Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][NH:18]3)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH3:24][O:23][C:21]1[CH:20]=[C:19]2[C:15]([CH:16]=[CH:17][NH:18]2)=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:22]=1
Reactant: COc1cc(N2CCN(Cc3ccccc3)CC2)c2cc[nH]c2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1cc(N2CCNCC2)c2cc[nH]c2c1
Yield: 78.6 %

Procedure:
A mixture of 4-(4-benzyl-piperazin-1-yl)-6-methoxy-1H-indole (0.37 g, 1.1 mmol), 10% Pd/C (0.05 g) and ammonium formate (0.15 g, 2.2 mmol) in ethanol (20 mL) was allowed to reflux for 2 hours. The catalyst was filtered off and the solvent removed under vacuum. Chromatography (10% methanol/methylene chloride plus ammonium hydroxide) afforded 0.2 g (75%) of product as a yellow foam. MS (EI) m/e 231.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[O:15][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12]3)=[N:6][CH:7]=1.[C:25]1(=O)[O:30][C:28](=[O:29])[CH2:27][CH2:26]1>C(O)(=O)C>[C:25]1(=[O:30])[N:1]([C:2]2[CH:3]=[CH:4][C:5]([O:8][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][CH:18]=3)[O:15][CH:14]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:13][CH2:12]4)=[N:6][CH:7]=2)[C:28](=[O:29])[CH2:27][CH2:26]1
Reactant: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: O=C1CCC(=O)O1
Solvent: CC(=O)O
Product: O=C1CCC(=O)N1c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1

Procedure:
5-Amino-2-(2-phenylchroman-6-yloxy)-pyridine of Example 26 (0.16 g) was dissolved in 7.5 ml of glacial acetic acid under nitrogen. Succinic anhydride (0.0563 g) was added and the solution refluxed 60 minutes and solution was cooled and evaporated to dryness. Toluene (25 ml) was added and evaporated again to dryness. Product was purified by column chromatography (CH2Cl2:i-PrOH /95:5 as the eluant. 1H-NMR (400 MHz; d6-DMSO): δ 8.03 (d, 1H, J=2.6 Hz), 7.73 (dd, 1H, J=8.7 Hz, J=2.6 Hz), 7.48-7.31 (m, 5H), 7.10 (d, 1H, J=8.7 Hz), 6.95 (d, 1H, J=2.6 Hz), 6.92 (dd, 1H, J=8.7 Hz, J=2.7 Hz), 6.88 (d, 1H, J=8.6 Hz), 5.13 (dd, 1H, J=10.2 Hz, J=2.2 Hz), 3.05-2.92 (m, 1H), 2.84-6.68 (m, 1H), 2.79 (s, 4H), 2.22-2.12 (m, 1H), 2.08-1.93 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6]([NH2:13])=[CH:5][N:4]=1)#[N:2].[C:14](Cl)(Cl)=[S:15]>O>[N:13]([C:6]1[CH:7]=[C:8]([C:9]([F:12])([F:10])[F:11])[C:3]([C:1]#[N:2])=[N:4][CH:5]=1)=[C:14]=[S:15]
Reactant: S=C(Cl)Cl
Reactant: N#Cc1ncc(N)cc1C(F)(F)F
Solvent: O
Product: N#Cc1ncc(N=C=S)cc1C(F)(F)F
Yield: 74 %

