Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: SCC(C(CS)O)O.[CH3:9][O:10][CH2:11][CH2:12][C:13]([NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([S:25][C:26]#[N:27])[CH:22]=[CH:21][C:19]=2[N:20]=1)=[O:14].ClC1N2[N:34]=[C:35]([O:38][CH2:39][CH3:40])[CH:36]=[CH:37][C:32]2=[N:31][N:30]=1>O.C(O)C.O1CCCC1.P([O-])(O)(O)=O.[K+]>[CH2:39]([O:38][C:35]1[CH:36]=[CH:37][C:32]2[N:27]([C:26]([S:25][C:23]3[CH:22]=[CH:21][C:19]4[N:20]=[C:16]([NH:15][C:13](=[O:14])[CH2:12][CH2:11][O:10][CH3:9])[S:17][C:18]=4[CH:24]=3)=[N:30][N:31]=2)[N:34]=1)[CH3:40]
Reactant: COCCC(=O)Nc1nc2ccc(SC#N)cc2s1
Reactant: CCOc1ccc2nnc(Cl)n2n1
Agent: O=P([O-])(O)O
Agent: OC(CS)C(O)CS
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1ccc2nnc(Sc3ccc4nc(NC(=O)CCOC)sc4c3)n2n1
Temperature: 80 °C
Yield: 41.2 %

Procedure:
7 mg of potassium dihydrogen phosphate in 0.2 cm3 of water and 699 mg of DL-dithiothreitol are added to a degassed solution of 443 mg of 2-[(3-methoxypropanoyl)amino]-1,3-benzothiazol-6-yl thiocyanate in 10 cm3 of ethanol and 10 cm3 of tetrahydrofuran. The reaction is heated at 80° C. for 15 min and then 301 mg of 3-chloro-6-ethoxy[1,2,4]triazolo[4,3-b]pyridazine are added and the reaction is heated for a further 24 h. The reaction medium is then evaporated to dryness under reduced pressure. The residue is taken up in 20 cm3 of ethanol and 57 mg of sodium borohydride are added and the mixture is then brought to reflux for 18 h. The reaction medium is concentrated under reduced pressure. The residue is chromatographed by solid deposit on Biotage Quad 12/25 (KP-SIL, 60 A; 32-63 μm), elution being carried out with a gradient of 100% dichloromethane to 97/3 dichloromethane/methanol. 268 mg of N-{6-[(6-ethoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulphanyl]-1,3-benzothiazol-2-yl}-3-methoxypropanamide are thus obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: P(F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:24][C:25]1[N:30]=[CH:29][C:28]([C:31]2[CH:32]=[N:33][N:34]([CH:36]([CH3:40])[C:37]([OH:39])=O)[CH:35]=2)=[CH:27][C:26]=1[O:41][CH:42]([C:44]1[C:49]([Cl:50])=[CH:48][CH:47]=[C:46]([F:51])[C:45]=1[Cl:52])[CH3:43].C(N(CC)CC)C.[CH3:60][N:61]([CH3:66])[CH2:62][CH2:63][CH2:64][NH2:65]>CN(C=O)C>[NH2:24][C:25]1[N:30]=[CH:29][C:28]([C:31]2[CH:32]=[N:33][N:34]([CH:36]([CH3:40])[C:37]([NH:65][CH2:64][CH2:63][CH2:62][N:61]([CH3:66])[CH3:60])=[O:39])[CH:35]=2)=[CH:27][C:26]=1[O:41][CH:42]([C:44]1[C:49]([Cl:50])=[CH:48][CH:47]=[C:46]([F:51])[C:45]=1[Cl:52])[CH3:43]
Reactant: CN(C)CCCN
Reactant: CC(Oc1cc(-c2cnn(C(C)C(=O)O)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: FP(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(Oc1cc(-c2cnn(C(C)C(=O)NCCCN(C)C)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reaction time: 3 h

