Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)(C)C.Br[CH2:13][C:14]1[CH:15]=[C:16]([CH2:22][CH:23]([O:27][CH:28]([CH3:30])[CH3:29])[C:24]([O-:26])=[O:25])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>>[CH:28]([O:27][CH:23]([CH2:22][C:16]1[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:14]([CH2:13][O:9][CH2:8][C:7]2[CH:6]=[CH:5][C:4]([O:20][CH:19]([CH3:18])[CH3:14])=[CH:11][CH:10]=2)[CH:15]=1)[C:24]([OH:26])=[O:25])([CH3:30])[CH3:29]
Reactant: COc1ccc(CC(OC(C)C)C(=O)[O-])cc1CBr
Reactant: CC(C)c1ccc(CO)cc1
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1COCc1ccc(OC(C)C)cc1

Procedure:
Using 4-isopropylbenzyl alcohol and 3-[3-(bromomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 2-isopropoxy-3-(3-[(4-isopropoxybenzyl)oxy]methyl-4-methoxyphenyl)propanoic acid was obtained in the same method as in Example 247).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[N:10][CH:9]=2)=[CH:4][C:3]=1[CH2:13][NH:14][C:15](=[O:18])[O:16][CH3:17].[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:19][C:20]3[CH:27]=[CH:26][C:23]([CH3:24])=[CH:22][CH:21]=3)[N:12]=2)=[CH:4][C:3]=1[CH2:13][NH:14][C:15](=[O:18])[O:16][CH3:17]
Reactant: COC(=O)NCc1cc(-c2cnn[nH]2)ccc1Cl
Reactant: Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)NCc1cc(-c2cnn(Cc3ccc(C)cc3)n2)ccc1Cl
Temperature: 100 °C

Procedure:
A mixture of methyl N-[[2-chloro-5-(1H-1,2,3-triazol-5-yl)phenyl]methyl]carbamate (i.e. the product of Step E, Example 9) (0.24, 0.9 mmol), 4-methylbenzyl bromide (0.17 g, 1.1 mmol) and potassium carbonate (0.25 g, 1.8 mmol) in N,N-dimethylformamide (4.5 mL) was heated at 100° C. for 24 h. The reaction mixture was allowed to cool and then partitioned between diethyl ether (50 mL) and water (30 mL). The organic layer was separated, washed with water (3×), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate and ethanol (2:1 mixture) and concentrated onto silica gel, and then purified by flash column chromatography using 5 g of silica gel (0 to 50% gradient of ethyl acetate in hexanes as eluant) to provide methyl N-[[2-chloro-5-[2-[(4-methylphenyl)methyl]-2H-1,2,3-triazol-4-yl]phenyl]methyl]carbamate, a compound of the present invention, as a colorless oil (0.11 g)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([F:18])[C:11]3[N:12]([C:14](I)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=1)#[CH:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([F:18])[C:11]3[N:12]([C:14]([C:20]#[C:19][C:21]4[CH:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=4)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Fc1cc(-c2ccc(Cl)cc2)cn2c(I)cnc12
Reactant: C#Cc1ccc(N)nc1
Product: Nc1ccc(C#Cc2cnc3c(F)cc(-c4ccc(Cl)cc4)cn23)cn1

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-8-fluoro-3-iodo-imidazo[1,2-a]pyridine (example C.30 step 2) (300 mg, 0.8 mmol) and 5-ethynyl-pyridin-2-ylamine (example D.1) (114 mg, 0.8 mmol) according to general procedure II. Obtained as a light brown solid (170 mg, 58%). MS (ISP) 363.2 [(M+H)+],365 [(M+2+H)+]; mp 259° C.
Reaction SMILES: [F:1][CH:2]1C(=O)[CH2:6][CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[F:18])[CH2:3]1.[CH3:19][O:20][CH:21](OC)[O:22][CH3:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:19][O:20][C:21]1([O:22][CH3:23])[CH2:6][CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[F:18])[CH2:3][CH:2]1[F:1]
Reactant: COC(OC)OC
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2F)CC1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC1(OC)CCN(c2ccc([N+](=O)[O-])cc2F)CC1F
Temperature: 45 °C
Yield: 78 %

