Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13]C)=[O:12])[CH:9]=2)[CH:4]=[CH:3]1.[OH-].[Na+]>CO.C1COCC1.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[CH:4]=[CH:3]1
Reactant: COC(=O)c1ccc2ccn(C)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cn1ccc2ccc(C(=O)O)cc21
Reaction time: 8 h
Yield: 248.6 %

Procedure:
Methyl 1-methyl-1H-indole-6-carboxylate 166 (1.24 mmol) was stirred with sodium hydroxide (0.59 g, 14.88 mmol) in a 2:2:1 mixture of methanol/THF/water (7.5 mL) for 36 hrs at rt to form a precipitate which was collected by filtration and lyophilized overnight to give the title compound 167 (0.54 g, 99% yield). MS: 175.06 (calc), 176.1 (obs).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[Cl:31])=[CH:13][CH:12]=2)=[O:10])=[N:6][CH:7]=1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:31][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:16]=1[O:15][C:14]1[CH:32]=[CH:33][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([C:38]4[CH:39]=[CH:40][C:35]([Cl:34])=[CH:36][CH:37]=4)=[CH:7][N:6]=3)=[CH:12][CH:13]=1)[O:23][CH2:22][CH2:21][CH:20]2[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(Br)cn4)cc3)c(Cl)cc21
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(-c5ccc(Cl)cc5)cn4)cc3)c(Cl)cc21
Temperature: 100 °C
Reaction time: 36 h
Yield: 56.4 %

Procedure:
Ethyl 7-(4-(5-bromopyridin-2-ylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (50 mg, 0.094 mmol), 4-chlorophenylboronic acid (15 mg, 0.094 mmol), Na2CO3 (25 mg, 0.24 mmol) and Pd(PPh3)4 (11 mg, 0.0094 mmol) were placed in a 1 mL vial and diluted with toluene (800 μL) and water (80 μL). The vial was purged with argon, sealed and heated to 100° C. After stirring for 36 hours, the reaction was loaded onto silica gel eluting with 5% ethyl acetate/hexanes to 70% ethyl acetate/hexanes to yield the desired compound (30 mg, 0.053 mmol, 57% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:15]#N)=[N:10][C:11]([CH3:14])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-:17].[Na+].[OH2:19]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:15]([OH:19])=[O:17])=[N:10][C:11]([CH3:14])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: Cc1ccc(-c2ccc(F)cc2)c(C#N)n1
Reactant: O
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(-c2ccc(F)cc2)c(C(=O)O)n1
Temperature: 100 °C

Procedure:
To the solution of 3-(4-fluorophenyl)-6-methylpicolinonitrile (0.555 g, 2.615 mmol) in MeOH (3 mL) was added NaOH (1.1 g, 27.5 mmol) and H2O (1.8 mL). The mixture was heated at 100° C. for 8 h. The reaction was cooled to rt and acidified to pH-5. The solvent was removed in vacuo. The crude was extracted with MeOH. The solvent was removed in vacuo and the obtained acid was dried in vacuum for next step with no further purification. ESI-MS (m/z): 233 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:17]C)[CH:5]=[C:6]([C:8]2([C:13]([O:15][CH3:16])=[O:14])[CH2:12][CH:11]=[CH:10][CH2:9]2)[CH:7]=1.B(Br)(Br)Br.C[Si](C=[N+]=[N-])(C)C.CCCCCC>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[C:6]([C:8]2([C:13]([O:15][CH3:16])=[O:14])[CH2:9][CH:10]=[CH:11][CH2:12]2)[CH:7]=1
Reactant: COC(=O)C1(c2cc(F)cc(OC)c2)CC=CC1
Agent: BrB(Br)Br
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CCCCCC
Product: COC(=O)C1(c2cc(O)cc(F)c2)CC=CC1
Reaction time: 1 h
Yield: 86.1 %

