Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[S:7])[CH2:2][CH2:3][CH3:4].[CH3:22][I:23]>CC(C)=O>[IH:23].[CH3:22][S:7][C:6](=[N:5][CH2:1][CH2:2][CH2:3][CH3:4])[NH:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: CCCCNC(=S)Nc1cc(Cl)ccc1N1CCOCC1
Reactant: CI
Solvent: CC(C)=O
Product: CCCCN=C(Nc1cc(Cl)ccc1N1CCOCC1)SC
Product: I

Procedure:
A mixture of 1-(n-butyl)-3-(5-chloro-2-morpholinophenyl)thiourea (2.6 g), methyl iodide (1.4 g) and acetone (20 ml) was heated under reflux for 3 hours to give 2-methyl-1-(5-chloro-2-morpholinophenyl)-3-(n-butyl)-2-thiopseudourea hydroiodide (m.p. 130°-132° C.).
Reaction SMILES: N1C=C[CH:3]=N1.CN([C@@H](C1C=CC=CC=1)C)C([C:10]1[C:14]([Br:15])=[C:13]([NH:16][C:17](=[O:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[NH:12][N:11]=1)=O.ClC1C=CC=CC=1C(Cl)=O.C(OC([N:54]1[CH2:60][CH2:59][CH2:58][CH2:57][C@@H:56]([NH:61][C:62]([O:64]C(C)(C)C)=O)[CH2:55]1)=O)C1C=CC=CC=1.N(C(OC(C)(C)C)=O)[C@@H](C(O)=O)CCCCN.N1(N)CCCCC1>>[NH:54]1[CH2:60][CH2:59][CH2:58][CH2:57][C@@H:56]([NH:61][C:62]([C:10]2[C:14]([Br:15])=[C:13]([NH:16][C:17](=[O:25])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[N:12]([CH3:3])[N:11]=2)=[O:64])[CH2:55]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCCN(C(=O)OCc2ccccc2)C1
Reactant: C[C@H](c1ccccc1)N(C)C(=O)c1n[nH]c(NC(=O)c2ccccc2Cl)c1Br
Reactant: c1cn[nH]c1
Agent: CC(C)(C)OC(=O)N[C@H](CCCCN)C(=O)O
Agent: NN1CCCCC1
Agent: O=C(Cl)c1ccccc1Cl
Product: Cn1nc(C(=O)N[C@@H]2CCCCNC2)c(Br)c1NC(=O)c1ccccc1Cl

Procedure:
The pyrazole acid, prepared by coupling methyl ester 85 (Procedure 26) with 2-chlorobenzoyl chloride (21) followed by hydrolysis and bromination as shown in Procedure 8, was coupled to (R)-3-tert-butoxycarbonylaminoazepane-1-carboxylic acid benzyl ester (prepared as described in Procedure 23 using Boc-D-Lys-OH (Bachem, A-2705) followed by Cbz protection of the piperidine amine using the method of Procedure 30) using Procedure 3. Removal of the Cbz group using the method of Procedure 20 afforded the title compound.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH:5]([C:6]([O:8]CC)=O)[C:4]1([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=1)[CH3:11].C(=O)([O-])O.[Na+].[CH2:25]([NH2:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CN(C)C=O>[CH2:25]([N:31]1[CH2:2][CH:3]2[CH:5]([C:4]2([C:12]2[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=2)[C:18]#[N:19])[CH3:11])[C:6]1=[O:8])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCOC(=O)C1C(CCl)C1(C)c1cccc(C#N)c1
Reactant: CCCCCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(C#N)c1
Temperature: 25 °C
Yield: 35.2 %