Procedure:
The mixture of 4-(3-fluoro-4-oxo-piperidin-1-yl)-3-fluoronitrobenzene (65 mmol), trimethylorthoformate (130 mmol), p-toluene-sulphonic acid monohydrate (67 mmol) in methanol was heated at 45° C. for 24 hours. Solvent was removed and residual mass was taken into ethyl acetate and saturated sodium bicarbonate solution mixture. The organic layer was dried and removal of the solvent afforded title compound as a solid in 78% yield.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[C:9]([CH3:17])([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH3:10])=[CH:4][CH:3]=1.[SH:19][CH2:20][C:21]([CH2:25][SH:26])([CH2:23][SH:24])[CH3:22].[H-].[Na+].O>CN(C)C=O>[SH:19][CH2:20][C:21]([CH2:25][SH:26])([CH3:22])[CH2:23][S:24][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[C:9]([CH3:17])([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C(=O)c1ccc(F)cc1)N1CCOCC1
Reactant: CC(CS)(CS)CS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CS)(CS)CSc1ccc(C(=O)C(C)(C)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.6 g (14.3 mmol) of 1-(4-fluorophenyl)-2-methyl-2-morpholin-4-yl-propan-1-one and 12 g (71.3 mmol) of 1,1,1-trismercaptomethylethane are dissolved in 70 ml of dry dimethylformamide, and 28.6 mmol of sodium hydride are added. The solution is stirred at room temperature for 2 h. Then the solution is poured into water. The crude product is extracted with methylene chloride, washed with water, dried over MgSO4, and concentrated. The residue is purified by column chromatography on silica gel with methylene chloride as an eluent. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm] 1.12 (s, 3H), 1.30 (t, 2H), 1.31 (s, 6H), 2.57 (t, 4H), 2.62-2.72 (m, 4H), 3.14 (s, 2H), 3.69 (t, 4H), 7.33 (d, 2H), 8.49 (d, 2H).
Reaction SMILES: [C:1]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:13])[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[H-].[Na+].[CH3:24][O:25][CH2:26][CH2:27]Br.O>O1CCCC1>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([CH2:27][CH2:26][O:25][CH3:24])[C:1]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCC(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.6 %

Procedure:
Dibenzyl malonate (28.43 g, 0.1 mole) was added dropwise over 1 hour to a stirred suspension of sodium hydride (3.15 g, 80% dispersion in oil; 0.105 mole) in dry tetrahydrofuran (100 ml) under nitrogen, the temperature being allowed to rise to 40° C. 2-Methoxyethyl bromide (13.9 g, 0.1 mole) was added to the resulting clear solution, which was stirred at room temperature for two hours, and then refluxed overnight. Water was added, and the mixture extracted with methylene chloride. The organic extract on washing with water, drying (MgSO4) and evaporation under vacuum gave a crude liquid (30.94 g). Chromatography on silica gel (700 g) eluting with a mixture of ether and hexane (2:8 by volume) gave 2-methoxyethyl-malonic acid dibenzyl ester as a colourless liquid (15.6 g). This was dissolved in dioxan (150 ml) and a solution of potassium hydroxide (2.55 g, 45.44 mmole) in water (40 ml) added at 0° C. with stirring. The mixture was stirred overnight at room temperature and the solvent was evaporated under vacuum. Water was added and the mixture was extracted with ether to remove unreacted diester. The aqueous phase was then acidified with 2N hydrochloric acid (50 ml) and extracted with ether. The organic extract on washing with water, drying (MgSO4) and evaporation under vacuum gave the mono-ester as a colourless oil (8.95 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=3[OH:18])=[N:8][C:7](=O)[C:6]=2[CH:20]=1.Cl.[NH:22]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)[NH2:23].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=3[OH:18])[N:22]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[N:23]=2)[CH:20]=1
Reactant: NNCc1ccccn1
Reactant: O=c1nc(-c2cc(Cl)ccc2O)oc2ccc(Cl)cc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Oc1ccc(Cl)cc1-c1nc(-c2cc(Cl)ccc2O)n(Cc2ccccn2)n1

