Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=O.BrC1C=CC=C2C=1C[CH:16]([C:22]1[NH:23][C:24](=[S:27])[NH:25][CH:26]=1)C2>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[CH2:16][C:22]1[NH:23][C:24](=[S:27])[NH:25][CH:26]=1
Reactant: S=c1[nH]cc(C2Cc3cccc(Br)c3C2)[nH]1
Reactant: O=C1CCc2c(Br)cccc21
Product: S=c1[nH]cc(CC2CCc3c(Br)cccc32)[nH]1

Procedure:
Use of 4-bromoindanone (obtained by the procedures in Example NINETEEN-1 (Compound 149) in Method TWENTYFOUR produced 4-(4-bromo-indan-1-ylmethyl)-1,3-dihydro-imidazole-2-thione (Compound 167).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]=1[CH:41]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:41][C:32]3[C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:39]=[CH:40][C:31]=3[O:30][CH3:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COc1ccc2ccccc2c1C=O
Product: COc1ccc2ccccc2c1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2-methoxy-naphthalene-1-carbaldehyde. MS (ESI) m/z 379.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]#[C:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=[C:7]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:6]=1[OH:21])([CH3:4])([CH3:3])[CH3:2].[C:22](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[C:1]([C:5]1[CH:10]=[C:9]([C:11]#[C:12][Si:13]([CH3:15])([CH3:16])[CH3:14])[CH:8]=[C:7]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:6]=1[O:21][CH3:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C#C[Si](C)(C)C)cc(C(C)(C)C)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(C(C)(C)C)cc(C#C[Si](C)(C)C)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
A solution 2,6-di-tert-butyl-4-trimethylsilanylethynyl-phenol (Intermediate 167, 0.302 g, 1 mmol) in acetone (5 mL) was treated with potassium carbonate (0.138 g, 1 mmol) and methyl iodide (0.142 g, 1 mmol) and stirred overnight at room temperature. The volatiles were distilled off in vacuo and the residue was purified by flash column chromatography on silica gel (230-400 mesh) using ethyl acetate as the eluent to afford the title compound as a white solid (0.28 g, 90%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11](OS(C1C=CC(C)=CC=1)(=O)=O)[C@@H:12]1[O:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C@H:12]2[CH2:13][O:14]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)ccc1OC[C@H]1CO1
Yield: 91.2 %

Procedure:
Preparation according to Preparation 1 using 5-bromo-2-hydroxybenzaldehyde (6 g, 29 mmol), (R)-glycidyltosylate (6.7 g, 29 mmol), K2CO3 (4.9 g, 35 mmol) and DMF (12 ml). The combined organic phases were washed with LiCl (5%, 100 ml), HCl (1 N, 100 ml), brine (100 ml) and were evaporated to dryness. The residue was purified by flash column chromatography (isooctane/EtOAc) to give the crude title compound (6.8 g). MS m/z (rel. intensity, 70 eV) 257 (M+, 38), 256 (M+, 39), 200 (bp), 199 (87), 57 (88).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([C:11]#[C:12][CH2:13]OS(C)(=O)=O)=[CH:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(#N)C>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([C:11]#[C:12][CH2:13][N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CN1CCNCC1
Reactant: CS(=O)(=O)OCC#Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CN1CCN(CC#Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of methanesulfonic acid 3-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-prop-2-ynyl ester (150 mg), potassium carbonate (64 mg), N-methylpiperazine (45 μL) and acetonitrile (5 ml) were stirred at 50° C. for 3 hours. The reaction mixture was then cooled, diluted with dichloromethane, washed with brine, dried (MgSO4) and the solvents reduced in vacuo to yield 2-chloro-6-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (101 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1.[CH3:15][C:16]1[C:21](/[CH:22]=[CH:23]/[N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=[CH:18][C:17]=1[NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH:22]([C:21]3[C:16]([CH3:15])=[C:17]([NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:18]=[CH:19][CH:20]=3)[CH2:23][N+:24]([O-:26])=[O:25])=[CH:11][NH:12]2)=[CH:8][CH:7]=1
Reactant: Cc1c(/C=C/[N+](=O)[O-])cccc1NC(=O)OCc1ccccc1
Reactant: COCCOc1ccc2cc[nH]c2c1
Solvent: C1CCOC1
Product: COCCOc1ccc2c(C(C[N+](=O)[O-])c3cccc(NC(=O)OCc4ccccc4)c3C)c[nH]c2c1
Yield: 62.1 %