Procedure:
To a solution of ethyl 3-(chloromethyl)-2-(3-cyanophenyl)-2-methylcyclopropanecarboxylate (Preparation 35, 5.82 g, 21.1 mmol) in N,N-dimethylformamide (20 ml) at room temperature was added sodium hydrogen carbonate (1.77 g, 21.1 mmol) followed by hexylamine (16.7 ml, 0.13 mol). The mixture was then heated under reflux for 16 h, cooled to room temperature and poured onto ice. After warming to room temperature, the mixture was partitioned against diethyl ether (50 ml). The two layers were separated and the aqueous layer was extracted with diethyl ether (2×30 ml). The ethereal extracts were washed with water (50 ml), dried (MgSO4), filtered and concentrated in vacuo. The crude oil was purified by silica column chromatography eluting with a gradient of hexane:ethyl acetate (5:1 to 0:100) to afford the title compound (2.2 g, 35%) as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=O)=[CH:5][CH:4]=1.C(NC(C)C)(C)C.C([Li])CCC.Cl.[CH2:30]([O:32]P(Cl)(=O)OCC)[CH3:31]>CCCCCC.C(N=CC)(C)(C)C.O1CCCC1>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6](/[C:7](/[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:31]/[CH:30]=[O:32])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2cccnc2)cc1
Reactant: CCOP(=O)(Cl)OCC
Agent: CC=NC(C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(/C(=C/C=O)c2cccnc2)cc1
Reaction time: 17 h

Procedure:
The compounds were prepared according to the procedure described in Example 84 except that the reaction was worked up after 17 hours. The following reagents were used: 3-(4-methoxybenzoyl)pyridine (22 g), diisopropylamine (32.2 mL), 1.55M n-butyl lithium in hexane (148 mL), acetaldehyde N-tert-butylimine (14.75 mL), diethylchlorophosphonate (16.6 mL) and tetrahydrofuran (200 mL). The work up, varied only in that the hydrolysis step was done by treating the intermediate imine with 2N HCl (300 ml) for 9 hours at 70° C. furnished, after basification and extraction, 24 g of crude material made up of a mixture of (E)-3-(4-methoxyphenyl)-3-(3-pyrdinyl)-2-propenal and (Z)-3-(4-methoxyphenyl)-3-(3-pyridinyl)-2-propenal. Purification of the crude by HPLC (ether; 3 recycles) provided 5.45 g of the less polar aldehyde, (E)-3-(4-methoxyphenyl)-3-(3-pyridinyl)-2-propenal along with 11 g of the isomer (Z)-3-(4-methoxyphenyl)-3-(3-pyridinyl)-2-propenal as oils.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[CH2:13]1[CH2:17][O:16][CH2:15][CH2:14]1>>[CH:13]1([C:17](=[O:16])[CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:14][CH2:15][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C1CCOC1
Reactant: [Li]CCCC
Reactant: Cc1ccccn1
Product: O=C(Cc1ccccn1)C1CCCCCC1
Temperature: -78 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
A 100 mL round bottom flask was charged with 2-picoline (2.52 mL, 25.5 mmol) and anhydrous THF (30 mL). The solution was cooled to −78° C. and n-butyllithium (17.5 mL of a 1.6 M solution in THF, 28.05 mmol) was added dropwise to the solution. After addition was complete, the reaction was warmed slowly to room temperature over one hour and then cooled again to −78° C. N-methoxy-N-methyl cycloheptyl amide (5.0 g, 27.03 mmol, formed above) was added to the reaction. The reaction mixture was allowed to warm to room temperature with stirring overnight. The reaction was carefully quenched with water and extracted with ethyl acetate. The organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography (ethyl acetate:hexane, 3:7, silica gel) to provide 1-cycloheptyl-2-(2-pyridyl)ethan-1-one (5.03 g, 91%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:16]([O:17][CH3:18])=[CH:15][C:14]([OH:19])=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.[OH-].[Na+].Cl.[C:28]([O-])(O)=[O:29].[Na+]>CN(C=O)C>[OH:19][C:14]1[C:13]([CH:28]=[O:29])=[C:11]2[CH:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[O:9][C:10]2=[C:16]([O:17][CH3:18])[CH:15]=1
Reactant: COc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(O)c(C=O)c2cc(-c3ccc(O)cc3)oc12

