Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][NH:11][CH2:12][CH2:13][CH:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:15][CH2:16][OH:17].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[OH:17][CH2:16][CH2:15][CH:14]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:13][CH2:12][N:11]([CH3:10])[C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CNCCC(CCO)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(CCC(CCO)c1ccccc1)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
N,N-Diisopropylethylamine (0.352 mL, 261 mg, 2.02 mmol) and 5-(methylamino)-3-phenylpentan-1-ol (300 mg, 1.68 mmol) from Example 180, Step B, were dissolved in 4.0 mL of dichloromethane. The solution was cooled to 0° C., benzoyl chloride (0.205 mL, 248 mg, 1.77 mmol) was added dropwise, and the mixture was stirred for an additional 30 min. The mixture was then partitioned between 15 mL of dichloromethane and 15 mL of saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with 2×15 mL of dichloromethane. The combined organic extracts were washed with 20 mL of brine, dried over sodium sulfate, and evaporated. The crude product was purified by flash column chromatography on silica gel, eluting with 10% ethyl acetate in dichloromethane, to give 467 mg of the title compound. 1NMR (400 MHz, CD3OD) was complicated by the presence of a mixture of rotamers: δ 7.45-7.06 (m, 9H), 6.97 (d, 1H, J=8 Hz), 3.53-3.23 (m, 2H), 3.17-3.00 (m, 2H), 3.02 and 2.85 (two singlets, 3H), 2.88-2.78 and 2.57-2.49 (two multiplets, 1H), 2.07-1.64 (m, 4H). Mass spectrum (ESI): m/z=298 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][C:22]([F:35])([F:34])[CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:31]([C:28]3[CH:27]=[CH:26][C:25]([O:24][CH2:23][C:22]([F:35])([F:34])[F:21])=[CH:30][N:29]=3)=[O:32])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: O=C(O)c1ccc(OCC(F)(F)F)cn1
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Product: CC1(C)OC(N)=N[C@](C)(c2cc(NC(=O)c3ccc(OCC(F)(F)F)cn3)ccc2F)C1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white foam. MS (ISP): m/z=491.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([C:8](Cl)=[O:9])[CH2:4][CH:3]=1.[OH-:11].[Na+]>CO.O1CCCC1>[CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:9])=[O:11])[CH2:4][CH:3]=1
Reactant: CC1=CCC(C(=O)Cl)CC1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1=CCC(C(=O)O)CC1

Procedure:
To a solution of 4-methylcyclohex-3-enecarbonyl chloride (2 ml) in a mixture of methanol (20 ml) and tetrahydrofuran (20 ml) was added aqueous sodium hydroxide (4N, 20 ml). The resultant mixture was stirred at ambient temperature for 1 hour, and evaporated. The residue was taken up into a mixture of water and ethyl acetate and adjusted pH to around 1. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure to give 4-methylcyclohex-3-enecarboxylic acid, which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:18].ClCCl>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]2[CH:10]([O:18]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC=CC1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2OC2C1
Temperature: 25 °C
Yield: 70.9 %

Procedure:
Stir a mixture of 2,5-dihydropyrrole-1-carboxylic acid tert-butyl ester (2 g, 11.8 mmol), 3-chloroperoxybenzoic acid (77%, 3.1 g, 14.2 mmol) and 3-tert-butyl-4-hydroxy-5-methylsulfide (254 mg, 0.7 mmol) in 1,2-dichloroethane (50 mL) at 85° C. for 4 h under nitrogen. Add extra 3-chloroperoxybenzoic acid (77%, 1.16 g, 4.7 mmol) and stir at 85° C. for 5 h. Allow to cool to room temperature and add dichloromethane (120 mL), wash with 5% aqueous sodium bisulfate, then with saturated aqueous sodium hydrogen carbonate and finally with saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and chromatograph on silica gel, eluting with 0:100 to 40:60 ethyl acetate:cyclohexane to give 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (1.55 g, 71%). 1H NMR (400 MHz, CDCl3) δ 3.82 (1H, d, J=13.20 Hz), 3.74 (1H, d, J=12.72 Hz), 3.67 (2H, d, J=3.42 Hz), 3.31 (2H, dd, J=13.45, 5.14 Hz), 1.44 (9H, s).
Reaction SMILES: [CH:1](=[O:4])[CH2:2][OH:3].C(NN[C:10](=[O:12])[CH3:11])(=[O:7])C.C([N:16]([CH2:21][CH2:22][OH:23])[NH:17]C(=O)C)(=O)C>NN>[C:1]([OH:4])(=[O:7])[CH3:2].[C:10]([OH:12])(=[O:3])[CH3:11].[C:22]([OH:23])(=[O:3])[CH3:21].[NH:16]([CH2:21][CH2:22][OH:23])[NH2:17]
Reactant: CC(=O)NNC(C)=O
Reactant: CC(=O)NN(CCO)C(C)=O
Reactant: O=CCO
Agent: NN
Product: CC(=O)O
Product: NNCCO
Reaction time: 16 h

