Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:15]3=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=[C:14]3[N:13]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=3)[C:12]2=[O:35])[CH2:7][CH2:6]1)(=O)C.CO.[OH-].[Na+]>O1CCCC1>[CH3:34][O:33][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[O:31][CH3:32])[CH2:24][N:13]1[C:14]2[C:15](=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=2)[N:11]([C@H:8]2[CH2:7][CH2:6][C@H:5]([OH:4])[CH2:10][CH2:9]2)[C:12]1=[O:35]
Reactant: COc1ccc(Cn2c(=O)n([C@H]3CC[C@H](OC(C)=O)CC3)c3ncc(C(F)(F)F)cc32)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Cn2c(=O)n([C@H]3CC[C@H](O)CC3)c3ncc(C(F)(F)F)cc32)cc1OC
Temperature: 25 °C

Procedure:
A mixture of 3-(trans-4-acetoxycyclohexyl)-1-(3,4-dimethoxybenzyl)-6-trifluoromethyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one (125 mg) in a mixture of tetrahydrofuran (1 mL), methanol (0.5 mL) and 1N-sodium hydroxide (0.507 mL) was refluxed for an hour. After cooling to room temperature, the mixture was concentrated in vacuo. Water was added to the residue, and the resulting precipitate was collected by filtration. The obtained solid was washed with water and subjected to a preparative silica gel column chromatography eluting with 5% methanol in chloroform. The obtained solid was washed with a mixture of diethyl ether and diisopropyl ether to give 1-(3,4-dimethoxybenzyl)-3-(trans-4-hydroxycyclohexyl)-6-trifluoromethyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one (62.9 mg) as a colorless solid.
Reaction SMILES: [C:1]([NH:5][S:6]([CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=O)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:25].[Na+]>CO>[C:1]([NH:5][S:6]([CH2:9][CH:10]([NH2:25])[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(C)(C)NS(=O)(=O)CC(=O)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)NS(=O)(=O)CC(N)c1ccc(F)cc1

Procedure:
A solution of 0.66 g of N-(tert-butyl)-2-(4-fluorophenyl)-2-oxoethanesulfonamide, 1.85 g of ammonium acetate and 0.17 g of sodium cyanoborohydride in 12 ml of methanol was stirred at 60° C. for 17 hours. After the removal of the solvent under reduced pressure, the residue was taken up in 50 ml of ethyl acetate and washed twice with 30 ml of 0.5 N aqueous sodium hydroxide solution and 30 ml of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4 and concentrated by rotary evaporation. The crude product was subjected to a chiral separation.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si](C(C)(C)C)(C)C)[CH:12]=[CH:11][C:10]=1[CH:23]1[CH2:28][CH2:27][C:26]([OH:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]1)(C(C)(C)C)(C)C>CO>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[CH:23]1[CH2:28][CH2:27][C:26]([OH:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]1
Reactant: CCOC(=O)C1(O)CCC(c2ccc(O[Si](C)(C)C(C)(C)C)cc2O[Si](C)(C)C(C)(C)C)CC1
Solvent: CO
Product: CCOC(=O)C1(O)CCC(c2ccc(O)cc2O)CC1
Reaction time: 1 h
Yield: 35.7 %

Procedure:
A solution of the other isomer of ethyl 4-(2,4-bis{[tert-butyl(dimethyl)silyl] oxy}phenyl)-1-hydroxycyclohexanecarboxylate (25 mg, 0.05 mmol) in methanol (2 ml) was stirred rapidly with Amberlyst A-26 (100 mg) for 18 hr. After this time the reaction mixture was filtered. The resin was then stirred rapidly for 1 hr in a solution of methanol (2 ml) and glacial acetic acid (5 drops). The reaction mixture was filtered and the combined filtrates concentrated in vacuo. Purification via flash column chromatography (SiO2, ethyl acetate/petrol, 2:1) afforded the title compound (5 mg, 34%) as a white solid. δH (d4-MeOH) 1.22 (3H, t), 1.40-1.54 (4H, m), 1.63-1.74 (2H, m), 2.18-2.25 (2H, m), 2.68-2.78 (1H, m), 4.14 (2H, q), 6.11 (1H, dd), 6.15 (1H, d), 6.71 (1H, d); m/z (ES−) 279 (M−H)−.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:16])[CH3:15])[C:10]([CH2:18][CH3:19])([CH3:17])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[OH-].[Pd+2]>[CH3:15][N:14]([CH3:16])[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1([CH2:18][CH3:19])[CH3:17]
Reactant: [H][H]
Reactant: CCC1(C)CN(Cc2ccccc2)CCC1N(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC1(C)CNCCC1N(C)C

