Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=N[C:3](OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:32]([O:39][C:40]([N:42]1[CH2:45][CH2:44][C@@H:43]1[CH2:46][OH:47])=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O[C:49]1[CH:50]=[N:51][CH:52]=[CH:53]C=1>C1COCC1>[CH2:32]([O:39][C:40]([N:42]1[CH:45]=[CH:44][CH:3]=[C:46]([O:47][CH2:53][C@H:52]2[CH2:49][CH2:50][NH:51]2)[CH2:43]1)=[O:41])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: Oc1cccnc1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: O=C(OCc1ccccc1)N1CC[C@@H]1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1C=CC=C(OC[C@H]2CCN2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 141.2 %

Procedure:
Diethyl azodicarboxylate (1.2 mL, 7.9 mmol) was added to a stirred solution of triphenylphosphine (2.1 g, 7.9 mmol) in THF (60 mL) at 0° C. After 15 minutes, (R)-1-(benzyloxycarbonyl)-2-azetidinemethanol (1.46 g, 6.6 mmol, Step 1e above) in THF (6.6 mL) was added to the reaction vessel followed by 3-hydroxypyridine (690 mg, 7.3 mmol, Aldrich). After stirring for 18 h at ambient temperature the solvent was removed and the residue was dissolved in CH2Cl2 and washed with saturated K2CO3, dried (MgSO4), concentrated and chromatographed (silica gel; EtOAc/hexane, 1:2) to afford a mixture (2.8 g) of (R)-1-(benzyloxycarbonyl)-3-((2-azetidinylmethyl)oxy)pyridine and triphenylphosphine oxide: MS (CI/NH3) m/z: 299 (M+H)+. A sample (1.6 g) of this mixture was dissolved in EtOH (25 mL) and stirred in the presence of 10% Pd/C (320 mg) under an atmosphere of H2 (1 atm) for 4 h. The reaction was filtered, concentrated and chromatographed (silica gel; CHCl3 /MeOH/NH4OH, 90:10 to 90:10:0.5) to afford the free base of the title compound as an amber oil (465 mg, overall yield 75%): [α]D20 +5.8 (c 1.6, CHCl3); MS (CI/NH3) m/z: 165 (M+H)+ ; 1H NMR (CDCl3, 300 MHz) δ 2.22-2.46 (m, 2H), 3.45-3.51 (m, 1H), 3.73 (dd, J=7.7, 8.5 Hz, 1H), 4.00-4.10 (m, 2H), 4.26-4.35 (m, 1H), 7.21-7.24 (m, 2H), 8.22 (dd, J=2.9, 3.0 Hz, 1H), 8.33 (dd, J=1.5, 2.2 Hz, 1H). The (R)-3-((2-azetidinylmethyl)oxy)pyridine (450 mg, 2.74 mmol) was slurried in Et2O (20 mL) and MeOH (~2 mL), then Et2O saturated with HCl gas was added at ambient temperature. The solvent was removed and the remaining solid recrystallized from MeOH/Et2O to afford the title compound as a deliquescent white solid (206 mg, 31%): mp 138-140° C.; [α]D20 +9.8 (c 0.5, MeOH). MS (CI/NH3) m/z: 165 (M+H)+ ; 1H NMR (D2O, 300 MHz) δ 2.71 (dd, J=8.5, 17.3 Hz, 2H) 4.05-4.21 (m, 2H), 4.57 (d, J=4.4 Hz, 2H), 4.96-5.03 (m, 1H), 7.99 (dd, J=5.7, 9.0 Hz, 1H), 8.21 (ddd, J=1.2, 2.8, 9.0 Hz, 1H), 8.46 (d, J=5.7 Hz, 1H), 8.59 (d, J=2.8 Hz, 1H); Anal. Calcd for C9H12N2O.2 HCl.0.2 H2O: C, 44.90; H, 6.03; N, 11.64. Found: C, 44.90; H, 5.98; N, 11.54.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:10]=[C:11]([C:17]2[CH:21]=[CH:20][N:19]([CH2:22][C@@H:23]([NH:25][C:26]([C:28]3[NH:32][N:31]=[C:30]([C:33]([OH:35])=O)[CH:29]=3)=[O:27])[CH3:24])[N:18]=2)[CH:12]=[CH:13][C:14]=1[C:15]#[N:16].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.O>[Cl:8][C:9]1[CH:10]=[C:11]([C:17]2[CH:21]=[CH:20][N:19]([CH2:22][C@@H:23]([NH:25][C:26]([C:28]3[NH:32][N:31]=[C:30]([C:33]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[O:35])[CH:29]=3)=[O:27])[CH3:24])[N:18]=2)[CH:12]=[CH:13][C:14]=1[C:15]#[N:16]