Procedure:
A solution of 2-hydroxy-3-(trifluoromethyl)pyridine C in a mixture of N-iodosuccinimide (NIS), acetonitrile, and dimethylformamide (DMF) is heated at 80° C. for 2 hours to produce 2-hydroxy-3-trifluoromethyl-5-(iodo)pyridine I (greater than 80% yield). The 2-hydroxy-3-trifluoromethyl-5-(iodo)pyridine I is then mixed with POCl3 in DMF and heated to 130° C. in a microwave for 20 minutes to produce 2-chloro-3-trifluoromethyl-5-(iodo)pyridine J (yield of 50 to 55%). The 2-chloro-3-trifluoromethyl-5-(iodo)pyridine K is reacted in a solution of pMBnNH2, palladium(II) acetate, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), triethylamine, and cesium carbonate in toluene to produce 5-((4-methoxyphenyl))methylamino)-2-chloro-3-(trifluoromethyl)pyridine K (yield of 40%). The 5-((4-methoxyphenyl))methylamino)-2-chloro-3-(trifluoromethyl)pyridine K is reacted in a solution of zinc cyanide, tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), and 1,1′-bis(diphenylphosphino)ferrocene (dppf) in DMF to provide 5-(4-methoxybenzylamine)-2-cyano-3-(trifluoromethyl)pyridine K (yield of 92%). The 5-(4-methoxybenzylamine)-2-cyano-3-(trifluoromethyl)pyridine K is reacted in a solution of dichloromethane and trifluoroacetic acid to provide 2-cyano-3-trifluoromethyl-5-(amino)pyridine H (yield greater than 95%). The 2-cyano-3-trifluoromethyl-5-(amino)pyridine H is reacted with thiophosgene in water at 25° C. for 2 hours to provide 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile A (yield of 74% to 95%).
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.Cl.[Cl:12][CH2:13][CH2:14][S:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([CH2:22]Cl)[C:17]=1[CH3:24].[OH-].[Na+]>>[Cl:12][CH2:13][CH2:14][S:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([CH2:22][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)[C:17]=1[CH3:24]
Reactant: Cc1c(SCCCl)ccnc1CCl
Reactant: Sc1nc2ccccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(SCCCl)ccnc1CSc1nc2ccccc2[nH]1

Procedure:
According to the procedure indicated in Example A1, reaction of 2-mercapto-1H-benzimidazole with 4-(2-chloroethylthio)-2-chloromethyl-3-methylpyridine hydrochloride and NaOH gives, after crystallization from ethyl acetate, the title compound (62% of theory) as a colorless solid of m.p. 178-180° C.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([O-:20])[C:17]([C:21](OC)=[O:22])=[CH:16][N:15]=2)=[N:6]1.[Na+:29].CO.[NH3:32]>>[C:21]([C:17]1[C:18]([O-:20])=[N:19][C:14]([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]([CH2:4][C:3]3[CH:25]=[CH:26][CH:27]=[CH:28][C:2]=3[F:1])[N:6]=2)=[N:15][CH:16]=1)(=[O:22])[NH2:32].[Na+:29]
Reactant: N
Reactant: COC(=O)c1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1[O-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1[O-]
Temperature: 60 °C
Reaction time: 24 h