Procedure:
A mixture of 20% Pd(OH)2 on carbon (0.7 g) and 1-benzyl-4-dimethylamino-3-ethyl-3-methyl piperidine (6 g, 23 mmol) in methanol (50 ml) was stirred in hydrogen atmosphere (1 atm.) for 48 hr at room temperature. The catalyst was filtered off, washed with methanol and filtrate was concentrated to afford 4-dimethylamino-3-ethyl-3-methylpiperidine. Yield 2.8 g (72%), C10H22N2, m/z 171 (M+1).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2C(=CC=[CH:10][CH:11]=2)[C:6](=[O:13])[C:5]1=O)[CH2:2]C.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[O:26].BrCCCN1CCOCC1>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:10][CH2:11][CH2:12][N:4]1[CH2:1][CH2:2][O:13][CH2:6][CH2:5]1)[C:20](=[O:25])[C:19]2=[O:26]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: CCCN1C(=O)C(=O)c2ccccc21
Agent: BrCCCN1CCOCC1
Product: O=C1C(=O)N(CCCN2CCOCC2)c2ccc(Cl)cc21

Procedure:
This compound was prepared in a similar method as 1-propylindoline-2,3-dione by reacting commercially available 5-chloro isatin (purchase from Fisher Scientific) with the 4-(3-bromopropyl)morpholine. 1H NMR δ 7.57 (m, 2H), 6.98 (d, 1H), 3.82 (t, 2H), 3.64 (m, 4H), 2.41 (m, 6H), 1.87 (m, 2H).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]=[O:17])=[C:8]2[N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:25]([OH:27])[CH3:26]>>[OH:27][CH2:25][CH2:26][N:21]1[CH2:22][CH2:23][N:18]([C:8]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:15]3[C:10]([C:9]=2[CH:16]=[O:17])=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:19][CH2:20]1
Reactant: CC(O)Br
Reactant: O=Cc1c(N2CCNCC2)n(-c2ccccc2)c2ccccc12
Product: O=Cc1c(N2CCN(CCO)CC2)n(-c2ccccc2)c2ccccc12
Yield: 87 %

Procedure:
1-Phenyl-2-piperazin-1-yl-1H-indole-3-carboxaldehyde is reacted with bromoethanol as described in Example 30 to afford 2-[4-(2-hydroxyethyl)piperazin-1-yl]-1-phenyl-1H-indole-3-carboxaldehyde (87% yield) as a yellow solid. TLC (ethyl acetate-10% methanol) Rf 0.13; ESI/MS 350 (M+H); RT 2.67 min; NMR 10.16 (1H, s); 8.13 (1H, d, J=6 Hz); 7.68 (5H, m); 7.20 (2H, m); 6.91 (1H, d, J=6 Hz); 4.39 (1H, t); 3.47 (2H, q); 3.2 (4H, m); 2.34 (6H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]([CH:23]2[CH2:25][CH2:24]2)[CH2:20][CH2:21][CH3:22])[C:13]=1[NH2:26].[C:27](OC)(=[O:31])[C:28]([CH3:30])=O>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13]2[N:26]=[C:28]([CH3:30])[C:27](=[O:31])[N:18]([CH:19]([CH:23]3[CH2:25][CH2:24]3)[CH2:20][CH2:21][CH3:22])[C:14]=2[N:15]=[CH:16][CH:17]=1
Reactant: COC(=O)C(C)=O
Reactant: CCCC(Nc1nccc(-c2ccc(OC(F)F)cc2Cl)c1N)C1CC1
Product: CCCC(C1CC1)n1c(=O)c(C)nc2c(-c3ccc(OC(F)F)cc3Cl)ccnc21