Procedure:
A solution of 62 (0.25 g, 1.0 mmol) in DMF (20 mL) was treated with POCl3 (1 mL, 11 mmol) and heated at 80° C.-100° C. for 15 minutes. The reaction mixture was worked up by allowing to cool and then poured into crushed ice. 2N NaOH aq was added and the solution stirred for several minutes and then the mixture was acidified with 2N HCl aq and then neutralized with NaHCO3 aq. The mixture was then extracted with EtOAc and washed with brine, dried over MgSO4, filtered, concentrated and chromatographed on silica gel (2:8 to 4:6 EtoAc/hexanes) to yield a solid which still contained some starting material, but that was purified by trituration with EtOAc to yield 47 mg the desired pdt as a white solid: Mp=254-255° C.; 1H NMR (DMSO-d6) δ 10.29 (s, 1 H), 10.0 (br s, 1 H), 7.73 (d, 2 H, J=8.7 Hz), 7.59 (s, 1 H), 6.88 (d, 2 H, J=8.7 Hz), 6.46 (s, 1 H), 4.00 (s, 3 H); MS 281 (M−H)−.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:18][N:19](C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CN>O1CCCC1.ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:19][CH3:18])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCN(Cc2ccccc2)CC1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CNC(=O)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-Benzyl 4-piperidinecarboxylic acid (5.00 g, 22.8 mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (5.25 g, 27.4 mmol) and 1-hydroxybenzotriazole hydrate (3.84 g, 25.1 mmol) were added to a solution of methylamine (11.4 ml of a 2.0M solution in tetrahydrofuran, 22.8 mmol) in dichloromethane (100 ml). The mixture was stirred for 1 hour at room temperature, then partitioned between dichloromethane and water. The organic layer was separated and washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure to furnish a pale yellow solid, 3.50 g.
Reaction SMILES: [S:1]([CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O)[C:2]#[N:3].O.S(=O)(=O)(O)[OH:15]>C(O)(=O)C>[OH:15][C:2]1[S:1][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]=1
Reactant: N#CSCC(=O)c1ccccc1
Reactant: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Oc1nc(-c2ccccc2)cs1
Reaction time: 8 h

Procedure:
Following the known process [Bull. Soc. Chem. France, 11, 2498 (1963)], 8.85 g (50 mmol) of α-thiocyanoacetophenone, 5 ml, of water and 1.3 ml of concentrated sulfuric acid were added to 40 ml of acetic acid and the resultant mixture was refluxed for 2 hours. The reaction mixture was then allowed to stand overnight at room temperature. Precipitated crystals were collected by filtration and then washed with water, whereby the title compound was obtained a colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:9](O)=[O:10]>>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][CH:9]=[O:10])=[CH:3][CH:4]=1
Reactant: O=CO
Reactant: Nc1ccc(Cl)nc1
Product: O=CNc1ccc(Cl)nc1

Procedure:
Was prepared according to Example 2 from 5-amino-2-chloropyridine and formic acid.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][C@@H:9]([N:11]([CH3:22])[S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][N:7]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:6]1)=[O:4].C(O)C.[Li+].[OH-]>O>[C:26]([O:25][C:23]([N:7]1[CH2:8][C@H:9]([N:11]([CH3:22])[S:12]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:14])=[O:13])[CH2:10][C@H:5]([C:3]([OH:4])=[O:2])[CH2:6]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=O)[C@H]1C[C@@H](N(C)S(=O)(=O)c2ccc(C)cc2)CN(C(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(C)[C@@H]2C[C@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of this ester (160 mg, 0.375 mmol), ethanol (4 ml) and 1N LiOH solution (1.88 ml, 1.88 mmol) is stirred for 14 h at RT. The mixture is diluted with H2O and extracted with methyl tert.-butyl ether. The organic layer is discarded, the aqueous phase acidified to pH 2 with a 10% NaHSO4 solution and extracted three times with methyl tert-butyl ether. The combined organic extracts are dried (Na2SO4) and evaporated to afford the title compound. MS (LC-MS): 413.4 [M+H]+; tR (HPLC, Symmetry C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 7 min, flow 1.5 ml/min): 4.31 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[NH:4][CH:5]([C:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[C:20]1[NH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)=[CH:23][N:24]=1)=[O:14])[C:6]([S:9]([CH3:12])(=[O:11])=[O:10])([CH3:8])[CH3:7].[CH3:41][O:42][C:43](=[O:68])[NH:44][CH:45]([C:49]([N:51]1[CH2:55][CH2:54][CH2:53][CH:52]1[C:56]1[NH:57][C:58]([C:61]2[CH:66]=[CH:65][C:64](Br)=[CH:63][CH:62]=2)=[CH:59][N:60]=1)=[O:50])[CH:46]([CH3:48])[CH3:47].C([O-])(O)=O.[Na+]>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.COCCOC.O>[CH3:1][O:2][C:3](=[O:40])[NH:4][CH:5]([C:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[C:20]1[NH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:64]3[CH:65]=[CH:66][C:61]([C:58]4[NH:57][C:56]([CH:52]5[CH2:53][CH2:54][CH2:55][N:51]5[C:49](=[O:50])[CH:45]([NH:44][C:43]([O:42][CH3:41])=[O:68])[CH:46]([CH3:48])[CH3:47])=[N:60][CH:59]=4)=[CH:62][CH:63]=3)=[CH:27][CH:26]=2)=[CH:23][N:24]=1)=[O:14])[C:6]([S:9]([CH3:12])(=[O:10])=[O:11])([CH3:7])[CH3:8]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)(C)S(C)(=O)=O
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: COCCOC
Solvent: O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)(C)S(C)(=O)=O)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 24 h
Yield: 15 %