Procedure:
100 mg of sodium 2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-(methoxycarbonyl)pyrimidin-4-olate (1-12-1, 0.25 mmol, 1 eq.) were dissolved in 26.8 ml of 7N ammonia in methanol (187 mmol, 750 eq.) and stirred under a nitrogen atmosphere at 60° C. bath temperature for 24 hours, then at 65° C. bath temperature for six hours and further 24 hours at 70° C. bath temperature. The reaction mixture was concentrated in vacuo to yield 96 mg (0.22 mmol, 89.8%) of the analytically pure target compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13](=[O:14])[N:12]3[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:11]3=[N:10][C:9]=2[CH2:20]O)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:41]1(=[O:51])[NH:45][C:44](=[O:46])[C:43]2=[CH:47][CH:48]=[CH:49][CH:50]=[C:42]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13](=[O:14])[N:12]3[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:11]3=[N:10][C:9]=2[CH2:20][N:45]2[C:41](=[O:51])[C:42]3[C:43](=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:44]2=[O:46])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1cccc2nc(CO)c(-c3cccc(F)c3)c(=O)n12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccc2nc(CN3C(=O)c4ccccc4C3=O)c(-c3cccc(F)c3)c(=O)n12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(3-fluorophenyl)-2-(hydroxymethyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.05110 g, 0.180 mmol) in THF (3.00 mL) was added triphenylphosphine (0.141 g, 0.539 mmol), phthalimide (0.0793 g, 0.539 mmol), and diisopropyl azodicarboxylate (0.106 mL, 0.539 mmol). The reaction mixture was stirred at rt. After 3 h, the mixture was concd under reduced pressure and partitioned between EtOAc (100 mL) and brine (100 mL). The organic layer was dried over Na2SO4, filtered, and concd under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 14 min and 50% isocratic of EtOAc for 15 min as eluent to give 2-((3-(3-fluorophenyl)-6-methyl-4-oxo-4H-pyrido-[1,2-a]pyrimidin-2-yl)methyl)isoindoline-1,3-dione as a solid: Mass Spectrum (ESI) m/e=414.1 (M+1).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10]O)/[CH3:8])[CH3:3].[OH:12]C/C=C(/C)\CCC=C(C)C>>[CH2:10]=[CH:9][C:7]([CH2:6][CH2:5][CH:4]=[C:2]([CH3:3])[CH3:1])([CH3:8])[OH:12]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: CC(C)=CCC/C(C)=C\CO
Product: C=CC(C)(O)CCC=C(C)C

Procedure:
In the fully continuous process variant, catalyst and geraniol or nerol, or a mixture of geraniol and nerol, are simultaneously and continuously metered into a continuous reactor and linalool which is formed is continuously distilled off. In addition, high boilers are discharged by likewise continuously withdrawing a fractional amount of the reactor contents and removing the geraniol, nerol and linalool products of value still present in this fraction from high boilers formed during the reaction by distillation, for example by a simple evaporation or using a column. The involatile catalyst either remains in the high boilers which are fed to a disposal operation, or it may be precipitated from the high boilers by cooling, removed and reused again. The products of value which have been distilled off are recycled back into the reactor.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.Br[CH:16]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[C:8]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH:16]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:7][CH:6]=1)(=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCC(=O)c1ccc(O)cc1
Reactant: CCCCCCCCC(Br)C(=O)OCC
Product: CCCCCCCCC(Oc1ccc(C(=O)CCCCC)cc1)C(=O)OCC
Yield: 80.4 %

