Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[OH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(O[C:22]1[C:27]([C:28]2[NH:29][C:30](=[O:47])[C:31]3[C:32](=[C:34]([CH2:44][CH2:45][CH3:46])[N:35]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=4)[N:36]=3)[N:33]=2)=[CH:26][C:25]([S:48]([N:51]2[CH2:56][CH2:55][N:54]([CH2:57][CH3:58])[CH2:53][CH2:52]2)(=[O:50])=[O:49])=[CH:24][N:23]=1)C>>[CH2:57]([N:54]1[CH2:55][CH2:56][N:51]([S:48]([C:25]2[CH:26]=[C:27]([C:28]3[NH:29][C:30](=[O:47])[C:31]4[C:32](=[C:34]([CH2:44][CH2:45][CH3:46])[N:35]([CH2:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=5)[N:36]=4)[N:33]=3)[C:22]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:23][CH:24]=2)(=[O:50])=[O:49])[CH2:52][CH2:53]1)[CH3:58]
Reactant: OCc1ccccn1
Reactant: CCCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCC)[nH]c(=O)c2nn1Cc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCc3ccccn3)[nH]c(=O)c2nn1Cc1ccccn1
Temperature: 100 °C
Reaction time: 14 h
Yield: 21 %

Procedure:
A stirred mixture of potassium bis(trimethylsilyl)amide (260 mg, 1.32 mmol) and 2-hydroxymethylpyridine (5 ml) was heated at 100° C. for 1 hour, then the title compound of Example 26 (150 mg, 0.26 mmol) added and the reaction mixture stirred at 100° C. for 14 hours. The resulting cool mixture was partitioned between dichloromethane (10 ml) and brine (10 ml), the phases separated and the aqueous phase extracted with dichloromethane (2×10 ml). The combined organic solutions were dried (MgSO4) and evaporated under reduced pressure, then the residual yellow oil purified by column chromatography on silica gel, using dichloromethane: ethyl acetate: methanol (47.5:47.5:5) as eluant, to afford the title compound (35 mg, 21%) as a white solid. δ (CDCl3): 0.94 (3H,t), 1.03 (3H,t), 1.73 (2H,m), 2.40 (2H,q), 2.55 (4H,m), 2.98 (2H,t), 3.14 (4H,m), 5.69 (2H,s), 5.92 (2H,s), 7.07 (1H,d), 7.21 (1H,m), 7.33 (2H,m), 7.62 (1H,m), 7.76 (1H,m), 8.58 (2H,m), 8.81 (1H,s), 8.85 (1H,d), 12.80 (1H,s). LRMS: m/z 630 (M+1)+.
Reaction SMILES: O[Li].O.[C:4]([O:8][C:9]([NH:11][CH2:12][CH:13]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:14]([O:16]C)=[O:15])=[O:10])([CH3:7])([CH3:6])[CH3:5].C1COCC1>O>[C:4]([O:8][C:9]([NH:11][CH2:12][CH:13]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:14]([OH:16])=[O:15])=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: COC(=O)C(CNC(=O)OC(C)(C)C)Cc1ccc(Cl)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCC(Cc1ccc(Cl)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
LiOH—H2O (0.09 g, 2.1 mmol) was added to a solution of methyl 3-(tert-butoxycarbonylamino)-2-(4-chlorobenzyl)propanoate (0.64 g, 1.9 mmol) in 2:1 THF:H2O (20 mL). The reaction was then stirred for 3 hours at room temperature and then diluted with H2O (50 mL) and washed with ether (50 mL). The aqueous layer was next acidified with solid KHSO4, saturated with solid NaCl, and extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered, concentrated, and dried in vacuo to give 3-(tert-butoxycarbonylamino)-2-(4-chlorobenzyl)propanoic acid (0.523 g, 85%) as a solid. MS ESI (−) m/z 312 detected.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:11](=[O:13])[CH3:12]
Reactant: Nc1ccc(F)c(F)c1F
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(F)c(F)c1F
Yield: 82.5 %

