Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[N:7]=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=2)[N:5]=1)[CH3:2].ClC1C=CC(N)=CC=1.[CH3:29][C:30]1[CH:31]=[CH:32][C:33]2[O:37][C:36]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)=[N:35][C:34]=2[CH:45]=1.[OH-].[K+]>CN(C)C=O.CO.O>[CH3:29][C:30]1[CH:31]=[CH:32][C:33]2[O:37][C:36]([C:38]3[CH:43]=[CH:42][C:41]([CH:44]=[CH:19][C:16]4[CH:15]=[CH:14][C:13]([C:6]5[N:7]=[C:8]([O:10][CH2:11][CH3:12])[CH:9]=[C:4]([O:3][CH2:1][CH3:2])[N:5]=5)=[CH:18][CH:17]=4)=[CH:40][CH:39]=3)=[N:35][C:34]=2[CH:45]=1
Reactant: CCOc1cc(OCC)nc(-c2ccc(C=O)cc2)n1
Reactant: Cc1ccc(-c2nc3cc(C)ccc3o2)cc1
Agent: Nc1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(OCC)nc(-c2ccc(C=Cc3ccc(-c4nc5cc(C)ccc5o4)cc3)cc2)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
3.82 g of the Schiff's base of the formula ##STR77## which is obtained from 4,6-diethoxy-2-(p-formylphenyl)-pyrimidine and p-chloroaniline and has a melting point of 129.5°-130° C., 2.23 g of 5-methyl-2-(p-tolyl)-benzoxazole of the formula ##STR78## and 3.75 g of potassium hydroxide powder with a water content of about 10% are stirred in 80 ml of dimethylformamide under nitrogen. The reaction mixture is warmed to 60° C. in the course of 15 minutes and is stirred for a further one hour at 60°-65° C. After adding 400 ml of methanol, the mixture is cooled to -10° C. and the product which has precipitated is filtered off with suction, washed with 100 ml of methanol and dried. 2.64 g (55.3% of theory) of 2-[4'-(5-methyl-benzoxazol-2-yl)-stilben-4-yl]-4,6-diethoxy-pyrimidine of the formula ##STR79## are obtained in the form of a pale yellow powder with a melting point of 233°-234° C. After twice recrystallising from toluene, and with the aid of bleaching earth, 2.12 g (44.4% of theory) of small, pale greenish-tinged yellow, matted needles are obtained, which melt at 236°-237° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)=[N:7][CH:8]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][C:24]=3[N:25]([CH3:28])[C:26]=2[CH:27]=1>>[CH3:28][N:25]1[C:26]2[CH:27]=[C:19]([N:12]3[CH:13]=[CH:14][C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:8][N:7]=4)=[CH:10][C:11]3=[O:15])[CH:20]=[CH:21][C:22]=2[C:23]2[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][C:24]1=2
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cn2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cn5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 38.6 %

Procedure:
4-(5-(Trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (100 mg, 0.41 mmol) and tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (152 mg, 0.416 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (83 mg, 38%) as a green solid: 1H NMR (500 MHz, CDCl3) δ 9.00 (s, 1H), 8.06 (dd, J=8.3, 2.1 Hz, 1H), 7.91 (d, J=8.3 Hz, 1H), 7.58 (d, J=7.2 Hz, 1H), 7.55 (d, J=8.2 Hz, 1H), 7.37 (d, J=1.6 Hz, 1H), 7.25 (d, J=1.6 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 7.03 (dd, J=7.1, 1.8 Hz, 1H), 4.66 (s, 2H), 3.85 (br m, 2H), 3.66 (s, 3H), 2.84 (br m, 2H), 1.51 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([OH:13])[CH:8]=[CH:9][C:10]=2[Cl:12])[N:5]=[CH:4][N:3]=1.[CH3:14][NH:15][CH3:16].Cl.C(OCC)(=O)C>ClCCl>[ClH:1].[Cl:12][C:10]1[CH:9]=[CH:8][C:7]([OH:13])=[C:6]2[C:11]=1[C:2]([N:15]([CH3:16])[CH3:14])=[N:3][CH:4]=[N:5]2
Reactant: Oc1ccc(Cl)c2c(Cl)ncnc12
Reactant: CNC
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C)c1ncnc2c(O)ccc(Cl)c12
Reaction time: 0.5 h