Procedure:
4-(2-Chloro-4-difluoromethoxy-phenyl)-N2-(1-cyclopropyl-butyl)-pyridine-2,3-diamine (0.300 g, 0.79 mmol) and methyl pyruvate (142 μL, 1.58 mmol) were treated substantially as described in Part F of Example 113 to give 8-(2-chloro-4-difluoromethoxy-phenyl)-4-(1-cyclopropyl-butyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 117). 1H NMR (300 MHz, CDCl3) δ 8.47–8.46 (2d, 1H, J=4.8 Hz), 7.37–7.28 (m, 2H), 7.20–7.10 (m, 2H), 6.85–6.37 (t, 1H, J=72.8 Hz), 5.18–5.02, 4.60–4.51 (2m, 1H), 2.49 (s, 3H), 2.40–2.32 (m, 1H), 2.29–2.17 (m, 2H), 2.10–2.00 (m, 1H), 0.92–0.88 (t, 3H, J=7.4 Hz), 0.87–0.77 (m, 1H), 0.59–0.42 (m, 2H), 0.40–0.31 (m, 2H). MS (AP) m/z 434.1 [(M+H)+, 100)].
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([CH2:16][O:17][CH:18]3[CH:23]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH:31]5[CH2:34][N:33]([C:35]6[S:36][CH:37]=[CH:38][N:39]=6)[CH2:32]5)=[CH:26][CH:25]=4)[CH2:22][CH2:21][N:20](C(OCC4C=CC=CC=4)=O)[CH2:19]3)[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH2:7]1.CO.[OH-].[K+]>O1CCOCC1.O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([CH2:16][O:17][CH:18]3[CH:23]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH:31]5[CH2:32][N:33]([C:35]6[S:36][CH:37]=[CH:38][N:39]=6)[CH2:34]5)=[CH:26][CH:25]=4)[CH2:22][CH2:21][NH:20][CH2:19]3)[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH2:7]1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OC4CN(c5nccs5)C4)cc3)cc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: COCCCN1CCOc2ccc(COC3CNCCC3c3ccc(OC4CN(c5nccs5)C4)cc3)cc21
Temperature: 100 °C
Reaction time: 5 h

Procedure:
0.190 g of benzyl 3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-[4-(1-thiazol-2-ylazetidin-3-yloxy)phenyl]piperidinecarboxylate is dissolved in 8 ml of dioxane. 8 ml each of methanol and 40% KOH are added and the reaction mixture is stirred at 100° C. in a sealed flask over 5 hours. The reaction mixture is subsequently cooled to room temperature, diluted with 40 ml of water and extracted with ethyl acetate (3×40 ml). The combined organic phases are washed with 40 ml of water, dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[I-].[Na+].[C:15]1([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Cl)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN(C)P(N(C)C)(N(C)C)=O>C(O)C.O>[C:15]1([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCCCCCc1ccccc1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCO
Product: CCOC(=O)c1ccc(NCCCCCc2ccccc2)cc1
Temperature: 110 °C

Procedure:
A mixture of 18.2 g. of ethyl p-aminobenzoate 10.2 g. of sodium iodide, 10.0 g. of 5-phenylpentyl chloride and 60 ml. of hexamethylphosphoramide is stirred and heated at 110° C. in an oil bath for 20 hours. The mixture is chilled, diluted with 25 ml. of water and 25 ml. of ethanol, chilled and filtered. The solid is washed with 50 ml. of ethanol-water (1:1), with water and once with cold ethanol to give pale yellow crystals, m.p. 63°-64° C. Recrystallization from ethanol gives off-white crystals, m.p. 73°-75° C.
Reaction SMILES: C([O-])(=O)C.[Na+].[Cl:6][C:7]1[CH:8]=[C:9]([C:13](=[N:15][O:16][C:17](=O)[C@H:18]([OH:20])[CH3:19])[NH2:14])[CH:10]=[CH:11][CH:12]=1>O.C(O)C>[Cl:6][C:7]1[CH:8]=[C:9]([C:13]2[N:14]=[C:17]([C@H:18]([OH:20])[CH3:19])[O:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: C[C@@H](O)C(=O)ON=C(N)c1cccc(Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@@H](O)c1nc(-c2cccc(Cl)c2)no1
Temperature: 90 °C