Procedure:
Glycolaldehyde (0.100 mmol, in dimeric form) was dissolved in 1.0 mL anhydrous hydrazine (Pierce or Aldrich Chemical Company) in a Pierce reacti-vial, and capped under nitrogen with a cap having a Pierce Tuf-bond teflon-silicone seal. The sample, after sitting at room temperature for 16 hours, was converted to the hydrazone derivative of glycolaldehyde which was evaporated to a resin-like material in a Speed-Vac concentrator. The sample was quantitatively transferred in a 1.0 mL volume of water into a 20 mL test tube, and 100 mg of sodium borohydride was added, which reduced the molecule to 2-hydrazinoethanol. After 24 hours, the sample was placed in an ice-water bath and 0.200 mL of glacial acetic acid was added, dropwise, over about a 30 second interval. The sample was diluted with 1.0 mL water. To it was added 200 mg of sodium bicarbonate and the bicarbonate was permitted to dissolve, with occasional mixing. Then, 0.100 mL acetic anhydride was added, followed by gentle swirling to dissolve all of it. After 10 minutes, another 0.100 mL acetic anhydride was added, the solution gently swirled to dissolve it, and, after an additional 50 minutes, the sample was diluted with 5.0 mL water and loaded on a column containing 10-12 mL of well-washed Dowex AG1-X8, 100-200 mesh, H+ form, to remove sodium. The column was washed with five additional washes of 10 mL water. The total eluate was rotary evaporated to near dryness, and then rotary evaporated to dryness five times with 20 mL of 1% acetic acid in methanol, and three times with 20 mL methanol alone, to remove boric acid, thereby resulting in 2-(N,N'-diacetylhydrazino)-ethanol. This sample contained some additional N,N'-diacetylhydrazine. It was either directly O-peracetylated on the free hydroxyl group as described below, or it was chromatographically purified prior to O-acetylation by high-performance liquid chromatography on a Waters GlycoPak N column (7.8×300 mm), using isocratic acetonitrile/water, at 85/15, vol/vol, at 1.0 mL/min, monitoring at a wavelength of 200 nm, giving a single product peak at 17 minutes. For O-acetylation, 1.0 μmol of 2-(N,N'-diacetylhydrazino)-ethanol, either before or after liquid chromatographic purification was dried in a Pierce reacti-vial in a Speed-Vac rotary concentrator. The dried samples were taken up in 100 μL of dry pyridine (Pierce, silylation grade) and 50 μL acetic anhydride was added. The samples were kept under argon for 24 hours at room temperature, whereupon the solvent was removed under a flow of nitrogen. The samples were solubilized in about 0.5 mL chloroform, and again concentrated under a flow of nitrogen. These data show that the product is 2-hydrazinoethanol triacetate.
Reaction SMILES: CO[C:3]([NH:5][C:6]1[NH:10][C:9]2[CH:11]=[CH:12][C:13]([O:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH:27]4[CH2:29][CH2:28]4)=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:14][C:8]=2[N:7]=1)=[O:4].NCC[CH:33]1[O:38][CH2:37][CH2:36][NH:35][CH2:34]1.C[N:40]1CC[CH2:42][C:41]1=O>O1CCCC1>[N:35]1([CH2:42][CH2:41][NH:40][C:3](=[O:4])[NH:5][C:6]2[NH:10][C:9]3[CH:11]=[CH:12][C:13]([O:15][S:16]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH:27]5[CH2:28][CH2:29]5)=[CH:21][CH:20]=4)(=[O:18])=[O:17])=[CH:14][C:8]=3[N:7]=2)[CH2:34][CH2:33][O:38][CH2:37][CH2:36]1
Reactant: COC(=O)Nc1nc2cc(OS(=O)(=O)c3ccc(NCC4CC4)cc3)ccc2[nH]1
Reactant: NCCC1CNCCO1
Reactant: CN1CCCC1=O
Solvent: C1CCOC1
Product: O=C(NCCN1CCOCC1)Nc1nc2cc(OS(=O)(=O)c3ccc(NCC4CC4)cc3)ccc2[nH]1