Procedure:
To a stirred solution of methyl 1-(5-fluoro-3-methoxyphenyl)cyclopent-3-ene-1-carboxylate (495 mg, 2.0 mmol) in dry dichloromethane (10 ml) was added a 1.0M solution of boron tribromide in dichloromethane (10 ml, 10 mmol) at -78° C. and the mixture stirred for 1 hr at the same temperature. The reaction mixture was quenched by the addition of water (20 ml) and the resulted mixture acidified with 1.0N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated under reduced pressure. The residue was dissolved in a mixture of methanol (5 ml) and toluene (15 ml) and a 2.0M solution of trimethylsilyldiazomethane in hexane (2 ml, 4 mmol) was added at ambient temperature with stirring. After 0.5 hr, the reaction mixture was partitioned between ethyl acetate and water, the organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with brine, dried with MgSO4 and concentrated in vacuo. The resultant oil was purified by column chromatography (SiO2, 150 g; hexane/ethyl acetate (4/1)) to afford 407 mg (87%) of methyl 1-(5-fluoro-3-hydroxyphenyl)cyclopent-3-ene-1-carboxylate white crystals.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([S:19](Cl)(=[O:21])=[O:20])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]>>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([S:19]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:20])=[O:21])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: Cc1noc(N)c1Br
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Product: COc1ccc(S(=O)(=O)Nc2onc(C)c2Br)cc1OC
Yield: 64 %

Procedure:
3,4-Dimethoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 3,4-dimethoxybenzenesulfonyl chloride according to the procedures described in Example 45. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 136°-138° C., yield 64%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH:28]([OH:30])[CH3:29].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:30][CH:28]([C:19]2[CH:20]=[CH:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=2)[CH3:29])[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: CC(O)c1ccc2ccccc2c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CC(Oc1nc(N)nc(-c2ccco2)c1C#N)c1ccc2ccccc2c1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, (RS)-1-(2-naphthyl)ethanol and DBU in DME. ES-MS m/e (%): 357 (M+H+, 100).
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][O:9][C:8]([NH:12][C@H:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15][CH2:14]3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C-:22]#[N:23].O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C@H:13]1([NH:12][C:8]2[O:9][CH2:10][C:11]3[C:2]([C:22]#[N:23])=[CH:3][CH:4]=[CH:5][C:6]=3[N:7]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: [C-]#N
Reactant: Brc1cccc2c1COC(N[C@@H]1CCc3ccccc31)=N2
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc2c1COC(N[C@@H]1CCc3ccccc31)=N2
Temperature: 160 °C
Yield: 49.2 %

Procedure:
A stirred mixture of (5-bromo-4H-benzo[d][1,3]oxazin-2-yl) -(R)-indan-1-yl-amine (Example 10) (1.03 g, 3.79 mmol), zink cyanide (528 mg, 4.5 mmol) and tetrakis-(triphenylphosphine)-palladium (347 mg, 0.3 mmol) in DMF (9 ml) was heated at 160° C. for 15 min in a microwave reactor. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine (2×40 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel to yield the title compound as white foam (540 mg, 62%). MS (ISN) m/e=288.2 [(M−H)−].
Reaction SMILES: CO.[C:3]([C:5]1[C:10]([F:11])=[C:9]([F:12])[C:8]([OH:13])=[C:7]([F:14])[C:6]=1[F:15])#[N:4].[C:16](Cl)(=[O:20])[C:17]([CH3:19])=[CH2:18].O>[Na]>[C:16]([O:13][C:8]1[C:7]([F:14])=[C:6]([F:15])[C:5]([C:3]#[N:4])=[C:10]([F:11])[C:9]=1[F:12])(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: C=C(C)C(=O)Cl
Reactant: N#Cc1c(F)c(F)c(O)c(F)c1F
Agent: [Na]
Solvent: CO
Solvent: O
Product: C=C(C)C(=O)Oc1c(F)c(F)c(C#N)c(F)c1F
Yield: 33.2 %

