Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][NH:6][C@@H:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:2].ClS([N:24]=[C:25]=[O:26])(=O)=O.O>ClCCl>[NH2:24][C:25]([N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:19])[C@@H:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])=[O:26]
Reactant: CCOC(=O)CN[C@H](C(=O)OC(C)(C)C)C(C)(C)C
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CN(C(N)=O)[C@H](C(=O)OC(C)(C)C)C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution containing the product from Example 46A (5.74 g, 20.0 mmol) in dichloromethane (40 mL) at 0° C. was treated with chlorosulfonyl isocyanate (2.26 mL, 26.0 mmol) and the mixture was stirred at 0° C. for 2 hours. Water (40 mL) was added to the cold reaction and the mixture was warmed to 25° C. and stirred for 2 hours. The reaction mixture was partitioned between dichloromethane and water, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound, which was used without further purification.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([N:13]1[C:17]2[N:18]=[C:19]([Cl:22])[N:20]=[CH:21][C:16]=2[C:15](I)=[CH:14]1)([CH3:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([CH:36]=1)[C:30](N(OC)C)=[O:31]>>[Br:24][C:25]1[CH:36]=[C:29]([C:30]([C:15]2[C:16]3[CH:21]=[N:20][C:19]([Cl:22])=[N:18][C:17]=3[N:13]([C:10]([CH3:12])([CH3:11])[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:14]=2)=[O:31])[CH:28]=[N:27][CH:26]=1
Reactant: CON(C)C(=O)c1cncc(Br)c1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(I)c2cnc(Cl)nc21
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(Br)c2)c2cnc(Cl)nc21

Procedure:
The title compound was prepared according to the method described for Preparation 28 using 7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-2-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (see Preparation 44) and 5-bromo-N-methoxy-N-methylnicotinamide to afford the title compound as a yellow solid in 42% yield, 1.40 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][C@H:7]([NH:15][C@@H](C3C=CC=CC=3)C)[CH2:6][C:5]2=1.CO.CC(O)=O>C1COCC1.[OH-].[OH-].[Pd+2]>[F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][C@H:7]([NH2:15])[CH2:6][C:5]2=1
Reactant: C[C@@H](N[C@H]1CCc2[nH]c3ccc(F)cc3c2C1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: N[C@H]1CCc2[nH]c3ccc(F)cc3c2C1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a degassed solution of (S)-6-fluoro-N—((R)-1-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (8.96 g, 0.029 mol) in a mixture of THF (60 ml), MeOH (20 ml) and AcOH (10 ml) was added 20% Pd(OH)2 (1.34 g). The mixture was evacuated three times and the reaction was set under 1 atm (balloon) H2. It was stirred at rt for 10 h and filtered over celite. The pad was rinsed with THF/MeOH and the filtrate was concentrated to 50 ml. The residue was dissolved in EA, and washed with 1N NaOH. The aqueous phase was extracted with EA and the combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]([CH:20]3[CH2:22][CH2:21]3)[C:16](=[O:19])[NH:17][N:18]=2)=[CH:10][CH:9]=1.Cl[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(#N)C>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][N:17]1[C:16](=[O:19])[N:15]([CH:20]2[CH2:22][CH2:21]2)[C:14]([C:11]2[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][CH:12]=2)=[N:18]1)[CH3:29]
Reactant: CCOC(=O)CCl
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Reaction time: 2 h