Procedure:
O-(7-azabenzotriazol-1-yl)-N,N, N′,N′-tetramethyluronium phosphorus pentafluoride (HATU) (66 mg, 0.17 mmol) was added to a solution of 2-(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-propionic acid (69 mg, 0.16 mmol), triethylamine (0.024 mL, 0.17 mmol) and 3-dimethylamino-propylamine (0.022 mL, 0.17 mmol) in 1.6 mL of DMF. After stirring for 3 hours, the reaction was concentrated by rotary evaporation. The residue was purified by silica gel chromatography using gradient elution of dichloromethane, methanol, ammonium hydroxide to afford 2-(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-N-(3-dimethylamino-propyl)-propionamide. (41 mg, 50%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11](=[O:12])[C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:7]=1
Reactant: O=c1ncc(Br)c[nH]1
Reactant: O=C(CBr)c1ccsc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Cn1cc(Br)cnc1=O)c1ccsc1
Temperature: 25 °C
Yield: 39.7 %

Procedure:
A mixture of 5-bromopyrimidin-2-one (700 mg) and 3-bromoacetylthiophene (1.025 g) in triethylamine (0.84 ml) and ethanol (25 ml) was stirred at room temperature. After 1 h. the mixture was cooled to 3° C. and the precipitate collected. The dried solid was crystallised from ethanol to give the title pyrimidinone (475 mg), m.p. 180°-182° C. (dec), λmax (EtOH) 250.5 nm (ε 14,930), 334.5 nm (ε 3,260).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH:16]([C:18](=[O:37])[C@H:19]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH2:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCOC(C)=O>CN1C(=O)CCC1>[NH2:1][C:2]1[C:3]([C:13]([NH:17][NH:16][C:18](=[O:37])[C@H:19]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:15])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: NNC(=O)[C@H](NC(=O)OCc1ccccc1)c1ccccc1
Reactant: Nc1cc(C(F)(F)F)c(Br)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Nc1cc(C(F)(F)F)c(Br)nc1C(=O)NNC(=O)[C@H](NC(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A suspension of 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid (Int. A) (200 mg, 0.702 mmol) in NMP (6 ml) was treated with (R)-benzyl 2-hydrazinyl-2-oxo-1-phenylethylcarbamate (Int. JR) (231 mg, 0.772 mg) followed by portionwise addition of HATU (293 mg, 0.772 mmol). After stirring at RT for 45 minutes, the reaction mixture was added to EtOAc (50 ml) and washed with 0.1 M NaOH (50 ml). The aqueous layer was back extracted with EtOAc (25 ml). The combined organic portions were washed with water (75 ml), brine (50 ml), dried (MgSO4) and concentrated in vacuo. The crude product was loaded in MeOH onto a pre-wetted (MeOH) Isolute® PE-AX (anion exchange) cartridge. The cartridge was eluted with MeOH (70 ml) and the filtrate was concentrated in vacuo to give a yellow solid which was placed under high vacuum to give the title compound as a yellow solid;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=O)[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.O.[NH2:14][NH2:15]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][CH:12]=1)[C:6](=[O:7])[NH:15][NH:14][C:9]2=[O:8]
Reactant: NN
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH][nH]c(=O)c2cc(Cl)ccc12
Yield: 92.6 %

Procedure:
A mixture of 4-chlorophthalic anhydride (1.81 g, 10 mmol) and acetic acid (15 mL) was added to a solution of hydrazine hydrate (0.62 mL, 10 mmol) in acetic acid (2 mL). The resulting mixture was stirred at reflux for 2 h. The precipitate was collected and dried to give the title compound as a white solid (1.82 g, 95%).
Reaction SMILES: [F:1][C:2]([C:5]1[S:9][C:8]([C:10]([O:12]CC)=[O:11])=[CH:7][CH:6]=1)([F:4])[CH3:3].[OH-].[Na+]>CO>[F:1][C:2]([C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][CH:6]=1)([F:4])[CH3:3]
Reactant: CCOC(=O)c1ccc(C(C)(F)F)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(F)(F)c1ccc(C(=O)O)s1