Reactant: CN1CCNCC1
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(C(=O)O)n[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(C(=O)N2CCN(C)CC2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.5 %

Procedure:
1-Methylpiperazine (126 mg; 1.25 mmol) and (S)-5-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)-1H-pyrazole-3-carboxylic acid (50 mg; 1.25 mmol), HOBt (254 mg; 1.88 mmol), DIPEA (0.33 ml; 1.88 mmol) and EDCl (361 mg; 1.88 mmol) were dissolved in 15 ml of DCM and stirred at RT overnight. 50 ml of DCM was added and washed with 3×15 ml of water. Combined water phases were washed with 2×20 mol of DCM, all organic phases were combined and dried over Na2SO4. Crude product was purified by chromatography (CombiFlash, silica column, eluent: 0-20% MeOH/DCM) to obtain 75 mg (12%) of the title compound. 1H-NMR (400 MHz; d1-CDCl3): δ 3.90-3.96 (m, 2H), 4.41 (t, 2H), 6.51-6.53 (m, 1H), 6.61 (d, 1H), 6.66 (d, 1H), 6.95 (s, 1H), 7.48-7.50 (m, 2H), 7.61 (broad s, 1H), 7.68 (d, 1H), 7.76-7.79 (m, 1H), 8.11 (s, 1H), 10.45 (broad s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:6]=1[N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:9]([CH3:20])[CH2:8]1.[C:26]([O:30][C:31]([NH:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47](O)=[O:48])=[O:32])([CH3:29])([CH3:28])[CH3:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[C:26]([O:30][C:31]([NH:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH2:21][C:22]([F:24])([F:25])[F:23])[C:6]=1[N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH:9]([CH3:20])[CH2:8]1)=[O:48])=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC1CN(c2c(N)cnn2CC(F)(F)F)CCN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CC1CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3NC(=O)OC(C)(C)C)cnn2CC(F)(F)F)CCN1C(=O)OC(C)(C)C
Temperature: 30 °C
Reaction time: 20 h
Yield: 32.6 %

Procedure:
To a solution of tert-butyl (±)-4-(4-amino-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)-2-methylpiperazine-1-carboxylate (300 mg, 0.83 mmol), 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (294 mg, 0.83 mmol), HATU (410 mg, 1.08 mmol) in DMF (15 mL) was added TEA (2 mL). The mixture was stirred at 30° C. for 20 hours, poured into water (100 mL), and extracted with EtOAc (40 mL×3). The combined organic layers was washed with water (50 mL×2) and brine (30 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a residue. The residue was purified by preparative HPLC to give tert-butyl (±)-4-(4-(5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)-2-methylpiperazine-1-carboxylate as white solid (190 mg, 33%). MS (ESI) m/z: 702 [M+H+].