Procedure:
[2-Methanesulfonyl-2-methyl-1-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (700 mg, 1.22 mmol) and (1-{2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (565 mg, 1.26 mmol) in 3:1 DME/H2O (15 mL) were treated with Pd(PPh3)4 (56 mg, 0.0050 mmol) and NaHCO3 (350 mg, 4.15 mmol). The mixture was stirred in a sealed tube at 80° C. for 24 hours. The mixture was filtered through a fritted glass funnel and concentrated. The mixture was subjected to a reverse phase HPLC column (5-95% MeCN—H2O; 0.1% TFA modifier) to afford (2-methanesulfonyl-1-{2-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (150 mg, 15%) as a white solid (TFA salt): 1H NMR (CD3OD, 300 MHz) 7.85 (m, 10H), 5.25 (m, 2H), 4.24 (d, J=7.5 Hz, 1H), 4.13 (m, 2H), 3.88 (app d, J=7.5 Hz, 2H), 3.71 (s, 3H), 3.66 (s, 3H), 2.99 (s, 3H), 2.57 (m, 2H), 2.16 (m, 10H), 1.81 (s, 3H), 1.79 (s, 1H), 0.93 (m, 6H); MS (ESI) m/z 818 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].Cl.[F:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[O:23][CH2:24][CH2:25][NH2:26].C(=O)([O-])O.[Na+].CS(C)=O>O>[ClH:1].[F:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[O:23][CH2:24][CH2:25][NH:26][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5]
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Reactant: NCCOc1cccc(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(Nc2cc(C)c(C#N)c(NCCOc3cccc(F)c3)n2)n[nH]1
Temperature: 100 °C
Reaction time: 27 h
Yield: 12.2 %