Procedure:
2,3,4-Trifluoroaniline (36.7 g, 0.25 mol) was acetylated using acetic anhydride (105 mL, 1.25 mol), using an analogous procedure to that described in preparation 1 (step 1) to yield N-(2,3,4-trifluorophenyl)acetamide (39.0 g, 83%) as a white solid. mp 87-88° C. ; IR (KBr) 3271, 1673, 1514 cm-1 ; 1H NMR (CDCl3) δ 2.16 (s, 3H, CH3), 6.90 (q, J=4.3 Hz, 1H), 7.60 (brs, 1H, NH), 7.90 (m, 1H); Mass (m/z) 189 (M+.).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6](Br)=[CH:5][N:4]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:12]=[CH:11][C:10]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][N:4]=1
Reactant: C=CC(=O)OCC
Reactant: COc1ncc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1cnc(OC)nc1
Temperature: 135 °C
Reaction time: 12 h

Procedure:
A mixture of 2-methoxy-5-bromopyrimidine (75.43 g, 0.399 mol), ethyl acrylate (47.5 ml, 0.439 mol), palladium (II) acetate (1.07 g, 0.0048 mol), tri-o-tolylphosphine (2.92 g, 0.0096 mol) and triethylamine (84 ml) were heated at 135° C. with stirring under argon for 12 h. After allowing to cool the solid mass was dissolved in water and ethyl acetate, filtered, and the aqueous phase separated and further extracted with ethyl acetate. The combined extracts were washed with saturated aqueous ammonium chloride, dried (MgSO4) and evaporated. The solid thus obtained was triturated with ether/light petrol (1:3, 350 ml), filtered, washed and dried, yield 52.41 g (63%). 1H-NMR (CDCl3) δ 1.33 (3H, t), 4.06 (3H, s), 4.28 (2H, q), 6.45 (1H, d), 7.58 (1H, d), 8.67 (2H, s); MS (APCI+) found (M+H)=209; C10H12N2O3 requires 208.
Reaction SMILES: [I-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].[CH3:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=1)[CH:28]=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[CH3:3][C:2]1([CH3:4])[C@@H:28]([C:27]2[CH:26]=[C:25]([CH3:24])[CH:37]=[CH:36][CH:35]=2)[C@@H:29]1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)C=Cc1cccc(C)c1
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Product: CCOC(=O)[C@H]1[C@H](c2cccc(C)c2)C1(C)C
Yield: 75.3 %

Procedure:
Isopropyltriphenylphosphonium iodide (17.3 g, 40 mmol) and ethyl 3-methylcinnamate (7.6 g, 40 mmol) were reacted as described under General Procedure B to furnish the title compound (7.0 g, 75%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.17 (t, J=7.4 Hz, 1H), 7.03-6.95 (m, 3H), 4.18 (q, J=7.2 Hz, 2H), 2.66 (d, J=5.8 Hz, 1H), 2.33 (s, 3H), 1.93 (d, J=5.8 Hz, 1H), 1.38 (s, 3H), 1.30 (t, J=7.2 Hz, 3H), 0.93 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(O)CCCC>[N:16]1([CH2:15][CH2:14][N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: ClCCN1CCCCC1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCO
Product: C1CCN(CCN2CCNCC2)CC1
Reaction time: 4 h