Procedure:
A solution of 1.53 g (18.6 mmol) sodium acetate in water (12 mL) was added to 3.88 g (16.0 mmol) 3-chloro-N′-{[(2R)-2-hydroxypropanoyl]oxy}benzenecarboximidamide dissolved in ethanol (50 mL). The mixture was heated to 90° C. for 5.5 h and then evaporated to dryness and purified via flash chromatography (Hep/EA=9/1) to give after drying 2.3 g (65%) of the title compound. 1H NMR: 8.09 (t, 1 H), 7.97 (td, 1 H), 7.45-7.51 (m, 1 H), 7.42 (t, 1 H), 5.15 (qd, 1 H), 2.57 (d, 1 H), 1.72 (d, 3 H)
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([CH2:13][OH:14])[CH2:5]1.[C:16]1(C)C=CC=CC=1.S(OC)(OC)(=O)=O>C1(C)C(C)=CC=CC=1.O>[CH3:3][C:4]1([CH3:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([CH2:13][O:14][CH3:16])[CH2:5]1
Reactant: Cc1ccccc1
Reactant: CC1(C)CC(CO)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: COS(=O)(=O)OC
Solvent: O
Product: COCC1CC(C)(C)c2ccccc21
Reaction time: 5 h
Yield: 92 %

Procedure:
A solution of 17.25 g (0.43 mol) of 60% sodium hydride in 500 ml of xylene was heated to 100° C. To this was dropwise added over 2 hours a mixture of 69 g (0.39 mol) of 1,1-dimethyl-3-hydroxymethylindane (IX) and 250 ml of toluene. After stirring for 5 hours, 27.1 g (0.215 mol) of dimethyl sulfate was added dropwise to the reaction mixture over 2 hours. After the addition, the mixture was stirred for 3 hours to complete the reaction. 250 ml of water was added to the resulting reaction mixture to separate the water and organic layers. The organic layer was washed with water, an aqueous solution of sodium sulfate, and saturated brine, and dried over anhydrous magnesium sulfate. After removing the solvent, the residue was distilled under reduced pressure to produce 68.3 g (0.36 mol) of 1,1-dimethyl-3-methoxymethylindane at a yield of 92%. The product was a colorless, transparent liquid having a green, herbal, woody odor.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10]C)=[O:9])=[CH:6][CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[NH:3]1.O.[OH-].[Li+]>CO.O>[O:1]=[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[C:4]([C:12]([F:14])([F:13])[F:15])[NH:3]1
Reactant: COC(=O)c1ccc(C(F)(F)F)[nH]c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(C(F)(F)F)[nH]c1=O

Procedure:
At room temperature, 4.73 g (21.4 mmol) of methyl 2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate were dissolved in 45 ml of methanol and 15 ml of water, 1.80 g (42.8 mmol) of lithium hydroxide monohydrate were added and the mixture was then heated under reflux for 2 h. The mixture was concentrated to about 15 ml and then washed with dichloromethane and the aqueous phase was adjusted to pH 2 by addition of 2N hydrochloric acid. The mixture was again extracted with dichloromethane, and the organic phase was dried and concentrated. This gave 4.2 g (94% of theory) of a colorless powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][O:23][CH2:24][CH2:25][N:26]1[CH2:32][CH2:31][C:30]2[CH:33]=[C:34]([NH2:37])[CH:35]=[CH:36][C:29]=2[CH2:28][CH2:27]1>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:37][C:34]2[CH:35]=[CH:36][C:29]3[CH2:28][CH2:27][N:26]([CH2:25][CH2:24][O:23][CH3:22])[CH2:32][CH2:31][C:30]=3[CH:33]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1cc(OC)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: CNC(=O)c1cc(OC)ccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl

