols) over 30 minutes from the dropping funnel, further stirring the reaction mixture for 5 hours after completion of the dropwise addition, adding ether (100 ml), allowing to stand for one hour, filtering off deposited insoluble substance, concentrating the filtrate under reduced pressure, and isolating and purifying the resulting pale brown oil by means of silica gel column chromatography, to obtain 1-(2-(1,3-dioxan-2-yl)ethylidene)-4-(3-fluoro-4-trifluoromethoxyphenyl)cyclohexane.
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[C:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12]3[N:20]=[CH:21][CH:22]=[CH:23][C:11]=3[N:10]2[CH:24]=1.[Br:26]N1C(=O)CCC1=O>C1COCC1>[Br:26][C:24]1[N:10]2[C:11]3[CH:23]=[CH:22][CH:21]=[N:20][C:12]=3[NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:9]2=[N:8][C:7]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:25]
Reactant: Cc1ccccc1-c1cn2c(n1)-c1ccccc1Nc1ncccc1-2
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: Cc1ccccc1-c1nc2n(c1Br)-c1cccnc1Nc1ccccc1-2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.4 %

Procedure:
To a solution of 2-(o-tolyl)-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.2 g, 1 eq.) in THF (5 mL) was added N-bromosuccinimide (0.11 g, 1 eq.). The reaction was stirred at room temperature for 15 minutes, poured onto water (30 mL) and extracted with ethyl acetate (2×30 mL). The organic extracts were combined, washed with saturated sodium bicarbonate (1×50 mL), water (1×50 mL), brine (1×50 mL) and dried over sodium sulfate. After filtration and concentration under reduced pressure, the crude product was purified by column chromatography (20% ethyl acetate in hexanes). The 3-bromo-2-(o-tolyl)-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.19 g, 77%) was obtained as an off-white solid. M.p.: 220-222° C.; 1H NMR (DMSO-d6) 400 MHz δ 8.64 (s, 1H), 8.27 (dd, JA=3.6 Hz, JB=1.6 Hz, 1H), 8.03 (dd, JA=7.2 Hz, JB=1.6 Hz, 1H), 7.78 (dd, JA=7.6 Hz, JB=1.2 Hz, 1H), 7.44 (d, J=6.8 Hz, 1H), 7.38-7.23 (m, 6H), 7.09 (t, J=7.6 Hz, 1H), 2.37 (s, 3H); LCMS: 403 [M+H].
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([NH2:20])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH:22]1([CH2:28][C:29](Cl)=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([NH:20][C:29](=[O:30])[CH2:28][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)CC1CCCCC1
Reactant: CC(C)(C)OC(=O)NCc1nn(N)c(=O)c2ccccc12
Product: CC(C)(C)OC(=O)NCc1nn(NC(=O)CC2CCCCC2)c(=O)c2ccccc12

Procedure:
The product of Example 41B and 2-cyclohexylacetyl chloride were treated using a method similar to that described in Example 4C to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 11.24 (s, 1H), 8.32 (dd, J=7.8, 1.4, 1H), 8.11 (d, J=8.0, 1H), 8.03-7.94 (m, 1H), 7.90 (td, J=7.5, 1.2, 1H), 7.45-7.36 (m, 1H), 4.48-4.41 (m, 2H), 2.16 (d, J=6.7, 2H), 1.85-1.58 (m, 6H), 1.39 (s, 9H), 1.28-0.95 (m, 5H); MS (ESI−) M/Z 413 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][N:7]1[C:11]([C:12]2[S:24][C:15]3[N:16]=[CH:17][N:18]=[C:19](S(C)(=O)=O)[C:14]=3[CH:13]=2)=[C:10]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:9]=[CH:8]1.C[N:37]1C(C2SC3N=CN=C(S(C)(=O)=O)C=3C=2)=C(C2C=CC=CC=2)N=C1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][N:7]1[C:11]([C:12]2[S:24][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:37])[C:14]=3[CH:13]=2)=[C:10]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:9]=[CH:8]1
Reactant: Cn1cnc(-c2ccccc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Reactant: COc1ccc(Cn2cnc(-c3ccccc3)c2-c2cc3c(S(C)(=O)=O)ncnc3s2)cc1OC
Product: COc1ccc(Cn2cnc(-c3ccccc3)c2-c2cc3c(N)ncnc3s2)cc1OC

