Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[P:11]([O:18]CC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>>[CH2:13]([O:12][P:11]([CH2:2][CH2:3][O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])([O:15][CH2:16][CH3:17])=[O:18])[CH3:14]
Reactant: CCOP(OCC)OCC
Reactant: CCOC(=O)COCCCl
Product: CCOC(=O)COCCP(=O)(OCC)OCC
Yield: 97.5 %

Procedure:
36.3 g (218 mmol) of ethyl chloroethoxyacetate and 37.4 ml (218 mmol) of triethyl phosphite are heated at 50° C. for 3 hours. The reaction medium is evaporated to dryness under vacuum. 57 g (100%) of crude ethyl (diethoxyphosphoryl)ethoxyacetate are obtained.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:11]2[N:12]=[C:13]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([S-:21])[N:16]=3)=[C:10]2[CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].I[CH3:30].[OH-].[Na+]>O>[CH2:1]([NH:5][C:6]1[N:11]2[N:12]=[C:13]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:30])[N:16]=3)=[C:10]2[CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CI
Reactant: CCCCNc1cccc2c(-c3ccnc([S-])n3)c(-c3ccc(F)cc3)nn12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCNc1cccc2c(-c3ccnc(SC)n3)c(-c3ccc(F)cc3)nn12
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.3 %

Procedure:
A mixture of 4-[7-(butylamino)-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinethiolate (2.87 g, 6.9 mmol) in 50 mL water was treated with iodomethane (0.86 mL, 13.8 mmol) and sodium hydroxide (4.1 mL, 5 N aqueous solution) and allowed to stir at room temperature for 4 hours. The mixture was diluted with additional water and extracted with dichloromethane. The organic layers were washed with brine, dried over magnesium sulfate and concentrated. Flash column chromatography eluting with 9:1 hexanes-ethyl acetate afforded N-butyl-2-(4-fluorophenyl)-3-[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo[1,5-α]pyridin-7-amine (1.64 g, 56%) as a yellow foam. 1H NMR (CDCl3): δ 8.15 (d, 1H), 7.73 (d, 1H), 7.56 (m, 2H), 7.33 (t, 1H), 7.13 (t, 2H), 6.62 (d, 1H), 6.02 (m, 2H), 3.35 (q, 2H), 2.55 (s, 3H), 1.76–1.41 (m, 4H), 0.95 (t, 3H); 19F NMR (CDCl3): δ −112.75; MS m/z 408 (M+1).
Reaction SMILES: [NH:1]([CH2:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].O>ClCCl>[CH3:30][S:31]([N:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)=[O:10])(=[O:33])=[O:32]
Reactant: O=C(CNc1ccccc1)Nc1ccc(-c2ccncc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)N(CC(=O)Nc1ccc(-c2ccncc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2-anilino-N-[4-(4-pyridinyl)phenyl]acetamide (40.0 mg) in dichloromethane (0.80 mL) were added pyridine (0.0533 mL) and methylsulfonyl chloride (0.0204 mL) at 0° C. and the mixture was stirred at ambient temperature for 2 days. Water (4.0 mL) was added to the mixture at ambient temperature and the mixture was extracted with ethyl acetate (6.0 mL). The organic layer was washed successively with saturated sodium bicarbonate aqueous solution and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (4% methanol in chloroform) to afford 2-[(methylsulfonyl)(phenyl)amino]-N-[4-(4-pyridinyl)phenyl]acetamide (31.4 mg) as white crystals.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)C=C.[CH3:15][C:16]1C=CC(C)=C[CH:21]=1>>[CH2:21]([C:6]1[C:5]([OH:4])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2)[CH:16]=[CH2:15]
Reactant: C=CCOc1ccc2ncccc2c1
Reactant: Cc1ccc(C)cc1
Product: C=CCc1c(O)ccc2ncccc12
Yield: 72 %