Procedure:
3.0 g of 6-chloro-2-(5-chloro-2-hydroxyphenyl)benz[e][1,3]oxazin-4-one are boiled under reflux for 5 h with 1.7 g of 2-hydrazinomethylpyridine hydrochloride and 3 ml of triethylamine in 50 ml of ethanol. The crystals precipitating on cooling are washed with ethanol. After drying, 3,5-bis(5-chloro-2-hydroxyphenyl)-1-(pyridin-2-ylmethyl)-1H-[1,2,4]triazole remains as colorless crystals of m.p. 227-229 C.
Reaction SMILES: C(O[C:9](=O)[N:10]([CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH3:22])=[CH:17][CH:16]=1)=[O:14])C)C1C=CC=CC=1>O1CCCC1.CO.[C].[Pd]>[C:27]([O:26][C:24](=[O:25])[NH:23][C@H:21]([C:18]1[CH:17]=[CH:16][C:15]([C:13](=[O:14])[CH2:12][NH:10][CH3:9])=[CH:20][CH:19]=1)[CH3:22])([CH3:29])([CH3:28])[CH3:30]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(=O)CN(C)C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CNCC(=O)c1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1
Reaction time: 2 h

Procedure:
159 mg of the compound [2-2] was dissolved in a mixed solvent of 4 mL of tetrahydrofuran and 2 mL of methanol, then 48 mg of 10% palladium carbon catalyst was added thereto, and the mixture was further stirred for 2 hours under hydrogen atmosphere. Thereto, 95 mg of 10% palladium carbon catalyst was further added and stirred for 3.5 hours under hydrogen atmosphere. The insolubles were filtered through celite and the filtrate was concentrated under reduced pressure, to obtain tert-butyl{(1S)-1-[4-(N-methylglycyl)phenyl]ethyl}carbamate [2-3] (hereinafter, referred to as the compound [2-3]) as crude and purified products. The compound [2-3] was used in the subsequent reaction without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=1)[O:6][CH2:7][CH:8]([OH:11])[CH2:9][NH2:10])#[N:2].O1CCCC1.C(=O)(O)[O-].[Na+].[C:25](Br)([CH3:28])([CH3:27])[CH3:26]>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=1)[O:6][CH2:7][CH:8]([OH:11])[CH2:9][NH:10][C:25]([CH3:28])([CH3:27])[CH3:26])#[N:2]
Reactant: N#Cc1cccc(OCC(O)CN)c1
Reactant: CC(C)(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)NCC(O)COc1cccc(C#N)c1

Procedure:
9.6 gm (0.05 mol) of 1-(3-cyanophenoxy)-2-hydroxy-3-amino propane were dissolved in 40 ml of dimethylformamide and 100 ml of tetrahydrofuran and 4.2 gm (0.05 mol) of pulverized sodium bicarbonate were added thereto. Then, 6.9 gm (0.05 mol) of tert.-butylbromide were added and the mixture was refluxed for 24 hours. After the mixture had been cooled, the inorganic solid was filtered off and the solvent mixture was distilled off in vacuo. The residue was dissolved by heating in ethyl acetate and the insoluble inorganic portions were vacuum filtered off and the filtrate was admixed with petroleum ether. The base precipitated in solid form and was isolated and recrystallized from ethyl acetate with an addition of petroleum ether to obtain 1-(3-cyanophenoxy)-2-hydroxy-3-tert.-butylamino propane having a melting point of 108°-110° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[CH:13]=O)[CH:3]=1.Cl.[NH2:16]O.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[C:13]#[N:16])[CH:3]=1
Reactant: O=Cc1sccc1-c1cc(Cl)ccn1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: N#Cc1sccc1-c1cc(Cl)ccn1
Temperature: 80 °C