Procedure:
586 mg (4.24 mmol) of potassium carbonate are added to 500 mg (2.12 mmol) of 5-(4-chlorophenyl)-4-cyclopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one from Example 36A and 260 mg (2.12 mmol) of ethyl chloroacetate in 10 ml acetonitrile and the mixture is heated under reflux with stirring for 2 hours. It is then concentrated, the residue taken up in water is extracted with dichloromethane, the organic phase dried over sodium sulphate and again concentrated. After purification by flash chromatography over silica gel (eluent: first dichloromethane, then dichloromethane/methanol 100:1) 448 mg (66% of theory) of the target compound are obtained.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@H:16]([CH2:19][CH3:20])[CH2:17][OH:18].[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[CH2:21]([NH:15][C@H:16]([CH2:19][CH3:20])[CH2:17][OH:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC[C@@H](N)CO
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC[C@H](CO)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
Sodium triacetoxyborohydride (4.63 g) was added portionwisely to a mixture of (R)-(-)-2-amino-1-butanol (1.5 g) and benzaldehyde (1.79 g) in dichloromethane (50 ml) at 0° C. and the whole was stirred at room temperature overnight. The mixture was washed with sodium carbonate solution and brine, dried over sodium sulfate, and evaporated in vacuo to give (R)-2-benzylamino-1-butanol (2.69 g) [IR (Neat): 3292, 1460, 1350, 1136, 1061 cm−1]. A solution of chloroacetyl chloride (2.1 g) in tetrahydrofuran (4 ml) was added to a mixture of the obtained oil (2.69 g) and potassium carbonate (4.6 g) in a mixture of acetone (20 ml) and water (20 ml) at 0° C. After 1 hour of stirring, the solvent was replaced with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give N-benzyl-N-[(2R)-2-(1-hydroxybutyl)]-2-chloroacet amide (2.73 g) [IR (Neat): 3430, 1640, 1450, 1420, 1355, 1045 cm−1, MASS (APCI): 256 (M+H)+, 220] as an oil. Potassium tert-butoxide (1.22 g) was added to a solution of the above obtained oil (2.7 g) in tert-butanol (20 ml) portionwisely at room temperature and the whole was stirred overnight. The mixture was evaporated in vacuo, and ethyl acetate and water were added to the residue. The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated in vacuo to give (5R)-4-benzyl-5ethyl-3-morpholinone (2.33 g) as an oil.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([C:19]([O:21]CC)=O)=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH3:24]>CO>[C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([C:19]([NH2:24])=[O:21])=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCOC(=O)c1sc(CNC(=O)OC(C)(C)C)nc1C(F)(F)F
Reactant: N
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1nc(C(F)(F)F)c(C(N)=O)s1

Procedure:
Ethyl 2-(N-BOC-aminomethyl)-4-trifluoromethylthiazole-5-carboxylate [sic] (15 g, 42.33 mol) was dissolved in methanol. Ammonia was passed into the solution at room temperature until all of the ester had been converted into the carboxamide. The solvent was removed on a rotary evaporator and the crude product was purified by flash chromatography. Yield: 4.6 g (14.14 mmol, 33%).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10](=[O:23])[CH2:11][C@H:12]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:13][CH2:14]O)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:25].Br>C(OCC)C>[C:1]1([C@@H:7]([NH:9][C:10](=[O:23])[CH2:11][C@H:12]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:13][CH2:14][Br:25])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrP(Br)Br
Reactant: C[C@H](NC(=O)C[C@@H](CCO)c1ccc(F)cc1)c1ccccc1
Agent: Br
Solvent: CCOCC
Product: C[C@H](NC(=O)C[C@@H](CCBr)c1ccc(F)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 72 h
Yield: 72 %