Procedure:
A solution of 4-(cyclopropylmethyl-amino)-benzenesulfonic acid 2-methoxycarbonylamino-3H-benzoimidazol-5-yl ester (example 67, 40 mg) and 2-(aminoethyl)-morpholine (125 mg) in tetrahydrofuran (2 ml) and N-methylpyrrolidinone (0.2 ml) was heated at 90° C. for 36 hours. The reaction mixture was then evaporated and purified by triggered LC/MS to give 4-(cyclopropylmethyl-amino)-benzenesulfonic acid 2-[3-(2-morpholin-4-yl-ethyl)-ureido]-1H-benzoimidazol-5-yl ester as an off-white solid (27 mg). Mass spectrum: 515 [M+H]+; retention time=5.97 minutes.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17].CCOC(C)=O>C1COCC1>[F:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:16](=[O:17])[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(F)nc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(F)nc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.4 %

Procedure:
6-Fluoropyridin-3-amine (224 mg, 2.00 mmol) was dissolved in THF (4 mL). Pyridine (202 μL, 2.50 mmol) was added, followed by phenyl chloroformate (258 μL, 2.06 mmol). The reaction was stirred at rt for 2 h, then EtOAc (20 mL) was added. The reaction was washed with 1 M HCl (10 mL), water (10 mL), saturated aqueous NaHCO3 (10 mL), and brine (10 mL), then dried (MgSO4), filtered, and concentrated in vacuo to give slightly impure 16A (471 mg, >100%). 16A had an analytical HPLC retention time=2.437 min (Phenomenex Luna 3.0×50 mm, 10-90% aqueous MeOH over 5 min containing 0.1% TFA) and a LC/MS M++1=233.
Reaction SMILES: C[N:2]1CCN(C2C=CC(NC3C4N(N=CN=4)C([C:21]4[CH:22]=[C:23]([C:26]([NH2:28])=[O:27])[S:24][CH:25]=4)=CN=3)=CC=2)CC1.Br[C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36]([NH:42][C:43]2[CH:44]=N[C:46]([N:49]3[CH2:54][CH2:53][N:52]([CH:55]([CH3:57])[CH3:56])[CH2:51][CH2:50]3)=[CH:47][CH:48]=2)=[N:35][CH:34]=1.[CH3:58]C1(C)C(C)(C)OB(C2C=C(C(N)=O)SC=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[NH3:2].[CH:55]([N:52]1[CH2:51][CH2:50][N:49]([C:46]2[CH:58]=[CH:44][C:43]([NH:42][C:36]3[C:37]4[N:38]([N:39]=[CH:40][N:41]=4)[C:33]([C:21]4[CH:22]=[C:23]([C:26]([NH2:28])=[O:27])[S:24][CH:25]=4)=[CH:34][N:35]=3)=[CH:48][CH:47]=2)[CH2:54][CH2:53]1)([CH3:56])[CH3:57]
Reactant: CC1(C)OB(c2csc(C(N)=O)c2)OC1(C)C
Reactant: CC(C)N1CCN(c2ccc(Nc3ncc(Br)n4ncnc34)cn2)CC1
Reactant: CN1CCN(c2ccc(Nc3ncc(-c4csc(C(N)=O)c4)n4ncnc34)cc2)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: C1COCCO1
Product: CC(C)N1CCN(c2ccc(Nc3ncc(-c4csc(C(N)=O)c4)n4ncnc34)cc2)CC1
Product: N
Yield: 61 %