Procedure:
The title compound was prepared by a similar process to that described for Example 8 but using 6-[1-(3,4-dimethoxybenzyl)-4-phenyl-1H-imidazol-5-yl]-4-(methylsulfonyl)-thieno[2,3-d]pyrimidine (intermediate 19) in place of 6-(1-methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (intermediate 17). White solid (35 mg, 91%);
Reaction SMILES: [H-].[Na+].[C:3]([O:6][C:7]1[C:12]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:11][C:10]([OH:17])=[C:9]([CH3:18])[C:8]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:5])[CH3:4].[CH2:23](Br)[CH2:24][CH3:25].[Cl-].[NH4+]>CN(C)C=O>[C:3]([O:6][C:7]1[C:12]([C:13]([CH3:14])([CH3:15])[CH3:16])=[CH:11][C:10]([O:17][CH2:23][CH2:24][CH3:25])=[C:9]([CH3:18])[C:8]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:5])[CH3:4]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(O)c(C)c1C(C)(C)C
Reactant: CCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCOc1cc(C(C)(C)C)c(OC(C)=O)c(C(C)(C)C)c1C
Reaction time: 0.33 h

Procedure:
Sodium hydride (100 mg) was suspended in N,N-dimethylformamide (5 ml) and a solution of 4-acetoxy-3,5-di-tert-butyl-2-methylphenol (0.5 g) in N,N-dimethylformamide (5 ml) was added dropwise to the suspension at 0° C. After stirring for 20 min, propyl bromide (0.2 ml) was added and the mixture was stirred for an additional 2 h. The reaction mixture was then poured into a saturated aqueous solution of ammonium chloride and extracted with diethyl ether. The extract was washed with water and saturated brine, then dried over anhydrous sodium sulfate. The solvent was distilled off to afford 1-acetoxy-2,6-di-tert-butyl-3-methyl-4-propyloxybenzene which was substantially pure on TLC. It was used in the subsequent reaction without further purification.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([F:12])=[CH:10][C:9]([C:13]3[O:14][C:15]4[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=O)[O:27]C(C)(C)C)[CH3:24])[N:18]=[CH:17][C:16]=4[N:33]=3)=[CH:8][C:7]=2[F:34])[CH2:3][CH2:2]1.[NH:35]1[CH2:38][CH2:37][CH2:36]1>>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([F:12])=[CH:10][C:9]([C:13]3[O:14][C:15]4[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]([NH:25][C:26]([N:35]5[CH2:38][CH2:37][CH2:36]5)=[O:27])[CH3:24])[N:18]=[CH:17][C:16]=4[N:33]=3)=[CH:8][C:7]=2[F:34])[CH2:3][CH2:2]1
Reactant: C1CNC1
Reactant: C[C@@H](COc1cc2oc(-c3cc(F)c(OCC4CC4)c(F)c3)nc2cn1)NC(=O)OC(C)(C)C
Product: C[C@@H](COc1cc2oc(-c3cc(F)c(OCC4CC4)c(F)c3)nc2cn1)NC(=O)N1CCC1

Procedure:
Using tert-butyl ((2S)-1-((2-(4-(cyclopropylmethoxy)-3,5-difluorophenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)carbamate and azetidine, and in the same manner as in Example 59, the title compound was obtained.
Reaction SMILES: FC(F)(C(F)(F)[C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])CCCCCCOC1(C)C=CC(S([O-])(=O)=O)=CC1.[F:32][C:33]1[C:38]([F:39])=[C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45](F)(F)[C:46](F)(F)[C:47]([F:53])([F:52])[C:48]([F:51])([F:50])F)[CH:36]=[CH:35][C:34]=1[I:58]>>[F:32][C:33]1[C:38]([F:39])=[C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([F:52])([F:53])[C:48]([F:50])([F:51])[C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[CH:36]=[CH:35][C:34]=1[I:58]
Reactant: Fc1c(I)ccc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c1F
Reactant: CC1(OCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C=CC(S(=O)(=O)[O-])=CC1
Product: Fc1c(I)ccc(OCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c1F
Yield: 89 %

