Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[O:7]2)[CH2:3][CH2:2]1.[O:16]1[C:20]2([CH2:25][CH2:24][CH:23]([NH:26][C:27](Cl)=[O:28])[CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1>CCOC(C)=O>[O:16]1[C:20]2([CH2:25][CH2:24][CH:23]([NH:26][C:27]([N:1]3[CH2:6][CH2:5][C:4]4([C:14]5[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=5)[C:8](=[O:15])[O:7]4)[CH2:3][CH2:2]3)=[O:28])[CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Reactant: O=C(Cl)NC1CCC2(CC1)OCCO2
Solvent: CCOC(C)=O
Product: O=C1OC2(CCN(C(=O)NC3CCC4(CC3)OCCO4)CC2)c2ccccc21
Temperature: 60 °C

Procedure:
Add spiro[isobenzofuran-1,4′-piperidin]-3-one (100 mg, 0.49 mmol) to 1 mL of the stock solution of (1,4-dioxa-spiro[4.5]dec-8-yl)-carbamoyl chloride (˜0.2 M in toluene) and heat to 60° C. for 16 hours. Cool the solution, dilute with EtOAc and wash with brine. Dry the solution (Na2SO4) and concentrate under reduced pressure. Purify the crude product using preparative plate chromatography and triturate the resulting material with ether to obtain 1′-(1,4-dioxa-spiro[4.5]dec-8-yl-carbamoyl)-spiro[isobenzofuran-1,4′-piperidin]-3-one as a white solid.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[C:8]2[NH:9][CH2:10][CH2:11][S:12][CH:13]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:7]=2[C:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[N:5]1.C(N(CC)C(C)C)(C)C.[C:35](Cl)(=[O:37])[CH3:36].O>C(Cl)Cl>[CH3:3][N:4]1[C:8]2[NH:9][CH2:10][CH2:11][S:12][CH:13]([CH:14]3[CH2:19][CH2:18][N:17]([C:35](=[O:37])[CH3:36])[CH2:16][CH2:15]3)[C:7]=2[C:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[N:5]1
Reactant: CC(=O)Cl
Reactant: Cn1nc(-c2ccccn2)c2c1NCCSC2C1CCNCC1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(C2SCCNc3c2c(-c2ccccn2)nn3C)CC1
Temperature: -10 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To a mixture of 1-methyl-4-(4-piperidyl)-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine dihydrochloride (0.10 g, 0.25 mmol) and N,N-diisopropylethylamine (0.14 mL, 0.8 mmol) in DCM (20 mL) was added dropwise a solution of acetyl chloride (0.018 mL, 0.25 mmol) in DCM (2 mL), at about −10° C. The resulting mixture was stirred at about −10° C. for about 2 h and about 1 h at rt, then water (10 mL) and DCM (20 mL) were added. The layers were separated and the organic layer was washed with water (10 mL) and brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, DCM/methanol 95:5) to give 1-[4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]-1-piperidyl]ethanone (0.090 g, 97%) as a white solid: LC-MS (Table 1, Method a) Rt=1.60 min; m/z 372 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) (The spectrum is described as a 1:1 mixture of two compounds (‘rotamers’), each contributing 25 protons) δ 1.11 (1H, td, J=12.4, 4.3 Hz) 1.17-1.37 (4H, m) 1.38-1.50 (2H, m) 2.01 (3H, s) 2.07 (3H, s) 2.08-2.28 (4H, m) 2.39 (1H, td, J=12.7, 2.9 Hz) 2.65-2.74 (2H, m) 2.86 (1H, td, J=12.8, 2.9 Hz) 2.96-3.13 (5H, m) 3.39-3.54 (4H, m) 3.65 (1H, br. d, J=13.6 Hz) 3.77 (3H, s) 3.78 (3H, s) 3.84 (1H, br. d, J=13.6 Hz) 4.40 (1H, br. d, J=13.5 Hz) 4.63 (1H, br. d, J=13.7 Hz) 5.04 (1H, d, J=9.5 Hz) 5.06 (1H, d, J=9.9 Hz) 7.11-7.17 (2H, m) 7.63-7.69 (2H, m) 7.84-7.92 (2H, m) 8.50-8.56 (2H, m).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[C:17]([C:19]2[C:28]3[C:29]4[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=4[S:31][C:27]=3[C:26]([Br:36])=[C:25]3[C:20]=2[CH:21]=[CH:22][CH:23]=[CH:24]3)[CH:16]=[C:15]([Br:37])[C:3]=1[O:4][C@H:5]([CH2:10][C:11]([O:13]C)=[O:12])[C:6]([O:8]C)=[O:7].O>Cl.O1CCOCC1>[Br:1][C:2]1[CH:18]=[C:17]([C:19]2[C:28]3[C:29]4[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=4[S:31][C:27]=3[C:26]([Br:36])=[C:25]3[C:20]=2[CH:21]=[CH:22][CH:23]=[CH:24]3)[CH:16]=[C:15]([Br:37])[C:3]=1[O:4][C@H:5]([CH2:10][C:11]([OH:13])=[O:12])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)C[C@@H](Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br)C(=O)OC
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C[C@@H](Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br)C(=O)O
Reaction time: 14 h
Yield: 46.7 %