Procedure:
A solution of 4,5-Dichloro-8-quinazolinol (0.6 g, 2.8 mmol) in dichloromethane is added to a saturated solution of dimethylamine gas in dichloromethane. The reaction mixture is stirred for 30 minutes, re-saturated with dimethylamine gas, stirred for 30 minutes and concentrated in vacuo to obtain a yellow solid. The solid is added to a 2.5% hydrochloric acid/ethyl acetate mixture. The mixture is filtered and the filter cake is washed with water and dried in a vacuum oven to give the title product as a white solid, 0.35 g, mp 232° C. (dec.).
Reaction SMILES: C([N:8]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]1)CCO)C1C=CC=CC=1>CO.[Pd]>[NH2:8][C@H:12]1[CH2:13][CH2:14][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH2:17]1
Reactant: COC(=O)[C@H]1CC[C@H](N(CCO)Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H](N)CC1

Procedure:
13 g of methyl trans-4-[N-benzyl-N-(2-hydroxyethyl)amino]-cyclohexanecarboxylate are hydrogenated in 150 ml of methanol with 3.5 g of palladium on activated charcoal (10% palladium) under a hydrogen pressure of 50 psi for 20 minutes at 50° C. The catalyst is suction filtered and the filtrate is evaporated to dryness. (The starting material is obtained from methyl trans-4-amino-cyclohexanecarboxylate by reacting with benzaldehyde and hydrogen in the presence of Raney-nickel and subsequently reacting with 2-bromoethanol in the presence of N-ethyl-diisopropylamine).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=O)=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN.O=C1[N:47]([ClH]P([ClH]N2CCOC2=O)=O)[CH2:46]CO1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:27])([F:28])[F:26])=[N:20][C:21]([C:22](=[O:24])[NH:47][CH3:46])=[C:15]2[CH2:14]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Yield: 98.6 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (150 mg, 0.27 mmol), methylamine hydrochloride (36.5 mg, 0.54 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (0.138 g, 0.54 mmol) were dissolved in 8 mL of dichloromethane under stirring, and triethylamine (0.25 mL, 1.62 mmol) was then added to the solution. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-(1-methylcarbamoyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 8a (150 mg, yield 98.6%) as a white solid.
Reaction SMILES: [H-].[Na+].Cl.[N:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.N1C=CC(CC#N)=CC=1.C(OCC[O-])C.[Na+].[NH2:29][C:30]1[N:35]=[C:34]([NH2:36])[C:33]([CH:37]=O)=[CH:32][N:31]=1>C(OCCO)C>[N:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([NH2:12])=[N:36][C:34]3[N:35]=[C:30]([NH2:29])[N:31]=[CH:32][C:33]=3[CH:37]=2)=[CH:6][CH:5]=1
Reactant: Nc1ncc(C=O)c(N)n1
Reactant: N#CCc1ccncc1
Agent: CCOCC[O-]
Agent: Cl
Agent: [H-]
Solvent: CCOCCO
Product: Nc1ncc2cc(-c3ccncc3)c(N)nc2n1
Reaction time: 0.17 h

Procedure:
To cooled (0° C.) 2-ethoxyethanol (13 mL) was added portionwise 0.30 g of sodium hydride (60% in mineral oil), and the suspension was stirred for 10 minutes. To this suspension was added 1.06 g of 4-pyridylacetonitrile hydrochloride, and the mixture was stirred at room temperature for 30 minutes. The neutralized solution of 4-pyridylacetonitrile in 2-ethoxyethanol was added to a reaction mixture containing sodium 2-ethoxyethoxide (prepared from 0.11 g of sodium hydride and 4.76 mL of 2-ethoxyethanol) and 0.9 g of 2,4-diamino-5-pyrimidinecarboxaldehyde. The resulting mixture was heated at reflux for 2 hours, cooled, and the insoluble product washed with diethylether and ethyl acetate to afford the title compound; mp >340° C.; MS (CI).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:5][C:6](=[O:29])[C@@H:7]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:8]C(OCC1C=CC=CC=1)=O.[ClH:35].[H][H]>[Pd].CO>[ClH:35].[CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:30][CH:31]([CH3:32])[CH3:33])[NH:5][C:6](=[O:29])[C@@H:7]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH2:8]
Reactant: [H][H]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Reaction time: 0.33 h

