Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[CH3:30][S:31]([O:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)(=[O:33])=[O:32].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH3:30][S:31]([O:34][C:35]1[CH:36]=[C:37]([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C@H:3]([NH:12][C:13]([C:15]3([NH:21][C:22]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:28])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:14])[C:2]([NH2:1])=[O:29])=[CH:6][CH:7]=2)[CH:38]=[CH:39][CH:40]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Oc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3cccc(OS(C)(=O)=O)c3)cc2)C(N)=O)CCOCC1
Reaction time: 20 h

Procedure:
(S)-tert-butyl 4-(1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 1, step (iii), 300 mg), 3-(methylsulfonyloxy)phenylboronic acid (Example 12, step (i), 125 mg) and potassium carbonate (240 mg) in acetonitrile (10 mL) and water (5 mL) were stirred and heated at 90° C. under a nitrogen atmosphere with 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (11 mg). After 20 h the reaction was complete and the solvents were removed under reduced pressure. The residue was partitioned between water (100 mL) and ethyl acetate (100 mL), and the organic phase collected and dried over magnesium sulfate. The extract was concentrated to a gum and the crude material purified by chromatography on silica eluting with ethyl acetate to afford the sub-titled is compound (120 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:6])[CH3:5])[CH3:2].Br[C:8]1[CH:9]=[C:10]([S:15][C:16]2[CH:26]=[CH:25][C:19]([O:20]CC(O)=O)=[C:18]([Cl:27])[CH:17]=2)[CH:11]=[C:12]([OH:14])[CH:13]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[CH:36])=[CH:31][CH:30]=1>C(N(CC)CC)C.CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:6])[CH2:5][O:20][C:19]1[CH:25]=[CH:26][C:16]([S:15][C:10]2[CH:11]=[C:12]([OH:14])[CH:13]=[C:8]([C:36]#[C:35][C:32]3[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=3)[CH:9]=2)=[CH:17][C:18]=1[Cl:27])[CH3:2]
Reactant: O=C(O)COc1ccc(Sc2cc(O)cc(Br)c2)cc1Cl
Reactant: C#Cc1ccc(Cl)cc1
Reactant: CCOC(C)=O
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1ccc(Sc2cc(O)cc(C#Cc3ccc(Cl)cc3)c2)cc1Cl

Procedure:
[4-(3-Bromo-5-hydroxy-phenylsulfanyl)-2-chloro-phenoxy]-acetic acid ethyl acetate (1.1 g; 2.63 mmol), 4-chlorophenylacetylene (1.08 g; 7.9 mmol), bis(triphenylphosphine)-palladium (II) chloride (0.15 g; 0.21 mmol) and copper iodide (0.03 g; 0.16 mmol) were dissolved in a mixture of triethylamine (5 mL) and DMF (5 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 100° C. for 1 h. The reaction mixture was evaporated to dryness and portioned between 5% aqueous citric acid and ethyl acetate. The organic phase was dried and evaporated to dryness. The crude product was purified by flash chromatography (ethyl acetate:heptane 1:3). Yield: 1.1 g. HPLC-MS: m/z: 473.3 (M+); Rt: 2.76 min.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH2:7]([O:9][C:10](=[O:17])[C:11](=O)[CH:12](Br)[CH2:13][CH3:14])[CH3:8]>C(O)C>[CH2:7]([O:9][C:10]([C:11]1[N:1]=[C:2]2[N:6]([C:12]=1[CH2:13][CH3:14])[CH:5]=[CH:4][S:3]2)=[O:17])[CH3:8]
Reactant: CCOC(=O)C(=O)C(Br)CC
Reactant: Nc1nccs1
Solvent: CCO
Product: CCOC(=O)c1nc2sccn2c1CC

Procedure:
A mixture of 2-aminothiazole (2 g, 20 mmol) and 3-bromo-2-oxo-pentanoic acid ethyl ester (4.4 g, 20 mmol) in ethanol (40 mL) is refluxed for 20 h. The solvent is removed in vacuo until dryness. The residue is purified by column chromatography (5% methanol in methylene chloride) to give 5-ethyl-imidazo[2,1-b]thiazole-6-carboxylic acid ethyl ester as an oil. Step 2. Preparation of 5-ethyl-6-hydroxymethyl-imidazo[2,1-b]thiazole
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][SH:12])=[CH:2]1.[C:13]([O:19][CH3:20])(=[O:18])[CH2:14][C:15]([CH3:17])=O.C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:20][O:19][C:13](=[O:18])[CH2:14][C:15]1([CH3:17])[C:2]2[NH:1][C:9]3[C:4]([C:3]=2[CH2:10][CH2:11][S:12]1)=[CH:5][CH:6]=[CH:7][CH:8]=3
Reactant: COC(=O)CC(C)=O
Reactant: SCCc1c[nH]c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)CC1(C)SCCc2c1[nH]c1ccccc21
Reaction time: 12 h