Procedure:
In 50 ml of methanol having 0.94 g (0.0236 mol) of sodium hydroide dissolved therein, 3.0 g (0.0157 mol) of 4-cyano-2,3,5,6-tetrafluorophenol was dissolved. The resultant solution was kept with ice at 0° C. To the cooled solution, 1.80 g (0.0173 mol) of methacrylic acid chloride as slowly added dropwise. After completion of this dropwise addition, the resultant mixture was stirred at the same temperature for two hours. It was then mixed with 50 ml of pure water and adjusted to pH 10 by addition of an aqueous 20% sodium hydroide solution. As the result, white crystals occurred. The white crystals were filtered, washed with cold water, and then dried to obtain 1.35 g of 4-cyano-2,3,5,6-tetrafluorophenyl methacrylate (purity 98% and yield 32 mol % based on 4-cyano-2,3,5,6-tetrafluorophenol). The analyses obtained of this novel substance for the determination of its chemical structure were the same as those of Example 2.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]([CH2:14][OH:15])[C:10]([O:12][CH3:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[F:30][C:31]([F:39])(S(F)(=O)=O)C(O)=O>C(#N)C>[CH2:16]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]([CH2:14][O:15][CH:31]([F:39])[F:30])[C:10]([O:12][CH3:13])=[O:11])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: COC(=O)C(CO)N(Cc1ccccc1)Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)C(COC(F)F)N(Cc1ccccc1)Cc1ccccc1
Yield: 4.8 %

Procedure:
To an acetonitrile solution of methyl 2-(dibenzylamino)-3-hydroxypropanoate (23 g, 76.8 mmol) and sodium sulfate (3.9 g, 27.4 mmol) at 40° C., difluoro(fluorosulfonyl)acetic acid (25 g, 140 mmol) was added dropwise for 1.5 hrs. The reaction mixture was concentrated to dryness and the residue mixed with silica gel in ethyl acetate, then again concentrated to dryness. The product was purified by column chromatography, eluting with 3-4% ethyl acetate in hexanes, to give methyl 2-dibenzylamino-3-difluoromethoxy-propionate (1.3 g, 4.8%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ(ppm) 7.20-7.40 (m, 10H), 6.18 (bt, 1H), 4.05-4.24 (m, 2H), 3.90 (d, 2H), 3.83 (s, 3H) and 3.64-3.71 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[Br:16])[CH:5]=[CH:4][N:3]=1.Cl[CH2:18][C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:9][CH2:10][CH2:11][CH:12]([CH3:15])[CH3:13].[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:18][C:19]#[N:20])[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[Br:16])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(Nc2ccnc(Cl)n2)c(Br)c1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCC(C)C
Product: Cc1ccc(N(CC#N)c2ccnc(Cl)n2)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-Chloro-4-(2-bromo-4-methylanilino)pyrimidine (500 mg, 1.68 mmol), chloroacetonitrile (0.13 ml, 2.02 mmol) and potassium carbonate (279 mg, 2.02 mmol) were dissolved in DMF (3 ml). The reaction mixture was stirred at room temperature for 12 hours. Chloroacetonitrile (0.13 ml, 2.02 mmol) and potassium carbonate (279 mg, 2.02 mmol) were again added, and the reaction mixture was stirred at room temperature for a further 48 hours. The reaction mixture was evaporated onto silica (5 ml) and purified by column chromatography eluting with EtOAc (0–40%):isohexane to give the title product as a solid on evaporation (537 mg). NMR (300 MHz): 2.38 (s, 3H), 4.82 (d, 1H), 4.99 (d, 1H), 6.09 (brs, 1H), 7.41 (m, 2H), 7.71 (s, 1H), 8.16 (brd, 1H); M.S. (ES+) 337.2 (MH+).
Reaction SMILES: [OH-].[Na+].[CH:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH:4]1[NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:25]3[CH:35]=[CH:34][C:28]([C:29]([O:31]CC)=[O:30])=[CH:27][C:26]=3[CH3:36])[C:20]=1[C:21]([CH3:24])([CH3:23])[CH3:22])=[O:15])[CH2:10]2>CO>[CH:3]12[CH2:10][CH:9]3[CH2:8][CH:7]([CH2:6][CH:5]([CH2:11]3)[CH:4]1[NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:25]3[CH:35]=[CH:34][C:28]([C:29]([OH:31])=[O:30])=[CH:27][C:26]=3[CH3:36])[C:20]=1[C:21]([CH3:23])([CH3:24])[CH3:22])=[O:15])[CH2:12]2
Reactant: CCOC(=O)c1ccc(-n2ncc(C(=O)NC3C4CC5CC(C4)CC3C5)c2C(C)(C)C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C(=O)O)ccc1-n1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1C(C)(C)C
Reaction time: 16 h
Yield: 80.4 %