Procedure:
To a mixture of anhydrous piperazine, 10.0 grams, (0.116 moles) and sodium carbonate (12.3 grams, 0.116 moles) in 70 cc of 1-pentanol brought to the boiling point, is added slowly over a period of four hours, N-(2-chloroethyl)piperidine, (11.3 grams; 0.077 moles) diluted with 150 cc of 1-pentanol. After boiling for an additional period of four hours, the mixture is allowed to cool, it is then filtered and evaporated under reduced pressure. The oily residue is subjected to column chromatography using methanol and concentrated ammonium hydroxide in the ratio of 95:5. The desired product is obtained as an oil, but after standing for a few hours, it solidifies. Melting point is 60°-62° from diisopropyl ether. It forms a picrate: melting point 235°-237° C. (from ethanol); Rf=0.21, (MeOH-NH4OH 9.5:0.5); IR (nujol) max: 3240, 2780, 2760, 1445, 1325, 1300, 1140, 1125, 1105, 865, 770 cm-1.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C(=O)(O)[O-].[Na+].[Br:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>CCOCC>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:18](=[O:19])[CH2:17][CH2:16][Br:15]
Reactant: O=C(Cl)CCBr
Reactant: Cc1cccc(C)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: Cc1cccc(C)c1NC(=O)CCBr
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a mixture of 2,6-dimethylaniline (2 g, 16.5 mmol), diethyl ether, and aqueous saturated sodium bicarbonate (50:50 v/v) was added dropwise 3-bromopropionoyl chloride (2 g, 19.8 mm) in ether (5 mL). The mixture was allowed to stir at 0° C. for 2 hours, and at room temperature for an additional 1 hour. The organic layer was washed with 10% citric acid, dried over MgSO4, then filtered. The solvent was evaporated to afford N-(2,6-dimethylphenyl)-3-bromopropanamide, a compound of formula (1), as a white solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([O:15][CH3:16])[CH:8]=1.CN(C)[CH:19]=[O:20].[OH-].[Na+]>>[F:6][C:7]1[CH:8]=[C:9]([O:15][CH3:16])[C:10]([CH:19]=[O:20])=[C:11]([O:13][CH3:14])[CH:12]=1
Reactant: CN(C)C=O
Reactant: COc1cc(F)cc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(F)cc(OC)c1C=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
Phosphorous oxychloride (1.8 mL, 19.3 mmol) was added slowly to a well-stirred mixture of 1-fluoro-3,5-dimethoxy benzene (2.6 mL, 19.25 mmol) and N,N-dimethylformamide (2.5 mL, 20 mmol) while temperature was kept below −5° C. Stirring was continued at room temperature for 1.5 h and at 60° C. for another 2 h. Reaction completion was monitored by TLC. The reaction mixture was cooled and hydrolyzed with ice-water (60 mL). The resulting suspension was neutralized by addition of 5N NaOH, extracted with ethyl acetate (2×30 mL), the aqueous phase was adjusted to pH 10 by 5N NaOH and re-extracted with ethyl acetate (2×30 mL). The combined organic phases were washed with saturated aqueous NaHCO3 solution (30 mL) and brine (30 mL) and dried over anhydrous sodium sulfate. The dried solution was concentrated to get the crude product which on purification by column chromatography afforded a colorless pure product. Yield: 75%; white solid mp 79-81° C. 1H NMR: δ 3.85 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 6.25 (S, 2H, Ar—H), 10.24 (s, 1H, CHO). Anal. Calcd for C18H19FO5S: C, 58.70, H, 4.92. Found: C, 58.64, H, 4.91.
Reaction SMILES: O[C:2]1[N:3]=[C:4]2[NH:11][C:10]([CH3:13])([CH3:12])[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.P(Cl)(Cl)([Cl:16])=O.[OH-].[Na+]>>[Cl:16][C:2]1[N:3]=[C:4]2[NH:11][C:10]([CH3:13])([CH3:12])[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1(C)Cn2c(nc(O)cc2=O)N1
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)Cn2c(nc(Cl)cc2=O)N1
Temperature: 120 °C

Procedure:
4.5 g of 7-hydroxy-2,2-dimethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one and 35 ml of phosphorus oxychloride are introduced into a round-bottomed flask. The resulting mixture is then heated at 120° C. for three hours. After cooling, the reaction mixture is concentrated to dryness under reduced pressure. Ice is added to the residue obtained, and then concentrated sodium hydroxide is added until a pH in the region of 5-6 is obtained. The solid formed is filtered off so as to give 1 g of 7-chloro-2,2-dimethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one, in the form of a brown solid, the characteristics of which are the following:
Reaction SMILES: [I:1]Cl.[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]2[N:11]=[CH:12][CH:13]=[C:6]2[N:5]=1>C(Cl)(Cl)Cl>[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]2[N:11]=[CH:12][C:13]([I:1])=[C:6]2[N:5]=1
Reactant: ClI
Reactant: Cc1cc(C)n2nccc2n1
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)n2ncc(I)c2n1