Procedure:
This compound may be prepared using methods as described for Compound 6, step 4, using 5-bromo-N-(6-(4-isopropylpiperazin-1-yl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-amine (100 mg, 0.24 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiophene-2-carboxamide (121 mg, 0.48 mmol), and Pd(PPh3)4 (69 mg, 0.059 mmol) in 1.5M Na2CO3 (1.28 mL, 1.92 mmol) and dioxane (3.84 mL). The crude product is purified by silica gel column chromatography eluting with DCM and 97:3 DCM:NH3 (7M in MeOH) to yield the title compound (68 mg, 61%) as a pale green solid. Conversion into the mesylate salt using 0.1M methanesulfonic acid in MeOH (1.47 mL, 0.147 mmol) followed by trituration with DCM and diethyl ether, affords the title compound (67 mg, 98.5%). 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 1.35 (6H, d), 2.34 (3H, s, MsOH), 3.00 (2H, t), 3.22-3.25 (2H, m), 3.56-3.61 (3H, m), 3.89 (2H, d), 7.09 (2H, d), 7.60 (1H, br s), 7.97 (2H, d), 8.10 (2H, s), 8.48 (1H, s), 8.67 (1H, s), 8.81 (1H, s), 9.23 (1H, br s), 10.03 (1H, s). LCMS: Rt 2.13 min (98.4%), m/z (APCI) 463 (M+H)+.
Reaction SMILES: N1[CH:6]=[CH:5]C=CC=1.[CH2:7]([C:9]1([OH:12])[CH2:11][CH2:10]1)[CH3:8].[Br:13][CH2:14][C:15](Br)=[O:16]>ClCCl>[Br:13][CH2:14][C:15]([O:12][C:9]1([CH2:7][CH3:8])[CH2:11][CH2:10][CH2:6][CH2:5]1)=[O:16]
Reactant: c1ccncc1
Reactant: O=C(Br)CBr
Reactant: CCC1(O)CC1
Solvent: ClCCl
Product: CCC1(OC(=O)CBr)CCCC1
Reaction time: 0.08 h
Yield: 81.9 %

Procedure:
Pyridine (67.5 g, 0.854 mol) was added dropwise to a solution of ethylcyclopropanol (75.0 g, 675 mmol) in anhydrous dichloromethane (750 mL) under N2 at 0° C. and stirred for 5 minutes. Bromoacetyl bromide (172 g, 74.4 mL, 854 mmol) in dichloromethane (75 mL) was added dropwise and the solution stirred at 0° C. for 20 h. The pyridinium bromide was filtered off, washed with dichloromethane (2×300 mL) and the solid pyridinium bromide discarded. The combined organic layers were washed with water (4×750 mL), and concentrated in vacuo. The crude oil was purified via of silica gel flash column chromatography (neutralized with TEA, 1:0 to 99:1 heptane:ethyl acetate). After concentration, the oil was filtered to afford the title compound (130 g, 84%) as a light orange oil. NMR (500 MHz, (CD3)2SO) δ: 3.93 (s, 2H), 2.07-2.14 (m, 2H), 2.00 (q, J=7 Hz, 2H), 1.59-1.77 (m, 4H), 0.89 (t, J=7 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([C:16]#[C:17][C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH:26]=3)[C:23](O)=[O:24])[CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][C:4]([CH3:27])=[N:3]1.[CH3:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])=[CH:34][CH:33]=1)(=[NH:31])=[O:30].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([C:16]#[C:17][C:18]3[CH:26]=[C:22]([C:23]([N:31]=[S:29]([C:32]4[CH:33]=[CH:34][C:35]([CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])=[CH:36][CH:37]=4)([CH3:28])=[O:30])=[O:24])[CH:21]=[N:20][CH:19]=3)[CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][C:4]([CH3:27])=[N:3]1
Reactant: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)O)c3)c2)n(C)n1
Reactant: COC(=O)CCc1ccc(S(C)(=N)=O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc(S(C)(=O)=NC(=O)c2cncc(C#Cc3cccc(NC(=O)c4cc(C)nn4C)c3)c2)cc1
Temperature: 50 °C
Yield: 44.7 %

