Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]([NH:14][C:15]([C:17]1[CH:21]=[C:20]([C:22]2[CH:27]=[C:26](Br)[C:25]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:24][C:23]=2[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:19][N:18]=1)=[O:16])[CH3:13].C(=O)([O-])O.[Na+].CN(C=O)C>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C.O>[CH2:12]([NH:14][C:15]([C:17]1[CH:21]=[C:20]([C:22]2[CH:27]=[C:26]([CH:8]=[CH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:25]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:24][C:23]=2[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:19][N:18]=1)=[O:16])[CH3:13]
Reactant: CCNC(=O)c1cc(-c2cc(Br)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Reactant: OB(O)/C=C/c1ccccc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)c1cc(-c2cc(C=Cc3ccccc3)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Temperature: 80 °C
Yield: 70.8 %

Procedure:
To a mixture of trans-2-phenylvinylboronic acid (0.472 g, 3.2 mmol) and 5-(2,4-Bis-benzyloxy-5-bromophenyl)-isoxazole-3-carboxylic acid ethylamide (1.079 g, 2.13 mmol) was added sodium hydrogen carbonate (536 mg, 6.39 mmol) followed by DMF (25 mL) and water (5 mL). The mixture was degassed by evacuation and flushing with nitrogen (three times), followed by bubbling nitrogen gas through mixture for five minutes. Dichlorobis(triphenylphosphine)palladium (II) (149 mg, 0.21 mmol) was added and reaction mixture was heated under a nitrogen atmosphere at 80° C. for seven hours (reaction mixture becomes dark brown in colour after 10 minutes). The reaction mixture was allowed to cool to ambient temperature and the majority of solvents were removed in vacuo. The resulting residue was partitioned between ethyl acetate (100 mL) and water (100 mL) and this mixture was filtered through a pad of celite to remove Palladium residues. The phases were separated and the organic phase was washed with water (2×50 mL), saturated aqueous sodium chloride solution (100 mL) then dried over sodium sulphate. The mixture was filtered and the filtrate solvents were removed in vacuo to afford a brown solid (800 mg). The celite filter cake was washed with dichloromethane then dried over sodium sulphate. The mixture was filtered and the filtrate solvents were removed in vacuo to afford a brown solid (541 mg). The combined product batches were purified by trituration with ethyl acetate-hexane mixture. This affords 5-(2,4-Bis-benzyloxy-5-styrylphenyl)-isoxazole-3-carboxylic acid ethylamide as a light brown solid (808 mg, 71%). LCMS: [M+H]+ 531. 1H NMR (400 MHz, CDCl3) δ 1.12 (t, 3H), 3.37 (m, 2H), 4.95 (s, 2H), 5.07 (s, 2H), 6.46 (s, 1H), 6.70 (brt, 1H). 7.11 (s, 1H), 7.17 (d, 1H), 7.23 (d, 1H), 7.32-7.44 (m, 15H), 8.09 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1.[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3S[N:25]=2)[CH2:20][CH2:19]1.C(=O)([O-])[O-:34].[K+].[K+].Cl.CCO>C(O)C.CC(C)=O>[ClH:1].[O:34]1[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:24]([CH:21]2[CH2:22][CH2:23][N:18]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]3[CH:16]=[C:15]4[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]4)=[CH:9][CH:8]=3)[CH2:19][CH2:20]2)=[N:25]1
Reactant: O=C([O-])[O-]
Reactant: O=C1CCc2ccc(OCCCCCl)cc2N1
Reactant: c1ccc2c(C3CCNCC3)nsc2c1
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCO
Product: O=C1CCc2ccc(OCCCCN3CCC(c4noc5ccccc45)CC3)cc2N1
Yield: 43.9 %

Procedure:
7-(4-chlorobutoxy)-3,4-dihydro-2(1H)-quinolinone (297 mg, 1 mmol), 3-(4-piperidinyl)-1,2-benzisothiazole (220 mg, 1 mmol), and anhydrous potassium carbonate powder (414 mg, 3.3 mmol) are added to 10 ml and react at reflux for 24 hours. The reaction solution is evaporated to dryness and dispersed with 20 ml of dichloromethane and 20 ml of water respectively. The organic layer is extracted with water (20 ml×2) and saturated saline (20 ml) successively, dried over anhydrous magnesium sulfate, and evaporated to dryness to obtain a light yellow powder, which is dissolved into 5 ml of acetone and stirred in an ice bath to precipitate a white solid. The white solid is filtered, washed with small amount of acetone, and dried to obtain 260 mg of a whiter powder. The whiter powder is dissolved into anhydrous ethanol and thereto is drop-added HCl/EtOH to adjust to pH=2 to precipitate a white deposit, which is filtered out and recrystallized in anhydrous ethanol to obtain 200 mg of a product, with a yield of 44%.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=[CH:6][C:3]=1[CH2:4][OH:5].[C:23](=O)([O-])[O-:24].[K+].[K+].C(Cl)(Cl)=O>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[C:17]1([S:15]([CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:2]3[NH:1][C:23](=[O:24])[O:5][CH2:4][C:3]=3[CH:6]=2)=[O:16])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ccc(OCCCCS(=O)c2ccccc2)cc1CO
Reactant: O=C([O-])[O-]
Agent: O=C(Cl)Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C1Nc2ccc(OCCCCS(=O)c3ccccc3)cc2CO1