Procedure:
6-(2-Methoxyethoxy)-1H-indole (1.461 g, 88% purity, 6.72 mmol) and (E)-benzyl 2-methyl-3-(2-nitrovinyl)phenylcarbamate (1.75 g, 5.60 mmol) were dissolved in THF (50 mL). The solution was then concentrated under vacuum to dryness. The solid mixture was melted at 125° C. and heated at this temperature for 16 hr. The mixture was subjected to ISCO (220 g silica gel, solid loading, 25-65% ethyl acetate/hexane) to afford the desired product (1.75 g, 3.48 mmol, 62% yield) as a beige solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:9]=[CH:8][C:7]=1[CH3:16])=[O:4].[C:17]([C:19]1[CH:20]=[C:21]([S:25]([N:28]2[C@H:33]([CH3:34])[CH2:32][NH:31][CH2:30][C@@H:29]2[CH3:35])(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1)#[N:18]>>[C:17]([C:19]1[CH:20]=[C:21]([S:25]([N:28]2[C@@H:33]([CH3:34])[CH2:32][N:31]([CH2:2][C:3]([NH:5][C:6]3[CH:11]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:9]=[CH:8][C:7]=3[CH3:16])=[O:4])[CH2:30][C@H:29]2[CH3:35])(=[O:26])=[O:27])[CH:22]=[CH:23][CH:24]=1)#[N:18]
Reactant: C[C@@H]1CNC[C@H](C)N1S(=O)(=O)c1cccc(C#N)c1
Reactant: Cc1ccc(S(C)(=O)=O)cc1NC(=O)CCl
Product: Cc1ccc(S(C)(=O)=O)cc1NC(=O)CN1C[C@@H](C)N(S(=O)(=O)c2cccc(C#N)c2)[C@@H](C)C1

Procedure:
The title compound was prepared from the product of step (i) (0.14 g) and the product of Example 80 step (ii) by the method of Example 80 step (iii) as a white solid. Yield: 0.03 g
Reaction SMILES: C[O:2][C:3]1[C:6](=[O:7])[C:5](=O)[C:4]=1[NH:9][C:10]1[CH:11]=[C:12]([N:16]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:17](=[O:26])[CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])[CH:13]=[CH:14][CH:15]=1.[NH3:35]>C(O)C>[NH2:35][C:5]1[C:6](=[O:7])[C:3](=[O:2])[C:4]=1[NH:9][C:10]1[CH:11]=[C:12]([N:16]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[C:17](=[O:26])[CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])[CH:13]=[CH:14][CH:15]=1
Reactant: N
Reactant: COc1ccc(N(C(=O)C(C)c2ccccc2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Solvent: CCO
Product: COc1ccc(N(C(=O)C(C)c2ccccc2)c2cccc(Nc3c(N)c(=O)c3=O)c2)cc1

Procedure:
In a similar manner to that described in Example (1d), a solution of N-[3-(2-methoxy-3,4-dioxo-1-cyclobutenylamino)phenyl]-N-(4-methoxyphenyl)-2-phenylpropionamide (600 mg) [prepared as described in step (b) above] in ethanol (4 ml) and a solution of ammonia in ethanol (2N, 6 ml) were reacted, to afford the title compound (521 mg) as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]3[NH:28][N:27]=[N:26][N:25]=3)[CH:22]=2)[O:17][C:4]2([CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]2)[CH2:3]1.[ClH:29]>CO>[ClH:29].[NH:28]1[C:24]([C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[O:17][C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3][C:2]3=[O:1])=[N:25][N:26]=[N:27]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(-c3nnn[nH]3)ccc1O2
Agent: Cl
Solvent: CO
Product: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21

