Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Cl)[N:3]=1.[CH3:10][O:11][C:12](=[O:24])[CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21](=[S:23])[NH2:22])[CH2:17][CH2:16]1.[CH3:25]OC(OC)N(C)C.C(N(CC)CC)C>C(O)C>[CH3:10][O:11][C:12](=[O:24])[CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[S:23][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[N:3]=3)=[CH:25][N:22]=2)[CH2:17][CH2:16]1
Reactant: ClCc1cccc(Br)n1
Reactant: COC(=O)CCC1CCN(C(N)=S)CC1
Reactant: COC(OC)N(C)C
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)CCC1CCN(c2ncc(-c3cccc(Br)n3)s2)CC1
Temperature: 25 °C
Yield: 164.2 %

Procedure:
To an solution of 2-bromo-6-chloromethylpyridine (1.88 g, 1.11 mmol) obtained in Step 1 of Example 1 in ethanol (20 ml), 3-(1-thiocarbamoylpiperidin-4-yl)propionic acid methyl ester (2.10 g, 9.12 mmol) obtained in Step 1 was added and the mixture was heated at reflux overnight. The reaction solution was cooled to room temperature, dimethylformamide dimethylacetal (1.8 ml, 14 mmol) and triethylamine (3.8 ml, 27 mmol) were added, and heated at reflux for 1 hour. After the reaction solution was concentrated, water was added, and it was extracted with ethyl acetate and washed with a saturated brine. The organic layer was dried over magnesium sulfate and the residue obtained by vacuum concentration was purified by chromatography on silica gel (n-hexane:ethyl acetate=50:50 to 0:100) and the title compound (748 mg, 20%) was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.ClCCCOC1C=C(C2C3SC=CC=3ON=2)C=CC=1.[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.C(=O)([O-])[O-].[K+].[K+]>>[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[N:46]1[CH2:51][CH2:50][N:49]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:12]3[C:16]4[S:17][CH:18]=[CH:19][C:15]=4[O:14][N:13]=3)[CH:9]=[CH:10][CH:11]=2)[CH2:48][CH2:47]1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Reactant: Fc1ccccc1N1CCNCC1
Agent: ClCCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccccc1N1CCN(CCCOc2cccc(-c3noc4ccsc34)c2)CC1
Yield: 100 %

Procedure:
The title compound is prepared from a mixture of 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 3-[3-(3-chloro-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 1-(2-fluorophenyl) piperazine and potassium carbonate essentially as described above in example 4 except that the column is eluted with a mixture of dichloromethane:methanol (98:2). Combine the appropriate fractions and concentrate to give the title compound (0.45 g, 100% Yield) as a solid. Purity by LC/MS (APCI)=100% area, [M+H]+=438 m/e.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(NC([N:17]1[CH2:22][CH2:21][CH:20]([N:23]2[N:32]=[C:31]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH3:41])=[C:35]([O:42][CH2:43][CH3:44])[CH:34]=3)[C@@H:30]3[C@@H:25]([CH2:26][CH:27]=[CH:28][CH2:29]3)[C:24]2=[O:45])[CH2:19][CH2:18]1)=O)(C)(C)C>>[C:1]1([NH:7][C:8]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[N:32]=[C:31]([C:33]4[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH3:41])=[C:35]([O:42][CH2:43][CH3:44])[CH:34]=4)[C@@H:30]4[C@@H:25]([CH2:26][CH:27]=[CH:28][CH2:29]4)[C:24]3=[O:45])[CH2:19][CH2:18]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCOc1ccc(C2=NN(C3CCN(C(=O)NC(C)(C)C)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC
Product: CCOc1ccc(C2=NN(C3CCN(C(=O)Nc4ccccc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC

Procedure:
Prepared from starting compound A1 and phenylisocyanate as described for compound 6. Crystallisation from ether. M. p. 109-112° C.
Reaction SMILES: [C:1]1([CH:7]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:9]([O:13][C:14]([NH:16][C@H:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1>[C:1]1([CH2:7][N:19]2[CH2:20][CH2:21][C@H:17]([NH:16][C:14](=[O:15])[O:13][C:9]([CH3:11])([CH3:10])[CH3:12])[CH2:18]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: O=CC1=CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(CC2=CCCCC2)C1
Reaction time: 0.25 h
Yield: 42.9 %