Procedure:
An amount of 4.2 gm (0.0133 mol) of 2-amino-5-(4-phenylsulfinylbutoxy)-benzyl alcohol [prepared from 2-nitro-5-(4-phenylsulfinyl-butoxy)-benzyl alcohol by catalytic hydrogenation] is dissolved in 150 ml of chloroform and mixed with 6.9 gm (0.05 mol) of potassium carbonate. Ten milliliters of a 20% solution of phosgene in toluene is slowly added dropwise to this mixture under stirring. After further stirring for two hours, the solution is washed with water and dried with sodium sulfate, and the solvents are distilled off in vacuo. The residue is recrystallized from ethyl acetate/cyclohexane.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:14][C:13]([C:23](O)=[O:24])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O1CCCC1.CO>C(OCC)(=O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]2[N:11]([C:8]3[CH:7]=[CH:6][C:5]([S:2]([NH2:1])(=[O:4])=[O:3])=[CH:10][CH:9]=3)[N:12]=[C:13]([CH2:23][OH:24])[CH:14]=2)=[CH:21][CH:20]=1
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(=O)O)cc2-c2ccc(Cl)cc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: NS(=O)(=O)c1ccc(-n2nc(CO)cc2-c2ccc(Cl)cc2)cc1
Yield: 71.5 %

Procedure:
4-[4-(Aminosulfonyl)phenyl-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid from Step 3 (3.8 g, 10 mmol) and tetrahydrofuran (100 mL) was stirred at room temperature during the dropwise addition of 1.0 M borane-tetrahydrofuran complex (30 mL, 30 mmol). The mixture was heated to reflux for 16 hours. The solution was cooled and methanol was added dropwise until gas evolution ceased. Ethyl acetate (100 mL) was added and the solution was washed with 1N hydrochloric acid, brine, and sat. aq. sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The resultant material was recrystallized from ethanol:water to yield 4-(5-(4-chlorophenyl)-3-hydroxymethyl-1H-pyrazol-1-yl]benzenesulfonamide (2.6 g, 71%) as a white solid: mp 192-194° C.; 1H NMR (DMSO-d6/300 MHz) δ7.81 (d, J=8.7 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 7.42 (brs, 2H), 7.40 (d, J=8.7 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 6.63 (s, 1H), 5.35 (t, J=8.0 Hz, 1H), 4.50 (d, J=8.0 Hz, 2H). Anal. Calc'd for C16H14N3SO2Cl: C, 52.82; H, 3.88; N, 11.55. Found: C, 52.91; H, 3.88; N, 11.50.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])(=O)[CH3:2].Cl.[F:20][C:21]([F:36])([F:35])[C:22]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:23]=1[CH2:24][O:25][NH2:26].CC([O-])=O.[Na+].CC(O)=O>CO.O>[F:20][C:21]([F:35])([F:36])[C:22]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][C:23]=1[CH2:24][O:25][N:26]=[C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])[CH3:2]
Reactant: CC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: NOCc1cc(C(F)(F)F)ccc1C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CC(=NOCc1cc(C(F)(F)F)ccc1C(F)(F)F)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Yield: 18.6 %