Procedure:
A mixture of 5-bromo-2-hydroxyacetophenone (104.35 g, 485.26 mmol), N-Boc-piperidin-4-one (98.62 g, 494.96 mmol), 20 mL of pyrrolidine (17.26 g, 242.63 mmol) and 261 mL of MeOH was heated under reflux until the reaction was complete. The mixture was cooled, then 87 mL of H2O were added, and the mixture was filtered and dried to give tert-butyl 6-bromo-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate. Alternatively, 10 mL of pyrrolidine (121.31 mmol) may be used in this procedure. To a solution of tert-butyl 6-bromo-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (6593 g, 16.6 mol) and DMF (33 L) was added Zn(CN)2 (1947 g, 16.6 mol) and Pd(PPh3)4 (192 g, 0.17 mol). The slurry was heated to 90° C. for 3 hours, then cooled to room temperature and filtered. Water (16 L) was added to the filtrate. The resulting slurry was cooled to 5° C., stirred for 1 hour and filtered. The solid was washed with DMF/water (2:1) and dried under vacuum to give tert-butyl 6-cyano-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate. A solution of 23 g of tert-butyl 6-cyano-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (67.17 mmol), 13.10 g sodium azide (201.52 mmol), 27.74 g of triethylamine hydrochloride (201.52 mmol), and 460 mL of dry DMF was stirred under a nitrogen atmosphere at 100° C. for 12 hours. After cooling to room temperature, 506 mL of EtOAc were added, followed by 322 mL of 1M HCl (322 mmol). Alternatively, 0.5M HCl may be added until pH=3. The resulting layers were separated, the organic layer was washed with water/methanol (115 mL/46 mL), and then concentrated to give tert-butyl 4-oxo-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidine]-1′-carboxylate. A solution of 5.08 g of tert-butyl 4-oxo-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidine]-1′-carboxylate (13.18 mmol), 8.8 mL of 12 M HCl (105.44 mmol) and 8 mL of methanol was heated to 50° C. until the reaction was complete. The resulting slurry was filtered, washed with 25 mL of methanol at room temperature, and dried to give 6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidine]-4-one hydrochloride salt.
Reaction SMILES: C(O[CH:4]([O:11]CC)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH:14](OCC)=[O:15].C(O[K])(C)(C)C>C1COCC1>[CH2:9]([O:8][C:6](=[O:7])[CH:5]([CH:4]=[O:11])[CH:14]=[O:15])[CH3:10]
Reactant: CCOC(=O)CC(OCC)OCC
Reactant: CCOC=O
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: CCOC(=O)C(C=O)C=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
Ethyl 3,3-diethoxypropionate (100 g, 525.7 mmol) was dissolved in THF (360 ml) at room temp. Ethyl formate (175.1 ml, 2.1 mol) was added at room temp. The solution was cooled in an ice-bath to 0° C. and tBuOK (1M solution in THF, 1,156 ml, 1.156 mol) was added via an addition funnel slowly over 30 min, maintaining internal temperature below 5° C. The color changed instantly from colorless to dark orange. The reaction mixture was allowed to warm up to room temp. and stirred for 2 h. The reaction was allowed to stir at room temp. for 18 h. The reaction mixture was concentrated in vacuo and 1 L of solvent was removed. The remaining brownish solution with white solid in it was cooled in an ice-bath and hydrochloric acid (6N, 200 ml) was added to adjust pH=3, maintaining internal temperature below 20° C. The resulting bright yellow suspension was then warmed up to room temp. and stirred for 1 h. Additional 700 ml solvent was removed in vacuo at room temp. Water (400 ml) was added to dissolve all the white solid and ethyl acetate (500 ml) was added and the mixture transferred to a separatory funnel. The aqueous was extracted once with ethyl acetate (200 ml). The combined organic extracts was washed once with brine (100 ml). After drying over MgSO4 and concentrating in vacuo, 2-formyl-3-oxo-propionic acid ethyl ester (75.85 g) was obtained as yellow oil.
Reaction SMILES: C([O:5][C:6](=[O:68])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:67])[NH:26][C@H:27]([C:60]([O:62]C(C)(C)C)=[O:61])[CH2:28][CH2:29][C:30](=[O:59])[NH:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][C:39](=[O:58])[NH:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][C:48]([O:50][N:51]1[C:55](=[O:56])[CH2:54][CH2:53][C:52]1=[O:57])=[O:49])(C)(C)C>C(O)(C(F)(F)F)=O>[C:60]([C@@H:27]([NH:26][C:25]([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:68])=[O:5])=[O:67])[CH2:28][CH2:29][C:30](=[O:59])[NH:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][C:39](=[O:58])[NH:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][C:48]([O:50][N:51]1[C:55](=[O:56])[CH2:54][CH2:53][C:52]1=[O:57])=[O:49])([OH:62])=[O:61]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)NCCOCCOCC(=O)NCCOCCOCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)NCCOCCOCC(=O)NCCOCCOCC(=O)ON1C(=O)CCC1=O)C(=O)O
Yield: 80 %

