Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=[CH:6][C:5]=1[OH:16])([O-])=O.[H][H].[C:19](N)(=O)[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[OH:22].C1CCCCC1>[Pd].C(O)C>[OH:22][C:21]1[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=1[C:19]1[O:16][C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:9][C:4]=2[N:1]=1
Reactant: CCCCCCc1ccc(O)c([N+](=O)[O-])c1
Reactant: NC(=O)c1ccccc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCCCC1
Product: CCCCCCc1ccc2oc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 22.8 g. (0.102 mole) of 2-nitro-4-hexylphenol and 0.25 g. of 5% palladium on carbon slurried in 150 ml of 95% ethanol was placed in a 250 ml hydrogenation bottle. The bottle was stoppered under an atmosphere of 45 psi of hydrogen and shaken at room temperature. The hydrogen was replenished during reaction. After three hours hydrogen uptake was complete. The mixture then was filtered through a sintered glass funnel and the filtrate was stripped of solvent under reduced pressure. The distillation residue then was added to a three neck flask fitted with a thermometer, mechanical stirrer, and a condenser with a Dean-Stark trap charged with 13.7 g. (0.1 mole) of salicylamide. The mixture was heated with stirring to 200° C and held at 200°-220° C for 4 hours. The reaction mixture then was cooled to room temperature and 150 ml of cyclohexane were added. The resulting mixture was filtered and the cyclohexane was removed from the filtrate by distillation under reduced pressure. The distillation residue weighed 22.4 g. and infrared analysis confirmed the composition as 2-(2-hydroxyphenyl)-5-hexylbenzoxazole.
Reaction SMILES: N#N.[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=[CH2:4].N1C=CC=CC=1.Cl[C:19]([O:21][CH:22]=[CH2:23])=[O:20]>C(Cl)(Cl)Cl>[C:19](=[O:20])([O:21][CH:22]=[CH2:23])[O:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]=[CH2:4])=[CH:6][CH:7]=1
Reactant: C=COC(=O)Cl
Reactant: C=Cc1ccc(O)cc1
Agent: N#N
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: C=COC(=O)Oc1ccc(C=C)cc1
Temperature: 5 °C

Procedure:
A 500 ml round bottom flask equipped with a reflux condenser, a mechanical stirrer, a thermometer, a dropping funnel and an efficient N2 blanket, is charged with 30.0 g (0.25 mole) of 4-vinylphenol, 21.8 g of pyridine and 300 ml of chloroform. The contents are then cooled down to 5 degrees C., and 25,3 g of vinyl chloroformate is added dropwise via the dropping funnel with constant stirring and the temperature maintained at 5 degrees or below. The temperature is then allowed to rise to ambient temperature and the mixture stirred overnight. The reaction mixture is then passed through a silica gel column and dried over magnesium sulfate and filtered. After the solvent is removed under pressure, the named product is recovered.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]3)[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][N:22]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:21]3)[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCC3CCCNC3)n2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCC3CCCN(S(C)(=O)=O)C3)n2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 12.5 %

Procedure:
To a mixture of 2-(3-acetamidophenylamino)-4-(piperidin-3-ylmethylamino)pyrimidine-5-carboxamide (40 mg, 0.104 mmol) and DIEA (0.100 mL, 0.575 mmol) in CH2Cl2 (2 mL), methanesulfonyl chloride (0.032 mL, 0.413 mmol) was added. The mixture was stirred at room temperature for 18 h. It was then purified by HPLC to give the titled compound (6 mg). MS 462.4 (M+H); UV 204.7, 248.6 nm.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:12](=[O:13])[NH:11][C:9]1=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:15][CH3:16]>CO>[IH:15].[CH2:1]([N:8]1[CH2:14][C:12](=[O:13])[N:11]=[C:9]1[S:10][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: O=C1CN(Cc2ccccc2)C(=S)N1