Procedure:
A solution of N-(2-acetyl-4-chlorophenyl)trifluoromethanesulfonamide 19 (300 mg, 0.99 mmol), O-(2,5-bistrifluoromethylbenzyl)hydroxylamine hydrochloride (296 mg, 1.0 mmol) and anhydrous NaOAc (53 mg, 0.65 mmol) in MeOH (5 mL) and H2O (15 mL) was adjusted to pH 4.5 with AcOH and heated for 15 h at reflux. The reaction mixture was concentrated under vacuum and the residue filtered through a pad of silica (eluting with CH2Cl2). Purification by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:19 to 1:9) afforded N-{2-[1-(2,5-bistrifluoromethylbenzyloxyimino)ethyl]-4-chlorophenyl}trifluoromethanesulfonamide 120 (100 mg, 19%), as a pale yellow solid. M.p. 73-75° C. 1H n.m.r. (200 MHz, CDCl3) δ 10.94, brs, 1H; 7.88-7.71, m, 3H; 7.60, d, J=8.8 Hz, 1H; 7.50, d, J=2.4 Hz, 1H; 7.33, dd, J=2.4 and 8.8 Hz, 1H; 5.46, s, 2H; 2.41, s, 3H.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8](OC)=[CH:7][C:3]=1[C:4]([NH2:6])=[NH:5].[C:13](OC)(=[O:19])[CH2:14][C:15](OC)=[O:16]>CS(C)=O>[C:3]1([C:4]2[N:5]=[C:15]([OH:16])[CH:14]=[C:13]([OH:19])[N:6]=2)[CH:2]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)CC(=O)OC
Reactant: COc1ccc(F)c(C(=N)N)c1
Solvent: CS(C)=O
Product: Oc1cc(O)nc(-c2ccccc2)n1
Reaction time: 24 h

Procedure:
A mixture of 2-Fluoro-5-methoxybenzamidine (10.3 g) and dimethyl malonate (8.09 g) in dry dimethyl sulfoxide (7 mL) was allowed to stand at room temperature for 24 h. The precipitated product was collected and washed with water and ether to afford 2-Phenyl-4.6-dihydroxy-pyrimidine as a white solid.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:28])[C:25]([CH3:27])=[CH2:26].C(N(CC)CC)C.[N-]=C=S>CN(C)C=O>[C:1]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:28])[C:25]([CH3:27])=[CH2:26])=[O:15])=[CH:16][CH:17]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)C(=O)NCCCN
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Agent: Cl
Agent: [N-]=C=S
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)NCCCNC(=O)c1ccc(C(=O)c2ccccc2)cc1
Reaction time: 8 h

Procedure:
N-[3-[(4-benzoylphenyl)formamido]propyl]methacrylamide (BPMA, C21H22O3N2, 350.4 g mol−1) monomer was synthesized via reaction of the succinimidyl ester of 4-benzoylbenzoic acid (BP-NHS, 323.3 g mol−1; 81577, Invitrogen) with N-(3-aminopropyl)methacrylamide hydrochloride (APMA, 178.7 g mol−1; 21200, Polysciences, Warrington, Pa.) in the presence of catalytic triethylamine (TEA) in dimethylformamide (DMF). A mixture of the reactants and TEA at 50 mM each in DMF was incubated overnight (18 hrs) at room temperature, centrifuged at 18,000 g for 5 minutes and the pellet discarded. The supernatant was incubated on a tube inverter for 24 hrs with 30 mg isothiocyanate-functionalized (primary amine-reactive) polystyrene beads (538604, Sigma) for every 100 μmol of APMA initially added to the reaction. The mixture was then spun at 18,000 g for 5 minutes and the supernatant passed through a 0.2 μm syringe filter. A 10-fold excess of acetone was added to the filtrate and the mixture dried in vacuo. The BPMA product (white powder) was verified by 1H NMR (400 MHz, d6-DMSO, δ 8.79 (t, 1H), 8.04 (t, 1H), 8.02 (d, 2H), 7.80 (d, 2H), 7.75 (d, 2H), 7.70 (t, 1H), 7.58 (t, 2H), 5.67 (s, 1H), 5.32 (s, 1H), 3.31 (q, 2H), 3.18 (q, 2H), 1.86 (s, 3H), 1.71 (quin, 2H)) and mass spectrometry (ESI, m/z 351.2, C21H22O3N2+H+). 100 mM stocks of BPMA in DMSO were stored at −20° C. until use, and were stable for at least 12 months.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:7]([CH3:8])[C:6]([CH2:9]Cl)=[N:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18]1[N:23]=[C:22]([SH:24])[N:21]=[C:20]([OH:25])[CH:19]=1>CC(C)=O>[Cl:2][C:3]1[N:7]([CH3:8])[C:6]([CH2:9][S:24][C:22]2[N:21]=[C:20]([OH:25])[CH:19]=[C:18]([CH3:17])[N:23]=2)=[N:5][CH:4]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Cn1c(Cl)cnc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(O)nc(SCc2ncc(Cl)n2C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
5-chloro-2-(chloromethyl)-1-methyl-1H-imidazole hydrochloride (1.0 g, 5.0 mmol), potassium carbonate (1.65 g, 12 mmol), and 6-methyl-2-sulfanylpyrimidin-4-ol (560 mg, 4.0 mmol) were mixed in acetone (20 mL). The mixture was stirred at room temperature overnight. Acetone was then removed under reduced pressure. The crude solid was purified by column chromatography to provide the title compound as a white solid (850 mg, 79% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.20 (s, 3H), 3.60 (s, 3H), 4.51 (s, 2H), 6.04 (br, 1H), 6.93 (s, 1H); M+271.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH3:11]O>>[O:1]([CH3:11])[CH:2]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: CO
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Product: COC1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
reacting D-ribose with an acidic solution of methanol to form 1-methyl D-ribofuranoside;
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[CH3:9][C:10]1[CH:11]=[CH:12][C:13]2[NH:18][N:17]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[S:15](=[O:24])(=[O:23])[C:14]=2[CH:25]=1.C(Cl)Cl>CN(C=O)C>[CH3:1][N:18]1[C:13]2[CH:12]=[CH:11][C:10]([CH3:9])=[CH:25][C:14]=2[S:15](=[O:23])(=[O:24])[C:16]([C:19]([O:21][CH3:22])=[O:20])=[N:17]1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C1=NNc2ccc(C)cc2S1(=O)=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C1=NN(C)c2ccc(C)cc2S1(=O)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.5 %

