Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24]([OH:26])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:31][N:32]1[CH:36]=[C:35]([C:37]2([NH2:40])[CH2:39][CH2:38]2)[N:34]=[CH:33]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:26])[NH:40][C:37]5([C:35]6[N:34]=[CH:33][N:32]([CH3:31])[CH:36]=6)[CH2:39][CH2:38]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Reactant: Cn1cnc(C2(N)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cn(C)cn5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.15 g, 0.37 mmol, 1 eq), 1-(1-methyl-1H-imidazol-4-yl)cyclopropanamine (0.061 g, 0.44 mmol, 1.2 eq), EDCI.HCl (0.078 g, 0.40 mmol, 1.1 eq), HOBT (0.049 g, 0.37 mmol, 1.0 eq) and TEA (0.15 ml, 1.1 mmol, 3 eq) were dissolved in dichloromethane and the above mixture was stirred at room temperature for 18 h. The mixture was then added with water. The organic layer was separated, washed with water, concentrated and the crude product purified by Prep. HPLC. Yield: 24.69 mg (10%). 1HNMR (400 MHz, DMSO-d6): δ1.04-1.07 (m, 2H), 1.17-120 (m, 2H), 2.29 (s, 3H), 2.82 (d, J=4.4 Hz, 3H), 3.54 (s, 3H), 6.7 (s, 1H), 7.37-7.43 (m, 5H), 7.58 (s, 1H), 7.74-7.77 (d, J=8.8 Hz, 1H), 7.81-7.82 (m, 2H), 7.97-8.01 (m, 2H), 8.46-8.47 (m, 1H), 9.06 (s, 1H) LCMS: (ES+) m/z=523.2 (M+H)+
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1.[H-].[Na+].[CH3:19]I>C1COCC1>[CH3:1][C:2]1([CH3:16])[C:7](=[O:8])[N:6]([CH3:19])[C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: CI
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)C(C)(C)Oc2ccc([N+](=O)[O-])cc21
Reaction time: 0.17 h
Yield: 90.9 %

Procedure:
A solution of 2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-3(4H)-one (300 mg, 1.35 mmol, 1 equiv) in 5 mL of THF was added dropwise to mixture of NaH (81 mg, 2.03 mmol, 1.5 equiv., 60%) in 3 mL of THF at 0° C. The mixture was stirred at this temperature for 10 min. Then MeI (0.25 mL, 4.05 mmol, 3 equiv.) was added and the reaction was left at room temperature overnight. The reaction mixture was partitioned between EtOAc and water. The organic layer was separated and concentrated. The residue was purified by column chromatography using a mixture of EtOAC/hexane (1:4) as eluent to give 290 mg (Yield=91%) of product as a pale yellow solid.
Reaction SMILES: C([BH3-])#N.[Na+].[Br:5][CH2:6][C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl>CO.C(OCC)C>[Br:5][CH2:6][CH:7]([OH:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(=O)CBr
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CCOC(=O)C(O)CBr
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of sodium cyanoborohydride (17.72 g, 282.0 mmol) in anhydrous MeOH (160 mL) under an atmosphere of nitrogen was added ethyl bromopyruvate (32.25 mL, 256.4 mmol, 80-85%) in anhydrous MeOH (160 mL). The mixture was treated with 1N HCl in diethyl ether to pH 4 and stirred for 1 h at 0° C. The solvent was removed in vacuo, and the resulting slurry was partitioned between diethyl ether and saturated aqueous NH4Cl solution. The aqueous layer was extracted several times into diethyl ether, and the organic extracts were combined, dried over Na2SO4 and concentrated to a pale yellow oil. The oil was diluted with diethyl ether (300 mL) and chilled to −78° C. for 1 hour. The resulting precipitate was collected by filtration to afford the alcohol as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 5.99 (dd, J=1.2, 6.0 Hz, 1H), 4.43-4.39 (m, 1H), 4.21-4.08 (m, 2H), 3.69 (d, J=0.8 Hz, 2H), 1.23-1.18 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[C:4]([F:28])[CH:3]=1.[CH3:29][C:30]1[O:34][C:33](B(O)O)=[CH:32][CH:31]=1.CC(C)([O-])C.[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:33]4[O:34][C:30]([CH3:29])=[CH:31][CH:32]=4)=[CH:3][C:4]=3[F:28])(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: Cc1ccc(B(O)O)o1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccc(C)o2)cc1F
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]-2-fluorobenzenesulfonamide (E103) (200 mg, 0.42 mmol) and (5-methyl-2-furanyl)boronic acid (106 mg, 0.84 mmol) in DME (3 ml) was added potassium tert-butoxide (430 mg, 3.8 mmol) and tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The solvent was evaporated in vacuo and residue purified using an SCX column followed by mass directed autoprep HPLC (with addition of 0.1 ml of 10% citric acid in water to the DMSO/MeCN sample to help dissolution) to afford the title compound (E309). MS (ES+) m/e 474 [M+H]+.