Procedure:
1-Cyclohexene-1-carboxaldehyde (1.48 ml, 13 mmol) was added to a mixture of (3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (2.0 g, 10.8 mmol), acetic acid (1.24 ml, 21.6 mmol) and tetrahydrofuran (dehydrated) (27 ml), followed by stirring at mom temperature for 15 minutes, and sodium triacetoxyborohydride (4.58 g, 21.6 mmol) was then added and the reaction mixture was stirred at mom temperature for 17 hours and 45 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was distilled off. The residue was purified by NH silica gel column chromatography (elution solvent: ethyl acetate/heptane) to give the title compound (1.3 g, yield: 42.9%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:18][C@H:19]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[CH3:20]>CS(C)=O.CCOC(C)=O>[OH:27][C:24]1[CH:25]=[CH:26][C:21]([C@@H:19]([NH:18][C:2]2[N:7]=[C:6]([N:8]3[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]3=[O:16])[CH:5]=[CH:4][N:3]=2)[CH3:20])=[CH:22][CH:23]=1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Reactant: C[C@H](N)c1ccc(O)cc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(O)cc2)n1
Yield: 5.2 %

Procedure:
A solution of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (42 mg, 0.17 mmol), (S)-4-(1-aminoethyl)phenol hydrochloride (107 mg, 0.616 mmol, 3.5 equiv) and iPr2Net (0.121 mL, 0.695 mmol, 4.0 equiv) in DMSO (1 mL) was heated at 110° C. for 3 h and at 130° C. for additional 2 h. The reaction mixture was diluted with EtOAc (8 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3×8 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 10 to 80%) provided (S)-3-(2-((S)-1-(4-hydroxyphenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one (3 mg) in 5% yield. 1H NMR (400 MHz, CD3OD) δ 8.11 (d, J=5.8 Hz, 1H), 7.33 (d, J=5.8 Hz, 1H), 7.12 (d, J 8.1 Hz, 2H), 6.72-6.68 (m, 2H), 4.95 (q, J=6.9 Hz, 1H), 4.69-4.65 (m, 1H), 4.35-4.28 (m, 2H), 1.47 (d, J=7.1 Hz, 3H), 0.75 (br s, 3H), 0.62 (br s, 3H); HRMS(B) m/z 343.1776 (M+H)+.
Reaction SMILES: I[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C1([Mg]Br)C=CC=CC=1.C(OCC)C.[F:21][C:22]1[CH:29]=[C:28]([CH:30]=[O:31])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]>ClCCl>[F:21][C:22]1[CH:29]=[C:28]([CH:30]([OH:31])[C:2]2[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=2)[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: N#Cc1ccc(C=O)cc1F
Reactant: Cn1cncc1I
Agent: Br[Mg]c1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: Cn1cncc1C(O)c1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-iodo-1-methyl-1H-imidazole (250 mg, 1.2 mmol) in dichloromethane (2 mL) at 0° C. was treated with 3M phenylmagnesium bromide in diethyl ether (0.4 mL, 1.2 mmol), stirred for 30 minutes, warmed to room temperature, stirred for 30 minutes, cooled to 0° C. and treated with a solution of Example 52C (150 mg, 1.0 mmol) in dichloromethane (1 mL). The mixture was warmed to room temperature, stirred for 2 days, and quenched with ethyl acetate and saturated ammonium chloride. The aqueous phase was extracted with ethyl acetate (2×100 mL), and the combined organic layers were dried (MgSO4), filtered, and concentrated. The concentrate was dissolved in 1:1 ethyl acetate/diethyl ether, filtered, rinsed with 1:1 ethyl acetate/diethyl ether and dried to provide the desired product. 1H NMR (400 MHz, CD3OD) δ 7.91 (dd, 1H), 7.56 (s, 1H), 7.51 (d, 1H), 7.42-7.38 (m, 1H), 6.42 (s, 1H), 6.28-6.24 (m, 1H), 5.93-5.91 (m, 1H), 3.52 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])[CH2:11][CH2:10]1.C(N(CC)CC)C.[O:30]1C[CH2:33][CH2:32][CH2:31]1.C(Cl)(=O)C=C>CCOCC>[C:31]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])[CH2:13][CH2:14]1)(=[O:30])[CH:32]=[CH2:33]
Reactant: OCCCCCCC[C@H]1CC[C@H](c2cccc(F)c2F)CC1
Reactant: C1CCOC1
Agent: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CC(=O)OCCCCCCC[C@H]1CC[C@H](c2cccc(F)c2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
First, 3.5 g of 1-[trans-4-(7-hydroxyheptyl)cyclohexyl]-2,3-difluorobenzene, 1.3 g of triethylamine, and 45 ml of dry tetrahydrofuran were placed in a 100 ml flask. Then, 1.1 g of acryloyl chloride was added dropwise to the reaction mixture under ice water cooling. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. Ether was added to the reaction mixture. An ether layer was washed with water and dried over anhydrous sodium sulfate. A solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: benzene/hexane=3/7 to 4/6) and recrystallized from hexane to obtain 2.23 g of 1-[trans-4-(7-propenoyloxyheptyl)cyclohexyl]-2,3-difluorobenzene (Y: 54%). The compound thus obtained had a purity of 99.6% by GC, 99.5% by HPLC, and of 1 spot by TLC. Furthermore, the compound had an m.p. of 34.0° C. to 35.3° C.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][N:14]2[C:18]3[C:19]([N+:37]([O-])=O)=[C:20]([O:23][CH:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]4)[CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:40]([CH3:42])[CH3:41])=[CH:5][CH:4]=1)#[N:2].O.O.[Sn](Cl)Cl>N1C=CC=CC=1>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][N:14]2[C:18]3[C:19]([NH2:37])=[C:20]([O:23][CH:24]4[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:28][CH2:29]4)[CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:40]([CH3:42])[CH3:41])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)c1nc2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)c([N+](=O)[O-])c2n1Cc1ccc(C#N)c2ccccc12
Agent: Cl[Sn]Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)c1nc2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)c(N)c2n1Cc1ccc(C#N)c2ccccc12
Temperature: 50 °C
Yield: 66.9 %