Procedure:
1-[4-Hydroxyphenyl]-1-hexanone (384 mg, 2.0 mmol) and ethyl (RS)-2-bromodecanoate (614 mg, 2.2 mmol) were reacted according to the procedure used for the preparation of I to give Ethyl (RS)-2-[4-Hexanoylphenoxy]decanoate (628 mg, 80%). 1H NMR (400 MHz, CDCl3): δ 7.86 (d, J=9.0 Hz, 2H), 6.84 (d, J=9.0 Hz, 2H), 4.60-4.65 (m, 1H), 4.15 (q, J=7.0 Hz, 2H), 2.83 (t, J=7.3 Hz, 2H), 1.86-1.97 (m, 2H), 1.61-1.70 (m, 2H), 1.38-1.52 (m, 2H), 1.20-1.34 (m, 14H), 1.18 (t, J=7.2 Hz, 3H), 0.78-0.87 (m, 6H); 13C NMR (101 MHz, CDCl3): δ 199.17, 171.36, 161.78, 130.95, 130.46 (2C), 114.72 (2C), 76.66, 61.51, 38.41, 32.84, 32.00, 31.76, 29.52, 29.35 (2C), 25.31, 24.41, 22.83, 22.74, 14.33, 14.26, 14.14. The resulting ester (628 mg, 1.6 mmol) was saponified with lithium hydroxide (193 mg, 8.0 mmol) according to the procedure used for the preparation of I to give (RS)-2-[4-Hexanoylphenoxy]decanoic Acid (468 mg, 80%). 1H NMR (400 MHz, CDCl3): δ 7.93 (d, J=9.0 Hz, 2H), 6.91 (d, J=9.0 Hz, 2H), 5.77 (br s, 1H), 4.70 (dd, J=5.8, 6.6 Hz, 1H), 2.89 (t, J=7.4 Hz, 2H), 1.97-2.03 (m, 2H), 1.67-1.74 (m, 2H), 1.44-1.60 (m, 2H), 1.23-1.37 (m, 14H), 0.90 (t, J=6.8 Hz, 3H), 0.87 (t, J=7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 199.76, 176.29, 161.56, 131.20, 130.70 (2C), 114.81 (2C), 76.12, 38.56, 32.78, 32.03, 31.80, 29.53, 29.40, 29.36, 25.36, 24.51, 22.87, 22.76, 14.33, 14.20. The acid (468 mg, 1.3 mmol) was then converted to the sodium salt according to the procedure used for the preparation of I to give Sodium (RS)-2-[4-Hexanoylphenoxy]decanoate (459 mg, 93%) as a white solid. mp 275-280° C.; 1H NMR (400 MHz, CD3OD): δ 7.91 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 4.44-4.48 (m, 1H), 2.89-2.96 (m, 2H), 1.88-1.96 (m, 2H), 1.63-1.71 (m, 2H), 1.44-1.61 (m, 2H), 1.24-1.38 (m, 14H), 0.84-0.93 (m, 6H); 13C NMR (101 MHz, CD3OD): δ 200.89, 177.86, 163.36, 130.27 (2C), 129.60, 114.75 (2C), 79.54, 37.94, 33.18, 31.86, 31.49, 29.44, 29.38, 29.21, 25.73, 24.55, 22.58, 22.45, 13.36, 13.23; LRMS (ESI): m/z 769.8 (M2H+), 747.8 (2M-Na++2H+), 363.2 (M-Na++2H+); HPLC: 3.min.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]#[N:22])=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[C:13]([NH:15][CH2:16][CH3:17])=[O:14].[S:23](Cl)(=[O:26])(=[O:25])[NH2:24]>CC(N(C)C)=O>[C:21]([C:3]1[C:2]([NH:1][S:23](=[O:26])(=[O:25])[NH2:24])=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[C:13]([NH:15][CH2:16][CH3:17])=[O:14])#[N:22]
Reactant: CCNC(=O)N1CCCCC1COc1cccc(N)c1C#N
Reactant: NS(=O)(=O)Cl
Solvent: CC(=O)N(C)C
Product: CCNC(=O)N1CCCCC1COc1cccc(NS(N)(=O)=O)c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 117.7 %

Procedure:
To a solution of 2-((3-amino-2-cyanophenoxy)methyl)-N-ethylpiperidine-1-carboxamide (Example 26b, 0.407 g, 1.35 mmol) in DMA (5 mL) was added sulfamoyl chloride (0.234 mg, 2.02 mmol) and the reaction mixture was stirred vigorously at r.t. for 2 h, then extracted with H2O/EtOAc. The combined organic phases were washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by Biotage purification system (120 g Silicycle column, DCM:THF=4:1 as eluent) to provide the desired product (0.606 g, 90%). MS 382 (MH+).
Reaction SMILES: C([O:8][C:9]1[CH:35]=[CH:34][C:12]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[C:11]([CH2:36][CH2:37][CH2:38][CH3:39])[CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH2:36]([C:11]1[CH:10]=[C:9]([OH:8])[CH:35]=[CH:34][C:12]=1[O:13][CH2:14][CH2:15][C:16]1[N:17]=[C:18]([C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:26][CH:27]=2)[O:19][C:20]=1[CH3:21])[CH2:37][CH2:38][CH3:39]
Reactant: [H][H]
Reactant: CCCCc1cc(OCc2ccccc2)ccc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Agent: [Pd]
Solvent: CCO
Product: CCCCc1cc(O)ccc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C