Solvent: CO
Product: CSC1=NC(=O)CN1Cc1ccccc1
Product: I

Procedure:
1-Benzyl-2-thiohydantoin (8.07 g), iodomethane (10 ml) and methanol (50 ml) were warmed at 40°-42° C. for 8 hours. The reaction mixture was evaporated under reduced pressure, the residue was washed with diethyl ether and recrystallised from methanol-ethanol to give 1-benzyl-2-methylthio-2-imidazolin-4-one hydroiodide (4.86 g) m.p. 185°-190° C., as an impure light-buff coloured solid which was taken on to the next stage.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[C:19]([F:21])[C:18]([Cl:22])=[CH:17][C:16]=2[C:23]2[N:27]([CH3:28])[C:26]([CH2:29]C)=[N:25][N:24]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.[NH4+:36].[OH-:37]>O.CCOC(C)=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[CH:20]=[C:19]([F:21])[C:18]([Cl:22])=[CH:17][C:16]=2[C:23]2[N:27]([CH3:28])[C:26]([C:29]([NH2:36])=[O:37])=[N:25][N:24]=2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCc1nnc(-c2cc(Cl)c(F)cc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C
Reactant: [OH-]
Reactant: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(C(N)=O)nnc1-c1cc(Cl)c(F)cc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
To a vial containing ethyl 5-[2-(4-tert-butyl-benzenesulfonylamino)-5-chloro-4-fluoro-phenyl]-4-methyl-4H-[1,2,4]triazole-3-carboxylic acid ethyl ester (synthesized according to general procedure C, 100 mg, 0.202 mmol) was added THF (2 mL) and 28% NH4OH in water (2 mL), and the resultant solution was stirred at room temperature for 1 h. The reaction mixture was subsequently diluted with EtOAc (30 mL) and the organics were washed with water (2×10 mL), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography (50→100% gradient of EtOAc in hexanes). The pure fractions were collected and the solvent was removed. The isolated product was dissolved in MeCN/H2O and the solvent removed via lyophilization to afford the title compound as a white powder: MS (ES) M+H expected 466.0, found 466.0.
Reaction SMILES: N1CCCCC1.[CH2:7]([Li])[CH2:8][CH2:9][CH3:10].[Br-:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([C:34]1[CH:51]=[C:50]([C:52]2[O:53][CH2:54][CH2:55][N:56]=2)C=C[C:35]=1[O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]1[O:46][N:45]=[C:44]([CH3:47])[CH:43]=1)=O>CCOCC.O1CCCC1>[Br:12][CH:7]=[CH:8][C:9]1[CH:10]=[C:50]([C:52]2[O:53][CH2:54][CH2:55][N:56]=2)[CH:51]=[CH:34][C:35]=1[O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]1[O:46][N:45]=[C:44]([CH3:47])[CH:43]=1
Reactant: [Br-]
Reactant: Cc1cc(CCCCCOc2ccc(C3=NCCO3)cc2C=O)on1
Reactant: [Li]CCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(CCCCCOc2ccc(C3=NCCO3)cc2C=CBr)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.255 g piperidine in 100 ml ether at 0° under nitrogen was added 12 ml n-butyllithium (1.23 m) followed by 5 g triphenylphosphine bromide. The mixture was then stirred two hours at room temperature and 4.78 g 5-{5-[2-formyl-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}-3-methylisoxazole (Example 70) in 35 ml tetrahydrofuran was added dropwise. The reaction mixture was kept overnight at room temperature and worked up by chromatography to give 0.53 g 5-{5-[2-(2-bromoethenyl)-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}-3-methylisoxazole, colorless needles, m.p. 94°-96° C. after recrystallization from isopropyl acetate and hexane.