Procedure:
Nα -Benzyloxycarbonyl-D-tryptophyl-L-leucine methyl ester, 2.75 g., and 2.65 ml. of 2.23 N hydrogen chloride are dissolved in 100 ml. of methanol followed by the addition of 300 mg. of 10% palladium-on-carbon. The reaction is stirred under a hydrogen atmosphere with hydrogen bubbling through the mixture for seventy minutes. Thin layer chromatography indicates the reaction to be complete in about 20 minutes. The mixture is filtered and the solvent evaporated. The residue is dried under reduced pressure, 2.21 g. of D-tryptophyl-L-leucine methyl ester hydrochloride, [α]D23 -73° (c 1.02, methanol).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.F[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[F:18][C:17]([F:20])([F:19])[C:14]1[CH:15]=[CH:16][C:11]([O:9][C:5]2[CH:4]=[C:3]([CH2:2][OH:1])[CH:8]=[CH:7][CH:6]=2)=[CH:12][CH:13]=1
Reactant: OCc1cccc(O)c1
Reactant: Fc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: OCc1cccc(Oc2ccc(C(F)(F)F)cc2)c1
Temperature: 110 °C
Reaction time: 16 h
Yield: 60.8 %

Procedure:
3-Hydroxymethyl-phenol (1.0 g, 8.1 mmol), 4-fluorobenzotrifluoride (1.32 g, 8.1 mmol) and cesium carbonate (3.28 g, 10.1 mmol) were suspended in dimethylsulfoxide (15 mL) and heated to 110° C. After stirring for 16 h, the reaction was partitioned between water (150 mL) and ethyl acetate (150 mL). The organic layer was separated and the aqueous was extracted again with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10-40%, EtOAc:heptane) to afford the title compound (1.32 g) as a thick oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24]
Reactant: ClCc1ccccn1
Reactant: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(O)c(OC)cc23)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCc4ccccn4)c(OC)cc23)cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
A starting compound (N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]phenyl)-N′-propylurea, 80 mg), potassium carbonate (138 mg), and 2-chloromethylpyridine hydrochloride (41 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at 80° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC to give 81 mg (yield 82%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:6]2.[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH:17]=[CH2:18].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCOCC1>[C:21]([O:20][C:16]([CH2:17][CH2:18][N:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[C:5]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CCOC(=O)c1cc2c(C)cccc2[nH]1
Reactant: C=CC(=O)OC(C)(C)C
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOC(=O)c1cc2c(C)cccc2n1CCC(=O)OC(C)(C)C
Reaction time: 8.5 h
Yield: 87 %

Procedure:
A mixture of ethyl 4-methyl-1H-indole-2-carboxylate (70.0 g, 344 mmol), tert-butyl acrylate (53.0 g, 413 mmol), benzyltrimethylammonium hydroxide (5.76 g, 34.4 mmol) and 1,4-dioxane (1,000 ml) was stirred at 60°-62° C. for 8.5 hours. The solvent was distilled off under reduced pressure and water (1,000 ml) and acetic acid (30 ml) were added to the residue, followed by extraction with ethyl acetate (twice). The extract solution was washed with a 5% aqueous sodium hydrogencarbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was crystallized from isopropanol (230 ml) to obtain ethyl 1-(2-tert-butoxycarbonylethyl)-4-methyl-1H-indole-2-carboxylate (99.2 g). M.p. 78°-79° C.
Reaction SMILES: BrC1N=CC(C(N2CCN(C3C(C)=CC(C)=C(C)N=3)CC2)=O)=CC=1.COC1C=CC(CN2CC(C)NC2=O)=CC=1.COC1C=CC(C[N:48]2[CH2:52][CH:51]([CH3:53])[N:50]([C:54]3[CH:59]=[CH:58][C:57]([C:60]([N:62]4[CH2:67][CH2:66][N:65]([C:68]5[C:73]([CH3:74])=[CH:72][C:71]([CH3:75])=[C:70]([CH3:76])[N:69]=5)[CH2:64][CH2:63]4)=[O:61])=[CH:56][N:55]=3)[C:49]2=[O:77])=CC=1>>[CH3:53][CH:51]1[N:50]([C:54]2[CH:59]=[CH:58][C:57]([C:60]([N:62]3[CH2:67][CH2:66][N:65]([C:68]4[C:73]([CH3:74])=[CH:72][C:71]([CH3:75])=[C:70]([CH3:76])[N:69]=4)[CH2:64][CH2:63]3)=[O:61])=[CH:56][N:55]=2)[C:49](=[O:77])[NH:48][CH2:52]1
Reactant: COc1ccc(CN2CC(C)N(c3ccc(C(=O)N4CCN(c5nc(C)c(C)cc5C)CC4)cn3)C2=O)cc1
Agent: COc1ccc(CN2CC(C)NC2=O)cc1
Agent: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)nc3)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)NCC4C)nc3)CC2)nc1C