Procedure:
Indole-3-ethanethiol (1.5 g.) and methyl acetoacetate are mixed with 50 ml. of benzene and the solution heated for 30 min. (bath temperature 70°-80° C.). p-Toluenesulfonic acid (0.15 g.) is added and the reaction mixture is subjected to reflux and stirring for 12 hours. Water formed in the reaction mixture during this period is collected by a water separator. After cooling the benzene solution is washed with a 10% solution of sodium bicarbonate, water, saturated brine and dried over sodium sulfate. Evaporation of the benzene solution yields the ester, 1-methyl-1, 3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acid methyl ester as a semi-solid, γmaxCHCl3 1715 cm-1.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(Cl)[Cl:24]>>[ClH:24].[CH2:21]([O:20][C:18](=[O:19])[CH2:17][NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:22]
Reactant: CCOC(=O)CBr
Reactant: ClCCl
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNCc1ccccc1
Product: Cl
Reaction time: 24 h
Yield: 28 %

Procedure:
In a 3 liter erlenmeyer flask was placed 107.2 g (1.0 mole) of benzylamine, 152.0 g (1.5 mole) of triethylamine and 1.5 liter of methylene chloride. The resulting solution was stirred while 167.0 g (1.0 mole) of ethyl bromoacetate was added dropwise. The mixture was washed with water (3×300 mL), dried over magnesium sulfate, filtered and solvent was removed by rotary evaporation. The resulting oil was dissolved in ether and hydrogen chloride saturated ether was then added slowly until precipitation was complete. The precipitate was a gummy solid and the mixture was stoppered and let sit for one day. Over this time the precipitate formed a hard solid which was filtered off and dried in vacuum to give 62.8 g (28%) of N-benzylglycine ethyl ester hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([OH:10])[CH:3]=1.CN(C=O)C.Br[CH2:17][C:18]([CH:20]=[CH2:21])=[CH2:19].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH2:19][C:18](=[CH2:17])[CH:20]=[CH2:21])[CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1O
Reactant: C=CC(=C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CC(=C)COc1cc(Cl)ccc1C=O
Temperature: 70 °C
Yield: 84.6 %

Procedure:
To a solution of 4.1 g (0.026 mol) of 4-chloro-2-hydroxybenzaldehyde and 27 mL of DMF was added 5 g (0.034 mol) of 2-bromomethyl-1,3-butadiene and 7.2 g (0.052 mol) of potassium carbonate. The resulting mixture was heated at 70° C. for 4 h and then cooled to room temperature and poured into a mixture of 100 mL of water and 100 mL of methylene chloride. The aqueous layer was extracted with two 100 mL portions of methylene chloride and the combined organic layers were washed twice with 100 mL of water, twice with 100 mL of saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated to give 4.9 g of an oil. Purification by flash chromatography using 250 g of silica gel and eluting with 10:1 hexanes-EtOAc gave 2.6 g of the desired product. 200 MHz 1H NMR (CDCl3): δ4.82 (s, 2H), 5.18-5.42 (m, 4H), 6.45 (dd, 1H), 7.01 (s, 1H), 7.05 (d, 1H), 7.79 (d, 1H), 10.48 (s, 1H).
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]([C:14]([OH:16])=[O:15])[CH2:3][CH2:2]1.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CCCc2[nH]c3ccccc3c21
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1CCCc2[nH]c3ccccc3c21