Procedure:
19-((S)-1-tert-Butoxycarbonyl-3-{2-[2-({2-[2-(2,5-dioxopyrrolidin-1-yloxycarbonylmethoxy)ethoxy]ethylcarbamoyl}methoxy)ethoxy]ethylcarbamoyl}propylcarbamoyl)nonadecanoic acid tert-butyl ester (3.4 g) was stirred in TFA (75 ml) for 45 min and then concentrated in vacuo. The residue was concentrated with toluene 3 times to give a solid. The residue was crystallised in 2-propanol and filtered to give a white crystalline compound. Yield 80% (2.4 g). LC-MS (electrospray): m/z: 859.44.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[NH2:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=1.C(N(CC)C(C)C)(C)C.Cl>C(O)C>[NH2:9][C:4]1[N:3]=[C:2]([NH:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=2)[CH:7]=[C:6]([Cl:8])[N:5]=1
Reactant: Nc1ccc(CO)cc1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1nc(Cl)cc(Nc2ccc(CO)cc2)n1
Reaction time: 2 h
Yield: 62.8 %

Procedure:
A mixture of 4,6-dichloro-pyrimidin-2-yl-amine (6.6 g, 40 mmol), 4-aminobenzyl alcohol (8.0 g, 65 mmol) and N,N-diisopropylethylamine (15 ml) in ethanol (200 ml) was heated under reflux for 72 hours. Concentration under reduced pressure provided a solid which was stirred with 1.0 M hydrochloric acid (200 ml) for 1 hour, filtered, dried under reduced pressure, stirred with ethyl acetate (200 ml) for 2 hours, filtered, and dissolved in methanol (300 ml). Aqueous sodium carbonate solution (1.0 M, 50 ml) was added. After stirring for 2 hours, volatiles were evaporated under reduced pressure and water (200 ml) was added. Filtration and drying provided [4-(2-amino-6-chloro-pyrimidin-4-yl-amino)-phenyl]-methanol (6.3 g, 63% yield) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH2:15]([O:18][C:19]1[CH:29]=[CH:28][C:22]([CH:23]=[CH:24][C:25](O)=O)=[CH:21][CH:20]=1)[CH2:16][CH3:17]>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:25](/[CH:24]=[CH:23]/[C:22]3[CH:21]=[CH:20][C:19]([O:18][CH2:15][CH2:16][CH3:17])=[CH:29][CH:28]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CCCOc1ccc(C=CC(=O)O)cc1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCCOc1ccc(/C=C/c2nc3c([nH]2)c(=O)n(CC)c(=O)n3CC)cc1
Yield: 54.3 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 3.00 g (15.1 mmol) of 5,6-diamino-1,3-diethyluracil and 3.43 g (16.6 mmol) of 4-propoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 3.02 g (yield 54%) of Compound 125 as pale yellow needles.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23][OH:24])[CH:19]=[C:20]([F:22])[CH:21]=1>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]=[C:20]([F:22])[CH:21]=1)[CH2:23][O:24][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1cc(F)cc(Cl)c1
Product: CN1c2cc(OCc3cc(F)cc(Cl)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (3-chloro-5-fluorophenyl)methanol.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:15](=[S:16])[N:14]([C:17]3[CH:18]=[C:19]([C:25]([F:28])([F:27])[F:26])[C:20]([C:23]#[N:24])=[N:21][CH:22]=3)[C:13](=[O:29])[C:9]32[CH2:12][CH2:11][CH2:10]3)=[CH:4][CH:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][CH:34](O)[CH2:33][CH2:32]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:30][N:31]1[CH2:36][CH2:35][CH:34]([O:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:15](=[S:16])[N:14]([C:17]4[CH:18]=[C:19]([C:25]([F:28])([F:27])[F:26])[C:20]([C:23]#[N:24])=[N:21][CH:22]=4)[C:13](=[O:29])[C:9]43[CH2:12][CH2:11][CH2:10]4)=[CH:4][CH:3]=2)[CH2:33][CH2:32]1
Reactant: CN1CCC(O)CC1
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(O)cc3)C2=S)cc1C(F)(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCC(Oc2ccc(N3C(=S)N(c4cnc(C#N)c(C(F)(F)F)c4)C(=O)C34CCC4)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.2 %