Procedure:
To a solution of 4.5 g of alcohol 8 250 mL of dry ethyl ether in an ice bath was added dropwise of 1.7 mL of phosphorous tribromide. After stirring for 3 days in an ice bath, 0.5 mL of conc. hydrobromic acid was added to this mixture. The resulting solution was stirred continuously at room temperature overnight, and 100 mL of ice was added to quench the reaction. The white solid was collected, dissolved in ethyl acetate, washed with saturated sodium hydrocarbonate solution and saturated brine. The organic layer was filtered through a silica gel pad. After the solvent evaporated, the crude solid was recrystallized from ethyl acetate and hexanes to form 3.8 g of the title compound as a white solid (72% yield, >95% de): mp 156.5-157.5 ° C.; [α]25D=−38.2 (c 1.0, CH3OH); 1H NMR (200 MHz, CDCl3) δ 7.40-7.10 (m, 7 H), 6.99 (m, 2 H), 5.52 (br d, J=7.6 Hz, 1 H), 4.98 (m, 1 H), 3.35-3.20 (m, 2 H), 3.05 (m, 1 H), 2.51 (dd, J=6.3, 14.0 Hz, 1 H), 2.37 (dd, J=8.7, 14.0 Hz, 1 H), 2.25-2.05 (m, 2 H), 1.25 (d, J=6.9 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 169.7, 161.8, 142.8, 137.7, 129.1, 128.6, 127.4, 126.1, 115.7, 48.6, 44.0, 40.6, 38.7, 30.9, 21.3. Anal. Calcd for C19H21BrFNO: C, 60.33; H, 5.60; N, 3.70. Found: C, 60.57; H, 5.54; N, 3.82.
Reaction SMILES: [OH-].[Li+].[C:3]1([S:9]([NH:12][C:13]2[C:22]([C:23]([O:25]C)=[O:24])=[C:21]3[C:16]([C@H:17]4[CH2:29][CH2:28][O:27][C@H:18]4[CH2:19][O:20]3)=[CH:15][CH:14]=2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)=O>O1CCOCC1.O>[C:3]1([S:9]([NH:12][C:13]2[C:22]([C:23]([OH:25])=[O:24])=[C:21]3[C:16]([C@H:17]4[CH2:29][CH2:28][O:27][C@H:18]4[CH2:19][O:20]3)=[CH:15][CH:14]=2)(=[O:10])=[O:11])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2)ccc2c1OC[C@@H]1OCC[C@H]21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=CO
Solvent: O
Product: O=C(O)c1c(NS(=O)(=O)c2ccccc2)ccc2c1OC[C@@H]1OCC[C@H]21
Yield: 24.6 %

Procedure:
Lithium hydroxide (0.048 g) was added to a solution of methyl cis-(3aRS,9bRS)-7-(benzenesulfonylamino)-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylate (Intermediate 1, 0.08 g) in a mixture of dioxane (10 mL) and water (5 mL) and the resultant mixture was irradiated in the microwave at 110° C. with air cooling for 20 minutes. Further lithium hydroxide (0.2 g) was added and the mixture was irradiated in the microwave at 110° C. with air cooling for a total of 80 minutes. After cooling, the solution was acidified by addition of aqueous formic acid solution (10%) and the resultant mixture was extracted with ethyl acetate, dried (MgSO4) and filtered. The filtrate was evaporated to dryness. The residue was dissolved in a mixture of methanol (10 mL) and water (5 mL) and treated with lithium hydroxide (0.2 g) then irradiated in the microwave at 110° C. with air cooling for 40 minutes. After cooling, the solution was acidified by addition of formic acid (10%) and the resultant mixture was extracted with ethyl acetate, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by preparative HPLC (C18) eluting with a mixture of acetonitrile and water, containing 0.1% formic acid, with a gradient of 30-50% to give cis-(3aRS,9bRS)-7-(benzenesulfonylamino)-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid (0.019 g) as a white solid.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=CC(N=NC2C=CC(CO)=CC=2)=CC=1)([O:3][CH3:4])=O.[N-:23]=[N+:24]=[N-:25].[Na+].CN([CH:30]=[O:31])C>>[N:23]([CH2:12][CH2:7][O:6][CH2:5][CH2:1][O:3][CH2:4][CH2:30][OH:31])=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: CN(C)C=O
Reactant: COC(=O)COc1ccc(N=Nc2ccc(CO)cc2)cc1
Agent: [Na+]
Product: [N-]=[N+]=NCCOCCOCCO
Temperature: 80 °C
Reaction time: 48 h
Yield: 75 %