Procedure:
A solution of ICl [5.0g (27 mmoles)] in CHCl3 (50 ml) was added to a stirred solution of 5,7-dimethyl pyrazolo[1,5-a]pyrimidine [2.96g (20 mmoles)] in CHCl3 (50 ml). Within a few minutes, the mixture became warm and crystals of the hydrochloride salt of the subject compound began to separate. The mixture was warmed on the steam bath for 2-3 minutes to complete the reaction, and then refrigerated overnight. The yellow hydrochloride salt was separated by filtration, washed with Et2O, and air dried. The yellow solid, which weighed 4.4g, was dissolved in water (100 ml) and this solution was made alkaline by the addition of NaOH solution (2.5N). The alkaline solution was extracted with CHCl3 3(25 ml), and the CHCl3 extracts were dried over Na2SO4. The CHCl3 extract was chromatographed on basic alumina, and the CHCl3 eluant evaporated to dryness. The residue was recrystallized from petroleum ether (30°-60°) to afford 2.02g (37%) of analytically pure product; mp 120°-2°.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[N:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[C:13]=[S:14].C(=O)([O-])O.[Na+].CC(O)C>O>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([N:12]2[C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:3][N:2]=[C:13]2[SH:14])=[CH:20][CH:19]=1
Reactant: COc1ccc(N=C=S)cc1
Reactant: NCC(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(-n2c(-c3ccccc3)cnc2S)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 17.5 parts of 2-amino-1-phenylethanone hydrochloride, 16.5 parts of 1-isothiocyanato-4-methoxybenzene, 10 parts of sodium hydrogen carbonate and 200 parts of 2-propanol is stirred first for 30 minutes at room temperature and further for 2 hours at reflux temperature. The reaction mixture is poured onto 500 parts of water. The product is filtered off and stirred and refluxed for 1 hour with 240 parts of hydrochloric acid solution 10%. After cooling, the product is filtered off, washed with water and 2-propanol, and dried, yielding 25.3 parts (90%) of 1-(4-methoxyphenyl)-5-phenyl-1H-imidazole-2-thiol; mp. 167.4° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][NH:27][CH2:26]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][N:27]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:26]2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: Fc1ccc2c(c1)CNC2
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1c(F)c(N2Cc3ccc(F)cc3C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 71.3 %

Procedure:
268 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 137 mg of 5-fluoroisoindoline, 274 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 266 mg of the target compound.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:12][C:13]1[CH:28]=[CH:27][C:16]([O:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=1.C(N(CC)CC)C>C(O)(C)C>[F:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][N:24]([C:2]3[N:11]=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=3)[CH2:25][CH2:26]2)=[CH:27][CH:28]=1
Reactant: Clc1ncc2ccccc2n1
Reactant: Fc1ccc(OCCCN2CCNCC2)cc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Fc1ccc(OCCCN2CCN(c3ncc4ccccc4n3)CC2)cc1

Procedure:
2.5 g 2-Chloro-quinazoline, 3.8 g 1-[3-(4-fluorophenoxy)propyl]piperazine and 2.5 ml triethylamine in 15 ml isopropanol are stirred under reflux for 5 hours. The solvent is then evaporated in vacuo and the residue partitioned between water and methylene chloride. The organic phase is dried and evaporated. The residue is recrystallized from ethanol to yield the title compound, m.p. 126°-128° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[C:10](#[N:13])[CH:11]=[CH2:12]>O.C(OCC)(=O)C>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:12][CH2:11][C:10]#[N:13]
Reactant: C=CC#N
Reactant: CNc1ccccc1O
Solvent: CCOC(C)=O
Solvent: O
Product: CNc1ccccc1OCCC#N
Yield: 378.3 %