Procedure:
A stirred mixture of 13 g. 1,2,3,4-tetrahydrocarbazole-4-carboxylic acid, 7.8 g. benzyl chloride and 6.5 g. sodium carbonate in dry dimethylformamide was heated on a steam bath for one hour and filtered. The dimethylformamide was evaporated under reduced pressure and the resulting oil was taken up in ether. The ether solution was washed with water, dried and evaporated to give, after recrystallization, 15.5 g. of the title compound, m.p. 108°-112°C. (heptane).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:42])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([OH:35])=O)[N:28]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CN(C([O:50][N:51]1N=N[C:53]2[CH:54]=[CH:55]C=[N:57][C:52]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CC[N:79]([CH:83]([CH3:85])[CH3:84])[CH:80]([CH3:82])C.C(O)(C(F)(F)F)=O>CN(C=O)C.C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:42])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([N:79]3[CH2:80][CH2:82][CH2:85][C@H:83]3[C:84]3[O:50][N:51]=[C:52]([CH:53]4[CH2:55][CH2:54]4)[N:57]=3)=[O:35])[N:28]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)O)n(-c3ccccc3)n2)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3c3nc(C4CC4)no3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 213 mg 4-{(S)-4-tert-Butoxycarbonyl-2-[(5-carboxymethoxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 7 ml DMF were added 138 mg HATU, 50 mg HOAT, 0.19 ml DIPEA and 65 mg 3-Cyclopropyl-5-(S)-pyrrolidin-2-yl-[1,2,4]oxadiazole. It was concentrated, the residue dissolved in dichloromethane and extracted with aqueous LiCl (4% w/w), aqueous NaHCO3 and 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated to furnish the crude coupling product as colorless oil. The latter one was dissolved in 10 ml DCM and treated with 403 μl TFA. After stirring for 12 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound.
Reaction SMILES: [C:1]1([N:11]2[CH2:17][CH2:16][C:15]3[C:18]([OH:22])=[N:19][CH:20]=[N:21][C:14]=3[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][N:2]=1.N1C2CCNCCC=2C(O)=NC=1.[Cl:35]C1C2C(=CC=CC=2)C(Cl)=NN=1.CCN(CC)CC>CN(C=O)C.O>[Cl:35][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]([N:11]2[CH2:17][CH2:16][C:15]3[C:18]([OH:22])=[N:19][CH:20]=[N:21][C:14]=3[CH2:13][CH2:12]2)=[N:2][N:3]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: Oc1ncnc2c1CCN(c1nncc3ccccc13)CC2
Agent: Oc1ncnc2c1CCNCC2
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ncnc2c1CCN(c1nnc(Cl)c3ccccc13)CC2
Temperature: 25 °C
Yield: 55 %

Procedure:
7-Phthalazin-1-yl-6,7,8,9-tetrahydro-5H-pyrimido-[4,5-d]azepin-4-ol. A solution of 6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol (50 mg, 0.33 mmol), 1,4-dichlorophthalazine (55 mg, 0.28 mmol), and Et3N (0.11 mL, 0.81 mmol) in DMF (5 mL) was heated at 120° C. for 2 h. The mixture was cooled to rt, diluted with water, and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated to give 7-(4-chloro-phthalazin-1-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol (50 mg, 55%), of which 23 mg (0.14 mmol) was treated with ammonium formate (116 mg, 1.85 mmol) and Pd(OH)2/C (14 mg, 0.08 mmol) in MeOH/dioxane (1:1; 4 mL). After 1 h at 100° C., the mixture was cooled rt, filtered through diatomaceous earth, and concentrated to give the title compound, which was carried on to Step D as in Example 1. MS (ESI−): mass calcd. for C26H28N6, 424.24; m/z found, 423.2 [M−H]−. 1H NMR (CDCl3): 9.13 (s, 1H), 8.51 (s, 1H), 8.08-8.04 (m, 1H), 7.91-7.80 (m, 3H), 7.48-7.36 (m, 4H), 6.56 (s, 1H), 4.04-3.97 (m, 2H), 3.96-3.89 (m, 2H), 3.37-3.30 (m, 2H), 3.20-3.08 (m, 2H), 1.32 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.[CH3:16][NH2:17]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([NH:17][CH3:16])=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=C(Cl)N1CC(Oc2ccc(Cl)cc2)C1
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)N1CC(Oc2ccc(Cl)cc2)C1
Reaction time: 18 h
Yield: 85.2 %