Reaction SMILES: COC1N=CC([C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][C:10]=2[CH3:22])=CC=1B1OC(C)(C)C(C)(C)O1.Br[C:33]1[CH:34]=[C:35]([Cl:40])[C:36]([Cl:39])=[N:37][CH:38]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[Cl:40][C:35]1[CH:34]=[C:33]([C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[CH:11][C:10]=2[CH3:22])[CH:38]=[N:37][C:36]=1[Cl:39]
Reactant: Clc1cc(Br)cnc1Cl
Reactant: COc1ncc(-c2ccc(C(=O)OC(C)(C)C)cc2C)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1-c1cnc(Cl)c(Cl)c1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A suspension of tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (from INTERMEDIATE 31 Step B, 1.0 g, 3.14 mmol), 5-bromo-2,3-dichloropyridine (0.784 g, 3.46 mmol), potassium phosphate (1.33 g, 6.29 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.077 g, 0.094 mmol) in dioxane (12 mL) and water (1 mL) was flushed with nitrogen and stirred at 70° C. for 4 hours. After cooling down, the mixture was filtered over celite and the filter cake washed with ethyl acetate. The filtrate was diluted with ethyl acetate and water and partitioned. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated. The crude isolate was purified by silica gel chromatography (0 to 80% ethyl acetate/hexane) to give the titled compound as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.3 (d, J=2.1 Hz, 1H), 7.95 (s, 1H), 7.92 (d, J=7.7 Hz, 1H), 7.78 (d, J=2.0 Hz, 1H), 7.27 (d, J=7.9 Hz, 1H), 2.35 (s, 3H), 1.65 (s, 9H).
Reaction SMILES: [CH:1]1([CH2:6][C:7]2([CH3:11])[CH2:10][O:9][CH2:8]2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[BrH:12]>C1COCC1>[Br:12][CH2:8][C:7]([CH2:6][CH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)([CH3:11])[CH2:10][OH:9]
Reactant: Br
Reactant: CC1(CC2C=CC=C2)COC1
Solvent: C1CCOC1
Product: CC(CO)(CBr)CC1C=CC=C1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
In a 500 ml Schlenk tube (8 cm diameter), 4.5 g (30 mmol) of 2 were dissolved in 150 ml of THF and cooled to -70° C. An aqueous solution of HBr was added dropwise over a period of 5 minutes and the solution was stirred further for 2 hours at this temperature. After removing the cooling bath, the solution thawed to -15° C. over a period of 1.5 hours. The reaction solution was hydrolyzed at this temperature by addition of 40 ml of 10% strength sodium hydroxide solution and was stirred for 1 hour without cooling. During this time, the solution came to room temperature. The aqueous phase was separated off and shaken three times with 30 ml of diethyl ether. The combined organic phases were subsequently washed with saturated sodium chloride solution and dried over sodium sulfate. Removal of the solvent gave a yellow oil. The crude product obtained in this way (6.97 g) can be reacted further without further purification. To characterize the material, part of the crude product was flash-chromatographed on a silica gel column (4*25 cm; eluant: PE/THF in a ratio of 9:1;
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[N:12]=[C:13]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=12.[CH:27]([C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=1)=O.C(N(CC)CC)C.C([BH3-])#N.[Na+]>O1CCOCC1>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[N:12]=[C:13]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)[CH2:23][CH2:22]2)[N:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=12