Procedure:
2,3-Difluoro-1-iodo-4-(7,7,8,8,9,9,10,10,10-nonafluoro-decyloxy)-benzene (10B) was prepared from 4-(7,7,8,8,9,9,10,10,10-nonafluoro-decyloxy)-tosylate (9B), prepared as described in [Sakaigawa], as described in the preparation of 2,3-difluoro-1-iodo-4-(5,5,6,6,7,7,8,8,8-nonafluoro-octyloxy)-benzene (10A) yielding 2,3-difluoro-1-iodo-4-(7,7,8,8,9,9,10,10,10-nonafluoro-decyloxy)-benzene (10B) as a colorless oil (89%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([O:12]CC1C=CC=CC=1)=[O:11]>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: O=C(CNc1ccccc1F)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(O)CNc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To a suspension of 10% Pd/C (200 mg) in reagent grade methanol (25 mL) which was degassed was added a solution of benzyl 2-((2-fluorophenyl)amino)acetate from Example 48 (2.0 g, 7.71 mmol) in methanol (10+5 mL). The solution was degassed, a balloon of hydrogen gas was added, and then the reaction mixture was stirred for 8 h at rt. The reaction mixture was filtered though celite and then concentrated to yield 1.27 g (97%) of the title compound as a white solid: mp 125.7°-126.6° C. (lit. 122°-123° C. (Walls, L. P. South African patent application 664864; Walls, L. P. GB 1,153,884); 1H NMR (CDCl3) δ7.06-6.99 (m, 2H), 6.77-6.70 (m, 1H), 6.33 (dt, J=8.8, J=1.2, 1H), 4.04 (s, 2H); 13C NMR (CDCl3) δ175.79, 151.71 (d, J=239); 135.01, 124.65 (d, J=3.5), 118.38 (d, J=6.4), 114.85 (d, J=18.4), 112.45, 45.30; MS (EI, m/z) 169 (M+). HRMS (EI) calcd for C8H8NO2F 169.0539, found 169.0538.
Reaction SMILES: N([C@H:4]([CH2:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:11]=1[F:18])[CH2:5][C:6](O)=[O:7])=[N+]=[N-].N1C=CN=N1>>[F:18][C:11]1[CH:12]=[C:13]([F:17])[C:14]([F:16])=[CH:15][C:10]=1[CH2:9][CH2:4][CH2:5][CH:6]=[O:7]
Reactant: [N-]=[N+]=N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: c1c[nH]nn1
Product: O=CCCCc1cc(F)c(F)cc1F

Procedure:
In step (iv), (3R)-3-azido-4-(2,4,5-trifluorophenyl)-butyric acid of formula (IV) obtained in step (iii) is subjected to a condensation reaction with a triazol derivative of formula (VI) to obtain (3R)-3-azido-1-(3-trifluoromethyl)-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-4-(2,4,5-trifluorophenyl)-butan-1-one of formula (V).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:15])[CH:13]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][CH:17]1[CH2:22][CH:21]([CH3:23])[CH2:20][NH:19][CH2:18]1.O.Cl>C1(C)C=CC=CC=1.C(O)=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:15])[CH2:13][N:19]2[CH2:20][CH:21]([CH3:23])[CH2:22][CH:17]([CH3:16])[CH2:18]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1CNCC(C)C1
Reactant: CC(C=O)Cc1ccc(C(C)(C)C)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O=CO
Solvent: O
Product: CC(Cc1ccc(C(C)(C)C)cc1)CN1CC(C)CC(C)C1
Temperature: 80 °C

Procedure:
67.8 g of 3-(p-tert.butyl-phenyl)-2-methyl-propionaldehyde and 50 g of 3,5-dimethyl-piperidine are heated at reflux in 50 ml of toluene in a water-separator under nitrogen gasification until the water-cleavage has been completed (16 hours). Subsequently, there are added dropwise at room temperature while stirring 16.8 g of formic acid, the temperature rising to 36°-40° C. The mixture is then heated to 80° C. for 1 hour. 165 ml of 2-N hydrochloric acid are added to the cooled solution, the toluene solution is separated, the aqueous-hydrochloric acid solution is made alkaline with 66 ml of 6-N sodium hydroxide and the product is extracted with ether. The combined ether extracts are washed with water, dried over sodium sulphate and evaporated. By distillation there is obtained pure 1-[3-(p-tert.butyl-phenyl)-2-methyl-propyl]-3,5-dimethyl-piperidine of boiling point 113°-114° C./0.09 Torr.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][C:19]3=[O:25])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:26][C:27]1[CH:35]=[C:34]([C:36]#[C:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)[C:30]2[O:31][CH2:32][O:33][C:29]=2[C:28]=1[NH2:44].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[Cl:26][C:27]1[CH:35]=[C:34]([C:36]#[C:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)[C:30]2[O:31][CH2:32][O:33][C:29]=2[C:28]=1[NH:44][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][C:19]3=[O:25])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Nc1c(Cl)cc(C#Cc2ccccn2)c2c1OCO2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(Cl)cc(C#Cc4ccccn4)c4c3OCO4)ncnc2cc1OCCCN1CCN(C)CC1=O
Yield: 81.4 %