Procedure:
Compound A (1.53 g, 6.25 mmol), 2-(3-fluorophenoxy)ethylamine hydrochloride (1.79 g) and sodium hydrogencarbonate (5.25 g) were added to DMSO (30 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added dropwise to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was purified by silica gel chromatography. This was converted to hydrochloride to give the object compound of 2-(2-(3-fluorophenoxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile hydrochloride (308 mg).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[N:15]=[CH:14][C:13]([C:16]4[N:17]=[C:18]([C:21]5([C:27]6[CH:35]=[CH:34][C:30]([C:31]([OH:33])=O)=[CH:29][CH:28]=6)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[S:19][CH:20]=4)=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[C:36]1([NH2:43])[C:37]([NH2:42])=[CH:38][CH:39]=[CH:40][CH:41]=1.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>[NH2:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[NH:43][C:31](=[O:33])[C:30]1[CH:29]=[CH:28][C:27]([C:21]2([C:18]3[S:19][CH:20]=[C:16]([C:13]4[CH:14]=[N:15][C:10]([N:7]5[CH2:8][CH2:9][N:4]([CH:1]6[CH2:2][CH2:3]6)[CH2:5][CH2:6]5)=[CH:11][CH:12]=4)[N:17]=3)[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[CH:35][CH:34]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)c1ccc(C2(c3nc(-c4ccc(N5CCN(C6CC6)CC5)nc4)cs3)CCOCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccccc1NC(=O)c1ccc(C2(c3nc(-c4ccc(N5CCN(C6CC6)CC5)nc4)cs3)CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(4-{4-[6-(4-cyclopropyl-piperazin-1-yl)-pyridin-3-yl]-thiazol-2-yl}-tetrahydro-pyran-4-yl)-benzoic acid (60 mg, 0.122 mmol), benzene-1,2-diamine (26 mg, 2.0 eq), HATU (56 mg, 1.2 eq), and DIPEA (0.042 mL, 2.1 eq) were dissolved in DMF and stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was extracted with EtOAc and water. The organic phase was dried with MgSO4 and evaporated. The solid was purified by reverse phase chromatography to afford title compound. MS found for C33H36N6O2S as (M+H)+ 581.56. 1H NMR (400 MHz, dmso-d6): δ: 9.24 (s, 1H), 8.35 (s, 1H), 7.68 (d, J=6.2 Hz, 1H), 7.60 (d, J=8.2 Hz, 2H), 7.51 (s, 1H), 7.23 (d, J=8.4 Hz, 2H), 6.79 (d, J=7.2 Hz, 1H), 6.62-6.51 (m, 2H), 6.41 (d, J=7.4 Hz, 1H), 6.22 (t, J=5.2 Hz, 1H), 4.51 (s, 2H), 3.45-3.38 (m, 2H), 3.32-3.25 (m, 2H), 3.18-3.11 (m, 4H), 2.38-2.22 (m, 6H), 2.15-2.05 (m, 2H), 1.31-1.23 (m, 1H), 0.12-0.1 (m, 4H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:18][C@H:19]3[O:23]C(C)(C)[N:21]([C:26]([O:28][C@@H:29]4[C@H:36]5[C@H:32]([O:33][CH2:34][CH2:35]5)[O:31][CH2:30]4)=[O:27])[C@H:20]3[CH2:37][C:38]3[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=3)[CH2:14][CH:15]([CH3:17])[CH3:16])(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.Cl.[OH-].[Na+]>O1CCOCC1.C(Cl)Cl.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:18][C@@H:19]([OH:23])[C@@H:20]([NH:21][C:26](=[O:27])[O:28][C@@H:29]3[C@H:36]4[C@H:32]([O:33][CH2:34][CH2:35]4)[O:31][CH2:30]3)[CH2:37][C:38]3[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)CN(C[C@H]1OC(C)(C)N(C(=O)O[C@H]2CO[C@H]3OCC[C@H]32)[C@H]1Cc1ccc(O)cc1)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 81 %

Procedure:
A solution of 0.60 g (0.95 mmol) of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (4S,5R)-5-{[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]methyl}-4-(4-hydroxybenzyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate in 5 mL of 1,4-dioxane was treated with 0.25 mL of water followed by 5 mL of 4N HCl in 1,4-dioxane and the resulting solution was stirred at RT. After 1.5 hours the solution was diluted with 25 mL of CH2Cl2 and the pH adjusted to approximately 12 by addition of 1N aqueous NaOH. The mixture was diluted with water and extracted with CH2Cl2 (3×). The combined CH2Cl2 extracts were washed with aqueous brine (3×), dried over MgSO4, and concentrated in vacuo. The residue was subjected to flash chromatography (SiO2, 8:2 EtOAc/hexane) to afford the desired compound as a white solid in 81% yield. 1H NMR (CDCl3): 7.29 (dd, 1H), 7.13 (s, 1H), 7.01 (d, 2H), 6.85 (d, 2H), 6.70 (d, 2H), 6.05 (s, 2H), 5.61 (d, 1H), 5.01 (m, 2H), 3.92 (dd, 1H), 3.80 (m, 4H), 3.68 (m, 2H), 3.08 (dd, 1H), 2.91 (m, 5H), 2.81-2.62 (m, 2H), 1.80 (m, 1H), 1.64 (m, 1H), 1.47 (m, 1H), 0.90 (d, 3H), 0.82 (d, 3H). MS(ESI): 593(M+H).
Reaction SMILES: C1(C)C=C[C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12](=[O:15])([O-])[O-].[K+].[K+].[N:18]1C=CC=CC=1>CN(C)C=O.[Pd]>[OH:15][CH2:12][CH:2]1[CH2:3][CH2:4][S:7](=[O:9])(=[O:8])[NH:18]1
Reactant: c1ccncc1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Pd]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S1(=O)CCC(CO)N1