Reactant: O=Cc1ccc2ccccc2n1
Reactant: Nc1nccn2c(C3CCNCC3)nc(-c3cc4ccccc4[nH]3)c12
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Nc1nccn2c(C3CCN(Cc4ccc5ccccc5n4)CC3)nc(-c3cc4ccccc4[nH]3)c12

Procedure:
A solution of 1-(1H-Indol-2-yl)-3-piperidin-4-ylimidazo[1,5-a]pyrazin-8-amine hydrochloride (30 mg, 0.09 mmol), 2-formylquinoline (17 mg, 0.11 mmol) and triethylamine (0.019 mL, 0.14 mmol) in 1,4-dioxane (1 mL) was treated with sodium cyanoborohydride (5.7 mg, 0.090 mmol) and microwaved at 300 watts, 120° C. for 20 min. The mixture was concentrated in vacuo, the residue was dissolved in methanol loaded onto an SCX ion exchange cartridge, and then eluted with 1M NH4OH in methanol. The semi-pure material thus obtained was then subjected to semi-preparative HPLC to afford desired product. 1H NMR (400 MHz, MeOD) δ ppm 2.13-2.33 (m, 4 H), 2.90 (t, J=10.86, 9.60 Hz, 2 H), 3.47 (d, J=10.11 Hz, 2 H), 4.29 (s, 2 H), 6.74 (s, 1 H), 7.02-7.11 (m, 2 H), 7.19 (t, J=8.08, 7.07 Hz, 1 H), 7.47 (d, J=9.09 Hz, 1 H), 7.58-7.65 (m, 3 H), 7.69 (d, J=8.59 Hz, 1 H), 7.80 (t, J=8.34, 6.82 Hz, 1 H), 7.96 (d, J=7.33 Hz, 1 H), 8.08 (d, J=8.34 Hz, 1H) and 8.39 (d, J=8.59 Hz, 1 H). MS (ES+): m/z 474.23 [MH+].
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)(=[O:21])=[O:20])=[CH:15][C:14]=2[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:32]([O:31][C:29](=[O:30])[C:14]1[CH:15]=[C:16]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)(=[O:20])=[O:21])[CH:17]=[CH:18][C:13]=1[CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH3:33]
Reactant: CCOC(=O)c1cc(S(=O)(=O)c2cccc(F)c2)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(S(=O)(=O)c2cccc(F)c2)ccc1C1CCNC1
Reaction time: 4 h

Procedure:
3-[2-Ethoxycarbonyl-4-(3-fluoro-benzenesulfonyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (71 mg, 0.149 mmol) was dissolved in 2 ml of CH2Cl2. TFA (0.5 ml) was added and the mixture was stirred for 4 hours. The solution was concentrated under reduced pressure to give 5-(3-Fluoro-benzenesulfonyl)-2-pyrrolidin-3-yl-benzoic acid ethyl ester, MS (M+H)=378.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([C:16]([OH:18])=O)[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=1)#[N:2].[K].CCN(C(C)C)C(C)C.[C:29]1([C:35]2[CH:40]=[C:39]([CH2:41][S:42]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)(=[O:44])=[O:43])[CH:38]=[CH:37][C:36]=2[NH2:51])[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:29]1([C:35]2[CH:40]=[C:39]([CH2:41][S:42]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)(=[O:44])=[O:43])[CH:38]=[CH:37][C:36]=2[NH:51][C:16]([C:5]2[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:13])([CH3:14])[CH3:15])[CH:7]=[C:3]([C:1]#[N:2])[N:4]=2)=[O:18])[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)O
Reactant: Nc1ccc(CS(=O)(=O)N2CCOCC2)cc1C1=CCCCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(CS(=O)(=O)N2CCOCC2)cc1C1=CCCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