Procedure:
1-(4-Cyanonaphth-1-yl)methyl-2-isopropyl-7-nitro-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)benzimidazole (12 g, 21 mmoL, 1 eq.) was dissolved in 400 mL dry pyridine and to this was added tin (II) chloride dihydrate (71 g, 315 mmoL, 15 eq.) which formed a finely divided suspension. The slurry was heated to 50° C. for 14 hours. The pyridine was stripped off, and the salts triturated in 1 L ethyl acetate. The salts were removed by filtration through Celite and the filtrate was concentrated to give a brown oil. Chromatography (3/2 ethyl acetate/hexanes) gave 7.6 g (67% yield) of 1-(4-cyanonaphth-1-yl)methyl-2-isopropyl-7-amino-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)benzimidazole as a tan foam.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH:12]=[C:13]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)[C:14]([F:17])([F:16])[F:15])=[CH:7][C:6]=1[CH3:27])[CH3:2].Cl.[CH3:30][NH:31][OH:32].C(N(CC)CC)C>C(O)C>[CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:31]([CH3:30])[O:32][C:13]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[CH:12]=2)=[CH:7][C:6]=1[CH3:27])[CH3:2]
Reactant: CNO
Reactant: CCOC(=O)c1ccc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1ccc(C2=CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)cc1C