Procedure:
A solution of Sodium hydroxide (1.904 mL, 3.81 mmol) was added in one portion to a stirred solution of ethyl 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]-3-methyl-benzoate (Intermediate#113) (353 mg, 0.76 mmol) in methanol (6 mL). The resulting suspension was stiffed at 20° C. for 16 hours. The resulting mixture was evaporated to remove the methanol and washed with ether (20 mL). The reaction mixture was acidified with 2M HCl. The precipitate was collected by filtration, washed with water (10 mL) and dried under vacuum to afford 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]-3-methyl-benzoic acid (266 mg, 80%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:6]=1[C:7](OCC)=[O:8].Cl.Cl[C:21]([NH2:23])=[NH:22].CS(C)(=O)=O.N>O>[NH2:23][C:21]1[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:6]=2[C:7](=[O:8])[N:22]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)csc1N
Reactant: N=C(N)Cl
Agent: CS(C)(=O)=O
Agent: Cl
Agent: N
Solvent: O
Product: Nc1nc(=O)c2c(-c3ccc(F)cc3)csc2[nH]1
Temperature: 135 °C
Yield: 111.5 %

Procedure:
A mixture of ethyl 2-amino-4-(4-fluorophenyl)thiophene-3-carboxylate (400 mg, 1.51 mmol), chloroformamidine hydrochloride (434 mg, 3.78 mmol) and dimethylsulfone (710 mg, 7.55 mmol) was heated at 135° C. for 45 minutes. Water was added and the mixture was cooled down to room temperature. An aqueous ammonia solution was added to adjust the solution to pH 9. The precipitate was filtered off, yielding the title compound (440 mg) as a white powder. δH (300 MHz, DMSO-d6) 10.85 (1H, NH, D2O exchangeable), 7.53 (2H, t), 7.17 (2H, t), 6.92 (1H, s), 6.58 (2H, NH2, D2O exchangeable).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([CH2:9][OH:10])=[C:4]([N:11]2[C:23](=[O:24])[C:22]3[S:21][C:20]4[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=4[C:14]=3[CH:13]=[N:12]2)[CH:3]=1.CCN(CC)CC.[C:32](Cl)([CH3:34])=[O:33]>C1COCC1.O>[C:15]12[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=1[S:21][C:22]1[C:23](=[O:24])[NH:11][N:12]=[CH:13][C:14]2=1.[C:32]([O:10][CH2:9][C:5]1[C:6]([Br:8])=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[N:11]1[C:23](=[O:24])[C:22]2[S:21][C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:14]=2[CH:13]=[N:12]1)(=[O:33])[CH3:34]
Reactant: CC(=O)Cl
Reactant: O=c1c2sc3c(c2cnn1-c1cc(F)cc(Br)c1CO)CCCC3
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)OCc1c(Br)cc(F)cc1-n1ncc2c3c(sc2c1=O)CCCC3
Product: O=c1[nH]ncc2c3c(sc12)CCCC3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-trien-6-one was prepared following the procedures of U.S. Pat. No. 8,716,274, Example 191d and converted to (4-fluoro-2-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-triene-5-yl}-6-(bromo)phenyl)carbinol 108a. To a mixture of 108a (4.1 g, 10 mmol) and Et3N (1.95 mL, 14 mmol) in THF (50 mL) was added AcCl (0.85 mL, 12 mmol). The mixture was stirred at rt for 1 h, diluted with water and extracted with EA. The combined organic layers were dried over Na2SO4, filtered and concentrated to give compound 108b (4.0 g) as yellow solid. MS-ESI: [M+H]+ 451.0
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](Cl)=[O:13])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:35][C@H:36]([CH3:46])[C:37]([N:39]1[CH2:43][CH2:42][CH2:41][C@H:40]1[C:44]#[N:45])=[O:38]>C(Cl)Cl>[C:44]([C@@H:40]1[CH2:41][CH2:42][CH2:43][N:39]1[C:37](=[O:38])[C@H:36]([NH:35][C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:2]=[CH:3][CH:4]=1)=[O:13])[CH3:46])#[N:45]
Reactant: O=C(Cl)c1ccnc2ccccc12
Reactant: C[C@@H](N)C(=O)N1CCC[C@H]1C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1ccnc2ccccc12)C(=O)N1CCC[C@H]1C#N