Procedure:
To a solution of 5-(5-(4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile (Compound 63, 150 mg, 0.36 mmol), 1-methylpiperidin-4-ol (50 μL, 0.39 mmol), and triphenylphosphine (125 mg, 0.47 mmol) in anhydrous THF (2 mL) was added diisopropyl azodicarboxylate (0.1 mL, 0.47 mmol) and the reaction mixture was stirred at room temperature overnight. Additional 1-methylpiperidin-4-ol (50 μL, 0.39 mmol), triphenylphosphine (125 mg, 0.47 mmol) and diisopropyl azodicarboxylate (0.1 mL, 0.47 mmol) was added and the reaction was allowed to stir an additional 16 h. The mixture was partitioned between EtOAc and water and the aqueous layer was extracted with EtOAc (2×). The combined organics were washed with water and brine, then dried over magnesium sulfate and concentrated in vacuo. Purification by silica gel chromatography (0 to 80% EtOAc/hexanes, then 0 to 5% MeOH/dichloromethane) gave impure product which was further purified by preparative HPLC (40 to 75% acetonitrile/water, 0.1% TFA) to afford 45 mg of 5-(5-(4-((1-methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 9.22 (d, 1H), 8.76 (d, 1H), 7.30 (d, 2H), 7.15 (d, 2H), 4.52-4.39 (m, 1H), 2.72-2.56 (m, 4H), 2.49-2.38 (m, 2H), 2.25-2.14 (m, 5H), 2.03-1.90 (m, 3H), 1.77-1.49 (m, 3H). LCMS [M+1]+ 516.0.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([OH:20])[C:5]=1[O:21][CH3:22])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[CH:30]([CH3:32])[CH3:31]>C(#N)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([O:20][CH2:29][CH:30]([CH3:32])[CH3:31])[C:5]=1[O:21][CH3:22])[CH3:2]
Reactant: CC(C)CBr
Reactant: CCOc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc(-c2cccc3c2CCC3=O)c(OCC(C)C)c1OC
Temperature: 80 °C
Yield: 21.1 %

Procedure:
To a stirring solution of 4-(4-ethoxy-2-hydroxy-3-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.268 mmol) in acetonitrile was added potassium carbonate (111 mg, 0.805 mmol) and isobutyl bromide (110 mg, 0.805 mmol) and the resultant reaction mixture was heated to 80° C. for 2 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded title compound as a solid (20 mg, 21%).
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([C:20]2[CH:21]=[C:22]([NH:25]C(=O)OC(C)(C)C)[S:23][CH:24]=2)=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:7]1([CH3:8])[CH:6]=[CH:5][C:4]([S:1]([N:11]2[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[C:13]([C:20]3[CH:21]=[C:22]([NH2:25])[S:23][CH:24]=3)=[CH:12]2)(=[O:3])=[O:2])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3csc(NC(=O)OC(C)(C)C)c3)c3cccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3csc(N)c3)c3cccnc32)cc1