Procedure:
Compound 3 (10.0 g, 59.50 mmol) was dissolved in anhydrous DMF (200 mL), to which NaN3 (77.3 g, 119.00 mmol) was added and reaction mixture stirred at 80° C. or 48 hours. Solvents were removed under reduced pressure and residue dissolved in DCM (200 mL), washed with water (400 mL) and brine (100 mL) before being dried over Na2SO4. Solvent was evaporated under reduced pressures and residue purified by silica gel column chromatography using EA:hexane (6:4) to obtain 4 as a liquid (7.80 g, 75% yield). 1H-NMR (500 MHz, CDCl3): δ 2.34 (d, 1H, J=5.5 Hz, OH), 3.93 (t, 2H, J=6.0 Hz, Ha), 3.61 (t, 2H, J=4.5 Hz, Hb), 3.65-3.68 (m, 6H, Hc, He, Hf), 3.73 (q, 2H, J=5.5 Hz, Hd); 13C-NMR (125 MHz, CDCl3): δ 50.62 (Ca), 61.73 (Cf), 70.02 (Cb), 70.36 (Ce), 70.63 (Cc), 72.45 (Cd). EI-MS: [M+Na]+ C6H13N3NaO3 calcd 198.08, obsd 198.07
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#N)=[CH:15][C:14]=2[Cl:21])=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2].S(=O)(=O)(O)[OH:29].[CH2:33]([OH:35])[CH3:34]>>[C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:35][CH2:33][CH3:34])=[O:29])=[CH:15][C:14]=2[Cl:21])=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2]
Reactant: CCO
Reactant: CCCc1c(OCCCOc2ccc(C#N)cc2Cl)ccc(C(C)=O)c1O
Reactant: O=S(=O)(O)O
Product: CCCc1c(OCCCOc2ccc(C(=O)OCC)cc2Cl)ccc(C(C)=O)c1O
Temperature: 25 °C

Procedure:
A mixture of 1-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-3-(2-chloro-4-cyanophenoxy)propane (1.86 g), ethanol (30 ml) and concentrated sulfuric acid (10 ml) was refluxed for 6 hours and then cooled to room temperature. The crystals were collected by filtration and dissolved in chloroform, the solution was washed with a saturated aqeuous sodium hydrogen carbonate solution and then with dilute hydrochloric acid and dried (sodium sulfate). Then, the chloroform was distilled off, and the residue was recrystallized from ethanol. There was obtained ethyl 4-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)propoxy]-3-chlorobenzoate as colorless needles (1.1 g). Melting point 101°-102° C.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[CH:23]=[CH:22][C:10]([O:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[CH2:18][CH2:19][CH2:20][NH2:21])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH:26](N(C(C)C)CC)(C)C.[S:35](Cl)(Cl)(=[O:37])=[O:36]>ClCCl>[ClH:1].[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[CH:23]=[CH:22][C:10]([O:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[CH2:18][CH2:19][CH2:20][NH:21][S:35]([CH3:26])(=[O:37])=[O:36])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CCN(C(C)C)C(C)C
Reactant: NCCCN1CCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)NCCCN1CCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Product: Cl
Temperature: -10 °C
Yield: 14.4 %

Procedure:
3-{(S)-2-[4-(4-Chloro-phenoxy)-phenoxymethyl]-pyrrolidin-1-yl}-propylamine (50 mg, 0.139 mmol) and Diisopropylethyl amine (26.9 mg, 0.208 mmol) were taken into dichloromethane (2 ml). The reaction was cooled to −10° C. and the sulfonyl chloride (0.013 mL, 0.166 mmol) was added dropwise over 5 minutes. The reaction was left to slowly warm to room temperature for 24 h. The mixture was then partitioned between sodium bicarbonate (aq) and dichloromethane. The aqueous layer was washed with dichloromethane (3×). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to dryness. The crude compound was purified by flash silica chromatography (40:1 silica ratio, eluted with 2% methanol in dichloromethane, 5% methanol in dichloromethane, and 10% methanol in dichloromethane). The pure product was then taken into 4M HCl in dioxane and left to react at room temperature for 3 h. The mixture was concentrated to dryness under vacuum to yield the title product (5.2 mg, 0.01 mmol, 7.8%); LCMS; m/z 439 (m of free amine); 1H NMR (400 MHz, DMSO-d6) 1.80-1.88 (m, 1H), 1.92-1.97 (m, 3H), 2.02-2.10 (m, 1H), 2.20-2.27 (m, 1H), 3.03 (s, 3H), 3.05-3.14 (m, 2H), 3.15-3.32 (m, 2H), 3.45-3.51 (m, 2H), 3.64-3.72 (m, 1H), 4.205-4.33 (m, 2H), 6.93-6.95 (m, 2H), 7.07 (s, 4H), 7.39-7.41 (m, 2H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[Cl:24][CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27]>C(O)C>[ClH:3].[ClH:24].[Cl:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH2:25][C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:27])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Reactant: O=C(CCl)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(CN1CCN(Cc2ccc(Cl)cc2)CC1)c1ccccc1
Yield: 129.4 %