Procedure:
A solution of 5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)-ethynyl]nicotinic acid (0.149 g, 0.414 mmol) in DMF (4 mL) was treated with methyl 3-(4-(S-methylsulfonimidoyl)phenyl)propanoate (0.100 g, 0.414 mmol), followed by BOP (0.238 g, 0.539 mmol) and DIPEA (0.144 mL, 0.830 mmol). The reaction mixture was heated to 50° C. for 3 h. After allowing the reaction to cool to room temperature it was taken up in EtOAc (10 mL) and extracted with brine (3×10 mL). The EtOAc layer was then washed with saturated aqueous Na2CO3 (2×10 mL). The organic layer was dried over anhydrous Na2SO4(s), filtered and concentrated. The crude residue was purified via column chromatography (silica gel, gradient elution, EtOAc in Hexanes: 0% to 100% EtOAc) affording the title compound (0.108 g, 45%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1.[NH2:32][C@@H:33]([CH2:35][OH:36])[CH3:34].C1C=CC2N(O)N=NC=2C=1.O.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[OH:36][CH2:35][C@H:33]([NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][C:13]3[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=3)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:30])[CH3:34]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Reactant: C[C@@H](N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)N[C@H](C)CO)[nH]2)c1
Reaction time: 30 h
Yield: 86 %

Procedure:
5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (2.00 g, 4.48 mmol) synthesized in Example (78k), D-alaninol (0.52 mL, 6.72 mmol), HOBT.H2O (0.73 g, 5.38 mmol) and N-methylmorpholine (0.99 mL, 8.96 mmol) were dissolved in methylene chloride (40 mL), and WSCI.HCl (0.94 g, 4.93 mmol) was added at room temperature, followed by stirring for 30 hours under nitrogen atmosphere. The reaction solution was diluted with methylene chloride (100 mL), washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=50%-90%) to afford the desired compound (1.94 g, 86%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([NH:14][CH2:15][CH2:16][NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:3]=1.[C:24](Cl)(Cl)=[O:25].C1(C)C=CC=CC=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:15][CH2:16][N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]2=[O:25])[CH:3]=1
Reactant: Clc1cc(NCCNc2ccccc2)nc(N2CCOCC2)n1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N(c2ccccc2)CCN1c1cc(Cl)nc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
To a solution of N1-(6-chloro-2-morpholinopyrimidin-4-yl)-N2-phenylethane-1,2-diamine (100 mg, 0.3 mmol) in DCM (15 mL) at 0° C. under nitrogen, a solution of phosgene in toluene (1.89 M, 0.32 mL, 0.6 mmol) was slowly added. After 20 minutes, the reaction was allowed to warm to RT. After 18 hours, DIEA (0.42 mL, 2.4 mmol) was added and the reaction solution was heated to 40-50° C. for 40 hours. The reaction mixture was evaporated under reduced pressure and the crude product was purified by silica gel chromatography eluting with 70% EtOAc/hexane to give 1-(6-chloro-2-morpholinopyrimidin-4-yl)-3-phenylimidazolidin-2-one as a white solid (94 mg, 87%). LC/MS (m/z): 360.1 (MH+), Rt 3.41 minutes.
Reaction SMILES: Cl.[N:2]1([CH2:7][C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19]([C:24]([OH:26])=O)=[CH:18]3)=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:49][C:50]1([F:56])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:49][C:50]1([F:56])[CH2:55][CH2:54][N:53]([C:24]([C:19]2[NH:20][C:21]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@H:8]2[CH2:7][N:2]2[CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:14])=[CH:23][CH:22]=3)=[O:26])[CH2:52][CH2:51]1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc2[nH]1
Reactant: FC1(F)CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc2[nH]1)N1CCC(F)(F)CC1
Yield: 74 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-indole-2-carboxylic acid hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4,4-difluoropiperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light yellow solid (74%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[C:21]1[S:25][C:24]([NH2:26])=[N:23][CH:22]=1>C1COCC1>[NH2:26][C:24]1[S:25][C:21]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:10][N:9]=3)=[CH:6][CH:7]=2)=[CH:22][N:23]=1
Reactant: Nc1ncc(Br)s1
Reactant: CCOC(=O)c1cc(-c2ccc(O)cc2)no1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccc(Oc3cnc(N)s3)cc2)no1
Reaction time: 0.17 h
Yield: 20.7 %