Procedure:
The preparation of intermediate III is seen to involve the following steps: (1) the Grignard reaction of vinylmagnesium bromide with phenoxyacetaldehyde and subsequent acetylation of the complex to yield 4-benzyloxy-3-acetoxy-1-butene; (2) the free radical addition of thiolacetic acid to the double bond of the latter product to yield S-acetyl-3-acetoxy-4-benzyloxy-1-butanethiol; (3) the oxidation of the thiol with chlorine in aqueous acetic acid and reaction of the resulting sulfonyl chloride with ammonia to yield 4-benzyloxy-3-hydroxy-1-butanesulfonamide; (4) tosylation of this compound with p-toluenesulfonyl chloride in pyridine and ring closure with potassium carbonate in dimethylformamide; (5) hydrogenolysis of the protecting benzyl group over a palladium catalyst to yield 3-(hydroxymethyl)isothiazolidine 1,1-dioxide; and (6) alkylation of the latter compound with a lower alkyl ester of 7-bromo-5-heptynoic acid, preferably ethyl 7-bromo-5-heptynoate in dimethylformamide in the presence of potassium carbonate to yield intermediate III.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[CH2:13][NH2:14])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C.C(OCC)(=O)C.C(O)(=O)C>[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[CH2:13][NH:14][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:10]
Reactant: O=Cc1ccccc1
Reactant: CCOC(CN)OCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCOC(CNCc1ccccc1)OCC

Procedure:
A solution of benzaldehyde (3.0 mL, 0.0295 mol) and 2-aminoacetaldehyde diethyl acetal (4.3 mL, 0.0295 mol) in dichloroethane (60 mL) was brought to pH 7 by the addition of acetic acid. Sodium triacetoxyborohydride (8.1 g, 0.038 mol) was added and the reaction stirred until complete. Saturated sodium bicarbonate was added and the reaction stirred for 30 min. Ethyl acetate was added and the organic phase washed with saturated sodium chloride, then dried over magnesium sulfate. The crude product was chromatographed on silica gel with 30% ethyl acetate in hexane. The title compound was obtained as a pale yellow oil (2.93 g). NMR (CDCl3, 300 MHz) δ 7.31 (5H, m), 4.62 (1H, t, J=5 Hz), 3.81 (2H, s), 3.68 (2H, m), 3.54 (2H, m), 2.75 (2H d, J=5 Hz), 1.20 (6H, t, J=7 Hz).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[NH:8][C:7]2[N:13]=[CH:14][C:15](I)=[CH:16][C:6]1=2.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]([C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)=[O:31])[CH2:26][CH2:25]1>>[F:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[NH:8][C:7]2[N:13]=[CH:14][C:15]([C:35]3[CH:34]=[CH:33][C:32]([C:30]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)=[O:31])=[CH:37][CH:36]=3)=[CH:16][C:6]1=2
Reactant: CC1(C)CN(Cc2cc(F)ccc2F)c2cc(I)cnc2N1
Reactant: CN1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)N(Cc3cc(F)ccc3F)CC(C)(C)N4)cc2)CC1
Yield: 55 %

Procedure:
1-(2,5-Difluorobenzyl)-7-iodo-3,3-dimethyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (44 mg) was reacted with (4-methylpiperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanone as in General Procedure 4A to give the title compound as an off-white solid (55% yield). M.p. 191-192° C., LCMS: m/z=492.10 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.34 (s, 6H), 2.32 (s, 3H), 2.38-2.50 (m, 4H), 3.13 (s, 2H), 3.45-3.58 (m, 2H), 3.65-3.85 (m, 2H), 4.52 (s, 2H), 4.90 (bs, 1H), 6.79 (d, J=1.3 Hz, 1H), 6.90-6.97 (m, 1H), 6.99-7.08 (m, 2H), 7.42 (dd, J=8.6 Hz, 4H), 7.74 (d, J=1.5 Hz, 1H).