Procedure:
A mixture of 3-(4-chloro-pyridin-2-yl)-thiophene-2-carbaldehyde (103 mg, 0.46 mmol) and hydroxylamine hydrochloride (70 mg, 1 mmol) in pyridine (1 mL) was heated at 80° C. for 30 minutes. Acetic anhydride (0.8 mL) was added and the resulting mixture was heated at the temperature for another 3 hours. Ice water was added, the water solution was extracted with EtOAc and organic layer was concentrated. The resulting residue was purified by silica gel column to yield 3-(4-chloro-pyridin-2-yl)-thiophene-2-carbonitrile.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([O:11][CH3:12])=[C:5]([Cl:13])[C:3]=1[NH2:4].C(Cl)(Cl)=O.C1(C)C=CC=CC=1.ClC1C(OC)=CC=C(Cl)C=1N[C:36](=[O:59])[N:37]([CH3:58])[C:38]1[CH:43]=[C:42]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([N:51]3[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]3)=[CH:47][CH:46]=2)[N:41]=[CH:40][N:39]=1>O1CCOCC1>[Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([O:11][CH3:12])=[C:5]([Cl:13])[C:3]=1[NH:4][C:36](=[O:59])[N:37]([CH3:58])[C:38]1[CH:43]=[C:42]([NH:44][C:45]2[CH:46]=[CH:47][C:48]([N:51]3[CH2:52][CH2:53][N:54]([CH3:57])[CH2:55][CH2:56]3)=[CH:49][CH:50]=2)[N:41]=[CH:40][N:39]=1
Reactant: COc1cc(OC)c(Cl)c(N)c1Cl
Reactant: COc1ccc(Cl)c(NC(=O)N(C)c2cc(Nc3ccc(N4CCN(C)CC4)cc3)ncn2)c1Cl
Agent: O=C(Cl)Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3ccc(N4CCN(C)CC4)cc3)ncn2)c1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 2,6-dichloro-3,5-dimethoxyaniline (preparation 2, 74 mg, 0.34 mmol, 1.25 eq.) in dioxane is added 20% phosgene solution in toluene (191 μl, 0.36 mmol, 1.35 eq.) under argon. The reaction mixture is stirred for further 6 h at room temperature under argon. Then, the solvent is evaporated and the colorless crystalline residue is taken up in dry toluene (2.5 ml). After the addition of N-methyl-N′-[4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-4,6-diamine (see example 1, 80 mg, 0.27 mmol, 1.0 eq.) the suspension is stirred at 70° C. for 36 h under argon. After cooling the precipitate is filtered off, washed with toluene, methanol/ether 1:1, and ether to give a beige powder. The crude product is purified by flash chromatography (1% MeOH in DCM to 16% MeOH in DCM within 30 min). The fractions containing the product are pooled, evaporated, and triturated with ether. The precipitate is filtered off, washed (1× cold methanol/ether 1:1, 1× ether), and vacuum dried at 45° C. over night to afford the title compound as colorless powder: m.p. 221° C. (dec.), ESI-MS: 546.1/548.0/550.0 [MH]+.
Reaction SMILES: Cl[S:2]([C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[C:15]([F:16])=[CH:14][C:13](/[CH:17]=[C:18](\[CH3:22])/[C:19]([OH:21])=[O:20])=[CH:12][C:11]=2[F:23])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH3:26]>>[F:23][C:11]1[CH:12]=[C:13](/[CH:17]=[C:18](\[CH3:22])/[C:19]([OH:21])=[O:20])[CH:14]=[C:15]([F:16])[C:10]=1[O:9][C:8]1[CH:24]=[CH:25][C:5]([S:2](=[O:4])(=[O:3])[NH2:26])=[CH:6][CH:7]=1
Reactant: N
Reactant: C/C(=C\c1cc(F)c(Oc2ccc(S(=O)(=O)Cl)cc2)c(F)c1)C(=O)O
Product: C/C(=C\c1cc(F)c(Oc2ccc(S(N)(=O)=O)cc2)c(F)c1)C(=O)O

Procedure:
(E)-3-(4-(4-(chlorosulfonyl)phenoxy)-3,5-difluorophenyl)-2-methylacrylic acid (Intermediate 51.2) was converted to intermediate 58.1 using procedures outlined in Example 58, with aqueous ammonia as the amine. The title compound was obtained as a yellow solid.
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: ClCCl
Solvent: O
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: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:10][CH:9]=1
Reactant: c1cn[nH]c1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.9 %

Procedure:
Copper (II) acetate (960 mg, 5.28 mmol) was added to a flame-dried flask charged with pyrazole (240 mg, 3.52 mmol), 4-methoxyphenylboronic acid (1.07 g, 7.04 mmol), 4 A molecular sieves (1.35 activated powder), and pyridine (570 μl, 7.04 mmol) in methylene chloride. The reaction was stirred for approximately two days at room temperature and then filtered through diatomaceous earth. The filtrate was concentrated in vacuo and purified by column chromatography (silica gel; isocratic 8% ethyl acetate/hexanes) to yield 381 mg (2.18 mmol, 62% yield) of the title compound. LRMS ([M+H]+)=175.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][N:12]2[C:13](=[O:22])[C:14]3[C:15](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:17])=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCOc1ccc(Br)cc1
Temperature: 50 °C