Procedure:
A solution of 2-methylaminophenol (0.74 g, 6.0 mmol), Triton B (60 μL, 40% in water) and acrylonitrile (4.0 mL, 60 mmol) was refluxed for 16 hrs. The mixture was diluted with ethyl acetate. The organic layer was then washed with water and brine, and was dried over MgSO4. After filtration and concentration, the residue was purified via silica gel flash column chromatography eluting with 20% ethyl acetate in hexane to give 3-(2-methylamino-phenoxy)-propionitrile (4.0 g) as a brown oil. [M+H]+ 177.1; tR=0.715 min (method 1).
Reaction SMILES: C(N(CC)[C:4](=[O:15])[CH2:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[OH:14])C.FC(F)(F)C(O)=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:13][O:12][C:11]1[C:6]2[CH2:5][C:4](=[O:15])[O:14][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CCN(CC)C(=O)Cc1c(O)cccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c1CC(=O)O2
Temperature: 125 °C
Reaction time: 1.18 h
Yield: 82.2 %

Procedure:
A solution of 0.47 g (2.0 mmol) of N,N-diethyl-(2-hydroxy-6-methoxyphenyl)acetamide in 5.0 mL of toluene was added with 0.92 mL (1.36 g, 12 mmol) of trifluoroacetic acid and heated and stirred on a 125° C. oil bath of for 71 minutes. The mixture was cooled under room temperature, and after that added with 24 mL of 0.5 N aqueous sodium hydroxide, while being stirred, and then transferred into a separatory funnel and settled. The aqueous layer was separated and discarded and after the organic layer was washed with 5 mL of water twice, the solvent was evaporated to obtain 0.27 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][C:8]([NH:12][C:13]1[N:14]=[C:15]([O:21][C@H:22]([CH3:27])[CH2:23][N:24]([CH3:26])[CH3:25])[C:16]([C:19]#[N:20])=[N:17][CH:18]=1)=[CH:7]2.ClC1C=C(C=CC=1)C(OO)=[O:33]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][C:8]([NH:12][C:13]1[N:14]=[C:15]([O:21][C@H:22]([CH3:27])[CH2:23][N+:24]([O-:33])([CH3:26])[CH3:25])[C:16]([C:19]#[N:20])=[N:17][CH:18]=1)=[CH:7]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@H](CN(C)C)Oc1nc(Nc2cc3cccc(Cl)c3cn2)cnc1C#N
Solvent: O
Solvent: ClCCl
Product: C[C@H](C[N+](C)(C)[O-])Oc1nc(Nc2cc3cccc(Cl)c3cn2)cnc1C#N
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 73.1 %