Procedure:
Potassium carbonate (2.25 g) and iodomethane (0.60 g) is added to a solution of methyl 6-methyl-1H-4,1,2-benzothiadiazine-3-carboxylate 4,4-dioxide (Preparation 39, 0.83 g) in DMF (20 mL). The mixture is stirred at room temperature for 5 hours and then added to CH2Cl2 (120 mL) and washed with water (4×100 mL). The organic layer is dried with Na2SO4, filtered and the solvent evaporated. The crude solid is recrystallized (1% CH2Cl2/MeOH) to obtain 0.74 g (85%) of the title compound as a yellow crystalline solid. Physical characteristics: MS (ESI+) m/z 269 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].Cl[CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[S:29][C:30]=1[CH3:31].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[S:29][C:30]=3[CH3:31])=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: Cc1sc(-c2ccccc2)nc1CCl
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nn(Cc2ccc(OCc3nc(-c4ccccc4)sc3C)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (1.20 g), 4-chloromethyl-5-methyl-2-phenylthiazole (0.95 g), potassium carbonate (1.06 g), and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). A mixture of the obtained oily substance, 1 N aqueous sodium hydroxide solution (10 ml), tetrahydrofuran (10 ml), and ethanol (10 ml) was stirred at room temperature for two hours, diluted with 1 N hydrochloric acid (10 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[3-ethoxy-1-[4-(5-methyl-2-phenyl-4-thiazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (1.46 g, yield: 81%) was obtained. This was recrystallized from ethyl acetate-hexane. Melting point: 73–74%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[OH:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([C:13]([C:15]3[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=3)=[O:14])=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: OC(c1ccncc1)c1cnc(-c2ccc(F)cc2)s1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1ccncc1)c1cnc(-c2ccc(F)cc2)s1
Reaction time: 1 h
Yield: 0.1 %

Procedure:
To a stirred solution of (2-(4-fluorophenyl)thiazol-5-yl)(pyridin-4-yl)methanol (0.55 g, 1.92 mol) in DCM (20 mL) was added Dess-Martin periodinane (1.6 g, 3.84 mol) at room temperature. The resulting solution was stirred for 1 h. To the reaction mixture was added NaHCO3 solution (20 mL) and ethyl acetate (50 mL). The organic layer was extracted with ethyl acetate (2×20 mL), washed with brine solution (2×20 mL), dried over anhydrous sodium sulfate and the solvent removed via distillation under reduced pressure. The crude was purified through silica gel (100-200 mesh) column chromatography using 10% methanol in DCM) to obtain (2-(4-fluorophenyl)thiazol-5-yl)(pyridin-4-yl)methanone as off-white solid (0.4 g, 67% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.86 (d, 2H), 8.51 (s, 1H), 8.19 (dd, 2H), 7.82 (d, 2H), 7.45 (t, 2H); LC-MS m/z calculated for [M+H]+ 285.04 found 284.98.
Reaction SMILES: F[C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C@H:8]2[CH2:24][N:12]3[CH2:13][CH2:14][N:15]([C:17]4[CH:22]=[CH:21][C:20](N)=[CH:19][CH:18]=4)[CH2:16][C@@H:11]3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N(OCCC(C)C)=O>C1COCC1>[O:6]([CH2:7][C@H:8]1[CH2:24][N:12]2[CH2:13][CH2:14][N:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:16][C@@H:11]2[CH2:10][CH2:9]1)[C:5]1[CH:25]=[CH:26][CH:2]=[CH:3][CH:4]=1
Reactant: Nc1ccc(N2CCN3C[C@H](COc4ccc(F)cc4)CC[C@H]3C2)cc1
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: c1ccc(OC[C@@H]2CC[C@H]3CN(c4ccccc4)CCN3C2)cc1
Yield: 16.5 %