Procedure:
A solution of (R)-2-[2,6-Dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d ]thiophen-11-yl)-phenoxy]-succinic acid, dimethly ester (0.317 g, 0.448 mmol) in 4M HCl in dioxane (5 mL) was combined with water (5 mL) and concentrated HCl (1 mL) in a sealed pressure bottle and heated for 9 hours. After remaining at ambient temperature for an additional 14 hours the reaction mixture was partitioned between water and ether. The layers were separated and acid treated silica gel (7 mL) was added to the ether layer. The solvent was removed and the adsorbate was purified by flash chromatography (acid treated silica gel, eluant 80:20 pet. ether:ethyl acetate) to provide the title compound as a white solid (0.142 g, 47%), mp 163-164° C.; [a]D25=+14.16° (8.825 mg/mL, methanol); NMR (DMSO-d6); δ13.6 - 13.2 (broad singlet, 1 H,), 12.7 - 12.6 (broad singlet, 1 H), 8.28 (d, J=8 Hz, 1 H), 8.07 (d, J=8 Hz, 1 H), 7.82 - 7.78(m, 3 H), 7.65 - 7.57(m, 2 H,), 7.52(dd, J=7, 1 Hz, 1 H), 7.31(dd, J=7, 1, 1H), 6.70(d, J=8 Hz, 1 H), 5.32 (t, J=8 Hz), 3.67(m, 2 H); MS (-FAB) [M-H]-; 3 bromine pattern detected, 675(25%), 677(10%), 679(25%), 681(10%); Anal. Calc. for C26H15Br3O5S: C, 45.78, H, 2.23, N, 0.00. Found: C, 46.42, H, 2.40, N, 0.05.
Reaction SMILES: N.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:13]=[C:14]([O:16][CH3:17])[CH:15]=1)[CH2:7][CH:8]1[O:12][CH2:11][CH2:10][O:9]1.[Li]>C(O)C>[CH3:2][O:3][C:4]1[CH2:15][C:14]([O:16][CH3:17])=[CH:13][CH:6]([CH2:7][CH:8]2[O:9][CH2:10][CH2:11][O:12]2)[CH:5]=1
Reactant: COc1cc(CC2OCCO2)cc(OC)c1
Agent: N
Agent: [Li]
Solvent: CCO
Product: COC1=CC(CC2OCCO2)C=C(OC)C1
Temperature: -33 °C
Reaction time: 0.38 h