Reaction SMILES: C1(O[C:8](=[O:25])[NH:9][CH:10]2[CH2:15][CH2:14][C:13]([N:22]([CH3:24])[CH3:23])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)C=CC=CC=1.[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>O1CCOCC1>[CH3:24][N:22]([CH3:23])[C:13]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11][CH:10]([NH:9][C:8]([N:39]2[CH2:40][CH2:41][CH:36]([C:30]3[C:29]4[C:33](=[CH:34][CH:35]=[C:27]([Cl:26])[CH:28]=4)[NH:32][CH:31]=3)[CH2:37][CH2:38]2)=[O:25])[CH2:15][CH2:14]1
Reactant: Clc1ccc2[nH]cc(C3CCNCC3)c2c1
Reactant: CN(C)C1(c2ccccc2)CCC(NC(=O)Oc2ccccc2)CC1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(NC(=O)N2CCC(c3c[nH]c4ccc(Cl)cc34)CC2)CC1

Procedure:
The non-polar diastereoisomer of (4-dimethylamino-4-phenylcyclohexyl)-carbamic acid phenyl ester (338 mg, 1.0 mmole) was added to a solution of 5-chloro-3-piperidine-4-yl-1H-indole (218 mg, 1.0 mmole) in dioxane (10 ml). The reaction mixture was then boiled under reflux for 32 hours. The reaction mixture was worked up by distilling off dioxane and diluting with water (10 ml). The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (3×20 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. The non-polar diastereoisomer of 4-(5-chloro-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexyl)-amide was recrystallised from methanol (5 ml). It was obtained in a yield of 120 mg (25%) as a colourless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].O.OC1C2N=NNC=2C=CC=1.Cl.[CH2:26]([O:28][C:29](=[O:49])[CH:30]([NH:42][C:43]([O:45][CH2:46][CH:47]=[CH2:48])=[O:44])[CH2:31][C:32]1[O:36][N:35]=[C:34]([CH:37]2[CH2:41][CH2:40][CH2:39][NH:38]2)[CH:33]=1)[CH3:27].C(N(CC)CC)C>CN(C)C=O.O>[CH2:26]([O:28][C:29](=[O:49])[CH:30]([NH:42][C:43]([O:45][CH2:46][CH:47]=[CH2:48])=[O:44])[CH2:31][C:32]1[O:36][N:35]=[C:34]([CH:37]2[CH2:41][CH2:40][CH2:39][N:38]2[C:11](=[O:13])[CH2:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH:33]=1)[CH3:27]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: C=CCOC(=O)NC(Cc1cc(C2CCCN2)no1)C(=O)OCC
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)Cc2ccc([N+](=O)[O-])cc2)no1)C(=O)OCC
Reaction time: 0.5 h
Yield: 16.3 %

Procedure:
A dimethyl formamide (82 mL) solution of 4-nitrophenylacetic acid (1.61 g, 8.87 mmol) in dimethyl formamide (82 mL) was stirred with 4-hydroxybenzotriazole monohydrate (1.40 g, 10.4 mmol) for 10 minutes. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimde hydrochloride (1.86 g, 9.72 mmol) was added and the mixture was stirred until all 1-(3-dimethylaminopropyl)-3-ethylcarbodiimde hydrochloride had dissolved. To this solution, 2-allyloxycarbonylamino-3-(3-pyrrolidin-2-yl-isoxazol-5-yl)-propionic acid ethyl ester hydrochloride from Example 1C (3.16 g, 8.25 mmol) was added and the mixture stirred 30 minutes followed by addition of triethyl amine (1.26 mL, 9.04 mmol). After the reaction had stirred at room temperature over night it was poured into water and extracted with ethyl acetate three times. The combined extracts were washed with a saturated solution of sodium bicarbonate, water (2×) and brine. The organic portion was dried over magnesium sulfate and concentrated. The resulting residue was chromatographed on a Biotage Flash 40S column eluting with ethyl acetate/hexanes (5:1) to yield the title compound as a yellow oil (674 mg, 15%). MS (CI) m/z 501.3 (M+1). Additionally, starting material 2-allyloxycarbonylamino-3-(3-pyrrolidin-2-yl-isoxazol-5-yl)-propionic acid ethyl ester was recovered (2.15 g, 75%). MS (Cl) m/z 338.1 (M+1)
Reaction SMILES: [CH2:1]([CH:11]1[C:16](=[O:17])[NH:15][C:14](=[O:18])[NH:13][C:12]1=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[BrH:20].BrBr>O>[Br:20][C:11]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:16](=[O:17])[NH:15][C:14](=[O:18])[NH:13][C:12]1=[O:19]
Reactant: Br
Reactant: CCCCCCCCCCC1C(=O)NC(=O)NC1=O
Agent: BrBr
Solvent: O