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:30][CH3:31])=[CH:12][CH:13]=[C:14]2[C:19]=1[O:18][C:17](=[O:20])[CH:16]=[C:15]2[NH:21][C:22]1[C:27]([Cl:28])=[CH:26][N:25]=[CH:24][C:23]=1[Cl:29]>CS(C)=O>[Cl:29][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([Cl:28])[C:22]=1[NH:21][C:15]1[C:14]2[C:19](=[C:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][N:2]([CH3:3])[CH3:1])[C:11]([O:30][CH3:31])=[CH:12][CH:13]=2)[O:18][C:17](=[O:20])[CH:16]=1
Reactant: CNC
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCBr
Solvent: CS(C)=O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCN(C)C
Reaction time: 1 h

Procedure:
A solution of dimethylamine (3 mL, 2M THF, 6 mmol) was added to a solution of 8-(4-bromobutoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (293 mg, 0.6 mmol, Example 25) and DMSO (6 mL). After 1 h, the reaction was concentrated and purified by reverse-phase HPLC (1:4→3:2; acetonitrile:water) to give 4-(3,5-dichloropyridin-4-ylamino)-8-(4-(dimethylamino)butoxy)-7-methoxy-2H-chromen-2-one: 1H NMR (400 MHz, DMSO-d6): δ 9.53 (br s, 1H), 8.58 (s, 2H), 7.87 (d, 1H), 7.07 (d, 1H), 4.22 (br s, 1H), 3.99 (t, 2H), 3.90 (s, 3H), 2.76 (br, 2H), 2.47 (s, 6H), 1.85-1.65 (m, 4H); MS (ESI): 451.9.
Reaction SMILES: C([Li])CCC.[I:6][C:7]1[CH:14]=C[C:10](C=O)=[CH:9][CH:8]=1.[C:15](OCC)(=[O:17])[CH3:16].[O:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>CCCCCC>[CH2:15]([O:17][C:25](=[O:21])[CH:24]=[CH:23][C:22]1[CH:10]=[CH:9][CH:8]=[C:7]([I:6])[CH:14]=1)[CH3:16]
Reactant: C1CCOC1
Reactant: CCOC(C)=O
Reactant: O=Cc1ccc(I)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CCOC(=O)C=Cc1cccc(I)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
A stirred, cooled (−78° C.) solution of triethylphosphonoacetate (11.44 g, 51 mmol) in anhydrous tetrahydrofuran (100 mL) was treated with a 1.6M solution of n-butyl lithium in hexanes (30 mL, 48 mmol). After 10 min, the reaction mixture was cannulated into a cooled (−78° C.) solution of 4-iodo-benzaldehyde (3.7 g, 16 mmol) in tetrahydrofuran (20 mL). The reaction mixture was allowed to warm to 0° C. over 1 h. It was quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford an oil that was subjected to flash column chromatography over silica gel (230-400 mesh) using 8-10% ethyl acetate in hexane as the eluent to afford the title compound (4.6 g, 95%).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH3:23])=[O:21])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.C[Si](C)(C)[O:46][NH2:47]>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]([CH3:23])[CH2:24][C:25]([O:27][CH3:28])=[O:26])=[O:21])[N:16]=2)[CH2:11][C:12]([NH:47][OH:46])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)ON
Reactant: COC(=O)CN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)CN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-(3-{[(2-methoxy-2-oxoethyl)(methyl)amino]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoic acid (Preparation 39) (273 mg, 0.70 mmol)and N-methylmorpholine (85 μl, 0.77 mmol) in anhydrous dichloromethane (10 ml) was cooled to 0° C., treated with isobutyl chloroformate (100 μl, 0.77 mmol) and the resulting mixture was stirred under a nitrogen atmosphere for 30 minutes. O-(Trimethylsilyl)hydroxylamine (250 μl, 2.10 mmol) was then added and the mixture stirred under a nitrogen atmosphere for 1 hour, being allowed to warm to room temperature over this time. The mixture was then quenched with methanol (10 ml) and stirred for 10 minutes. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The layers were separated and the organic layer was sequentially washed with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by HPLCa to afford the title compound as a colourless oil (187 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)=[O:10].[H-].[Na+].CO.C(Cl)Cl>CN(C)C(=O)C>[CH:13]1[N:12]2[C:4]3[C:3]([NH:8][C:9](=[O:10])[C:11]2=[N:15][CH:14]=1)=[CH:2][CH:7]=[CH:6][CH:5]=3