Procedure:
A solution of 4-[2-(4-benzyloxy-2-butylphenoxy)ethyl]-5-methyl-2-biphenyl-4-yl-oxazole (3.16 mmol) in ethanol (100 mL) was treated with 5% Pd/C (160 mg) and hydrogen (60 psi) at ambient temperature for 18 h. The mixture was filtered and concentrated in vacuo to give 3-butyl-4-[2-(5-methyl-2-biphenyl-4-yl-oxazole-4-yl)ethoxy]phenol as a tan solid.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([O:7][P:8]([CH:10]1[CH2:14][CH2:13][CH2:12][O:11]1)[OH:9])[CH3:6].[O-]CC.C(O)(=O)C>C(O)C>[C:1]([CH2:2][CH2:3][P:8]([CH:10]1[CH2:14][CH2:13][CH2:12][O:11]1)(=[O:9])[O:7][CH2:5][CH3:6])#[N:4]
Reactant: CCOP(O)C1CCCO1
Reactant: C=CC#N
Agent: CC[O-]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOP(=O)(CCC#N)C1CCCO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.68 g of acrylonitrile and 2.11 g of tetrahydrofuran-2-yl phosphonous acid ethyl ester in 5 ml of absolute ethanol is cooled to 0° under argon and treated, dropwise, with an ethanolic solution ofsodium ethoxide (from 0.15 g of sodium metal and 15 ml of absolute ethanol)at such a rate so that the temperature does not exceed 5° (extremelyexothermic). After the addition is completed the reaction mixture is stirred at room temperature for 30 minutes and 0.4 g of glacial acetic acid are added. The solvent is removed in vacuo and the residue partitioned between dichloromethane water. The organic layer is dried withanhydrous magnesium sulphate and removed in vacuo to afford ethyl 2-cyanoethyl(tetrahydrofuran-2-yl)-phosphinate; 1H-NMR (CDCl3): δ4.15 (3 H, m), 3.90 (2 H, m), 2.72 (2 H, m, CH2CN), 2.34-1.87(6 H, m), 1.32 (3 H, m, CH3).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([O:11][CH3:12])[C:5]([CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:4]([O:20][CH3:21])[CH:3]=1.[CH3:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([CH3:32])[C:30]=1[OH:31])[CH:26]=O.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.O>[OH:31][C:30]1[C:29]([CH3:32])=[CH:28][C:25]([C:26]2[NH:10][C:8](=[O:9])[C:7]3[C:2](=[CH:3][C:4]([O:20][CH3:21])=[C:5]([CH2:13][N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[C:6]=3[O:11][CH3:12])[N:1]=2)=[CH:24][C:23]=1[CH3:22]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1CN1CCOCC1
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc2nc(-c3cc(C)c(O)c(C)c3)[nH]c(=O)c2c(OC)c1CN1CCOCC1
Temperature: 115 °C
Reaction time: 6 h
Yield: 6.5 %