Procedure:
tert-Butyl 4-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)thiophen-2-ylcarbamate (120 mg, 0.26 mmol) was dissolved in 2 mL CH2Cl2, 2 mL TFA. After 15 minutes the reaction mixture was concentrated to an oil, dissolved in EtOAc, and washed with 0.1 NaOH. The organic layer was dried to a brown oil which was used as obtained.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si](O[CH2:27][C:28]1[C:29]([N+:40]([O-:42])=[O:41])=[C:30]([CH:37]=[CH:38][CH:39]=1)[C:31]([NH:33][CH2:34][C:35]#[CH:36])=[O:32])(C(C)(C)C)(C)C.C(N(CC)CC)C.[Br:50][C:51]([CH3:56])([CH3:55])[C:52](Br)=[O:53]>C1COCC1>[Br:50][C:51]([CH3:56])([CH3:55])[C:52]([CH2:27][C:28]1[C:29]([N+:40]([O-:42])=[O:41])=[C:30]([CH:37]=[CH:38][CH:39]=1)[C:31]([NH:33][CH2:34][C:35]#[CH:36])=[O:32])=[O:53]
Reactant: C#CCNC(=O)c1cccc(CO[Si](C)(C)C(C)(C)C)c1[N+](=O)[O-]
Reactant: CC(C)(Br)C(=O)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCNC(=O)c1cccc(CC(=O)C(C)(C)Br)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
TBAF (4.19 mL of a 1.0 M solution in THF) was added dropwise to a stirring solution of Compound 11 (487 mg, 1.40 mmol) in THF (14 mL). TLC analysis showed complete reaction after 5 minutes, after which time the THF was removed on a rotary evaporator and the resulting oil was dissolved in EtOAC (50 mL), washed with saturated NH4Cl (2×20 mL), water (2×50 mL), dried over MgSO4, concentrated in vacuo. The resulting white solid (Compound 12) was dissolved in anhydrous THF (14 mL), triethylamine (184 mg, 1.81 mmol) was added, and the resulting solution was added dropwise to a stirring solution of □-bromoisobutyrylbromide (225 mg, 1.82 mmol) in THF (5 mL) at 0° C., A white precipitate formed immediately. The mixture was allowed to warm to room temperature and stirred overnight under argon atmosphere after which time the solid salts were filtered, and the solvent was removed on a rotary evaporator. The resulting yellow oil was dissolved in ethyl acetate (50 mL) and washed with water (3×20 mL), dried over MgSO4, concentrated in vacuo, and purified by silica gel chromatography (50% EtOAc:hexane) to yield Compound 13 (321 rag, 60%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:20])[CH2:16][C:17](=[O:19])[CH3:18])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[Br:21]Br>CC(O)=O>[Br:21][CH2:18][C:17](=[O:19])[CH2:16][C:15]([NH:14][C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)=[C:2]([F:1])[CH:3]=1)=[O:20]
Reactant: CC(=O)CC(=O)Nc1ccc(N2CCOCC2)c(F)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)CC(=O)Nc1ccc(N2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47 %

Procedure:
To a solution of N-(3-fluoro-4-morpholinophenyl)-3-oxobutanamide (11.2 g, 40.0 mmol) and AcOH (100 mL) under N2 was added Br2 (2.4 mL) at rt. At end of addition, the mixture was stirred further at rt for 24 h. The mixture was then concentrated in vacuo and 40 mL of water was added. The resulting mixture was extracted with EtOAc (30 mL×4). The combined organic phases were washed with brine (40 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:1) to give the title compound as a yellow solid (6.80 g, 47%).