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (156 mg) described in Preparation Example 205 and 1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (106 mg) described in Preparation Example 52 and by the reaction and treatment in the same manner as in Example 505, the title compound (101 mg) was obtained via 1-(4-methoxybenzyl)-4-methyl-3-{5-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]pyridin-2-yl}imidazolidin-2-one.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[NH2:17][C:18]1[C:19](=[O:24])[NH:20][CH:21]=[CH:22][CH:23]=1>O1CCCC1>[O:24]=[C:19]1[C:18]([NH:17][C:7](=[O:8])[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:23][CH:22]=[CH:21][NH:20]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc[nH]c1=O)OCc1ccccc1
Reaction time: 7 h
Yield: 63.2 %

Procedure:
Sodium bicarbonate (1.70 g, 16.89 mmol) and benzyl chloroformate (1.58 g, 9.29 mmol) were added to a solution of 3-aminopyridin-2(1H)-one (0.930 g, 8.45 mmol) in tetrahydrofuran (20 mL). After 7 h, the mixture was extracted with ethyl acetate and saturated sodium bicarbonate. The organic extract was washed with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated. Purification by chromatography [silica gel, 1% to 5% methanol (10% ammonium hydroxide) in dichloromethane gradient elution] gave the title compound (1.304 g). MS 245 (M+1)
Reaction SMILES: Br[C:2]([CH3:13])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F-].[K+].[N+:16]([C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1)([O-:18])=[O:17]>CN(C=O)C.O>[CH3:13][C:2]([O:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([N+:16]([O-:18])=[O:17])[CH:20]=1)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)(Br)C(=O)OCC
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(Oc1cccc([N+](=O)[O-])c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.4 %

Procedure:
Diethyl 2-bromo-2-methylmalonate (1.0 g, 3.95 mmole) was added to a stirred suspension of potassium fluoride (0.57 g, 9.8 mmole) in dry DMF (5 mL). After stirring for 20 min at room temperature, 3-nitrophenol (0.55 g, 3.95 mmole) was added. The resulting mixture was stirred at 60° C. for 6 h, cooled to room temperature, diluted with water (30 mL) and extracted with ethyl acetate (3×200 mL). The organic layer was washed with aq. 1N NaOH (2×75 mL), dried over anhydrous Na2SO4, filtered and evaporated in vacuo to provide diethyl 2-methyl-2-(3-nitrophenoxy)malonate (0.89 g, 80%). 1H NMR (CDCl3): δ 7.92 (dd, 1H, J=2.3 and 8.2 Hz), 7.82 (t, 1H, J=2.3 Hz), 7.41 (t, 1H, J=8.2 Hz), 7.30 (dd, 1H, J=2.3 and 8.2 Hz), 4.28 (qt, 4H, J=7.0 Hz), 1.81 (s, 3H), 1.26 (t, 6H, J=7.0 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[S:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[CH:4][CH:3]=1.CC1C=CC=C(SC2SC(=O)NC2=O)C=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]#[C:39][CH2:40]Br)=[CH:34][CH:33]=1.FC1C=C(C#CCBr)C=C(F)C=1>>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]#[C:39][CH2:40][C:9]2([S:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[S:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[CH:34][CH:33]=1
Reactant: O=C1NC(=O)C(Sc2ccc(F)cc2)S1
Reactant: Clc1ccc(C#CCBr)cc1
Agent: Cc1cccc(SC2SC(=O)NC2=O)c1
Agent: Fc1cc(F)cc(C#CCBr)c1
Product: O=C1NC(=O)C(CC#Cc2ccc(Cl)cc2)(Sc2ccc(F)cc2)S1