Procedure:
A stirred solution of 5 g (0.02 mole) of 3-(4-chlorophenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was treated with 4.7 g (0.06 mole) of 40% aqueous monomethylamine. After stirring for 18 hr, the reaction mixture was diluted with 200 ml of water and the solid which separated was collected by filtration, 5.7 g. Recrystallization from benzene-ligroin was accomplished by adding magnesium sulfate to absorb the water which separated from the wet product. After filtering and cooling the hot filtrate, the precipitated solid was collected by filtration to yield 4.1 g (85.2%) of white crystals, m.p. 144°-145° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1.[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C.O.Cl>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][C:8]=1[C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C1CCC(=O)O1
Reactant: c1ccc2ccccc2c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O
Product: O=C(O)CCC(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Yield: 41.6 %

Procedure:
Naphthalene (5.0 gm, 0.039 moles) and succinic anhydride (4.68 gm, 0.0468 moles) were taken up in dichloroethane (50 ml). Aluminium chloride (11.44 g, 0.0858 moles) was added at room temperature and the resulting mixture heated under reflux for 1 hr with stirring. The reaction mixture was cooled to room temperature, diluted with 25 ml of 1:1 mixture of water and Conc. hydrochloric acid. After stirring for 10 min the separated solid was filtered under suction, washed with water and dilute hydrochloric acid. Subsequent column chromatography gave a buff coloured solid. Subsequent chromatography gave 3.7 gm (41%) the title compound, mp 173-174° C.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:16][C:17]([CH:19]1[CH2:21][CH:20]1[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([CH3:29])[C:23]=1[CH3:30])=[O:18])C>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:28][C:25]3[CH:26]=[CH:27][C:22]([CH:20]4[CH2:21][CH:19]4[C:17]([OH:18])=[O:16])=[C:23]([CH3:30])[C:24]=3[CH3:29])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccnc1SC1CCC1
Reactant: CCOC(=O)C1CC1c1ccc(O)c(C)c1C
Product: Cc1c(OCc2cccnc2SC2CCC2)ccc(C2CC2C(=O)O)c1C
Yield: 82.3 %

Procedure:
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (0.032 g, 0.149 mmol) obtained in Step C of Preparation Example 23 and 2-(4-hydroxy-2,3-dimethyl-phenyl)-cyclopropane carboxylic acid ethyl ester (0.035 g, 0.149 mmol) obtained in Step C of Preparation Example 48 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.047 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C@@H:20]([OH:33])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([OH:32])([CH3:31])[CH3:30])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:41](OC(=O)C)(=[O:43])[CH3:42]>ClCCl>[C:41]([O:33][C@H:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14](/[CH:13]=[CH:12]/[C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=2)[CH:15]=1)[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([OH:32])([CH3:31])[CH3:30])(=[O:43])[CH3:42]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(O)c1ccccc1CC[C@H](O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H](CCc1ccccc1C(C)(C)O)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 2-[2-[3(S)-[3-[2-(7-Chloro-2-quinolinyl)ethenyl]phenyl]-3-hydroxy propyl]phenyl]-2-propanol (100 gm) in dichloromethane (500 ml) at 25-30° C. 4-di(methyl amino)pyridine (5.32 gm) was added and cooled to 0° C. To the reaction mixture Triethylamine (26.4 gm) was added at 0° C. Acetic anhydride (26.7 gm) was added slowly at temp. 0-5° C. over 30-60 min and maintained the reaction at temp. 0-5° C. over 30 min. Reaction completion was monitored by TLC. After reaction completion the reaction mass was quenched into 7% NaHCO3(500 ml) and stirred for 15 min. Temperature was raised to 25-30° C. and maintained for 30 min. Reaction mass was settled for 15 min and separated the organic layer. Aq.layer was extracted with dichloromethane (250 ml). The combined organic layer was washed with 25% NH4Cl solution (500 ml). Organic layer was distilled below 40° C. to get the desired product as residue.
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[CH2:3][C@H:4]([C@H:8]([OH:10])[CH3:9])[C:5]([OH:7])=O.[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:18][NH2:19].[CH2:20](Cl)[CH2:21]Cl>ClCCl>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:18][NH:19][C:5](=[O:7])[C@H:4]([CH2:3][CH:2]([CH3:1])[CH3:11])[C@H:8]([OH:10])[CH2:9][CH2:20][CH3:21]
Reactant: ClCCCl
Reactant: CC(C)C[C@@H](C(=O)O)[C@@H](C)O
Reactant: NOC1CCCCO1
Solvent: ClCCl
Product: CCC[C@@H](O)[C@@H](CC(C)C)C(=O)NOC1CCCCO1
Yield: 49.8 %