Procedure:
Ammonia (pre-dried using sodium and iron (III) chloride) (approx 60 mL) is allowed to distil into a flask containing 2-(3,5-dimethoxybenzyl)-[1,3]-dioxolane (1.0 g, 4.46 mmol) in ethanol (3 mL), and lithium wire is added portionwise to the reaction mixture until the reaction mixture retains a blue colour for ten minutes. Ethanol (1 mL) is then added, and the mixture stirred for 20-25 minutes at −33° C. The ammonia is evaporated, and the resultant mixture is taken up into saturated aqueous ammonium chloride solution (20 ml), and extracted with ethyl acetate (3×25 ml). The organic extracts are washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo to give 2-(3,5-dimethoxy-cyclohexa-2,5-dienylmethyl)-[1,3]-dioxolane.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22](OS(C(F)(F)F)(=O)=O)=[C:23]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[F:38][C:39]([F:51])([F:50])[O:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.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.C(OCC)(=O)C>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22]([C:44]4[CH:43]=[CH:42][C:41]([O:40][C:39]([F:38])([F:50])[F:51])=[CH:46][CH:45]=4)=[C:23]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cccc(COc2cnc(OS(=O)(=O)C(F)(F)F)c(CC(C)(C)C)c2)c1)C1CC1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)Cc1cc(OCc2cccc(C(CC(=O)O)C3CC3)c2)cnc1-c1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Yield: 23.5 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((5-neopentyl-6-(((trifluoromethyl)sulfonyl)oxy)pyridin-3-yl)oxy)methyl)phenyl)propanoate (65.2 mg) in toluene (1.5 mL) were added (4-(trifluoromethoxy)phenyl)boronic acid (24.7 mg), 2M aqueous sodium carbonate solution (720 μL), and tetrakis(triphenylphosphine)palladium(0) (13.8 mg), and the mixture was heated in a microwave synthesizer (Anton Parr, Synthos3000) at 100° C. for 90 min. Water (1 mL) and ethyl acetate (3 mL) were added to the reaction solution and the mixture was stirred. The organic layer was passed through a phase separation filter, and the solvent was evaporated by an air blowing apparatus. The residue was purified by HPLC (column: YMC Triart C18, mobile phase: acetonitrile/10 mM aqueous ammonium hydrogen carbonate solution) and the solvent was evaporated by an air blowing apparatus. To the residue were added ethanol (1 mL) and 2M aqueous lithium hydroxide solution (180 μL), and the mixture was stirred at 60° C. for 1 hr. 1M Hydrochloric acid (360 μL) was added and the obtained solution was purified by HPLC (column: YMC Triart C18, mobile phase: acetonitrile/10 mM aqueous ammonium hydrogen carbonate solution), and the solvent was evaporated by an air blowing apparatus to give the title compound (14.9 mg).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2([CH2:17]C)[CH2:15]C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2([CH3:17])[CH3:15]
Reactant: CCC1(CC)C(=O)Nc2ccc(CCCCl)cc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)Nc2ccc(CCCCl)cc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
Under nitrogen atmosphere, add 5-(3-chloropropyl)-3,3-diethyl-1,3-dihydro-indol-2-one (3.08 g, 12.24 mmol) to trifluoroacetic acid (9.4 mL, 122.4 mmol). Cool the resulting suspension to 0° C. and then add triethylsilane (4.5 mL, 28.2 mmol) dropwise over 2 min. Heat at 45° C. for 30 min then stir at ambient temperature overnight. Pour the reaction mixture onto ice/water (100 mL) and extract with EtOAc (2×100 mL). Dry the combined extracts over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (1:0 to 4:1 gradient), to give the title compound as a yellow-orange solid (2.12 g, 73%).
Reaction SMILES: [C:1]1([NH:7][N:8]=[C:9]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:26])[CH3:25])[CH2:20][CH2:19]2)[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2F)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[H][H].O>CN(C)C=O.ClCCl.CO>[C:24]([N:21]1[CH2:22][CH2:23][CH:18]([C:9]2[C:10]3[C:15](=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:19][CH2:20]1)(=[O:26])[CH3:25]
Reactant: CC(=O)N1CCC(C(=NNc2ccccc2)c2ccc(F)cc2F)CC1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(c2nn(-c3ccccc3)c3cc(F)ccc23)CC1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 84.7 %