Procedure:
A solution of 6-allyloxyquinoline (intermediate 4) (1.14 g, 6.2 mmol) in p-xylene (30 ml) was allowed to reflux for 3 days. The organic solvent was removed under vacuum. Chromatography (30% hexanes-ethyl acetate) afforded 0.82 g (72%) of 5-allyl-quinolin-6-ol as a white solid: mp 162–164° C. Elemental Analysis for C12H11NO: Calculated: C, 77.81; H, 5.99; N, 7.56. Found: C, 77.82; H, 5.99; N, 7.45.
Reaction SMILES: NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4C(=O)CCCC=4N=3)=CC=2)CCC1.C(OC(=O)[NH:35][C:36]1([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[C:55]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)=[CH:54][C:53]4[C:52]5=[N:62][NH:63][C:64](=[O:65])[N:51]5[CH2:50][CH2:49][C:48]=4[N:47]=3)=[CH:42][CH:41]=2)[CH2:39][CH2:38][CH2:37]1)(C)(C)C>>[NH2:35][C:36]1([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[C:55]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)=[CH:54][C:53]4[C:52]5=[N:62][NH:63][C:64](=[O:65])[N:51]5[CH2:50][CH2:49][C:48]=4[N:47]=3)=[CH:42][CH:41]=2)[CH2:37][CH2:38][CH2:39]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-c3n[nH]c(=O)n3CC4)cc2)CCC1
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)CCC4)cc2)CCC1
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-c3n[nH]c(=O)n3CC4)cc2)CCC1
Yield: 77.1 %

Procedure:
Following the procedure for 2-(4-(1-aminocyclobutyl)phenyl)-3-phenyl-7,8-dihydroquinolin-5(6H)-one, tert-butyl(1-(4-(3-oxo-9-phenyl-2,3,5,6-tetrahydro-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-8-yl)phenyl)cyclobutyl)carbamate (10 mg, 0.019 mmol) was reacted to afford the title compound (6 mg, 58%). LCMS (Method A): RT=3.51 min, M+2=411.2. 1H NMR (500 MHz, MeOD): 8.23 (1H, S), 7.52 (2H, d), 7.43 (2H, d), 7.34-7.32 (3H, m), 7.26-7.24 (2H, m), 4.09 (2H, t), 3.46 (2H, t), 2.81-2.75 (2H, m), 2.62-2.56 (2H, m), 2.28-2.22 (1H, m), 2.01-1.95 (1H, m).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[C@@H:5]([C:18]([OH:20])=O)[CH2:4][CH2:3]1.[NH2:21][CH:22]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:23]([OH:27])[C:24]([NH2:26])=[O:25].O[NH-].O=[N-]>>[NH2:26][C:24](=[O:25])[C:23](=[O:27])[CH:22]([NH:21][C:18]([C@H:5]1[CH2:4][CH2:3][C:2](=[O:1])[N:6]1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:15])([F:16])[F:17])=[O:20])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(O)[C@H]1CCC(=O)N1Cc1ccccc1C(F)(F)F
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Agent: [N-]=O
Agent: [NH-]O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1C(F)(F)F

Procedure:
Coupling of (R)-5-Oxo-1-(2-trifluoromethyl-benzyl)-pyrrolidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([NH:12][C:13](=[O:38])[NH:14][C:15]2[CH:37]=[CH:36][C:18]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[O:29][CH:30]=[C:31]([C:33]([OH:35])=O)[N:32]=4)[CH2:23][CH2:22]3)=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10][CH2:9]1.[C:39]([NH2:43])([CH3:42])([CH3:41])[CH3:40].C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:39]([NH:43][C:33]([C:31]1[N:32]=[C:28]([CH2:27][N:24]2[CH2:25][CH2:26][N:21]([C:19]([C:18]3[CH:36]=[CH:37][C:15]([NH:14][C:13]([NH:12][CH:8]4[CH2:9][CH2:10][CH2:11]4)=[O:38])=[CH:16][CH:17]=3)=[O:20])[CH2:22][CH2:23]2)[O:29][CH:30]=1)=[O:35])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)N
Reactant: O=C(Nc1ccc(C(=O)N2CCN(Cc3nc(C(=O)O)co3)CC2)cc1)NC1CCC1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1coc(CN2CCN(C(=O)c3ccc(NC(=O)NC4CCC4)cc3)CC2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.6 %