Procedure:
0.62 g of 4-[3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoic acid ethyl ester (XVIIa) was mixed with 0.21 g of N-methylhydroxylamine hydrochloride and 0.42 ml of triethylamine in 10 ml of dry ethanol. The mixture was refluxed for 20 hours, evaporated to dryness and purified on silica gel giving 0.275 g (42%) of 4-[5-(3,5-Dichloro-phenyl)-2-methyl-5-trifluoromethyl-2,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid ethyl ester (VIIIa) as a colorless oil 1H-NMR (CDCl3, δ in ppm): 7.93 (d, 1H), 7.30-7.45 (m, 5H), 5.43 (s, 1H), 4.37 (q, 2H), 2.99 (s, 3H), 2.61 (s, 3H), 1.40 (t, 3H).
Reaction SMILES: [CH2:1]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:2][CH:3]([CH3:5])[CH3:4].[CH2:19]=O>C(O)=O>[CH2:1]([N:6]([CH3:19])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:2][CH:3]([CH3:4])[CH3:5]
Reactant: C=O
Reactant: CCCCCCCCCCCCNCCC(C)C
Solvent: O=CO
Product: CCCCCCCCCCCCN(C)CCC(C)C

Procedure:
To 30 g of N-isoamyldodecanamine in 100 ml of formic acid was added 30 ml of formalin (40% formaldehyde) and the reaction mixture was refluxed for 8 hours. Most of the solvent was removed under vacuum and the remaining material was made alkaline with 3 N sodium hydroxide solution and the amine extracted into hexane. The hexane phase was washed with water, and then dried over sodium hydroxide pellets. Removal of the hexane under vacuum gave 28 g of N-isoamyl-N-methyldodecanamine, ND20 1.4507.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:30][C:29]=1B(O)O>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:33]2[CH:32]=[C:31]([O:34][CH:35]([CH3:36])[CH3:37])[CH:30]=[CH:29][C:28]=2[F:27])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(F)c(B(O)O)c1
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(I)cc1)c1ccc(Cl)c(Cl)c1
Product: CC(C)Oc1ccc(F)c(-c2ccc(C(=O)C(NC(=O)OC(C)(C)C)c3ccc(Cl)c(Cl)c3)cc2)c1

Procedure:
The title compound was prepared from rac-[1-(3,4-dichloro-phenyl)-2-(4-iodo-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and 2-fluoro-5-isopropoxyphenylboronic acid in analogy to Example 2b): MS (ISP): 532.1 and 534.1 (M+H)+, 432.2 and 434.1 ((M-Boc)+H)+.
Reaction SMILES: [C:1]([CH:3]([OH:18])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[F:17])#[N:2].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=1)[CH2:23][OH:24].[F:35][C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:37]=1[NH:46][CH:47]([CH:51]([CH3:53])[CH3:52])[C:48](O)=[O:49]>>[F:35][C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:37]=1[NH:46][CH:47]([CH:51]([CH3:53])[CH3:52])[C:48]([O:18][CH:3]([C:1]#[N:2])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[F:17])=[O:49].[F:35][C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:37]=1[NH:46][CH:47]([CH:51]([CH3:53])[CH3:52])[C:48]([O:24][CH2:23][C:22]1[CH:25]=[C:26]([O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:27]=[C:20]([F:19])[CH:21]=1)=[O:49]
Reactant: N#CC(O)c1cc(Oc2ccccc2)ccc1F
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)cc1F)C(=O)O
Reactant: OCc1cc(F)cc(Oc2ccccc2)c1
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1F)C(=O)OC(C#N)c1cc(Oc2ccccc2)ccc1F
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1F)C(=O)OCc1cc(F)cc(Oc2ccccc2)c1

Procedure:
The alcohol, α-cyano-2-fluoro-5-phenoxybenzyl alcohol and 3-fluoro-5-phenoxybenzyl alcohol, is reacted with 2-(2-fluoro-4-trifluoromethylphenylamino)-3-methylbutanoic acid to yield α-cyano-2-fluoro-5-phenoxybenzyl 2-(2-fluoro-4-trifluoromethylphenylamino)3-methylbutanoate and 3-fluoro-5-phenoxybenzyl 2-(2-fluoro-4-trifluoromethylphenylamino)-3-methylbutanoate, respectively.
Reaction SMILES: I[CH2:2][CH3:3].C[O-].[Na+].[C:7]([O:11][C:12]([NH:14][C@@H:15]([CH2:19][OH:20])[C:16]([OH:18])=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8]>C1COCC1>[C:7]([O:11][C:12]([NH:14][C@@H:15]([CH2:19][O:20][CH2:2][CH3:3])[C:16]([OH:18])=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: CCI
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.8 %