Reactant: O=C(Nc1ccccc1F)c1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: O=c1[nH]c2ccccc2n2ccnc12
Yield: 78.6 %

Procedure:
10 (2 g, 9.75 mmol) is solubilized in N,N-dimethylacetamide (DMA) (80 ml) before adding sodium hydride (NaH 60% by weight) (1.5 g, 62 mmol). The mixture thus obtained is carried at reflux for 15 h. The reaction is monitored by TLC, eluent: MeOH/CH2Cl2 (10/90). This not being complete, 2 equivalents of NaH are added. The mixture is left at reflux for 30 h. Once the reaction is complete, the mixture is concentrated under vacuum, then to the dry residue are added water and a saturated ammonium chloride aqueous solution. A brown precipitate is formed, which is collected by filtration, washed with water and dried under vacuum. A beige solid (1.42 g, 79%) is obtained. Analysis calculated for C10H7N3O: C, 64.86; H, 3.81; N, 22.69. Experimental: C, 64.44; H, 4.03; N, 22.98.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[C:5]([Cl:22])=[CH:4][N:3]=1.[CH3:23][O:24][CH2:25][CH2:26][N:27]1[CH2:33][CH2:32][C:31]2[CH:34]=[C:35]([NH2:38])[CH:36]=[CH:37][C:30]=2[CH2:29][CH2:28]1.Cl.CCOCC>COCCO.O1CCOCC1>[Cl:22][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])=[N:7][C:2]([NH:38][C:35]2[CH:36]=[CH:37][C:30]3[CH2:29][CH2:28][N:27]([CH2:26][CH2:25][O:24][CH3:23])[CH2:33][CH2:32][C:31]=3[CH:34]=2)=[N:3][CH:4]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: O=C(N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl)C(F)(F)F
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: COCCO
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NC(=O)C(F)(F)F)n3)cc2CC1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-2,2,2-trifluoro-acetamide (776 mg, 2.17 mmol) was added into a Vial, followed by a solution of 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (447 mg, 2.03 mmol) in 2-Methoxyethanol (15 mL). 4.00 M of Hydrogen chloride in 1,4-Dioxane (1.1 mL) was added and the reaction was heated at 120° C. After 3 h, the reaction was cooled to room temperature, and 85 mL ether was added. The HCl salt formed as an oil, not a solid, so it was redissolved by adding MeOH and DCM. Macroporous carbonate resin (3.16 mmol/g loading; 2.45 g, 7.7 mmol) was then added and stirred for 1 h and filtered before concentration. The residue was dissolved in DCM, then chromatographed (2×12 g SiO2, ISCO, 0-10% MeOH:DCM) to afford N-((1R,2R)-2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-2,2,2-trifluoro-acetamide (414 mg, 38%) as a beige solid. m.p.=180-182° C.; LCMS (m/e) 541 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.92 (s, 1H), 7.88 (m, 1H), 7.23 (s, 1H), 7.22 (d, 1H, J=8.5 Hz), 7.04 (d, 1H, J=8.5 Hz), 6.81 (s, 1H), 5.22 (d, 1H, J=7.5 Hz), 4.0 (m, 1H), 3.68 (m, 1H), 3.54 (t, 1H, J=5.5 Hz), 3.36 (s, 3H), 2.92 (m, 4H), 2.74 (m, 4H), 2.28 (m, 1H), 2.15 (m, 1H), 1.80 (m, 4H), 1.2-1.5 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=2[F:19])[N:4]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=1.[F:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[C:30]=1[C:31](O)=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C.CCOC(C)=O>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:31](=[O:32])[C:30]3[C:34]([O:38][CH3:39])=[CH:35][CH:36]=[CH:37][C:29]=3[F:28])=[CH:14][C:13]=2[F:19])[N:4]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(Br)c2c(Oc3ccc(N)cc3F)ccnc21
Reactant: COc1cccc(F)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