Procedure:
A mixture of N-(4-chlorobenzyl)piperazine dihydrochloride (5 g, 20 mmol), triethylamine (5.58 ml, 40 mmol) and 2-chloro-1-phenylethanone (4.08 g, 26 mmol) in 40 ml of anhydrous ethanol was refluxed for 8 hours, and then treated according to general preparation 2 to give 5.2 g of compound (IV-3), yield 59.51%, mp 256-258° C. M+ 328.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]#N)=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:4][N:3]=1.[OH:15]S(O)(=O)=O.N([O-])=O.[Na+].[OH2:24]>>[Cl:1][C:2]1[C:6]([C:7]([OH:15])=[O:24])=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:4][N:3]=1
Reactant: N#Cc1c(Cl)nsc1-c1ccccc1
Reactant: O
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Product: O=C(O)c1c(Cl)nsc1-c1ccccc1
Temperature: 135 °C
Reaction time: 3 h

Procedure:
Into a 50-mL round-bottom flask, was placed 3-chloro-5-phenyl-1,2-thiazole-4-carbonitrile (700 mg, 3.01 mmol, 1.00 equiv, 95%), con.H2SO4 (4 mL). The resulting solution was stirred for 3 hr at 135° C. in an oil bath. This was followed by the addition of a solution of NaNO2 (318 mg, 4.61 mmol, 1.45 equiv) in water (15 mL) dropwise with stirring at 0° C. The resulting solution was allowed to react, with stirring, for an additional 0.5 h while the temperature was maintained at 50° C. in an oil bath. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×50 mL of sodium hydroxide/H2O(10%). The resulting solution was extracted with 3×100 mL of ethyl acetate. The aqueous phase was adjusted to 3 with 2N HCl. The resulting solution was extracted with 3×100 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. This resulted in 500 mg (66%) of 3-chloro-5-phenyl-1,2-thiazole-4-carboxylic acid as a white solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]=[CH:13][C:12]2=[O:17])=[CH:7][CH:6]=1.[CH2:20]([N:27]([CH2:31][Si](C)(C)C)[CH2:28]OC)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:20]([N:27]1[CH2:31][CH:14]2[CH:13]([C:12](=[O:17])[N:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][C:2]([F:1])([F:18])[F:19])=[CH:6][CH:7]=3)[CH2:16][CH2:15]2)[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1C=CCCN1c1ccc(OCC(F)(F)F)cc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1C2CN(Cc3ccccc3)CC2CCN1c1ccc(OCC(F)(F)F)cc1
Temperature: 45 °C
Reaction time: 30 h
Yield: 309.1 %

Procedure:
A mixture of 1-[4-(2,2,2-Trifluoro-ethoxy)-phenyl]-5,6-dihydro-1H-pyridin-2-one (0.27 g, 0.1 mmol), N-benzyl(methoxy)-N-((trimethylsilyl)methyl)methanamine (0.71 g, 0.3 mmol) and TFA (0.114 g, 0.1 mmol) in 20 mL of DCM was stirred at 45° C. for 30 h. The mixture was evaporated to dryness and the residue was purified by silica-gel column chromatography (eluting with petroleum ether/ethyl acetate=1:1) to obtain the title compound as colorless oil (0.125 g, 31%). LC-MS: 405.2 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][CH3:12].C([Li])(C)(C)C.CN(C)[CH:20]=[O:21]>C1COCC1>[CH2:11]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([CH:20]=[O:21])[CH:3]=2)[NH:7][N:6]=1)[CH3:12]
Reactant: CCc1n[nH]c2ccc(Br)cc12
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCc1n[nH]c2ccc(C=O)cc12