Procedure:
To a methanol solution (1.0 mL) of ethyl 5-(1,1-difluoroethyl)thiophene-2-carboxylate (28.6 mg, 0.130 mmol) synthesized in Reference Synthesis Example 123, 1 M sodium hydroxide aqueous solution (312 μL, 0.312 mmol) was added and the resultant mixture was stirred at room temperature for 1 day. After completion of the reaction, the reaction solution was concentrated under reduced pressure and separated with toluene-water. To the water phase, 12 M hydrochloric acid was added until pH reached 2 and extraction from the resultant mixture with ethyl acetate was performed. The organic layer was concentrated under reduced pressure to obtain a crude product of the title compound. The crude product was used in the next step as it was.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH2:4][CH2:3]2.[C:49]1([CH:55]([CH3:59])[C:56]([OH:58])=O)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][N:43]1[CH2:44][CH2:45][N:46]([C:56](=[O:58])[CH:55]([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[CH3:59])[CH2:47][CH2:48]1)[CH2:4][CH2:3]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCNCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(C(=O)O)c1ccccc1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)C(C)c4ccccc4)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound (4.1 mg) was prepared from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the general procedure as described above using 2-phenylpropionic acid as the acylating agent. LCMS: m/e 774.9 (M+H)+, 3.87 min (method 14). 1H NMR (500 MHz, METHANOL-d4) δ 7.89 (d, J=7.0 Hz, 2H), 7.41-7.31 (m, 2H), 7.29-7.22 (m, 3H), 7.18 (dd, J=8.2, 3.1 Hz, 2H), 5.30 (d, J=4.9 Hz, 1H), 4.77 (s, 1H), 4.67 (s, 1H), 4.11 (quin, J=6.4 Hz, 1H), 3.89-3.44 (m, 4H), 2.99-2.92 (m, 1H), 2.86-2.67 (m, 3H), 2.67-2.57 (m, 1H), 2.51 (d, J=13.7 Hz, 2H), 2.46-2.27 (m, 2H), 2.21-2.09 (m, 2H), 2.07-1.85 (m, 4H), 1.80-1.15 (m, 16H), 1.74 (s, 3H), 1.40 (d, J=6.7 Hz, 3H), 1.09 (d, J=8.5 Hz, 3H), 1.07 (d, J=13 Hz, 3H), 1.04 (s, 3H), 1.01 (s, 3H), 0.98 (s, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[Li]CCCC.[C:13]([Si:15]([CH3:18])([CH3:17])[CH3:16])#[CH:14]>C1COCC1>[CH3:16][Si:15]([C:13]#[C:14][C:3]1([OH:7])[CH2:4][CH2:5][CH2:6][O:1][CH2:2]1)([CH3:18])[CH3:17]
Reactant: C#C[Si](C)(C)C
Reactant: O=C1CCCOC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CC1(O)CCCOC1
Reaction time: 3 h
Yield: 50.4 %

Procedure:
A solution of dihydro-2H-pyran-3(4H)-one (200 mg, 2 mmol) in THF was treated with n-BuLi (2 mL) at −78° C. for about 30 min. Ethynyltrimethylsilane (300 mg, 3 mmol) was then added and the reaction mixture was stirred for 3 hr. Purification by gel chromatography afforded the title compound (200 mg, 50%); 1H NMR (400 MHz, DMSO) delta 0.15 (s, 9H), 1.52-1.55 (m, 1H), 1.62-1.67 (m, 1H), 1.80-1.88 (m, 1H), 3.23-3.26 (m, 1H), 3.37-3.44 (m, 1H), 3.49-3.56 (m, 2H), 5.52 (s, 1H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:21]#[N:22])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(=O)([O-])O.[K+].O>ClCCl>[C:21]([C:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:12][CH2:13][N:8]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:9][CH2:10]1)#[N:22]
Reactant: Cc1ccccc1C1(C#N)CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)N1CCC(C#N)(c2ccccc2C)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
1-Benzyl-4-cyano-4-(2-methylphenyl)piperidine (406 mg) was dissolved in dichloromethane (8 ml), added with ethyl chloroformate (0.16 ml) and potassium hydrogencarbonate (168 mg) and stirred at room temperature for 24 hours. The reaction mixture was added with water (10 ml) and extracted twice with dichloromethane (10 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=5:1→4:1) to obtain 381 mg of the title compound. Yield: 100%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:11]([O:13][CH:14]=[CH:15][C:16](Cl)=[O:17])[CH3:12]>C(OCC)C>[C:5]([C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][CH:8]=1)[NH:1][C:16](=[O:17])[CH:15]=[CH:14][O:13][CH2:11][CH3:12])([OH:7])=[O:6]
Reactant: CCOC=CC(=O)Cl
Reactant: Nc1cccc(C(=O)O)c1
Solvent: CCOCC
Product: CCOC=CC(=O)Nc1cccc(C(=O)O)c1
Temperature: 40 °C