Procedure:
To a stirred solution of 3.0 g of 1-acetyl-4-(2,4-difluorobenzoyl)piperidine phenylhydrazone in 30 ml of dimethylformamide, under nitrogen, was added 0.44 g of a 50% oil dispersion of sodium hydride. The reaction mixture was heated, and at about 40° C. a vigorous evolution of hydrogen occurred. The temperature was then raised to 80° C. and held there for 1.5 hrs. The reaction mixture was poured into water and the aqueous suspension was extracted with ethyl acetate. The ethyl acetate extracts were washed with water, dried over anhydrous magnesium sulfate and concentrated to yield an oil. The oil was combined with the oil from another experiment and a total of 13.5 g of material was chromatogrphed on a Water's Prep LC 500. Two silica gel columns were utilized and dichloromethane-methanol (3%) was used as the eluent. The appropriate fractions were evaporated. The residue was recrystallized twice from isopropyl alcohol-water (one charcoal treatment) to yield 2.4 g (18%) of product, mp 126°-128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[CH:11][N:10](COCC[Si](C)(C)C)[N:9]=2)[CH:5]=[CH:4][C:3]=1[C:21]1[CH:22]=[N:23][N:24]2[CH:29]=[CH:28][C:27]([N:30]3[C@@H:34]([CH:35]([CH3:37])[CH3:36])[CH2:33][O:32][C:31]3=[O:38])=[N:26][C:25]=12.ClC1C=C(C2N(COCC[Si](C)(C)C)N=CN=2)C=CC=1C1C=NN2C=CC(N3[C@@H](C(C)C)COC3=O)=NC=12>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:21]1[CH:22]=[N:23][N:24]2[CH:29]=[CH:28][C:27]([N:30]3[C@@H:34]([CH:35]([CH3:36])[CH3:37])[CH2:33][O:32][C:31]3=[O:38])=[N:26][C:25]=12
Reactant: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3Cl)c2n1
Agent: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncnn4COCC[Si](C)(C)C)cc3Cl)c2n1
Product: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)cc3Cl)c2n1
Yield: 65 %

Procedure:
(4S)-3-(3-(2-Chloro-4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropyloxazolidin-2-one (0.078 g, 65%) was prepared by the procedure described in Example 1, Step 9, using a mixture of (4S)-3-(3-(2-chloro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropyloxazolidin-2-one and (4S)-3-(3-(2-chloro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropyloxazolidin-2-one (0.158 g, 0.285 mmol), to produce a yellow solid. LCMS (APCI+) m/z 424.6 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ 14.21 (broad s, 1H), 9.13 (d, J=7.8 Hz, 1H), 8.64 (s, 1H), 8.29 (s, 1H), 8.15 (s, 1H), 8.08 (m, 1H), 8.00 (d×d, J=8.2, 1.5 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 4.85-4.81 (m, 1H), 4.45-4.44 (m, 2H), 2.70-2.66 (m, 1H), 0.95 (d, J=7.1 Hz, 3H), 0.84 (d, J=7.0 Hz, 3H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH2:20])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([N:31]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:30]=1)[C:25](O)=[O:26]>>[N:31]1([C:29]2[CH:28]=[C:24]([CH:23]=[C:22]([F:21])[CH:30]=2)[C:25]([NH:20][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)=[O:26])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Reactant: O=C(O)c1cc(F)cc(N2CCCCCC2)c1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cc(F)cc(N2CCCCCC2)c1

Procedure:
Compound is prepared from [4-(2-morpholin-4-ylethoxy)-1-naphthyl]amine (0.11 g, 0.40 mmol) and 3-fluoro-5-azepan-1-ylbenzoic acid (0.40 mmol) according to conditions described in general procedures E and F. A pink solid is produced (78 mg). Mp: 142-144° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.48 (bs, 4H), 1.74 (bs, 4H), 3.33 (bs, 2H), 3.51 (t, J=5.7 Hz, 4H), 3.53-3.76 (m, 6H), 4.01 (bs, 2H), 4.56 (t, J=4.2 Hz, 2H), 6.67 (d, J=13.2 Hz, 1H), 6.99-7.01 (m, 1H), 7.07 (d, J=8.1Hz, 1H), 7.17 (s, 1H), 7.46 (d, J=8.1Hz, 1H), 7.56-7.61 (m, 2H), 7.85-7.88 (m, 1H), 8.30-8.33 (m, 1H), 10.22 (s, 1H); MS 492 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][C:33]([CH3:38])([CH2:36][OH:37])[CH2:34][OH:35]>C1COCC1>[OH:35][CH2:34][C:33]([NH:32][C:16]1[N:17]=[C:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[CH3:26])[C:13]2[CH:12]=[CH:11][C:10](=[O:31])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1)([CH3:38])[CH2:36][OH:37]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CC(N)(CO)CO
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(NC(C)(CO)CO)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 72 h