Procedure:
2-(2,5-Dichloro-pyrimidin-4-ylamino)-5-methoxy-N-methyl-benzamide of Example 607 was reacted with 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine, in a similar manner as Example 601b, to yield desired product 2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-5-methoxy-N-methyl-benzamide as a lyophylate (29%); 1H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 9.71 (bs, 1H), 9.43 (s, 1H), 8.75 (bs, 1H), 8.54 (d, J=8.59 Hz, 1H), 8.18 (s, 1H), 7.53 (s, 1H), 7.42 (d, J=8.85 Hz, 1H), 7.32 (d, J=2.78 Hz, 1H), 7.12-7.06 (m, 2H), 3.83 (s, 3H), 3.8-3.6 (m, 6H), 3.45 (m, 2H), 3.34 (s, 3H), 3.25-2.9 (m, 4H), 2.9 (d, J=4.04 Hz, 3H); MS (m/e) 511.37 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:11]=[C:10]([CH3:12])[C:9](=[O:13])[NH:8][C:7]1=[O:14].[C:15]([O-:18])(=[S:17])[CH3:16].[K+]>CC(C)=O>[C:15](=[O:18])([S:17][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:11]=[C:10]([CH3:12])[C:9](=[O:13])[NH:8][C:7]1=[O:14])[CH3:16]
Reactant: Cc1cn(COCCCl)c(=O)[nH]c1=O
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)SCCOCn1cc(C)c(=O)[nH]c1=O
Yield: 67.1 %

Procedure:
92.0 mg (421 μmol) 1-[(2-chloroethoxy)methyl]-5-methyl-2,4(1H,3H)-pyrimidinedione were suspended in 6 ml acetone and 60.1 mg (526 μmol) potassium thioacetate were added and the reaction mixture was heated to reflux for 6 hours. The suspension was concentrated in vacuo and ethyl acetate was added. The organic layer was washed with water, dried over Na2SO4 and evaporated. The crude product was purified by flash chromatography on silica gel (ethyl acetate/hexane 9:1) to give 73 mg of the desired product. MS (ISP): 259.1 (MH+), 281.1 (MNa+). 1H-NMR (DMSO-d6): 1.76 (d, 3H), 2.32 (s, 3H), 3.01 (t, 2H), 3.58 (t, 2H), 5.04 (s, 2H), 7.57 (d, 1H), 11.32 (s, br, 1H).
Reaction SMILES: Cl[CH:2]([CH3:4])[CH3:3].[Mg].[C:6]1([C:12]2[NH:13][C:14]([CH3:19])=[C:15]([CH:17]=[O:18])[N:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1COCC1>[C:6]1([C:12]2[NH:13][C:14]([CH3:19])=[C:15]([CH:17]([OH:18])[CH:2]([CH3:4])[CH3:3])[N:16]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)Cl
Reactant: Cc1[nH]c(-c2ccccc2)nc1C=O
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1[nH]c(-c2ccccc2)nc1C(O)C(C)C
Yield: 57.9 %