Procedure:
100 Grams of m-aminobenzoic acid was suspended in 1 liter of diethyl ether, and at a room temperature with stirring 44.6 g of β-ethoxyacrylic chloride was added dropwise. Then the reaction mixture was heated at 40° C. for 5 hours. After the reaction was completed, the precipitated matter was collected by filtration and washed with water three times, and dried, and recrystallized from methanol to obtain 60 g of m-carboxy-N-(β-ethoxyacryloyl)aniline.
Reaction SMILES: [NH2:1][C:2]1[C:10]([I:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.N([O-])=O.[Na+].[N-:18]=[N+:19]=[N-].[Na+]>FC(F)(F)C(O)=O.O>[N:1]([C:2]1[C:10]([I:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1)=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(N)c(I)cc1C(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N=[N+]=[N-])c(I)cc1C(=O)O
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
To a solution of 4-amino-5-iodo-2-methoxybenzoic acid (300 mg, 1.02 mmol) in trifluoroacetic acid (4 ml) at 5° C., was added sodium nitrite (283 mg, 4.1 mmol) portionwise, and the mixture allowed to stir for 30 min. Sodium azide (200 mg, 3.07 mmol) was then added portionwise and the mixture stirred for a further 30 min at 0° C. The mixture was diluted with water, and a yellow solid precipithated. The solid was filtered, washed with cold water and dried, to afford the title compound (274 mg, 84%).
Reaction SMILES: [Li].N.[CH2:3]([OH:6])[C:4]#[CH:5].[CH2:7](Br)[CH2:8][CH2:9][CH2:10][CH3:11]>O.CCOCC>[CH2:3]([OH:6])[C:4]#[C:5][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCBr
Reactant: C#CCO
Agent: N
Agent: [Li]
Solvent: CCOCC
Solvent: O
Product: CCCCCC#CCO
Reaction time: 8 h
Yield: 57.5 %

Procedure:
Under argon atmosphere, a small amount of lithium pieces was added to liquid ammonia (250 ml). The reaction mixture became dark blue in color. A catalytic amount of ferric nitrate nonahydrate was added and the mixture was stirred until the dark blue color disappeared. Lithium pieces (2.75 g, 396 mmol) were further added and the reaction mixture was stirred for one hour. Subsequently, propargyl alcohol (8.16 g, 146 mmol) was added and the mixture was stirred for 30 minutes. Then, n-pentyl bromide (20 g, 132 mmol) was added, and the mixture was stirred for 10 minutes and allowed to stand overnight at room temperature. Water-containing ether (50 ml) and water (200 ml) were added and the resulting mixture was extracted with ether (200 ml, 100 ml, 50 ml×3). The organic layers were combined, washed with water (400 ml) and with brine (400 ml), dried over anhydrous sodium sulfate (50 g) to concentrate. The residue was distilled (b.p.=58°-61° C. at 0.3 mmHg), yielding a colorless oil, 2-octyne-1-ol (9.5758 g, 52% yield). The above described structure of this product was confirmed by the following data.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.[CH3:35][S:36]([C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1)(=[O:38])=[O:37]>>[CH3:35][S:36]([C:39]1[CH:44]=[CH:43][C:42]([C:27]2[CH:26]=[C:25]([C:28]([F:30])([F:31])[F:29])[CH:24]=[CH:23][C:22]=2[O:21][C:16]2[CH:15]=[C:14]([CH:19]=[C:18]([CH3:20])[CH:17]=2)[O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:34])=[O:3])=[C:8]([CH3:33])[CH:9]=2)=[CH:41][CH:40]=1)(=[O:38])=[O:37]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2ccc(C(F)(F)F)cc2-c2ccc(S(C)(=O)=O)cc2)c1