A mixture of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid, potassium salt (as prepared in the Example 1, step (d), 33.6 mg, 0.110 mmol), DIEA (34 μL, 0.20 mmol), 2-cyclohex-1-enyl-4-(morpholine-4-sulfonylmethyl)-phenylamine (as prepared in the previous step, 33.6 mg, 0.110 mmol) and PyBroP (69.9 mg, 0.150 mmol) in DCM (2 mL) was stirred at RT for 12 h. The reaction mixture was diluted with DCM (10 mL) and washed with satd aq NaHCO3 (10 mL) and water (10 mL). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The residue was purified on silica (20-40% EtOAc/hexane) to afford 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(morpholine-4-sulfonylmethyl)-phenyl]-amide (56 mg, 95%). Mass spectrum (ESI, m/z): Calcd. for C28H39N5O5SSi, 586.2 (M+H). found 586.1.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([C:13]([OH:15])=O)=[CH:8][CH:9]=2)[N:4]=[CH:3]1.O=S(Cl)[Cl:18]>>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([C:13]([Cl:18])=[O:15])=[CH:8][CH:9]=2)[N:4]=[CH:3]1
Reactant: Cn1cnc2cc(C(=O)O)ccc2c1=O
Reactant: O=S(Cl)Cl
Product: Cn1cnc2cc(C(=O)Cl)ccc2c1=O

Procedure:
A solution of 3-methyl-4-oxo-3,4-dihydroquinazoline-7-carboxylic acid (110 mg, 0.54 mmol) in SOCl2 (8 mL) was stirred at reflux for 5 h. The excess SOCl2 was then removed under reduced pressure. The crude 3-methyl-4-oxo-3,4-dihydroquinazoline-7-carbonyl chloride was used without further purification for the next step.
Reaction SMILES: [CH3:1][C:2](O)([CH2:5][CH2:6][CH:7]=[C:8]([CH3:19])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:18])[CH2:13][O:14][CH2:15][O:16][CH3:17])[C:3]#[CH:4].C(O)(=[O:28])C1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH3:17][O:16][CH2:15][O:14][CH2:13][C:12]([CH3:18])=[CH:11][CH2:10][CH2:9][C:8]([CH3:19])=[CH:7][CH2:6][CH2:5][C:2]([CH3:1])=[CH:3][CH:4]=[O:28]
Reactant: C#CC(C)(O)CCC=C(C)CCC=C(C)COCOC
Reactant: O=C(O)c1ccccc1
Solvent: Cc1ccccc1C
Product: COCOCC(C)=CCCC(C)=CCCC(C)=CC=O
Temperature: 25 °C
Yield: 506.2 %

Procedure:
A solution of 3,7,11-trimethyl-12-(methoxymethyl) oxy-6,10-dodecadien-1-in-3-ol (175 mg, 0.62 mmol), tris (triphenylsilyl)vanadate (49 mg, 0.062 mmol), and benzoic acid (7.6 mg, 0.062 mmol) in xylene (2 ml) was stirred on an oil bath at 140° C. After two-hour-stirring, the solution was allowed to cool to room temperature and concentrated. The resultant residue was subjected to silica gel column chromatography to obtain 12-(methoxymethyl)oxy-3,7,11-trimethyl-2,6,10-dodecatrienal (88 mg, 50%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[F:9][C:10]([F:22])([F:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>[Pd]>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:15]2[CH:14]=[CH:13][C:12]([O:11][C:10]([F:9])([F:21])[F:22])=[CH:17][CH:16]=2)[N:3]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Clc1cncc(Cl)n1
Agent: [Pd]
Product: FC(F)(F)Oc1ccc(-c2cncc(Cl)n2)cc1

Procedure:
The compound was prepared by palladium-catalyzed arylation of 2,6-dichloropyrazine and 4-trifluoromethoxyphenyl boronic acid: mp 58-60° C.; 1H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 8.57 (s, 1H), 8.10 (d, J=9.0 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H); EIMS m/z 274 (M+).