Procedure:
4-Bromophenol, N-(2-bromoethyl)phthalimide and potassium carbonate were suspended in dimethylformamide and heated to 50° C. overnight under nitrogen. The dimethylformamide was removed under reduced pressure. The resulting residue was partitioned between ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The organics were combined, washed several times with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Yield: 2 g, 98%; LCMS: RT method: 2, RT: 5.33 min, MI: 382-384 [M+1].
Reaction SMILES: Br[C:2]1[C:3]([O:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:15][C:16]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[CH:18][C:17]=1[C:31]1[CH:32]=[N:33][C:34]([NH2:37])=[N:35][CH:36]=1>>[F:15][C:16]1[CH:21]=[C:20]([C:2]2[C:3]([O:8][CH:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:19]=[CH:18][C:17]=1[C:31]1[CH:36]=[N:35][C:34]([NH2:37])=[N:33][CH:32]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: Brc1cccnc1OC1CCOCC1
Product: Nc1ncc(-c2ccc(-c3cccnc3OC3CCOCC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 3-bromo-2-((tetrahydro-2H-pyran-4-yl)oxy)pyridine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C20H19FN4O2, 366.15; m/z found, 367.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J=1.5, 2H), 8.15 (dd, J=4.9, 1.9, 1H), 7.84 (dd, J=7.4, 1.9, 1H), 7.64-7.48 (m, 3H), 7.07 (dd, J=7.4, 4.9, 1H), 6.86 (s, 2H), 5.30 (m, 1H), 3.81-3.72 (m, 2H), 3.49 (m, 2H), 1.98 (m, 2H), 1.70-1.55 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1>O>[Cl:9][C:4]1[N:3]=[C:2]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)[CH:7]=[C:6]([I:8])[CH:5]=1
Reactant: Clc1cc(I)cc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(Nc2cc(I)cc(Cl)n2)C1
Temperature: 120 °C
Yield: 42.6 %

Procedure:
A mixture of 2,6-dichloro-4-iodopyridine (1 g, 3.65 mmol) and tert-butyl 3-aminopiperidine-1-carboxylate (3.66 g, 18 mmol) in a sealed tube was heated at 120° C. for 3 days. After cooling, the mixture was poured into 100 mL of water. The solid was collected by filtration and purified by flash chromatography on silica gel eluting with ethyl acetate to provide 680 mg of the title compound. Yield: 43%. MS (DCI/NH3) m/z 438 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[C:16]1=[CH:22][C:23]([NH:27][C:28]3[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=3[CH3:36])=[N:24][C:25](=[O:26])[N:15]1[CH2:14][CH2:13]2.[C:37](Cl)(=[O:39])[CH3:38]>C(Cl)(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[C:16]1=[CH:22][C:23]([N:27]([C:37](=[O:39])[CH3:38])[C:28]3[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=3[CH3:36])=[N:24][C:25](=[O:26])[N:15]1[CH2:14][CH2:13]2
Reactant: COc1cc2c(cc1OC)-c1cc(Nc3c(C)cc(C)cc3C)nc(=O)n1CC2
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2c(cc1OC)-c1cc(N(C(C)=O)c3c(C)cc(C)cc3C)nc(=O)n1CC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.2 ml of triethylamine are added first to an ice-cold solution of 9,10-dimethoxy-2-(2,4,6-trimethyl-anilino)-6,7-dihydro-4H-pyrimido(6,1-a)isoquinolin-4-one (1.6 g) in chloroform (40.0 ml), and then a solution of acetyl chloride (0.64 ml) in chloroform (10.0 ml) is added dropwise. The mixture is stirred for 2 hours. The chloroform solution is washed successively with water, sodium carbonate solution and water, and is then dried over anhydrous sodium sulfate. The solution is filtered and the filtrate evaporated to dryness in vacuo. The residue is triturated with diethyl ether to yield the desired compound in solid form. Yield 1.6 g, m.p. 210°-212° C. (dichloromethane-petroleum ether b.p. 60°-80° C.).