Procedure:
A solution of 0.400 g (1.13 mmol) of (7R,9aS)-7-(4-fluorophenoxy)methyl-2-(4-aminophenyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine in 20 mL of THF was added dropwise to a solution of 0.33 mL (2.48 mmol) of isoamyl nitrite in 15 mL of THF. After the addition was complete, the solution was refluxed for 24 h. The solvent was evaporated, the residue dissolved in ethyl acetate, washed with 1M sodium hydroxide (3×), washed with brine (1×), dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with ethyl acetate gave 0.060 g (16%) of the title compound. mp (.HCl) 247–252° C. HRMS calcd for C21H25FN2O: 340.1951, found: 340.1989.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1>C(Cl)Cl.C1CCCCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[N:7][N:8]2[CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][O:24]2)=[CH:4][CH:3]=1
Reactant: O=Cc1n[nH]c2cc(Br)ccc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: C1CCCCC1
Product: O=Cc1nn(C2CCCCO2)c2cc(Br)ccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
To a solution of 6-bromo-1H-indazole-3-carbaldehyde (13.97 g, 61.9 mmol) in DCM (150 mL) was added p-TsOH (2.36 g, 12.4 mmol) and the mixture was cooled to 0° C. 3,4-Dihydro-2H-pyran (8.47 mL, 92.8 mmol) was added dropwise to the solution and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with DCM (200 mL) and washed with a solution of saturated aqueous sodium hydrogen carbonate (500 mL). The aqueous layer was re-extracted with DCM (500 mL) and the combined organic layers were washed with brine (2×1 L), dried over MgSO4 and concentrated in vacuo to yield a black oil. The crude material was refluxed in cyclohexane (20 mL) and filtered while hot. The filtrate was concentrated in vacuo and the residue was stirred in heptane for 48 hours. The resulting solid was collected by filtration to give the title compound (13.87 g) in a 73% yield.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:26]([CH:27](O)[C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[C:25]([CH:39]([CH3:41])[CH3:40])[CH:24]=[C:23]3[C:18]=2[C:19](=[O:44])[CH2:20][C:21]([CH3:43])([CH3:42])[O:22]3)=[CH:13][CH:12]=1.O>ClCCl>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:26]([CH:27]([F:7])[C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:37])[F:36])=[CH:30][CH:29]=3)=[C:25]([CH:39]([CH3:41])[CH3:40])[CH:24]=[C:23]3[C:18]=2[C:19](=[O:44])[CH2:20][C:21]([CH3:42])([CH3:43])[O:22]3)=[CH:13][CH:12]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(F)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Reaction time: 2.5 h
Yield: 45 %

Procedure:
At −78° C., a solution of 51 μl (380 μmol) of diethylaminosulfur trifluoride in 1 ml of dichloromethane is slowly added dropwise to a solution of 170 mg (350 μmol) of rac-5-(4-fluorophenyl)-6-{hydroxy[4-(trifluoromethyl)phenyl]methyl}-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 21A) in 4.5 ml of dichloromethane, and the mixture is stirred at this temperature for 2.5 h. The mixture is then allowed to thaw slowly to −20° C. Water is then added, and the mixture is extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated under reduced pressure. Crystallization of the residue from cyclohexane/ethyl acetate (10:1) gives 77 mg of the target product. Column chromatography of the concentrated mother liquor on silica gel (mobile phase: cyclohexane/ethyl acetate 20:1) gives a further 60 mg of the target compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN.[CH2:20]([N:22](CC)CC)C>ClCCl>[CH3:20][NH:22][C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a solution of (2S)-2-tert-butoxycarbonylamino-3,3-dimethylbutanoic acid (120 g, 519 mmol) in dichloromethane (800 mL) is added 1,1-carbonyldiimidazole (88.4 g, 545 mmol). The resulting solution is stirred at 25.degree. C. for 1 h and methylamine hydrochloride (52.5 g, 779 mmol) and triethylamine (157.3 g, 1557 mmol) are added and the reaction is stirred for an additional 18 h. The mixture is diluted with dichloromethane (600 mL) and washed with 1 M hydrochloric acid and saturated aqueous sodium chloride. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo to provide (2S)-2-tert-butoxycarbonylamino-3,3-dimethylbutanoic acid methylamide as a white solid (126 g, 100% yield).