Procedure:
To a stirred solution of ethyl 3-(4-hydroxyphenyl)isoxazole-5-carboxylate (0.97 g, 4.16 mmol) in dry THF, sodium hydride (60%, 0.25 g, 6.09 mmol) was added at room temperature and stirred for 10 min. 5-bromothiazol-2-amine (0.5 g, 2.77 mmol) dissolved in 10 mL dry THF was added and continued to stir for additional 1 hr. Reaction mixture was poured on ice cold water and extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with water, brine and dried over sodium sulfate, filtered and concentrated under reduced pressure to get crude material which was purified by silica gel column chromatography using 40-50% ethyl acetate in hexane to provide the title compound (0.19 g).
Reaction SMILES: [N+:1]([CH:3](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:4])#[C-:2].[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][C:17]=1[F:24].C([O-])([O-])=O.[K+].[K+].O>CO.[N+](C(S(C1C=CC(C)=CC=1)(=O)=O)C)#[C-]>[Br:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]2[O:21][CH:2]=[N:1][C:3]=2[CH3:4])=[CH:18][C:17]=1[F:24]
Reactant: O=Cc1ccc(Br)c(F)c1
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ncoc1-c1ccc(Br)c(F)c1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
A mixture of 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (1.67 g, 7.97 mmol), 4-bromo-3-fluorobenzaldehyde (1.62 g, 7.97 mmol), and K2CO3 (2.20 g, 15.9 mmol) in MeOH (40 mL) was heated to reflux. After 1.5 hr additional 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (106 mg, 0.51 mmol) was added and the reaction mixture was again heated at reflux for 1.5 hr. The reaction was cooled to ambient temperature, water (200 mL) was added and the product was extracted with EtOAc (200 mL). The organic layer was washed with brine and dried over Na2SO4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (Analogix® SF25-40G column, 0%-30% EtOAc/hexanes, 30 mL/min), which yielded 1.86 g (91%) of the title compound as an orange solid. 1H NMR (300 MHz, CH3OH-d4) δ 8.18 (s, 1H), 7.73 (dd, J=8.4, 7.3 1H), 7.49 (dd, J=9.9, 2.0 1H), 7.41 (dd, J=8.3, 1.8 1H), 2.42 (s, 3H). MS (DCI+) m/z 256/258 (M+H).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:5]([NH:7][C:8](=[O:10])[CH:9]=1)=[O:6].[CH2:11](N(CC)CC)[CH3:12].ClC(Cl)([O:21][C:22](=[O:28])[O:23]C(Cl)(Cl)Cl)Cl>C(Cl)Cl>[C:22](=[O:21])([OH:28])[OH:23].[CH2:3]([C:4]1[C:5](=[O:6])[NH:7][C:8](=[O:10])[C:9]=1[CH2:11][CH3:12])[CH3:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: O=C1C=C(CCO)C(=O)N1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCC1=C(CC)C(=O)NC1=O
Product: O=C(O)O
Temperature: 0 °C
Yield: 154.9 %

Procedure:
Hydroxy ethylmaleimide (10.0 g, 70.1 mmol) was dissolved in a solution of methylene chloride (71 mL) and triethylamine (9.87 mL, 70.8 mmol) and cooled with an ice bath to 0° C. Triphosgene (3.504 g, 12 mmol) was added over a period of 4 hours and the resulting solution filtered. The supernatant was washed with 1N hydrochloric acid, 5% potassium carbonate solution and water. The solution was dried over magnesium sulfate and purified using activated carbon to yield white crystals (4.0 g, 18.5%). 1H-NMR (CDCl3, δ, ppm): 3.82 (4H, --NCH2 --, t), 4.27 (2H, --CH2O--, t), 6.73 (2H, --CH=CH--, s). 13C-NMR (CDCl3, δ, ppm): 36.6 (2C, --NCH2 --), 64.9 (2C, --CH2O--), 134.2 (2C, --CH=CH--), 154.5 (1C, C=O) 170.8 (2C, --NC=O).