Procedure:
The title compound is prepared by reacting the compound of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester with 4-(methylsulfonyl)phenyl boronic acid as in Example 38 to afford 0.062 g (48%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C31H27O6SF3 584, found 585 (M+1, 100%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:8]([CH:26]=1)[C:9]([NH:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=1)=[O:10])(=[O:3])[CH3:2].[Br-:35].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.O>O1CCCC1>[CH2:28]([O:27][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH2:2][Br:35])=[CH:26][C:8]=1[C:9]([NH:11][C:12]1[CH:17]=[C:16]([C:18]([F:20])([F:19])[F:21])[CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=1)=[O:10])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(CBr)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.7 %

Procedure:
5-Acetyl-2-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide (compound of Example 58(3); 4.81 g, 10 mmol) was dissolved in tetrahydrofuran (30 ml). Phenyltrimethylammonium tribromide (3.75 g, 10 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with aqueous sodium hydrogen sulfite, water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=4:1), and recrystallized (ethyl acetate/n-hexane) to give the title compound (2.39 g, 42.7%) as a white solid.
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([N:10]([CH3:22])[C:11]([C:13]2[CH:21]=[CH:20][C:16]3=[N:17][O:18][N:19]=[C:15]3[CH:14]=2)=[O:12])[CH2:6][CH2:5]1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N>N1C=CC=CC=1>[NH2:1][C@H:4]1[CH2:9][CH2:8][C@H:7]([N:10]([CH3:22])[C:11]([C:13]2[CH:21]=[CH:20][C:16]3=[N:17][O:18][N:19]=[C:15]3[CH:14]=2)=[O:12])[CH2:6][CH2:5]1
Reactant: CN(C(=O)c1ccc2nonc2c1)[C@H]1CC[C@H](N=[N+]=[N-])CC1
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: CN(C(=O)c1ccc2nonc2c1)[C@H]1CC[C@H](N)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(trans-4-Azidocyclohexyl)-N-methyl-[2,1,3]-benzoxadiazole-5-carboxamide (0.18 g, 0.6 mmol) was dissolved in pyridine (4 ml), Ph3P (0.26 g, 1.0 mmol) was added, and the mixture stirred for 1 hour at room temperature. Conc. ammonia solution (6 ml) was slowly added and the mixture stirred for 2 h at 20° C. before evaporating under vacuum and purifying the crude product on silica gel, eluting with chloroform/methanol/triethylamine (90:10:1), to give a white solid after trituration with diethyl ether (0.067 g). Mp=145-146° C., 1H NMR (300 MHz, DMSO+CDCl3, rotamers) δ 7.93 (d, J=8.7 Hz, 1H); 7.82 (s, 1H); 7.41 (d, J=8.7 Hz, 1H); 4.60-4.50 and 3.55-3.35 and 2.80-2.55 (m, 2H); 3.00 and 2.88 (s+s, 3H); 2.10-0.90 ppm (s, 8H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:18][C@H:17]2[C@H:13]([N:14]=[C:15]([N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[S:16]2)[C@@H:12]([F:28])[C@@H:11]1[OH:29])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(Cl)Cl.CCOCC>[Si:1]([O:8][CH2:9][C@H:10]1[O:18][C@H:17]2[C@H:13]([N:14]=[C:15]([N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[S:16]2)[C@@H:12]([F:28])[C:11]1=[O:29])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](F)[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Solvent: ClCCl
Solvent: CCOCC