Procedure:
35 Grams (0.45 mol) of 2-chloropropane was added to 10.8 g (0.45 mol) of magnesium in 100 ml of diethyloxyde. Then 55.8 g (0.3 mol) of 2-phenyl-4-formyl-5-methyl-1H-imidazole in 100 ml of THF were added. At the end of the addition, the mixture was refluxed for 30 minutes and then cooled and poured on ice water. The aqueous layer was extracted twice with 100 ml of diethyl ether. Evaporation of the solvent gave a residue which was recrystallized in ethanol to yield 40 grams of 2-phenyl-4-(1-hydroxy-2-methylpropyl)-5-methyl-1H-imidazole, which melted at 214° C.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:15][CH3:16])[CH3:14])=[CH:9][CH:8]=1)=[O:5].[OH:22][CH2:23][CH2:24][O:25][C:26]1[C:33]([CH3:34])=[CH:32][C:29]([CH:30]=O)=[CH:28][C:27]=1[CH3:35]>C(O)C>[CH:13]([C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:20][CH:19]=[C:18]([F:21])[CH:17]=3)[N:1]=[C:30]2[C:29]2[CH:32]=[C:33]([CH3:34])[C:26]([O:25][CH2:24][CH2:23][OH:22])=[C:27]([CH3:35])[CH:28]=2)=[CH:12][CH:11]=1)([CH2:15][CH3:16])[CH3:14]
Reactant: CCC(C)c1ccc(NC(=O)c2cc(F)ccc2N)cc1
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Solvent: CCO
Product: CCC(C)c1ccc(-n2c(-c3cc(C)c(OCCO)c(C)c3)nc3ccc(F)cc3c2=O)cc1
Temperature: 25 °C

Procedure:
Anhydrous CuCl2 (0.21 g, 1.6 mmol) was added to a solution of 2-amino-N-(4-sec-butylphenyl)-5-fluorobenzamide (0.15 g, 0.52 mmol), and 4-(2-hydroxyethoxy)-3,5-dimethyl-benzaldehyde (0.12 g, 0.63 mmol) in ethanol (30 mL). The resulting green solution was heated at reflux for 3 hours. After cooling to room temperature, the mixture was concentrated under vacuum. The residue was stirred with water (20 mL), and extracted with ethyl acetate (2×25 mL). The organic layer was separated, washed with brine, and dried over Na2SO4. The solvent was evaporated under vacuum, and the residue was purified by flash column chromatography on a Biotage (25 M silica column) using a gradient of hexane:ethyl acetate (8:2 to 5:5) mixture as eluent to afford the title compound. Yield: 0.19 g (77%). MP 70-72° C. 1H-NMR (400 MHz, CDCl3): 7.99 (m, 1H), 7.82 (m, 1H), 7.53 (m, 1H), 7.15 (m, 2H), 7.09 (d, 2H), 6.97 (s, 2H), 3.91 (m, 2H), 3.78 (m, 2H), 2.59 (m, 1H), 2.15 (s, 6H), 2.02 (t, 1H), 1.54 (m, 2H), 1.21 (d, 2H), 0.73 (t, 3H).
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([N:12]3[CH2:15][CH:14]([CH2:16][C:17]([O:19]CC)=[O:18])[CH2:13]3)[O:11][C:7]=2[C:6]([N:22]2[CH2:26][CH2:25][C@H:24]([N:27]([CH3:29])[CH3:28])[CH2:23]2)=[C:5]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:4]=1[CH3:36])#[N:2].[OH-].[Na+].Cl>O1CCCC1>[C:1]([C:3]1[C:8]2[N:9]=[C:10]([N:12]3[CH2:15][CH:14]([CH2:16][C:17]([OH:19])=[O:18])[CH2:13]3)[O:11][C:7]=2[C:6]([N:22]2[CH2:26][CH2:25][C@H:24]([N:27]([CH3:29])[CH3:28])[CH2:23]2)=[C:5]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:4]=1[CH3:36])#[N:2]
Reactant: CCOC(=O)CC1CN(c2nc3c(C#N)c(C)c(-c4ccccc4)c(N4CC[C@H](N(C)C)C4)c3o2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N3CC(CC(=O)O)C3)nc2c1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.9 %