Procedure:
The product of Example 48 (300 mg, 0.67 mmol) and 2-amino-2-methyl-1,3-propanediol (158 mg, 1.5 mmol) were combined in THF (10 mL) and stirred under Ar at 50° for 3 days. The solvents were removed in vacuo, and the residue was flash chromatographed with 0-25% EtOAc/CH2Cl2. Recrystallization from CH2Cl2/hexane gave the title compound as a white-crystalline solid. mp 158-160°, LC MS m/z=471 (MH+) Retention time=1.75 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[C:17]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[C:26](NCC)[N:25]=3)[O:21][N:20]=2)[CH:16]=[C:15]([CH3:34])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])C.CC1N=CN=[C:38]([C:42](O)=[O:43])C=1>>[CH2:42]([O:43][C:26]1[N:25]=[C:24]([C:22]2[O:21][N:20]=[C:19]([C:17]3[CH:16]=[C:15]([CH3:34])[C:4]([O:5][CH2:6][CH:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])=[C:3]([CH3:1])[CH:18]=3)[N:23]=2)[CH:29]=[C:28]([CH3:30])[N:27]=1)[CH3:38]
Reactant: Cc1cc(C(=O)O)ncn1
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(CC)c3)no2)n1
Product: CCOc1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CNC(=O)CO)c(C)c3)no2)n1

Procedure:
rac-N-(3-{4-[5-(2-Ethoxy-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide is prepared in analogy to N—((S)-3-{2-ethyl-4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide using 2-ethoxy)-6-methyl-pyrimidine-4-carboxylic acid and 2-hydroxy-N-{2-hydroxy-3-[4-(N-hydroxycarbamimioyl)-2,6-dimethyl-phenoxy]-propyl}-acetamide; LC-MS: tR=0.92 min; [M+H]+=458.20.
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[C:10]([CH3:12])[CH:9]=[N:8]1.[CH2:13]([CH:15]([C:18]1[C:19]2[N:20]([C:25](I)=[C:26]([CH3:28])[N:27]=2)[N:21]=[C:22]([CH3:24])[CH:23]=1)[CH2:16][CH3:17])[CH3:14].O>C1COCC1.[Cl-].[Zn+2].[Cl-]>[CH3:6][N:7]1[C:11]([C:25]2[N:20]3[N:21]=[C:22]([CH3:24])[CH:23]=[C:18]([CH:15]([CH2:13][CH3:14])[CH2:16][CH3:17])[C:19]3=[N:27][C:26]=2[CH3:28])=[C:10]([CH3:12])[CH:9]=[N:8]1
Reactant: Cc1cnn(C)c1
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)cnn3C)c(C)nc12
Temperature: -72 °C
Reaction time: 0.08 h
Yield: 0.7 %