Procedure:
(R)-5-(8-Chloroisoquinolin-3-ylamino)-3-(1-(dimethylamino)propan-2-yloxy)pyrazine-2-carbonitrile (30 mg, 0.078 mmol) was dissolved in DCM (1 mL) and cooled to −10° C. 3-Chloroperoxybenzoic acid (77% wt., 12 mg, 0.086 mmol) dissolved in DCM (1 mL) was added dropwise to the solution. The reaction mixture was stirred at −10° C. for 15 minutes, and was then warmed to room temperature. The reaction mixture was diluted with water, the layers partitioned and the aqueous phase extracted with DCM. The combined organic phases were washed with brine, dried (Na2SO4) and concentrated to dryness. The residue was dissolved in methanol and absorbed on to an SPE (TsOH) cartridge. The cartridge was washed with methanol and the compound eluted with 2 M and 7 M ammonia in methanol. Preparative HPLC afforded the title compound (23 mg, 0.057 mmol, 73%). 1H NMR (d6-DMSO, 400 MHz) δ 9.25 (s, 1H), 8.39 (s, 1H), 8.30 (s, 1H), 8.12 (s, 1H), 7.73-7.71 (m, 1H), 7.57-7.56 (m, 1H), 6.10-6.07 (m, 1H), 4.16-4.10 (m, 1H), 3.77 (br d, 1H, J=14 Hz), 3.43 (s, 3H), 3.28 (s, 3H), 1.44 (d, 3H, J=6.6 Hz). LC-MS (2) Rt=2.20 min; m/z (ESI+) 399 & 401 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3](O[C:6](=[O:8])[CH:7]=1)=[O:4].[CH3:9][NH2:10].C1COCC1.C([O-])(=O)C.[Na+]>C(OCC)C>[CH3:9][N:10]1[C:6](=[O:8])[CH:7]=[C:2]([Br:1])[C:3]1=[O:4]
Reactant: O=C1C=C(Br)C(=O)O1
Reactant: CN
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN1C(=O)C=C(Br)C1=O
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Pursuant to steps a and b of Reaction Scheme 14, a solution of bromomaleic anhydride (52.8 g, 0.298 mol) in diethyl ether (250 mL) was cooled to 5° C. A 2 M solution of methylamine in THF (298 mL, 0.596 mol, 2 eq.) was added dropwise over 1 hour and the reaction stirred for a further 30 minutes, maintaining the temperature below 10° C. The resulting precipitate was filtered, washed with diethyl ether (2×100 mL) and air-dried for 30 minutes, then suspended in acetic anhydride (368 mL) and sodium acetate (12.2 g, 0.149 mol, 0.5 eq.) added. The reaction was heated to 60° C. for 2 hours and solvent was then removed in vacuo. The residue was taken up in DCM (500 mL) and washed with saturated sodium bicarbonate solution (2×500 mL) and water (2×300 mL). Organics were dried over MgSO4 (89 g), filtered and reduced in vacuo. The resulting oil was azeotroped with toluene (4×100 mL) to give N-methyl bromomaleimide as a beige solid. Yield=41.4 g (73%); 1H NMR (300 MHz, CDCl3) δ 6.95 (1H, s, CH), 3.07 (3H, s, NCH3).
Reaction SMILES: [N:1]1([C:6]2[S:7][CH:8]=[C:9]([C:11](OCC)=[O:12])[N:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CO>C(Cl)(Cl)Cl>[N:1]1([C:6]2[S:7][CH:8]=[C:9]([CH2:11][OH:12])[N:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1csc(N2CCCC2)n1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: OCc1csc(N2CCCC2)n1
Yield: 4 %

Procedure:
Using the procedure of Example 9C but replacing ethyl 2-(4-morpholinyl)thiazole-4-carboxylate with ethyl 2-(1-pyrrolidinyl)thiazole-4-carboxylate provided, after silica gel chromatography using 2-4% methanol in chloroform, the desired compound (Rf 0.26, 4% methanol in chloroform)in 53% yield. 1H NMR (CDCl3)δ2.04 (m, 4H), 2.75 (br, 1H), 3.45 (m, 4H), 4.56 (s, 2H), 6.32 (s, 1H). Mass spectrum: (M+H)+ =185.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[CH:17]1([OH:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:17]1([O:23][C:10]2[C:11]([I:12])=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[N:7]=[C:8]([NH2:16])[N:9]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: OC1CCCCC1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(OC2CCCCC2)c(I)c(-c2ccco2)n1

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine, cyclohexanol and DBU in THF. ES-MS m/e (%): 386 (M+H+, 100).
Reaction SMILES: [CH2:1]([N:3]([C:13]1[CH:18]=[C:17]([O:19]C)[CH:16]=[CH:15][C:14]=1[CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:31]C)[CH:27]=2)[CH2:22]1)[C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:2].Cl.Cl[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[CH2:1]([N:3]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[CH:9][CH:10]=1)[C:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=1[CH:21]1[CH2:30][CH2:29][C:28]2[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24][C:23]=2[CH2:22]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Reactant: ClCCN1CCOCC1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCOCC2)cc1)c1cc(O)ccc1C1CCc2cc(O)ccc2C1
Yield: 77.3 %

Procedure:
Synthesized from N-ethyl-4-hydroxy-N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]benzamide (250 mg) and 4-(2-chloroethyl)morpholine hydrochloride (140 mg) according to an analogous synthetic method to Example 368, the title compound (225 mg) was obtained.