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: COc1cccc(F)c1C(=O)Nc1ccc(Oc2ccnc3c2c(Br)cn3COCC[Si](C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a stirred solution of 4-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorobenzenamine (400 mg, 0.85 mmol), 2-fluoro-6-methoxybenzoic acid (226 mg, 1.33 mmol), and HATU (641 mg, 1.33 mmol) in DMF (6 mL) was added DIPEA (387 mg, 3 mmol), followed by DMAP (50 mg). The resulting mixture was stirred at rt overnight, diluted with EtOAc, and washed with saturated aq. K2HPO4 solution and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, eluting with 30% EtOAc/CH2Cl2) to give the desired product (370 mg, 72%) as a white solid. LC/MS(ESI+) m/z 605 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]3[C@H:22]([C:23]([F:26])([F:25])[F:24])[CH2:21][CH2:20][C@H:19]([C:27]([NH:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=O)[CH2:18]3)[CH:10]=2)=[CH:5][C:4]=1F)#[N:2].[OH2:37].[NH2:38][NH2:39].CCOC(C)=O>C(O)C>[NH2:2][C:1]1[C:3]2[C:4](=[CH:5][C:6]([C:9]3[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]4[C@H:22]([C:23]([F:26])([F:25])[F:24])[CH2:21][CH2:20][C@H:19]([C:27]([NH:29][CH:30]5[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)=[O:37])[CH2:18]4)[CH:10]=3)=[CH:7][CH:8]=2)[NH:39][N:38]=1
Reactant: O
Reactant: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](C(=O)NC3CCCCC3)CC[C@H]2C(F)(F)F)n1
Reactant: NN
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2C[C@@H](C(=O)NC3CCCCC3)CC[C@H]2C(F)(F)F)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
To cis-1-[6-(4-cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-N-cyclohexyl-6-(trifluoromethyl)-3-piperidinecarboxamide (152 mg, 0.301 mmol) in ethanol (6 mL) was added hydrazine monohydrate (0.4 mL, 8.16 mmol), and the reaction mixture was stirred overnight at 100° C. into a sealed tube. The reaction was allowed to cool to room temperature and poured onto water and EtOAc. The organic layer was separated, and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100% CH2Cl2 to 90:10:1 CH2Cl2:CH3OH:NH4OH) afforded the title compound (116 mg) as an off-white solid. LC-MS (ES) m/z=517 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.05-1.34 (m, 5H), 1.56 (m, 1H), 1.62-1.85 (m, 7H), 2.08. (m, 1H), 2.34 (m, 1H), 2.84 (s, 3H), 3.07 (bs, 1H), 3.53 (m, 1H), 5.39 (s, 2H), 6.73 (bs, 1H), 6.78 (s, 1H), 7.63-7.69 (m, 1H), 7.70-7.75 (m, 1H), 7.84 (d, J=7.8 Hz, 1H), 8.02 (bs, 1H), 11.52 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH2:13]([OH:20])[C:14]#[C:15][C:16]#[C:17][CH2:18][OH:19].[OH-:21].[K+].[Cl-].[Na+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:19][CH2:18][C:17]#[C:16][C:15]#[C:14][CH2:13][O:20][S:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:10])=[O:21])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: OCC#CC#CCO
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: [OH-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)OCC#CC#CCOS(=O)(=O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
Fifty grams of p-methoxybenzenesulfonyl chloride was reacted, at 15° to 18° C., with 11 grams of 2,4-hexadiyn-1,6-diol in 100 ml tetrahydrofuran, while a solution of 20 grams potassium hydroxide in 180 ml water was added dropwise over a 10 minute period. The resulting exothermic reaction was cooled at 15° to 18° C. with the aid of an ice-water bath. After the addition of the potassium hydroxide solution, the solution was allowed to stir overnight at room temperature. The mixture was then poured into 500 ml cold aqueous sodium chloride solution which resulted in a yellow precipitate. The precipitate was collected by filtration, washed with water and dried. Obtained was 41.6 grams (93% yield of theory) of a yellow brown solid, melting point 120° to 122° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[N:4]([CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([NH2:38])[CH:29]=1)[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[CH:19]=[CH:18][C:17]=1[O:25][CH3:26].[CH3:40][S:41](Cl)(=[O:43])=[O:42].C(N(CC)C(C)C)(C)C.O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:39])[N:4]([CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[CH:19]=[CH:18][C:17]=1[O:25][CH3:26])[CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([NH:38][S:41]([CH3:40])(=[O:43])=[O:42])[CH:29]=1