Procedure:
To a solution of 2-((4-(4-(3-cyclobutylureido)benzoyl)piperazin-1-yl)methyl)-oxazole-4-carboxylic acid 2,2,2-trifluoroacetate (8 mg, 15 μmol) in N,N-dimethyl-acetamide (1 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyl uronium hexafluorophosphate (5.7 mg, 154 μmol; HATU), tert-butylamine (1.6 μL, 15 μmol) and N,N-diisopropylethylamine (3.9 μL, 23 μmol). The reaction mixture was stirred at room temperature for 20 hours and was then concentrated under vacuum. The crude residue was purified by acidic reverse phase HPLC to give the title compound (5.6 mg). MS (ESI) m/z 483.1 [M+H]+
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:5]([OH:18])=[CH:6][C:7]2[C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1.[CH3:19][N:20]([CH3:24])[C:21](Cl)=[S:22].O>CN(C=O)C>[CH3:19][N:20]([CH3:24])[C:21]([O:18][C:5]1[C:4]([CH3:3])=[CH:13][C:12]2[C:11]([CH3:14])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:17])([CH3:16])[C:7]=2[CH:6]=1)=[S:22]
Reactant: CN(C)C(=S)Cl
Reactant: Cc1cc2c(cc1O)C(C)(C)CCC2(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1OC(=S)N(C)C)C(C)(C)CCC2(C)C

Procedure:
In a round bottom flask there are introduced 1.7 g (57 mmoles) of sodium hydride (80% in oil) and 50 ml of dimethylformamide. There is slowly added a solution of 10.3 g (47 mmoles) of 3-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol in 100 ml of DMF and the reaction mixture is stirred until the cessation of gas evolvement. There are then added 8.1 g (66 mmoles) of dimethylthio-carbamoylchloride in 100 ml of DMF and the reaction mixture is stirred for 4 hours at ambient temperature. The reaction mixture is poured into water and extracted with ethylether. The organic phase is decanted, washed with water, dried on MgSO4 and the solvent evaporated. The residue is purified by chromatography on a silica column (eluant: 20/80 mixture of CH2Cl2 /hexane). 13.2 g (92%) of 2-(N,N-dimethylthiocarbamoyloxy)-3-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthalene which melts at 102-103° C. are recovered.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-])=O)=[C:6]([NH:8][C:9]2[S:10][C:11]([CH3:16])=[CH:12][C:13]=2[C:14]#[N:15])[CH:7]=1.Cl.[Sn](Cl)[Cl:22]>CCO>[ClH:22].[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:17]=[C:14]([NH2:15])[C:13]3[CH:12]=[C:11]([CH3:16])[S:10][C:9]=3[NH:8][C:6]=2[CH:7]=1
Reactant: Cl[Sn]Cl
Reactant: Cc1cc(C#N)c(Nc2cc(F)ccc2[N+](=O)[O-])s1
Agent: Cl
Solvent: CCO
Product: Cc1cc2c(s1)Nc1cc(F)ccc1N=C2N
Temperature: 85 °C
Yield: 87.2 %

Procedure:
Stir 2-(5-fluoro-2-nitro-phenylamino)-5-methyl-thiophene-3-carbonitrile (113 g, 0.408 mol) as a suspension in EtOH (1.1 L) at ambient temperature. Add aqueous 6N HCl (1.1 L) and tin (II) chloride (232 g, 1.22 mol) with stirring. Heat to gentle reflux (85° C.) for 3-4 hours, and then allow cooling to ambient temperature. Filter the crude product and rinse with 1:1/EtOH:6N HCl, then deionized water, and dry in a vacuum oven at 50° C. to constant weight. Stir the crude product (139 g) as a suspension in aqueous 1N HCl (6 L) at gentle reflux (95° C.) for 2 hours, and then allow cooling to ambient temperature. Filter the product and rinse with 1N HCl and water, then dry at 50° C. to give 101 g (87%) the title compound: 1H NMR (400 MHz, DMSO-d6) δ 11.33 (bs, 1H), 9.80 (s, 1H), 9.16 (bs, 1H), 8.88 (bs, 1H), 6.99 (m, 1H), 6.89 (m, 1H), 6.84 (s, 1H), 2.28 (s, 3H). HRMS (ES) exact mass M+H calcd for C12H11ClFN3S 248.0658; found 248.0657.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[C:6](F)=[N:7][CH:8]=[CH:9][C:10]=1[I:11].[NH4+:13].[OH-].C([O-])(=O)C.[NH4+].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.CN(C=O)C>[I:11][C:10]1[CH:9]=[CH:8][N:7]=[C:6]2[C:5]=1[CH2:4][CH2:3][CH2:2][NH:13]2
Reactant: Fc1nccc(I)c1CCCCl
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Ic1ccnc2c1CCCN2
Temperature: 60 °C
Yield: 67.9 %