Product: CN(C(=O)OC(C)(C)C)C1=N[C@H]2[C@H](O[C@H](CO[Si](C)(C)C(C)(C)C)C(=O)[C@@H]2F)S1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of tert-butyl ((3aR,5R,6R,7R,7aR)-5-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-6-hydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (9.28 g, 20.6 mmol) in DCM (150 mL) was added DMP (13.1 g, 30.9 mmol). After stirring at room temperature for 1 h the reaction was diluted with Et2O (400 mL). The resulting suspension was filtered through Celite cake, and the filtrate was concentrated to dryness at room temperature. The residue was loaded onto a layered NaHCO3/silica gel plug, and the product was eluted with (EtOAc/hexanes, 1:4), affording tert-butyl ((3aR,5R,7R,7aR)-5-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-6-oxo-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a white crystalline solid (8.96 g, 97%). 1H NMR (400 MHz, CDCl3) δ 6.29 (d, J=7.0 Hz, 1H), 5.09 (dd, J=4.7, 48.4 Hz, 1H), 4.75-4.69 (m, 1H), 4.12-4.05 (m, 2H), 3.96-3.93 (m, 1H), 3.28 (s, 3H), 1.54 (s, 9H), 0.86 (s, 9H), 0.056 (s, 3H), 0.050 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7][CH2:6]2.[H][H]>[C].[Pd].CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7][CH2:6]2
Reactant: CCOC(=O)C=C1CCc2cc(OC)ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC1CCc2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed ethyl 2-(5-methoxy-2,3-dihydro-1H-inden-1-ylidene)acetate (500 mg, 2.15 mmol, 1.00 equiv), methanol (3 mL), Palladium carbon (500 mg). To the mixture hydrogen was introduced in. The resulting solution was stirred overnight at room temperature. The solids were filtered out. The mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (15:85). This resulted in 300 mg (59%) of ethyl 2-(5-methoxy-2,3-dihydro-1H-inden-1-yl)acetate as colorless oil.
Reaction SMILES: [CH:1]1([C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=2)[CH2:8]O)[CH2:4][CH2:3][CH2:2]1.P(Br)(Br)[Br:14]>C(Cl)Cl>[CH:1]1([C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=2)[CH2:8][Br:14])[CH2:4][CH2:3][CH2:2]1
Reactant: BrP(Br)Br
Reactant: OCc1cccc(C2CCC2)c1
Solvent: ClCCl
Product: BrCc1cccc(C2CCC2)c1
Yield: 89 %

Procedure:
According to example 17, 1.29 g of 3-cyclobutylbenzyl alcohol was treated with 0.26 mL of PBr3 in 15 mL of anhydrous CH2Cl2 to afford 1.69 g of crude product (92% pure by 1H-NMR). This material was purified by flash chromatography on 65 g of silica gel (hexane) to afford 1.59 g (89%) of 3-cyclobutyl benzyl bromide as a clear liquid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[O:8][C@@H:7]1[C:9]([OH:11])=O)=[O:5])[CH3:2].[NH2:12][C@@H:13]([CH:22]([CH3:25])[CH2:23][CH3:24])[C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[OH:15]>>[OH:15][C@@H:14]([C@@H:13]([NH:12][C:9]([C@H:7]1[O:8][C@@H:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:11])[CH:22]([CH3:25])[CH2:23][CH3:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)O
Reactant: CCC(C)[C@H](N)[C@H](O)c1ccccc1
Product: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](C(C)CC)[C@H](O)c1ccccc1

Procedure:
The procedures of Example 1a were repeated employing (2S,3S)-3-ethoxycarbonyloxirane-2-carboxlic acid and (1R,2S)-2-amino-3-methyl-1-phenyl-1-pentanol (its preparation is described in the after-mentioned Reference Example 1), to prepare the titled compound.