Product: CCCCCCCCCCC1(Br)C(=O)NC(=O)NC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 5-decylbarbituric Acid (0.537 g) in 2.9 ml of water are added under stirring at room temperature 0.29 ml of 48% hydrobromic acid. The mixture is cooled to 0° C. and 0.113 ml of bromine are dropped. The reaction mixture is stirred at room temperature for 1 hour 30 minutes, then the white precipitate is filtered and it is washed with water. The solid is partitioned between water and diethyl ether, the organic phase is separated, washed with brine and finally dried over sodium sulfate. By evaporation of the solvent under reduced pressure 0.62 g of the product are recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[CH2:43]([N:45]([C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH3:55])[CH:50]=1)[CH2:46][CH2:47][NH2:48])[CH3:44]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:35]([NH:48][CH2:47][CH2:46][N:45]([CH2:43][CH3:44])[C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH3:55])[CH:50]=1)=[O:41]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: CCN(CCN)c1cccc(C)c1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN(CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1Cl)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.8 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (134 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1-ethyl-N1-(3-methylphenyl)-1,2-ethanediamine (80 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (100 mg, yield 62%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[NH2:12]/[C:13](/[CH3:23])=[CH:14]\[C:15]([O:17][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:16].[N+:24]([CH2:27][C:28](=O)[CH3:29])([O-:26])=[O:25]>C(O)C>[CH3:29][C:28]1[NH:12][C:13]([CH3:23])=[C:14]([C:15]([O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:16])[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:27]=1[N+:24]([O-:26])=[O:25]
Reactant: C/C(N)=C/C(=O)OC1CCCC1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)C[N+](=O)[O-]
Solvent: CCO
Product: CC1=C(C(=O)OC2CCCC2)C(c2cccc([N+](=O)[O-])c2)C([N+](=O)[O-])=C(C)N1

Procedure:
15.1 g (0.1 mol) of 3-nitrobenzaldehyde, together with 16.9 g (0.1 mol) of cyclopentyl β-aminocrotonate and 10.3 g (0.1 mol) of nitroacetone in 150 ml of ethanol, were heated under reflux for 6 hours. After the reaction mixture had cooled, the solvent was distilled off in vacuo, and the oily residue was taken up in a small amount of chloroform and was chromatographed on a silica gel column, using chloroform with the addition of methanol. The fractions containing the reaction product were concentrated, the residue was taken up in a small amount of isopropanol, and the nitrodihydropyridine crystallized in yellow crystals of melting point 174° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10]C(OC)=O)=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1.[N+](C1C=CC=CC=1)([O-])=O.[Al+3].[Cl-].[Cl-].[Cl-].[C:39]([O:42][CH2:43]C)(=[O:41])C>>[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([C:8]2[CH:7]=[C:6]([CH:9]([CH3:10])[C:39]([O:42][CH3:43])=[O:41])[CH:5]=[CH:4][C:3]=2[O:2][CH3:1])=[O:22])=[CH:19][CH:18]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)CCc1ccc(OC)cc1
Reactant: CCOC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COC(=O)C(C)c1ccc(OC)c(C(=O)c2ccc(OC)cc2)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
The methyl 3-(4-methoxyphenyl)propionate (10.8 g, 55.6 mmol) prepared in Example 1 and 4-methoxybenzoyl chloride (11.4 g, 66.8 mmol) were dissolvedin nitrobenzene (200 ml). To the ice-chilled solution, AlCl3 (26.7 g, 200.3 mmol) was added in 6 portions with vigorous stirring over a period of 3 hours. After all portions of AlCl3 were added, stirring was continued for an additional 1 hour. The reaction mixture was poured into abeaker containing a mixture of ice and 120 ml of 1N CHl and stirred vigorously. The mixture was transferred into a separating funnel, which was shaken well after the addition of ethyl acetate. The organic layer in the solution was washed twice with a saturated aqueous solution of sodium bicarbonate, then twice with a saturated aqueous solution of sodium chloride. After drying over unhydrous