Procedure:
Quinoline-4-carbonyl chloride hydrochloride (0.067 g, 0.295 mmol) was added to a mixture of DIPEA (0.160 ml, 0.913 mmol) and (S)-1-((R)-2-aminopropanoyl)pyrrolidine-2-carbonitrile 4-methylbenzenesulfonate (0.100 g, 0.295 mmol) in DCM. After 3 h the mixture was washed with 1N citric acid and saturated sodium bicarbonate and brine. The organic layer was dried sodium sulfate, filtered and purified by column chromatography using a mixture of ethylacetate and methanol as eluents.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:30]3[C:25](=[CH:26][C:27]([O:31][C@H:32]([C:36]4[CH:37]=[N:38][C:39]5[C:44]([CH:45]=4)=[CH:43][CH:42]=[CH:41][CH:40]=5)[C@@H:33]([NH2:35])[CH3:34])=[CH:28][CH:29]=3)[CH:24]=[N:23]2)=[CH:18][CH:17]=1.C(N(CC)CC)C.[CH:53]1([S:56](Cl)(=[O:58])=[O:57])[CH2:55][CH2:54]1>C1COCC1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:30]3[C:25](=[CH:26][C:27]([O:31][C@H:32]([C:36]4[CH:37]=[N:38][C:39]5[C:44]([CH:45]=4)=[CH:43][CH:42]=[CH:41][CH:40]=5)[C@@H:33]([NH:35][S:56]([CH:53]4[CH2:55][CH2:54]4)(=[O:58])=[O:57])[CH3:34])=[CH:28][CH:29]=3)[CH:24]=[N:23]2)=[CH:18][CH:17]=1
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1cnc2ccccc2c1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H](NS(=O)(=O)C1CC1)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1cnc2ccccc2c1

Procedure:
(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(quinolin-3-yl)propan-2-amine bis(2,2,2-trifluoroacetate) (42a, 65 mg, 0.10 mmol) was dissolved in THF (1.5 mL), triethylamine (75 μl, 0.54 mmol) was added followed by cyclopropanesulfonyl chloride (15 μl, 0.15 mmol). The reaction mixture was stirred at room temperature, after 1.5 hours another portion of triethylamine (75 μl, 0.54 mmol) and excess of cyclopropanesulfonyl chloride (50 μl, 0.49 mmol) was added. The reaction mixture was left over night at room temperature. Solvent was removed by evaporation and the residual material was purified by HPLC. Yield 18 mg (34%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[F:22][C:23]([F:47])([F:46])[CH2:24][NH:25][C:26]([C:28]1([CH2:41][CH2:42][CH2:43][CH2:44]Br)[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:27]>>[F:22][C:23]([F:46])([F:47])[CH2:24][NH:25][C:26]([C:28]1([CH2:41][CH2:42][CH2:43][CH2:44][N:17]2[CH2:18][CH2:19][N:14]([C:12]3[CH:11]=[CH:10][CH:9]=[C:8]([O:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=4)[N:13]=3)[CH2:15][CH2:16]2)[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:27]
Reactant: COc1ccc(Oc2cccc(N3CCNCC3)n2)cc1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: COc1ccc(Oc2cccc(N3CCN(CCCCC4(C(=O)NCC(F)(F)F)c5ccccc5-c5ccccc54)CC3)n2)cc1