Procedure:
A mixture of 3-(3-chloropropyl)-2-fluoro-4-iodopyridine (5.0 g, 17 mmol), NH4OH (100 mL, 800 mmol), ammonium acetate (18 g, 230 mmol), potassium iodide (5.5 g, 33 mmol), potassium carbonate (12 g, 87 mmol) and DMF (26 mL) was heated at 60° C. for 8 h. The mixture allowed to cool, and diluted with EtOAc. The layers were separated and the organic layer was washed with brine, dried with MgSO4, then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CombiFlash® apparatus, eluting with 0 to 50% EtOAc in hexanes, to give the sub-title compound (3.0 g, 69% yield). LCMS calc. for C8H10IN2(M+H)+: m/z=261.0. Found: 261.1.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:32])=[C:7]2[C:12](=[C:13]([C:15]#[N:16])[N:14]=1)[N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[C:9]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:8]2)=[O:4].[NH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37].C[O-].[Na+]>>[CH2:17]([N:11]1[C:12]2[C:7](=[C:6]([OH:32])[C:5]([C:3]([NH:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:4])=[N:14][C:13]=2[C:15]#[N:16])[CH:8]=[C:9]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:10]1=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(C#N)c2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: N#Cc1nc(C(=O)NCCC(=O)O)c(O)c2cc(Cc3ccccc3)c(=O)n(Cc3ccccc3)c12
Temperature: 25 °C
Yield: 130.5 %

Procedure:
A mixture of 1,3-dibenzyl-8-cyano-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (23 mg, 0.054 mmol), β-alanine (2.57 g, 28.8 mmol) and NaOMe solution (43 mL, 21.6 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH 2 with 4M HCl, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 34 mg of the title compound. MS: (−) m/z 481.13 (M−1).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][C:18](=[CH:21][C:22]3[CH:30]=[C:29]4[C:25]([CH2:26][C:27](=[O:31])[NH:28]4)=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)[N:3]=1.C([O-])=O.[NH4+]>CO.O1CCCC1.[Pd]>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][C:22]3[CH:30]=[C:29]4[C:25]([CH2:26][C:27](=[O:31])[NH:28]4)=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)[N:3]=1
Reactant: Cc1ccc2c(OCCN3CCC(=Cc4ccc5c(c4)NC(=O)C5)CC3)cccc2n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc2c(OCCN3CCC(Cc4ccc5c(c4)NC(=O)C5)CC3)cccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
6-{1-[2-(Methylquinolin-5-yloxy)ethyl]piperidin-4-ylidenemethyl}-1,3-dihydroindol-2-one (150 mg; 0.36 mmol) was dissolved in a mixture of methanol (20 ml) and tetrahydrofuran (20 ml). Ammonium formate (229 mg; 3.6 mmol) was added, followed by 10% palladium on carbon (150 mg), and the resulting mixture stirred vigorously at ambient temperature for 2 h. The reaction mixture was filtered through Kieselguhr and the filtrate evaporated to dryness under reduced pressure. Chromatography on SiO2, eluting with 10% aq. ammoniacal methanol in dichloromethane (5:95), gave the title compound (150 mg; 100%) as a white foam.
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=2[C:5]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:4][CH:3]=1.[I-].[CH3:19][O-:20].[Na+]>CO.CN(C)C=O.O>[CH2:14]([CH:13]([C:5]1[C:6]2[N:7]([CH3:12])[C:8](=[O:11])[NH:9][C:10]=2[C:2]([O:20][CH3:19])=[CH:3][CH:4]=1)[CH2:16][CH3:17])[CH3:15]
Reactant: CCC(CC)c1ccc(Br)c2[nH]c(=O)n(C)c12
Reactant: C[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CCC(CC)c1ccc(OC)c2[nH]c(=O)n(C)c12
Yield: 91 %