sodium sulfate, the solvent was removed in vacuo. The residue was purified by flash column chromatography using 30% ethyl acetate/hexane to produce a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:21][O:22][CH3:23].O>ClCCl>[CH3:21][O:22][CH2:23][O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: COCCl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCOCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4-bromophenyl)ethanol (1.0 g) and diisopropylethylamine (1.3 mL) in dichloromethane (5 mL) was added chloromethylmethyl ether (0.75 mL), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added water, and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=15/1-10/1) to give 4-[2-(methoxymethyloxy)ethyl]bromobenzene (1.2 g).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)O1.Br[C:18]1[N:22]([CH3:23])[C:21]([CH3:24])=[N:20][CH:19]=1.[F-].[Cs+]>COCCOC.CO.CCOC(C)=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>[CH3:23][N:22]1[C:18]([C:9]2[CH:10]=[CH:11][C:12]([NH2:13])=[CH:14][CH:15]=2)=[CH:19][N:20]=[C:21]1[CH3:24]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: Cc1ncc(Br)n1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1ncc(-c2ccc(N)cc2)n1C
Temperature: 150 °C
Yield: 56.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0.053 g, 0.046 mmol) was added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.1 g, 0.456 mmol), 5-bromo-1,2-dimethyl-1H-imidazole (0.088 g, 0.502 mmol) and cesium fluoride (0.208 g, 1.369 mmol) in DME/MeOH (2/1, 2.9 mL). The reaction mixture was heated for 10 minutes at 150° C. under microwave irradiation. The reaction was diluted with EtOAc and quenched with water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude mixture was purified using Biotage silica gel column chromatography eluting with 1 to 5% MeOH/aq. NH3 (10/1) in DCM followed by filtration through a SCX-2 column to afford the title product as a white solid (48 mg, 56%). 1H NMR (500 MHz, CDCl3): δ 2.42 (s, 3H), 3.46 (s, 3H), 3.81 (br s, 2H), 6.71-6.74 (m, 1H), 6.85 (s, 1H), 7.12-7.14 (m, 1H).
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]=1)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(OCC)(=O)C>ClCCl.CCCCCC>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]2[CH2:2][CH2:3][N:4]([CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[C:5](=[O:6])[C:7]=12)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccc(Cl)cc4)CCCC3)n2CCN1C1CCOCC1
Reaction time: 1 h
Yield: 57 %

Procedure:
5-Benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-(tetrahydro-pyran-4-yl)-amide (334) (90 mg, 0.16 mmol) and triphenylphosphine were taken up in dichloromethane (3 ml) at room temperature and diisopropyl azodicarboxylate was added slowly. Stirring was continued for 1 h while silica thin layer chromatography was performed (ethyl acetate:hexane=1:1, Rf=0.6). Dichloromethane (15 ml) was added to the reaction mixture, which was thereafter washed with water (10 ml) and brine (10 ml). The organic part was dried and concentrated under reduced pressure. The obtained residue was purified by nor mal silica gel (100-20 mesh) column chromatography using 30% ethyl acetate in hexane to get 9-benzyloxy-6-[1-(4-chlorophenyl)-cyclopentylmethyl]-2-(tetrahydro-pyran-4-yl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (335) (50 mg, 60%; 2 steps yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:11][C:12]([O:14][CH3:15])=[O:13]>>[CH3:15][O:14][C:12](=[O:13])[CH2:11][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COC(=O)CBr
Product: COC(=O)Cn1ccc2ccccc21

Procedure:
This compound was prepared from indole and methyl bromoacetate by the method described in Example 10, part i. The reaction mixture was worked up by concentrating in vacuo, diluting with water and extracting with ethyl acetate (3x). The combined extracts were washed with water (3x) and brine, dried and evaporated to an oil. The residue was purified by chromatography on flash silica eluting with petroleum spirit 40°-60° C.--diethyl ether (5:1, 2:1) to give the product.