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[F:9][C:10]([F:20])([F:19])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]([F:19])([F:20])[F:9])=[CH:16][C:15]=1[C:21](=[O:23])[CH3:22]
Reactant: COc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)C(F)(F)F
Product: COc1ccc(C(F)(F)F)cc1C(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.7 %

Procedure:
2′-methoxy-5′-trifluoromethyl-acetophenone was prepared as follow (US2003/0109574): In a water bath at room temperature, to a solution of trifluoromethane sulfonic acid (5 ml, 56.7 mmol) under argon was slowly added a solution of 4-trifluoromethyl-anisol (2.0 g, 11.35 mmol) in acetic anhydride (2.15 ml, 22.7 mmol). The resulting dark mixture was stirred for 3 hours at room temperature then poured onto ice water (26 ml). The product was extracted several times with ether. The ethereal layer was washed with a 10% solution of sodium hydrogenocarbonate, water, dried over sodium sulfate and concentrated to dryness. The residue was purified by flash chromatography over silica gel (gradient cyclohexane/dichloromethane: 0-50%) to yield 2′-methoxy-5′-trifluoromethyl-acetophenone (1.7 g, 67%) as a white solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([C:12]2[CH:16]=[C:15]([C:17](=[O:19])[NH2:18])[N:14]([CH3:20])[CH:13]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[N:30]([CH3:31])[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:27]=2)[C:22]1=[O:36])(=O)C.[OH-].[Na+]>O1CCCC1.C([O-])(O)=O.[Na+].ClCCl>[C:32]([C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:36])[N:21]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:16]=[C:15]([C:17]([NH2:18])=[O:19])[N:14]([CH3:20])[CH:13]=3)[CH:10]=[CH:9][CH:8]=1)[N:30]([CH3:31])[CH2:29]2)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(=O)OCc1c(-c2cc(C(N)=O)n(C)c2)cccc1N1C(=O)c2ccc(C(C)(C)C)cc2CN1C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1Cc2cc(C(C)(C)C)ccc2C(=O)N1c1cccc(-c2cc(C(N)=O)n(C)c2)c1CO
Temperature: 60 °C
Yield: 98.9 %

Procedure:
To 2-(6-tert-butyl-3-methyl-1-oxo-3,4-dihydrophthalazin-2(1H)-yl)-6-(5-carbamoyl-1-methyl-1H-pyrrol-3-yl)benzyl acetate (31 mg, 63.4 μmol, Eq: 1.00) in tetrahydrofuran was added NaOH (1.0 M (aqueous) 1.0 mL, 1.00 mmol, Eq: 15.8). The reaction mixture heated at 60° C. for 4 h. The mixture was cooled to room temperature. The solution was diluted with sat NaHCO3 (aqueous) and dichloromethane. The layers were separated. The aqueous layer was extracted once with dichloromethane. The organic extracts were combined and dried over MgSO4. The solution was filtered. Concentrated in vacuo to give 4-[3-(6-tert-Butyl-3-methyl-1-oxo-3,4-dihydro-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-1H-pyrrole-2-carboxylic acid amide (28 mg, 99%): 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26-1.40 (m, 9H) 2.56 (s, 3H) 3.95 (s, 3H) 4.53 (br. s., 2H) 5.23 (s, 2H) 6.93 (d, J=1.89 Hz, 1H) 7.14 (d, J=1.89 Hz, 1H) 7.24-7.38 (m, 3H) 7.39-7.53 (m, 1H) 7.64 (dd, J=5.67, 3.40 Hz, 1H) 8.01 (d, J=8.31 Hz, 1H). LC/MS-ESI observed [M+H]+ 447.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH3:13]I>CS(C)=O.O>[CH3:13][N:9]1[C:10]2[C:6](=[CH:5][C:4]([Br:3])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1
Reactant: CI
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cn1ccc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of sodium hydroxide (0.4 g.,10 mmol.) in DMSO (20 mL.) was heated to 80°-85° C. for 6 hours to dissolve most of the solids then allowed to cool to room temperature. To the stirred mixture was added 5-bromoindole (2.0 g., 10 mmol.) followed in 1 hour by methyliodide (0.62 mL., 10 mmol.). After stirring for an additional 3 hours the reaction was shown by TLC analysis to be complete. The reaction mixture was diluted with water then extracted with ether. The extracts were washed 2× with water, dried with Na2SO4, and concentrated in vacuo to give 2.08 g. of 1-methyl-5-bromoindole as a yellow oil which crystallized on standing.