Procedure:
A solution of 4-bromo-7-(1-ethylpropyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (250 mg, 0.841 mmol), anhydrous cuprus iodide (192 mg, 1.01 mmol) and 28% sodium methoxide in methanol (5.2 mL) in N,N-dimethylformamide (5 mL) was heated at 100° C. for 1 h. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The organics were dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (190 mg, 0.765 mmol, 91%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:13])=[CH:5][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:7]=1.[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([NH:22]C(=O)OC(C)(C)C)=[C:18]([O:30][CH3:31])[CH:17]=1)=O.N1CCCCC1>CCO>[NH2:22][C:19]1[CH:20]=[CH:21][C:16](/[CH:14]=[CH:13]/[C:4]2[O:3][C:2]([CH3:1])=[CH:7][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:5]=2)=[CH:17][C:18]=1[O:30][CH3:31]
Reactant: COc1cc(C=O)ccc1NC(=O)OC(C)(C)C
Reactant: CC1=CC(=C(C#N)C#N)C=C(C)O1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cc(/C=C/C2=CC(=C(C#N)C#N)C=C(C)O2)ccc1N
Temperature: 80 °C
Reaction time: 7 h

Procedure:
A mixture of 2-(2,6-dimethyl-4H-pyran-4-ylidene)malononitrile (1, 20.7 mg, 0.12 mmol) and aldehyde 2c (25.1 mg, 0.1 mmol) were dissolved in anhydrous EtOH (0.67 ml) at 65° C. Piperidine (0.5 μl) was added and the mixture was stirred at 80° C. for 7 hours. The solvent was removed with a stream of N2, the crude mixture was dissolved in EtOAc at 5 mg/ml and purified by normal phase preparative HPLC using hexanes/ethyl acetate as eluent. Yield: 10.6 mg (26%). LCMS ESI+m/z 406 (M+H+) H-NMR (400 MHz, CD2Cl2): 8.16 (1H, d, J=8 Hz) 7.47 (1H, d, J=16 Hz) 7.29 (1H, s) 7.19 (1h, dd, J=8 Hz, 0.4 Hz) 7.1 (1H, d, J=0.4 Hz) 6.67-6.74 (2H, m) 6.56 (1H, m) 3.97 (3H, s) 2.43 (3H, s) 1.55 (9H, s). C-NMR (400 MHz, CD2Cl2) 163.02, 160.11, 157.01, 152.81, 148.32, 138.31, 131.33, 129.29, 122.99, 118.01, 116.81, 115.74, 108.45, 107.26, 106.77, 81.27, 56.35, 28.56, 20.31. This compound was treated with a 4N HCl solution in dioxane (4 N, 1.3 ml) for 3 hrs. The mixture was diluted with hexanes, the precipitate centrifuged, re-suspended and washed with hexanes, then dried under vacuum. LCMS ESI+ m/z: 306 (M+H+). H-NMR (400 MHz, CD2Cl2) 7.37 (1H, d, J=16 hz) 7.12 (1H, dd, J=16 Hz, 0.4 Hz) 7.02 (1H, d, J=0.4 Hz) 6.56-6.63 (3H, m) 6.12 (1H, m) 3.97 (3H, s) 2.42 (3H, s). C-NMR (400 MHz, CD2Cl2) 164.58, 156.12, 151.52, 140.90, 139.05, 129.73, 127.19, 121.74, 115.48, 110.73, 109.95, 102.81, 101.68, 100.79, 90.2, 55.89, 21.02.
Reaction SMILES: [CH:1]1([N:6]([CH3:40])[C:7]2[CH:8]=[C:9]([C:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH:28]=3)[CH:10]=[C:11]([C:14](=[O:26])[NH:15][CH2:16][C:17]3[C:18](=[O:25])[NH:19][C:20]([CH3:24])=[CH:21][C:22]=3[CH3:23])[C:12]=2[CH3:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([N:6]([CH3:40])[C:7]2[C:12]([CH3:13])=[C:11]([CH:10]=[C:9]([C:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH:28]=3)[CH:8]=2)[C:14]([NH:15][CH2:16][C:17]2[C:18](=[O:25])[NH:19][C:20]([CH3:24])=[CH:21][C:22]=2[CH3:23])=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCNCC3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To a stirred solution of tert-butyl 4-(3-(cyclopentyl(methyl)amino)-5-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-4-methylphenyl)-5,6-dihydropyridine-1(2H)-carboxylate (0.800 g, 1.45 mmol) in DCM was added TFA (3 mL) and the reaction mixture was stirred at RT for 2 h. On completion, reaction was concentrated to dryness. Residue was basified with aqueous sodium bicarbonate till pH 8 and aqueous layer extracted with 20% MeOH/DCM. Combined organic layers were dried over sodium sulfate and concentrated to afford crude material which was purified by preparative HPLC to afford the desired compound (0.620 g, 95%).
Reaction SMILES: [OH:1][C:2]([CH3:23])([CH3:22])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[N:13][C:12]2=[O:19])=[CH:7][C:6]=1[O:20][CH3:21].[Cl:24][C:25]1[CH:30]=[CH:29][C:28](CS)=[CH:27][CH:26]=1>C(Cl)Cl>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:18][S:17][C:14]2[CH:15]=[CH:16][N:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][C:2]([OH:1])([CH3:23])[CH3:22])=[C:6]([O:20][CH3:21])[CH:7]=3)[C:12](=[O:19])[N:13]=2)=[CH:27][CH:26]=1
Reactant: COc1cc(-n2ccc(SC)nc2=O)ccc1OCC(C)(C)O
Reactant: SCc1ccc(Cl)cc1
Solvent: ClCCl
Product: COc1cc(-n2ccc(SCc3ccc(Cl)cc3)nc2=O)ccc1OCC(C)(C)O
Temperature: 145 °C
Yield: 69.8 %