Procedure:
n-BuLi (1.3 ml, 2.09 mmol) is stirred in THF (4 ml), under N2, and cooled to −72° C. 1,4-dimethyl-1H-pyrazole (170 mg, 2.04 mmol, in THF, 1 ml) is added slowly, stirred for 5 min. then allowed to warm to ambient temp. and stirred for 45 min. The mixture is cooled to −72° C. and a zinc chloride solution (4.3 ml, 2.14 mmol, 0.5 M in toluene) added, warmed to ambient temp. and treated with 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine and PdCl2(dppf)-CH2Cl2 complex (Aldrich, 40 mg, 0.05 mmol). The mixture is heated to 65° C. overnight, cooled to ambient temp., added to water and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product is purified by chromatography using a hexane-ethyl acetate gradient (100% hexane to 50% ethyl acetate in hexane) to elute the product. The title compound is obtained (0.7% yield). ES-MS (m/z): calc'd for C18H25N5: 311.4; found 312.2 (M+H)+. 1H NMR (400 mHz, CDCl3): δ 7.51 (s, 1H), 6.75 (s, 1H), 3.72 (s, 3H), 3.33 (m, 1H), 2.53 (s, 3H), 2.43 (s, 3H), 2.00 (s, 3H), 1.87 (m, 4H), 0.92 (m, 6H).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[C:22]([CH3:37])=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[CH:25][CH:26]=1.O>CN(C)C=O>[CH3:37][C:22]1[C:21]([CH2:20][O:18][C:15]2[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][N:3]3[CH:7]=[CH:6][N:5]=[N:4]3)=[CH:17][CH:16]=2)=[CH:26][CH:25]=[C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:29][CH:28]=2)[N:23]=1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1COc1ccc(CCCCn2ccnn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
14 mg (0.55 mmol) of 95% sodium hydride were added to at 0° C. to a solution of 109 mg (0.50 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 4.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 143 mg (0.50 mmol) 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine were given to the reaction mixture and stirring continued at room temperature (r.t.) overnight. After addition of 8 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed twice with water, and twice with heptane. The residue was dried at 40° C. in vacuum to give 191 mg (82%) of the title compound as white powder.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8].[CH2:16]([O:23][CH2:24][CH2:25][C@H:26]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:27](O)=[O:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][CH2:24][CH2:25][C@H:26]([NH:30][C:31](=[O:32])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C:27](=[O:28])[NH:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:8])[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nn1cccc1C(=O)Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)Nn1cccc1C(=O)Nc1ccccc1
Yield: 99.6 %

Procedure:
The title compound was prepared from 1-amino-N-phenyl-1H-pyrrole-2-carboxamide (0.65 g, 3.2 mmol) and (S)-4-(benzyloxy)-2-(tert-butoxycarbonylamino)butanoic acid (1.0 g, 3.2 mmol) following the experimental procedure described in Preparation 73a. 1.57 g (96% yield) of the desired compound were obtained.
Reaction SMILES: C[O:2][C:3]1[CH:16]=[CH:15][C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=1.CC(C)=O.C(=O)=O.B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:16]=[CH:15][C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=1
Reactant: COc1ccc2cc3ccccc3cc2c1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: Oc1ccc2cc3ccccc3cc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2 g of 2-methoxyanthracene and 25 ml methylene chloride were stirred and chilled at -70° C. (acetone/dry-ice bath) under a dry atmosphere. A solution of 60 ml of methylene chloride and 11 ml of 1N boron tribromide in methylene chloride was added slowly through a compensating addition funnel. The mixture was then allowed to warm slowly to ambient temperature under a dry atmosphere. After 24 hours, 20 ml of water were added and the mixture was extracted with ether (4×25 ml). A brown solid, 1.7 g (92%), decomp. ca. 200° C. (lit.** decomp. 200° C.) was obtained after ether evaporation and drying under vacuum for 16 hours. IR (KBr): 3540-3460, 3460-3100 (--OH), 1630, 1480, 1460, 1410, 1380, 1320, 1280-1270, 1200-1170, 950, 880, 800, 735 cm-1. 1H NMR (CD3COCD3 /TMS): δ8.3, 8.44, 8.8; 8.13-7.8; 7.15-7.52 (ArH).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[O:5]1[C:7]([CH3:9])([CH3:8])[CH2:6]1>>[CH:1]([NH:4][CH2:6][C:7]([CH3:9])([CH3:8])[OH:5])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CC1(C)CO1
Product: CC(C)NCC(C)(C)O

Procedure:
Isopropylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-isopropyl-N-(2,2-dimethyl-2-hydroxyethyl)amine. N-Isopropyl-N-(2,2-dimethyl-2-hydroxyethyl)amine was reacted with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2f to afford 2-(2-methyl-4-nitrophenylimino)-3-isopropyl-5,5-dimethyl-1,3-thiazolidine.