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]1([C:17]([NH:19][C@H:20]([C:25]([O:27]C)=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>CO>[C:1]([S:5][CH2:6][C:7]1([C:17]([NH:19][C@H:20]([C:25]([OH:27])=[O:26])[CH2:21][CH:22]([CH3:23])[CH3:24])=[O:18])[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)C1(CSC(C)(C)C)CCc2ccccc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)C[C@H](NC(=O)C1(CSC(C)(C)C)CCc2ccccc2C1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dissolve N-[[1,2,3,4-tetrahydro-2-[[(t-butyl)thio]methyl]-2-naphthalenyl]carbonyl]-L-leucine, methyl ester (146 mg, 0.36 mmol) in methanol (3 mL). Add a solution of lithium hydroxide monohydrate (1 mL in water, 1 mmol) and stir at room temperature under argon for 16 hours. Evaporate the solvent in vacuo without heat and acidify with 2N hydrochloric acid. Extract into methylene chloride (2X), dry (MgSO4) and evaporate the solvent in vacuo to give the title compound as as white foam (142 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=3)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: O=C(O)c1cccnc1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1cccnc1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine and nicotinic acid as starting materials, MS (LC/MS): 408.0 (M+H).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH3:14][N:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1>>[OH:21][C:18]1([C:2]2[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=2[CH2:4][OH:5])[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]1
Reactant: OCc1ccc(C(F)(F)F)cc1Br
Reactant: CN1CCC(=O)CC1
Product: CN1CCC(O)(c2cc(C(F)(F)F)ccc2CO)CC1

Procedure:
Reaction of 2-bromo-4-trifluoromethylbenzyl alcohol and 1-methyl-4-piperidone by the method described in Example 16a provides 4-hydroxy-4-(α-hydroxy-4-trifluoromethyl-2-tolyl)-1-methylpiperidine.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[CH2:11]([O:18][NH:19][CH2:20][C:21]1([C:28]([OH:30])=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[CH2:11]([O:18][N:19]([CH2:20][C:21]1([C:28]([OH:30])=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH:1]=[O:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CO
Reactant: O=C(O)C1(CNOCc2ccccc2)CCCCCC1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: O=CN(CC1(C(=O)O)CCCCCC1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To a cold solution of formic acid (40.2 mL, 1.04 mol) in dichloromethane (150 mL) at 0° C. under a nitrogen atmosphere was added acetic anhydride (15.2 mL, 160 mmol). After 1 h, a solution of 1-(benzyloxyamino-methyl)-cycloheptanecarboxylic acid from Preparation 37 (16.1 mmol theoretical) in dichloromethane (150 mL) was added. The reaction was stirred at 0° C. for 3 h and was concentrated in vacuo. Water (150 mL) was added and the mixture was extracted with dichloromethane (50 mL×5). The combined organic extracts were dried (MgSO4) and were evaporated in vacuo. Purification by preparative, reverse-phase HPLC provided the title compound (2.56 g, 52%). MH+306.