Procedure:
(2R,3R)-2-(2-Methyl-1-propyl)-3-hydroxybutanoic acid (6.6 g, 41.2 mmol) and 5.3 g (45.3 mmol) of 2-tetrahydropyranyloxyamine are stirred in 60 mL of dichloromethane as 8.7 g (45.3 mmol) of EDC is added. After 4 h at 25° C. the reaction mixture is partitioned between 1 N aqueous hydrochloric acid and dichloromethane and the organics are washed with saturated aqueous sodium bicarbonate. The organics are dried over magnesium sulfate and concentrated under reduced pressure to afford 5.9 g (55%) of (2R,3R)-2-(2-methyl-1-propyl)-3-hydroxyhexanoic acid 2-tetrahydropyranyloxyamide as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11].C[Si]([N:36]=[C:37]=[O:38])(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:27][CH2:28][N:29]([C:37]([NH2:36])=[O:38])[CH2:30][CH2:31]4)[CH:25]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11]
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CCNCC4)c3)cc12
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CCN(C(N)=O)CC4)c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine (8.0 mg, 0.0174 mmol), trimethylsilyl isocyanate (4.02 mg, 0.0349 mmol), DIPEA (0.02 mL, 0.09 mmol) and DCM (1 mL) was stirred at rt for 30 min. The solution was concentrated in vacuo, redissolved in MeOH and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.89 (d, J=7.1 Hz, 3 H), 1.93-2.05 (m, 2H), 2.07-2.16 (m, 2 H), 2.95-3.06 (m, 2 H), 4.17 (d, J=13.6 Hz, 2 H), 4.41 (tt, J=11.5, 4.2 Hz, 1 H), 5.25-5.34 (m, 1 H), 7.19 (t, J=8.7 Hz, 1 H), 7.36 (d, J=1.5 Hz, 1 H), 7.38-7.52 (m, 2 H), 7.58 (s, 1 H), 7.90 (s, 1 H), 8.32 (d, J=1.8 Hz, 1 H). MS (ES+): m/z 501.02 (100) [MH+]. HPLC: tR=3.15 min (ZQ3, polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:4]=1[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12](=[O:16])[N:11]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:19][CH:18]=3)[C:10](=[S:29])[NH:9][C:8]=2[C:7]1=[O:30].[OH-].[Na+].I[CH2:40][CH3:41].Cl>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:4]=1[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12](=[O:16])[N:11]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:21][CH:22]=3)[C:10]([S:29][CH2:40][CH3:41])=[N:9][C:8]=2[C:7]1=[O:30]
Reactant: CCI
Reactant: COc1ccc(CN2CCc3c([nH]c(=S)n(-c4ccc(OCC(F)(F)F)cc4)c3=O)C2=O)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCSc1nc2c(c(=O)n1-c1ccc(OCC(F)(F)F)cc1)CCN(Cc1ccc(OC)cc1OC)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-(2,4-dimethoxybenzyl)-2-thioxo-3-[4-(2,2,2-trifluoroethoxy)phenyl]-1,2,3,5,6,7-hexahydropyrido[3,4-d]pyrimidine-4,8-dione (68 mg) in N,N-dimethylformamide (2 ml) were added 1M aqueous sodium hydroxide solution (140 μl) and iodoethane (11 μl), and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into 0.5M hydrochloric acid (4 ml), and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the colorless title compound (72 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[O:8][C:7](=[O:13])[C:6]=2[CH:14]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:15]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:11])([CH3:12])[O:8][C:7](=[O:13])[C:6]=2[CH:14]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)OC(=O)c2cc(O)ccc2O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OC(=O)c2cc(OCc3ccccc3)ccc2O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 500 mg 6-hydroxy-2,2-dimethyl-benzo[1,3]dioxin-4-one (2.57 mmol), 550 mg benzyl bromide (3.22 mmol), and 922 mg cesium carbonate (2.8 mmol) in 8.6 mL of anhydrous DMF were stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate and washed successively with water, saturated sodium bicarbonate, and brine solutions. The organic fraction was dried over sodium sulfate and concentrated under reduced pressure to give a crude residue which was further purified by column chromatography, eluting from silica gel with a gradient of 10 to 50% ethyl acetate in hexanes, to give the desired product as a pale yellow solid. MS: (+) m/z 285.10 (M+1)