Procedure:
Ethyl (1-{4-cyano-7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-methyl-6-phenyl-1,3-benzoxazol-2-yl}azetidin-3-yl)acetate (I-191) (220 mg, 0.45 mmol) was dissolved in tetrahydrofuran (5 ml), then 1 N sodium hydroxide (4.5 ml, 4.5 mmol) was added, followed by stirring at room temperature for 18 hours. After the reaction, the solvent was evaporated away under reduced pressure, then 1 N hydrochloric acid (4.5 ml, 4.5 mmol) was added, followed by extraction with a mixed solvent of chloroform:methanol (10:1) and by washing with saturated sodium hydrogencarbonate solution, then the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was subjected to preparative silica gel column chromatography. The eluate with chloroform/methanol (4:1, v/v) gave the entitled compound (35 mg, 17%) as a pale yellow crystal.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]1[N:14]=[C:13]([Cl:15])[N:12]=[C:11]([C:16]([O:18]C)=O)[CH:10]=1)(=[O:3])[NH2:2].[NH3:20]>CO>[C:1]([C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]1[N:14]=[C:13]([Cl:15])[N:12]=[C:11]([C:16]([NH2:20])=[O:18])[CH:10]=1)(=[O:3])[NH2:2]
Reactant: COC(=O)c1cc(N2CCC[C@H]2C(N)=O)nc(Cl)n1
Reactant: N
Solvent: CO
Product: NC(=O)c1cc(N2CCC[C@H]2C(N)=O)nc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
A mixture of (S)-methyl 6-(2-carbamoylpyrrolidin-1-yl)-2-chloropyrimidine-4-carboxylate (0.849 g, 2.98 mmol) in 7M ammonia in MeOH (5.0 mL) was stirred at ambient temperature overnight and then filtered. The filter cake was washed with methanol (1×2 mL)) and dried under vacuum at 40° C. to give (S)-6-(2-carbamoylpyrrolidin-1-yl)-2-chloropyrimidine-4-carboxamide as a white powder (0.611 g, 2.27 mmol, 76% yield). LC/MS: m/z=270.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]1=[O:21].[CH2:22]([O:24]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:23].Cl>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:22]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]1=[O:21])(=[O:24])[CH3:23]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc2c(c1)CCC(Cc1ccncc1Br)C2=O
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CCC(Cc1ccncc1C(C)=O)C2=O
Temperature: 110 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
A toluene solution (9 mL) of compound 99 (1.0 g, 2.89 mmol), Pd(dba)2 (70 mg, 0.12 mmol) and PPh3 (30 mg, 0.12 mmol) was stirred at room temperature under argon for 15 min. Then, (1-ethoxyvinyl)tri(n-butyl)stannane (1.08 mL, 3.18 mmol) in toluene (6 mL) was added and the resulting mixture was stirred overnight at 110° C., cooled to room temperature and filtered on Celite, washed with EtOAc and concentrated under reduced pressure. Purification on silica gel (Petroleum ether 100% to EtOAc 100%) afford the product which was placed in presence of an aqueous solution of HCl 1M for 30 minutes at room temperature. After neutralization with a saturated aqueous solution of NaHCO3, aqueous phase was extracted with dichloromethane and the combined organic layers were dried over magnesium sulfate to afford the title compound 103 (Yield 475 mg, 96%) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][S:4][CH2:5][C:6]1[N:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][CH:7]=1.N>[Ni].C(O)C>[NH2:13][CH2:12][C:9]1[CH:10]=[N:11][C:6]([CH2:5][S:4][CH2:3][C:2]([CH3:15])([CH3:14])[CH3:1])=[CH:7][CH:8]=1
Reactant: CC(C)(C)CSCc1ccc(C#N)cn1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CC(C)(C)CSCc1ccc(CN)cn1
Yield: 105.1 %

Procedure:
To a slurry of Raney Nickel (0.5 g, 50% in water) in ethanol (100 mL) add a solution of 6-[(2,2-dimethylpropyl)thiomethyl]-pyridine-3-carbonitrile (1 g) in ethanol (10 mL) followed by aqueous ammonia (0.88 M, 5 mL) and hydrogenate the mixture in a Parr shaker at 60 psi for 3 h. Filter the mixture through Celite® washing the filter cake with ethanol (50 mL). Remove the solvent in vacuo to obtain the title compound as a colourless oil (1.07 g, 100%).