Procedure:
Prepared analogously to Example 2 b from 1-[6-(4-methoxy-phenoxy)-pyridin-2-yl]-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:27])[CH2:11][CH2:12][C:13]1[N:14]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([OH:26])[CH:19]=2)[O:16][CH:17]=1)[CH3:2].N12CCCN=C1CC[CH2:31][CH2:30][CH2:29]2.C(Br)C=C>C(O)C>[CH2:31]([O:26][C:20]1[CH:19]=[C:18]([C:15]2[O:16][CH:17]=[C:13]([CH2:12][CH2:11][C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][CH2:1][CH3:2])=[O:27])[N:14]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25])[CH:30]=[CH2:29]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC)c(O)c2)n1
Solvent: CCO
Solvent: C=CCBr
Product: C=CCOc1cc(-c2nc(CCC(=O)c3ccccc3OCC)co2)ccc1OC
Reaction time: 3 h

Procedure:
A 0.3 g quantity of 1-(2-ethoxyphenyl)-3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one obtained in Example 101 was suspended in 10 ml of ethanol, 0.37 g of 1,8-diazabicyclo[5,4,0]undec-7-ene and 0.14 ml of allyl bromide were added thereto, and stirring was conducted for 3 hours while heating and refluxing. After distilling off ethanol under reduced pressure, water was added, ethyl acetate extraction was performed, followed by drying over anhydrous magnesium sulfate and distilling the solvent off. The residue was subjected to silica gel column purification (n-hexane:ethyl acetate=3:1), thereby yielding 0.2 g of white powdery 3-[2-(3-allyloxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]([NH2:14])[S:12][CH:13]=1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:12][CH:13]=1
Reactant: COc1ccccc1-c1csc(N)n1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: COc1ccccc1-c1csc(NC(=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(2-Methoxy-phenyl)-thiazol-2-ylamine (41.3 mg, 0.200 mmol) and benzoyl chloride (28.1 mg, 0.200 mmol) were dissolved in 1 mL of pyridine. The reaction mixture was stirred at room temperature overnight and then purified by reverse-phase preparative liquid chromatography (11.4 mg, 0.0367 mmol, 18.4%). ESI-MS m/z calc. 310.1, found 311.2 (M+1)+ Retention time 3.55 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH:43]1[CH:47]=[CH:46][CH:45]=[C:44]1[C:48]1[CH:53]=[C:52]([O:54][C:55]2[CH:56]=[C:57]([CH:59]=[CH:60][CH:61]=2)[NH2:58])[CH:51]=[CH:50][N:49]=1>CN(C=O)C.O>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:58][C:57]1[CH:59]=[CH:60][CH:61]=[C:55]([O:54][C:52]2[CH:51]=[CH:50][N:49]=[C:48]([C:44]3[NH:43][CH:47]=[CH:46][CH:45]=3)[CH:53]=2)[CH:56]=1)=[O:9]
Reactant: Nc1cccc(Oc2ccnc(-c3ccc[nH]3)c2)c1
Reactant: Cc1ccoc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccoc1C(=O)Nc1cccc(Oc2ccnc(-c3ccc[nH]3)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-methyl-2-furoic acid (60 mg, 0.48 mmol), HBTU (198 mg, 0.52 mmol) and N,N-diisopropylethylamine (129 mg, 1.0 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of 3-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}aniline (100 mg, 0.40 mmol). The mixture was stirred at 70° C. for 3 hours and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3-5% MeOH/CHCl3 to give 3-methyl-N-(3-{[2-(1H-pyrrol-2-yl)pyridin-4-yl]oxy}phenyl)-2-furamide as white solid. Yield: 52 mg, 36%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[C:11]([O:14][C:15](=O)[CH3:16])(=[O:13])[CH3:12]>C(O)C>[C:11]([O:14][CH2:15][C:16]1[NH:10][C:8](=[O:9])[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1nccnc1N
Solvent: CCO
Product: CC(=O)OCc1nc2nccnc2c(=O)[nH]1

Procedure:
Obtained using the procedure described in Example 1, starting with 5.3 g (0.038 mole) of 3-amino-2-pyrazinecarboxamide, 34.5 g (0.157 mole) of triethyl orthoacetoxyacetate and 34.5 ml of acetic anhydride. Refluxing time: 1 hour 45 minutes. Yld: 5.4 g (65%), m.p. 210°-212° C. (ethanol).