Procedure:
A solution of 6-tert-butoxycarbonylamino-2,4-dimethoxy-3-morpholin-4-ylmethyl-benzoic acid (1.8 g, 4.54 mmol), EDCl.HCl (1.31 g, 6.82 mmol), HOBt (1.23 g, 9.09 mmol), and triethylamine (3.3 mL, 23.7 mmol) in THF (50 mL) was stirred at room temperature for 1 h. Ammonium hydroxide (50% aqueous, 10 mL) was then added to the reaction mixture. The resulting mixture was stirred at room temperature for 6 h. The reaction was quenched by adding water (50 mL), extracted with DCM (3×100 mL), and concentrated using a rotary evaporator. The residue was further purified by column (SiO2, DCM/MeOH/EtOAc=2:1:4) to provide 0.9 g of (2-carbamoyl-3,5-dimethoxy-4-morpholin-4-ylmethyl-phenyl)-carbamic acid tert-butyl ester (50%). A solution of (2-carbamoyl-3,5-dimethoxy-4-morpholin-4-ylmethyl-phenyl)-carbamic acid tert-butyl ester (0.9 g, 2.74 mmol) in HOAc (20 mL) and 12 N HCl aqueous (20 mL) was stirred at 50° C. for 1 h and then concentrated to dryness using a rotary evaporator. The residue was mixed with saturated sodium bicarbonate aqueous (40 mL), extracted with DCM (3×100 mL), and concentrated. The residue was further purified by column (SiO2, DCM/MeOH/EtOAc=3:2:3) to provide 0.6 g of 6-amino-2,4-dimethoxy-3-morpholin-4-ylmethyl-benzamide (89%). A mixture of 6-amino-2,4-dimethoxy-3-morpholin-4-ylmethyl-benzamide (0.6 g, 2.03 mmol), 3,5-dimethyl-4-hydroxy benzaldehyde (0.61 g, 4.06 mmol), sodium hydrogensulfite (1.24 g, 7.0 mmol) and p-toluenesulfonic acid (1.14 g, 6 mmol) in N,N-dimethyl acetamide (20 mL) was stirred at 115° C. for 6 h. The reaction mixture was cooled to room temperature, diluted with water (50 mL), extracted with EtOAc, and concentrated. Purification by column chromatography afforded a solid residue, which was made into slurry in a mixed solvent of DCM-hexanes (3 mL-20 mL). The slurry was filtered and washed with hexanes to provide 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-6-(morpholinomethyl)quinazolin-4(3H)-one (56 mg, 6.6%) as a light yellow solid. Selected data: MS (ES) m/z: 426.0; MP 237.0-239.1° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.Br[C:17]1[CH:18]=[N:19][CH:20]=[N:21][CH:22]=1.C([Li])CCC.[Cl-].[NH4+]>O1CCCC1.CCOCC.CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]([C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)([OH:13])[C:9]([CH3:11])([CH3:12])[CH3:10])=[CH:4][CH:3]=1
Reactant: Brc1cncnc1
Reactant: CC(C)(C)C(=O)COc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)C(O)(COc1ccc(Cl)cc1)c1cncnc1
Temperature: -110 °C
Reaction time: 2 h
Yield: 40.1 %

Procedure:
A solution of 22.65 g (0.1 mol) of 1-(4-chlorophenoxy)-3,3-dimethyl-butan-2-one in 110 ml of absolute tetrahydrofuran and 70 ml of absolute ether was cooled to -120° C. under a dry nitrogen atmosphere. A solution of 15.9 g (0.1 mol) of 5-bromopyrimidine in 50 ml of absolute tetrahydrofuran was added dropwise to the above solution. 50 ml of a 15% strength solution of n-butyllithium in n-hexane was then slowly added dropwise to the mixture at -120° C. The mixture was first stirred for 2 hours at a temperature of approximately -110° C., and was thereafter stirred overnight at -78° C. The reaction mixture was warmed to room temperature and 100 ml of 10% strength ammonium chloride solution and 200 ml of ethyl acetate were added to it, and the aqueous phase was separated off. The organic phase was washed successively once with 1N hydrochloric acid and twice with saturated sodium chloride solution, and was dried over sodium sulphate and concentrated. The residue was suspended in ether, and the solid material was filtered off under suction and recrystallized from acetonitrile. 12.3 g (50% of theory relative to n-butyllithium) of 1-(4-chlorophenoxy)-3,3-dimethyl-2-(pyrimidin-5-yl)-butan-2-ol of melting point 172°-174° C. were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>C(#N)C>[CH2:23]([NH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:5]([NH:7][CH:8]1[CH2:9][CH2:10]1)=[O:6])[CH:22]=[CH2:21]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCNc1cc(C(=O)NC2CC2)ccc1C
Temperature: 80 °C
Reaction time: 17 h