Procedure:
To a suspension of sodium hydride (17.73 g, 702 mmol) in THF (600 mL) at 0° C. was added MeOH (18 mL) dropwise. The mixture was stirred at RT for 1 h to yield a sodium methanolate solution. Iodoethane (25.5 mL, 316 mmol) and a portion of the sodium methanolate solution (120 mL) were added to a solution of (S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (18 g, 88 mmol) in THF (600 mL). After stirring at RT for 1 h, the remaining sodium methanolate solution (480 mL) was added, followed by additional iodoethane (9.9 mL, 123 mmol). The mixture was stirred at RT overnight. The mixture was subsequently concentrated and the residue was dissolved in water. The aqueous layer was washed with ether (250 mL), acidified to pH 2 using 1N HCl, and extracted with EtOAc (3×300 mL). The combined organic layers were washed with 1M Na2S2O3 (300 mL), dried, and concentrated. The resulting crude material was reconstituted in MeOH, DCM and DMF (total volume: 50 mL) and purified via reverse phase preparative HPLC. The fractions were collected and the ACN was removed via rotary evaporation. The resulting aq solution was neutralized with saturated aq NaHCO3, washed with EtOAc (2×200 mL), dried over Na2SO4, filtered, and the organic phase stripped to dryness via rotary evaporation to yield the title compound as a clear oil (1.81 g, 9%). [M+H] calc'd for C10H19NO5, 234. found, 234.
Reaction SMILES: CO[C:3]1[CH:31]=CC(CS[C@@H]2CN(C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C@H](C(O)=O)C2)=C[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.FC(F)(F)C(O)=O.[N+](C1C=CC(COC(N=C(NC(OCC2C=CC([N+]([O-])=O)=CC=2)=O)NC[CH2:66][C:67]([NH:69][CH:70]2[CH2:73]N[CH2:71]2)=O)=O)=CC=1)([O-])=O>C(#N)C>[CH:3]([N:69]([CH2:67][CH3:66])[CH:70]([CH3:71])[CH3:73])([CH3:31])[CH3:4]
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: O=C(CCNC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC1CNC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S,4S)-4-(4-methoxybenzyl)thio-1-(4-nitrobenzyloxycarbonyl)-L-proline (909 mg) in anhydrous acetonitrile (13 ml), N,N-carbonyldiimidazole (346 mg) was added, followed by stirring at room temperature for 30 minutes. To the reaction mixture, N,N-diisopropylethylamine (338 μl) and a solution of the compound (1.68 g), which had been obtained in (2), in anhydrous acetonitrile (15 ml) were added and the mixture was stirred overnight at room temperature. Dichloromethane was added to the reaction mixture. The resulting mixture was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column (ethyl acetate-methanol), whereby 1.88 g of the title target compound were obtained as a colorless amorphous substance.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]([C:10]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:11]=3[O:12][C:13]3[C:18]([Cl:19])=[CH:17][C:16]([S:20]([NH:23][C:24]4[N:25]=[CH:26][S:27][CH:28]=4)(=[O:22])=[O:21])=[C:15]([F:29])[CH:14]=3)=[CH:8][CH:7]=[N:6]2)[CH2:2]1.CO.C=O.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:19][C:18]1[C:13]([O:12][C:11]2[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:10]=2[C:9]2[N:5]([CH:3]3[CH2:4][N:1]([CH3:39])[CH2:2]3)[N:6]=[CH:7][CH:8]=2)=[CH:14][C:15]([F:29])=[C:16]([S:20]([NH:23][C:24]2[N:25]=[CH:26][S:27][CH:28]=2)(=[O:21])=[O:22])[CH:17]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=S(=O)(Nc1cscn1)c1cc(Cl)c(Oc2ccc(F)cc2-c2ccnn2C2CNC2)cc1F