Procedure:
A mixture of 1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)-4-(methylthio)pyrimidin-2(1H)-one (90 mg, 0.268 mmol) and (4-chlorophenyl)methanethiol (707 μl, 5.35 mmol) was heated to 145° C. (neat) for 30 min. The mixture was diluted with methylene chloride, washed with water, dried (Na2SO4) and concentrated. The crude product was subjected to ISCO flash chromatography (silica gel/hexanes:ethyl acetate 100:0 to 0:100 gradient) to afford the title compound 4-(4-chlorobenzylthio)-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-2(1H)-one A-1 (83.5 mg, 0.187 mmol, 69.8% yield) as a yellow solid. LC/MS 447 (M+H)+, tR 0.93 (method 5); 1H NMR (400 MHz, chloroform-D) δ 7.33-7.44 (3H, m), 7.24-7.31 (2H, m), 6.91-6.99 (2H, m), 6.86 (1H, dd, J=8.53, 2.51 Hz), 6.24 (1H, d, J=7.03 Hz), 4.48 (2H, s), 3.86 (3H, s), 3.85 (2H, s), 1.35 (6H, s).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:16]=[N:17][NH:18][CH:19]=4)[C:11]=3[CH:20]=2)=[N:5][N:6]=1.[CH3:21][O:22][CH2:23]Cl.[H-].[Na+].O>CN(C)C=O>[CH3:21][O:22][CH2:23][N:18]1[CH:19]=[C:15]([C:12]2[C:11]3[CH:20]=[C:7]([C:4]4[O:3][C:2]([CH3:1])=[N:6][N:5]=4)[CH:8]=[CH:9][C:10]=3[O:14][CH:13]=2)[CH:16]=[N:17]1
Reactant: COCCl
Reactant: Cc1nnc(-c2ccc3occ(-c4cn[nH]c4)c3c2)o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCn1cc(-c2coc3ccc(-c4nnc(C)o4)cc23)cn1
Reaction time: 0.17 h
Yield: 51.6 %

Procedure:
To a solution of 2-methyl-5-[3-(1H-pyrazol-4-yl)-1-benzofuran-5-yl]-1,3,4-oxadiazole (213 mg, 0.80 mmol) and (chloromethyl) methyl ether (0.091 mL, 1.2 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 60 mg, 1.2 mmol) by small portions at room temperature, and the resulting mixture was stirred for 10 min. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=1/1) and crystallized from hexane/ethyl acetate to give the title compound (128 mg, yield 52%) as colorless crystals.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:27]=[CH:26][C:25]([O:28][Si:29]([C:42]([CH3:45])([CH3:44])[CH3:43])([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][C:10]=1[CH2:11][NH:12][C:13](=[O:23])[CH2:14][NH:15]C(OC(C)(C)C)=O>C(Cl)Cl>[Br:8][C:9]1[CH:27]=[CH:26][C:25]([O:28][Si:29]([C:42]([CH3:45])([CH3:44])[CH3:43])([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][C:10]=1[CH2:11][NH:12][C:13](=[O:23])[CH2:14][NH2:15]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCc1cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ccc1Br
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[Si](Oc1ccc(Br)c(CNC(=O)CN)c1)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
Trifluoroacetic acid is added to a solution of product from Step C in methylene chloride. After one hour at room temperature, the solution is evaporated, and the residue is partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase is washed with saturated NaCl, dried over magnesium sulfate, filtered and evaporated to provide the title compound.