Reactant: COC(=O)N(Cc1cc(N)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COC(=O)N(Cc1cc(NS(C)(=O)=O)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Temperature: 25 °C

Procedure:
To a solution of methyl[3-amino-5-(trifluoromethyl)benzyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (8 mg, 0.014 mmol) (Example 33) and methanesulfonyl chloride (3.3 μL, 0.043 mmol) in CH2Cl2 (1 mL) was added N,N-diisopropylethylamine (15 μL, 0.086 mmol). The reaction was stirred at room temperature for thirty minutes and then was poured into H2O (10 mL). The mixture was extracted with EtOAc (50 μL), and the organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purification by preparative thin layer chromatography with 25% EtOAc/hexanes followed by a preparative thin layer chromatography in 2:2:1 (CH2Cl2:Hex:Et2O) and then a third and final purification by silica gel chromatography with 2% to 25% EtOAc/hexanes afforded methyl{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}[3-[(methylsulfonyl)amino]-5-(trifluoromethyl)benzyl]carbamate. Rf=0.40 (25% EtOAc/hexanes). 1H NMR (C6D6, 500 MHz, 70° C.) δ 7.69 (s, 1H), 7.52 (s, 1H), 7.38-7.25 (m, 3H), 7.08-7.04 (m, 2H), 6.86 (s, 1H), 6.30 (d, J=8.5 Hz, 1H), 4.40 (broad singlet, 2H), 4.04-3.99 (m, 2H), 3.33 (s, 3H), 3.26 (s, 3H), 2.74 (m, 1H), 2.67 (s, 3H), 1.22 (d, J=6.5 Hz, 6H).
Reaction SMILES: [CH3:1][N:2]([CH2:19][CH2:20][CH3:21])[C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]2[O:15][CH:16]=[CH:17][N:18]=2)[CH:13]=1)[C:8]([OH:10])=O)=[O:4].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:57][C@@H:58]([CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)[C@H:59]([OH:71])[CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH2:69][CH3:70])[CH:64]=1>CN(C=O)C>[CH2:72]([C@H:58]([NH:57][C:8](=[O:10])[C:7]1[CH:11]=[C:12]([C:14]2[O:15][CH:16]=[CH:17][N:18]=2)[CH:13]=[C:5]([C:3]([N:2]([CH3:1])[CH2:19][CH2:20][CH3:21])=[O:4])[CH:6]=1)[C@H:59]([OH:71])[CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH2:69][CH3:70])[CH:64]=1)[C:73]1[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=1
Reactant: CCCN(C)C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2ccccc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCN(C)C(=O)c1cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CNCc2cccc(CC)c2)cc(-c2ncco2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 3-{[methyl(propyl)amino]carbonyl}-5-(1,3-oxazol-2-yl)benzoic acid (206 mg, 0.71 mmol) in DMF (5 mL) is added diisopropylethylamine (174 μL, 1.1 mmol), HATU (323 mg, 0.85 mmol), then (2R,3S)-3-amino-1-[(3-ethylbenzyl)amino]-4-phenylbutan-2-ol dihydrochloride prepared by the method of EXAMPLE SP-272 (292 mg, 0.79 mmol). The reaction is stirred 4 h at room temperature. The reaction is partitioned between chloroform and water. The organic layer is washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 8% methanol/chloroform) gives the title compound. ESI MS m/z 569.3 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][OH:4].[CH2:5]([CH:7]1[O:9][CH2:8]1)[Cl:6]>>[Cl:1][CH2:2][CH:3]([OH:4])[CH2:8][O:9][CH2:7][CH2:5][Cl:6]
Reactant: OCCCl
Reactant: ClCC1CO1
Product: OC(CCl)COCCCl
Yield: 74.9 %

Procedure:
A mixture consisting of 100 g 2-chloroethanol (12.4 mol), 573 g epichlorohydrin (6.2 mol) and 20 g of an acidic ion exchange resin were refluxed for 24 hours. The mixture was then filtered to remove the ion exchange resin and the excess alcohol and unreacted epichlorohydrin were removed by distillation. The residue was distilled under vacuum and the product 1-chloro-3-(2-chloroethoxy)-2-propanol (804 g, 75% yield) distilled between 89 and 91° C. at 0.05 mm Hg.