Procedure:
To a solution of 3-amino-N-cyclopropyl-4-methylbenzamide (2 g) in acetonitrile (10 ml) was added with potassium carbonate (2.6 g). The mixture was heated to 80° C. and a solution of allyl bromide (1.1 ml) in acetonitrile (6 ml) was added dropwise and heating was continued for 17 hours. The insoluble material was removed by filtration. The filtrate was concentrated and the residue was recrystallised from 50% ethyl acetate/hexane. The mother liquors was concentrated and by column chromatography on a silica column eluting using a gradient of iso-hexane to 50% ethyl acetate/iso-hexane to yield 3-(allylamino)-N-cyclopropyl-4-methylbenzamide as a colourless oil which solidified to a white solid (688 mg); NMR Spectrum: (DMSOd6) 0.53 m, 2H), 0.78 (m, 2H), 2.10 (s, 3H), 2.81 (m, 1H), 3.67 (s, 1H), 3.81 (d, 2H), 5.13 (d, 1H), 5.23 (d, 1H), 5.93 (m, 1H), 6.11 (s, 1H), 6.83 (d, 1H), 6.98 (m, 2H); Mass Spectrum: M+H+ 231.
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C:6]([C:7]3[CH:8]=[CH:9][C:10]([N+:18]([O-:20])=[O:19])=[C:11]4[C:17]=3[CH:14]([CH2:15]2)[CH2:13][NH:12]4)=[CH:5][C@H:4]([NH:21][C:22](=[O:28])[N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH2:3]1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.O>[CH3:1][N:2]1[C@H:16]2[C:6]([C:7]3[CH:8]=[CH:9][C:10]([N+:18]([O-:20])=[O:19])=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)=[CH:5][C@H:4]([NH:21][C:22](=[O:28])[N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH2:3]1
Reactant: CCN(CC)C(=O)N[C@H]1C=C2c3ccc([N+](=O)[O-])c4c3C(CN4)C[C@H]2N(C)C1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Product: CCN(CC)C(=O)N[C@H]1C=C2c3ccc([N+](=O)[O-])c4[nH]cc(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.9 %

Procedure:
A solution is prepared from 150 mg of 3-(9,10-didehydro-2,3-dihydro-6-methyl-14-nitro-8α-ergolinyl)-1,1-diethylurea in 5 ml of methylene chloride; 250 mg of pyridinium dichromate, dissolved in 2 ml of methylene chloride, is added to the reaction mixture and the latter is agitated for one hour at room temperature. Then the mixture is diluted with water, extracted by shaking with methylene chloride, the organic phase is dried and evaporated. The residue is chromatographed on silica gel with methylene chloride/methanol (5%), thus obtaining 70 mg of 3-(9,10-didehydro-6-methyl-14-nitro-8α-ergolinyl)-1,1-diethylurea.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]2[O:29][N:28]=[C:27]([CH3:30])[C:26]=2[CH3:31])(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C>O1CCCC1>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]2[O:29][N:28]=[C:27]([CH3:30])[C:26]=2[CH3:31])(=[O:23])=[O:22])=[CH:17][CH:16]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: Cc1noc(NS(=O)(=O)c2ccc(N)cc2)c1C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2ccc(Nc3ccc([N+](=O)[O-])cc3[N+](=O)[O-])cc2)c1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.6 %

Procedure:
2,4-Dinitrofluorobenzene (0.457 ml, 3.6 mmol) and 4-amino-N-(3,4-dimethyl-5-isoxazolyl)benzenesulfonamide (818 mg, 3.0 mmol) were dissolved in dry tetrahydrofuran (25 ml) and triethylamine (1.0 ml, 7.5 mmol) was added slowly. The reaction was stirred at room temperature for 48 h. The solvent and volatiles were removed under reduced pressure and the residue was partitioned between 1N HCl and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated and the residue was recrystallized from methanol to give 1.1 g (85%) yellow solid, m.p. 187° C.