Procedure:
This was prepared by the method described in example 4 but using 1-{3-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]propyl}-4-methylpiperazin-2-one (137 mg, 0.37 mmol), 5-chloro-7-(pyridin-2-ylethynyl)-1,3-benzodioxol-4-amine (113 mg, 0.41 mmol) and sodium bis(trimethylsilyl)amide (1.0M in THF, 0.8 ml) in DMF (2 ml). The crude product was purified by column chromatography on silica using 10% methanol in dichloromethane as eluent. There was thus obtained the title compound (181 mg, 80%) as a pale yellow solid; NMR Spectrum:(DMSOd6) 2.21 (quintet, 2H), 2.31 (s, 3H), 2.63 (t, 2H), 3.09 (s, 2H), 3.38 (t, 2H), 3.61 (t, 2H), 3.97 (s, 3H), 4.20 (t, 2H), 6.08 (s, 2H), 7.18 (d, 2H), 7.25 (m, 3H), 7.54 (d, 1H), 7.70 (t, 1H), 8.62 (m, 2H); Mass Spectrum: M+H+ 601/603.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+:15]([CH:18](C(OCC)=O)[C:19]([O:21][CH2:22]C)=[O:20])([O-])=[O:16].F[P-](F)(F)(F)(F)F.C([N+]1C=CN(C)C=1)CCC>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:7]1([C:6]2[O:16][N:15]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:5]=2[CH2:4][CH2:3][C:2]([F:13])([F:14])[F:1])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: FC(F)(F)CCC#Cc1ccccc1
Reactant: CCOC(=O)C(C(=O)OCC)[N+](=O)[O-]
Agent: CCCC[n+]1ccn(C)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1noc(-c2ccccc2)c1CCC(F)(F)F
Yield: 22.1 %

Procedure:
A solution of (5,5,5-trifluoropent-1-ynyl)benzene (215 mg, 1.09 mmol), diethyl nitromalonate (0.758 mL, 4.34 mmol), and 1-butyl-3-methylimidazolium hexafluorophosphate (0.023 mL, 0.108 mmol) in toluene (3 mL) was heated to 170° C. for 150 minutes. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (10 mL), washed with brine (10 mL), and dried over anhydrous sodium sulfate. Concentration followed by purification by silica gel chromatography with hexanes/ethyl acetate (9/1) provided methyl 5-phenyl-4-(3,3,3-trifluoropropyl)isoxazole-3-carboxylate (72 mg). The compound had an HPLC ret. time=3.61 min.−Column. YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH−90% Water−0.2% H3PO4; Solvent B=90% MeOH−10% water−0.2% H3PO4; Start % B=0; Final % B=100.
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6]([O:8]C)=[O:7])[CH2:3][CH2:2]1.Cl.NO.C([N:16](CC)CC)C>CO>[CH:1]1([C:4]2[NH:16][O:8][C:6](=[O:7])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)CC(=O)C1CC1
Reactant: CCN(CC)CC
Agent: Cl
Agent: NO
Solvent: CO
Product: O=c1cc(C2CC2)[nH]o1

Procedure:
A solution of methyl 3-cyclopropyl-3-oxopropionate (4.8 g, 34 mmol) in methanol (80 mL) is mixed with hydroxylamine hydrochloride (2.6 g, 38 mmol) and triethylamine (5.3 mL, 38 mmol), and the mixture is heated under reflux for 2 h. The solvent is distilled out in vacuo. The residue is taken up in EtOAc and filtered through silica gel.
Reaction SMILES: C([C:3]1[CH:24]=[CH:23][C:6]([CH2:7][S:8][C:9]2[CH:10]=[C:11]([O:19][CH2:20][O:21][CH3:22])[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=2)=[CH:5][CH:4]=1)C.ClCC1C=C[C:30]([O:33]C)=CC=1>>[CH3:30][O:33][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[CH:10]=[C:11]([O:19][CH2:20][O:21][CH3:22])[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=2)=[CH:23][CH:24]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCc1ccc(CSc2cc(OCOC)c(=O)n(COC)c2)cc1
Product: COCOc1cc(SCc2ccc(OC)cc2)cn(COC)c1=O

Procedure:
Prepared as described for 5-[(4-ethylbenzyl)sulfanyl]-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (Intermediate 17) but using 1-(chloromethyl)-4-methoxybenzene instead of 1-(chloromethyl)-4-ethylbenzene.