Procedure:
Prepared from 5-(4-fluorophenyl-sulfanyl)-thiazolidine-2,4-dione of formula (III), Example 5 and [3-(4-chlorophenyl)-prop-2-ynyl]-bromide of formula (IX), from Example 21: mp 116°-117° C.; Anal. Calc. for C18H11ClFNO2S2 : C, 55.17; H, 2.83; N, 3.57; Found: C, 54.58; H, 2.65; N, 3.39.
Reaction SMILES: [C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]#[N:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27]([O:30][C@H:31]1[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:34](OC(=O)C)[O:33][C@@H:32]1[CH2:44][O:45][C:46](=[O:48])[CH3:47])(=[O:29])[CH3:28].C[Si](OS(C(F)(F)F)(=O)=O)(C)C.C(OCC)(=O)C>ClC(Cl)(Cl)C>[C:27]([O:30][C@H:31]1[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:34]([N:14]2[CH:13]=[N:12][C:11]3[C:15]2=[N:16][C:17]([C:19]#[N:20])=[N:18][C:10]=3[NH:9][CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:33][C@@H:32]1[CH2:44][O:45][C:46](=[O:48])[CH3:47])(=[O:29])[CH3:28]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N#Cc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Yield: 47.3 %

Procedure:
N,O-Bistrimethylsilylacetamide (44 ml, 0.18 mol) was added to a suspension of 6-[(2,2-diphenylethyl)amino]-9H-purine-2-carbonitrile (10.0 g, 0.03 mol) (see WO-A-00/23457) in 1,1,1-trichloroethane (250 ml). The suspension was heated to reflux. When all suspended solid had dissolved the reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was twice dissolved in toluene (50 ml) and the solvent removed under reduced pressure. The residue was then dissolved in toluene (100 ml) and (2R,3R,4R,5S)-4,5-bis(acetyloxy)-2-[(acetyloxy)methyl]tetrahydro-3-furanyl acetate (10.3 g, 0.032 mol) was added. The solution was stirred at room temperature and trimethylsilyltrifluoromethanesulphonate (16 ml, 0.088 mol) was carefully added. The resulting solution was heated under reflux for 2 hours and then allowed to cool to room temperature. The reaction mixture was diluted by the addition of ethyl acetate (100 ml) and then washed with saturated aqueous sodium hydrogen carbonate (ten portions of 100 ml) and saturated aqueous sodium chloride solution (100 ml). The aqueous extracts were combined and washed with ethyl acetate (three portions of 100 ml). The combined organic layers were dried (anhydrous magnesium sulphate) and the solvent was removed under reduced pressure to give a solid that was purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 concentrated aqueous ammonia (97:3:0.5 by volume gradually changing to 80:20:3 by volume) to give the title compound as a foam (8.5 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.CN([C:33]([O:37][N:38]1N=NC2C=CC=C[C:39]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CNOC>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:38]([O:37][CH3:33])[CH3:39])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.7 %

Procedure:
To a solution of 4-fluorobenzoic acid (6.8 g, 48.57 mmole) in 100 mL of DMF at room temperature, is added diisopropylethylamine (25.3 mL, 145.7 mmole). After stirring at room temperature for 20 minutes, HOBT (7.22 g, 53.43 mmole), HBTU (20.26 g, 53.43 mmole) and N,O-dimethyl hydroxylamine hydrochloride (5.69 g, 58.29 mmole) are added to the reaction solution. After stirring at room temperature for 2 hours, the reaction solution is diluted with 200 mL of EtOAc and washed with 4×50 mL of water. The combined organic layers is concentrated and purified by flash column chromatography (hexane 70%, EtOAc 30%) to yield 4-fluoro-N-methoxy-N-methyl-benzamide (4a) (7.0 g, yield 79%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:29][CH2:28][CH2:27][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]([OH:26])[CH2:21][S:22][CH:23]([CH3:25])[CH3:24])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:41])C=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:29][CH2:28][CH2:27][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]([OH:26])[CH2:21][S:22]([CH:23]([CH3:24])[CH3:25])=[O:41])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)SCC(O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: ClCCl
Product: CC(C)S(=O)CC(O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1

Procedure:
(2S)-1-(N-Benzyloxycarbonyl-L-prolyl)-2-[1-hydroxy-2-(isopropylthio)ethyl]pyrrolidine (1.61 g) was subjected to oxidation as in Example 2-A) in dichloromethane using 1.1 equivalent of m-chloroperbenzoic acid to give 1.40 g of the title compound.