Procedure:
A solution of 6.90 g (30.7 mmol) 5-bromo-3-ethyl-1H-indazole (Example 16A) in THF (300 ml) was cooled to −78° C. At this temperature, 63.1 ml (107 mmol) of tert-butyllithium solution (1.7 M in n-pentane) were slowly added. The mixture was stirred at −78° C. for 30 minutes before N,N-dimethylformamide (80.0 ml) was slowly added. The cooling bath was removed, and stirring was continued until room temperature was reached. Then, water (250 ml) was added carefully. The mixture was extracted several times with ethyl acetate (500 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure to yield 4.5 g (84% of th.) of the crude title compound which was used in the next step without further purification.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1[O:12][C:11]([Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:10][C:9]=1[CH:20]=[O:21]>O1CCCC1>[CH3:7][C:8]1[O:12][C:11]([Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:10][C:9]=1[CH2:20][OH:21]
Reactant: CC[Si](CC)(CC)c1cc(C=O)c(C)o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1cc(CO)c(C)o1
Temperature: 25 °C

Procedure:
LiAlH4 (1.0M solution in hexane, 0.51 ml, 0.51 mmol) was added dropwise to a solution of 5-methyl-2-triethylsilyl-4-furaldehyde (230 mg, 1.03 mmol) in tetrahydrofuran (15 ml) at 0 degrees under argon. The stirring solution was allowed to warm to room temperature gradually over 1/2 hour. The reaction was quenched with 10% aqueous HCl and the organics were extracted into ethyl ether. The combined fractins were washed with H2O and brine. Evaporation of the dried (magnesium sulfate) extracts gave an oil which was purified by filtration through silica using 10% ethyl ether/hexanes to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][N:25]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18](OCC)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.[BH4-].[Li+].O>O1CCCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][N:25]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][CH2:18][OH:19])[CH2:15][N:16]=1)=[CH:8]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cn4)cc(OC)c3[nH]2)S1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C3=NCC(CCO)S3)[nH]c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.6 %

Procedure:
Ethyl [2-(7-methoxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetate (270 mg) was dissolved in a mixture of tetrahydrofuran (3 mL) and methanol (1.5 mL). Lithium borohydride (62 mg) was added to the mixture at 0° C. and the mixture was stirred at room temperature for 4 h. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80 to 100/0, volume ratio), followed by basic silica gel column chromatography (methanol/ethyl acetate/hexane=0/20/80 to 10/90/0) to give the title compound (110 mg, 43%) as a white amorphous solid. MS 448 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[OH:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].C(N(CC)CC)C.CN(C)C=O>O>[C:6]([O:5][C:3]([CH2:2][O:10][N:11]1[C:12](=[O:21])[C:13]2=[CH:20][CH:19]=[CH:18][CH:17]=[C:14]2[C:15]1=[O:16])=[O:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CON1C(=O)c2ccccc2C1=O
Reaction time: 4 h
Yield: 72.1 %

Procedure:
t-Butyl chloroacetate (13.0g, prepared according to Org. Synth., Coll.Vol. 4, 263) was added dropwise to a stirred mixture of N-hydroxyphthalimide (14.2g), triethylamine (23.0g), and dimethylformamide (30ml), and the resulting mixture was stirred for 4 hr. The mixture was poured into water (500 ml), and the precipitated solid was collected, washed with water, and dried. Recrystallisation from ethanol gave N-t-butoxycarbonylmethoxyphthalimide (17.26g. 72%); m.p. 145.6°; τ values (DMSO-d6) 2.09 (4 Ar--H), 5.28 (CH2), 8.56 (But).