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CC(n2nccc2-c2cc(F)ccc2Oc2cc(F)c(S(=O)(=O)Nc3cscn3)cc2Cl)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-[2-(1-Azetidin-3-yl-1H-pyrazol-5-yl)-4-fluorophenoxy]-5-chloro-2-flouro-N-1,3-thiazol-4-ylbenzenesulfonamide (Example 808, 29 mg, 0.052 mmol) was stirred in dichloromethane (2 ml), methanol (0.2 ml), aqueous formaldehyde (0.015 ml of 37% wt/vol) added and the reaction stirred at room temperature for a further 30 minutes. Sodium triacetoxyborohydride (37 mg, 0.172 mmol) was added and the solution stirred for 3 hours. The solvents were removed in vacuo and the residue dissolved in ethyl acetate and extracted with saturated aqueous sodium hydrogencarbonate solution (2×10 ml) and brine (2×10 ml). The organic layer was separated, dried over sodium sulphate, filtered and evaporated to give a solid. The compound was purified using preparative HPLC to afford the title compound. Yield 15.9 mg 57%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:6][CH:5]=[CH:4][N:3]=1.[O-]CC.[Na+].[N:17](OCCC(C)C)=O.[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[OH:35]>C(O)C>[CH2:9]([O:8][C:7]1[C:2]([N:1]=[N:17][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][C:26]=2[OH:35])=[N:3][CH:4]=[CH:5][CH:6]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CC(C)CCON=O
Reactant: Oc1ccc2ccccc2c1
Reactant: CCCCOc1cccnc1N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCOc1cccnc1N=Nc1c(O)ccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Next, a reaction flask was loaded with the crystals of 2-amino-3-butoxypyridine (4.4 g), ethanol (25 ml), and sodium ethoxide (2.2 g), followed by dropwise addition of isopentyl nitrite (3.8 g) to the flask in 30 minutes with stirring. The resultant mixture was heated and stirred at 75 to 80° C. for four hours for reaction. The heating was stopped, and the reaction mixture was cooled to room temperature, followed by dropwise addition of 2-naphthol (2.6 g) dissolved in ethanol (10 ml) to the mixture in 10 minutes. The resultant mixture was stirred at room temperature for one hour, heated, and stirred at 75 to 80° C. for additional two hours, followed by stopping the heating and then leaving the mixture to stand overnight. The reaction mixture was condensed by an evaporator. The residue was dissolved in ethyl acetate and, after being successively washed with an aqueous solution of sodium hydroxide and water, the ethyl acetate layer was condensed by an evaporator, followed by addition of methanol to the residue for crystallization. The resultant was filtrated and the crystals were dried to give intended crystals (2.5 g).
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:7][O:6][CH:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:4]1[CH2:14][CH2:15][CH2:16][OH:17].[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1>CN(C)C=O>[Si:18]([O:17][CH2:16][CH2:15][CH2:14][CH:4]1[CH:3]([OH:2])[CH2:7][O:6][CH:5]1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: OCCCC1C(O)COC1c1cccnc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCC1C(O)COC1c1cccnc1

Procedure:
A solution of 10 g (0.0448 mole) of 4-hydroxy-3-(3-hydroxyprop-1-yl)-2-(3-pyridyl)tetrahydrofuran hydrochloride, 7.68 g (0.048 mole) of t-butyldimethylsilyl chloride and 6.86 g (0.0977 mole) of imidazole in 105.8 ml of dimethylformamide is stirred at room temperature for 15 h and evaporated. The residue is triturated with ethyl acetate and washed with water and brine, dried (MgSO4) and evaporated. The residue is purified by flash chromatography using methylene chloride-ethyl acetate-methanol (20:4:1) to give 3-(3-t-butyldimethylsilyloxyprop-1-yl)-4-hydroxy-2-(3-pyridyl)tetrahydrofuran as an oil.