Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].I[C:27]1[CH:28]=[C:29]([C:34]([F:37])([F:36])[F:35])[C:30]([NH2:33])=[N:31][CH:32]=1>>[F:37][C:34]([F:35])([F:36])[C:29]1[C:30]([NH2:33])=[N:31][CH:32]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:28]=1
Reactant: Nc1ncc(I)cc1C(F)(F)F
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Nc1ncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1C(F)(F)F

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl -5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 g, 1.0 mmol) and 5-iodo-3-trifluoromethyl-pyridin-2-ylamine (example B.48) (288 mg, 1.0 mmol) according to general procedure II. Obtained as an off-white solid (370 mg, 72%). MS (ISP) 516.2 [(M+H)+]; mp 230° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:17]=2)[C:11]([O:13]C)=[O:12])=[N:6][CH:7]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].Cl>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:17]=2)[C:11]([OH:13])=[O:12])=[N:6][CH:7]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cn2)cc(S(C)(=O)=O)c1
Agent: Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2cc(C(=O)O)cc(S(C)(=O)=O)c2)nc1
Temperature: 25 °C

Procedure:
Into a round-bottom flask were charged methyl 3-(5-methylpyridin-2-yl)-5-(methylsulfonyl)benzoate (0.60 g, 1.96 mmol), barium hydroxide octahydrate (1.23 g, 3.90 mmol) and methanol (50 mL). The mixture was stirred at room temperature until the completion of the reaction. The mixture was acidified with HCl (2M ethyl ether solution, 20 mL). The mixture was concentrated to afford a mixture of the desired product and BaCl2 as a white solid (1.4 g, 40% purity). LC-MS: 291.5 [M+1]; 1H NMR (400 MHz, DMSO-d6): 8.90 (s, 1H), 8.80 (d, J=1.7 Hz, 1H), 8.63 (s, 1H), 8.43 (d, J=1.5 Hz, 1H), 8.16 (d, J=8.1 Hz, 1H), 7.89 (d, J=7.8 Hz, 1H), 7.64-7.55 (m, 1H), 3.38 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([B:9]([OH:11])[OH:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH:12]([CH2:16][CH2:17]O)[CH2:13][CH2:14]O>>[Cl:8][C:6]1[CH:5]=[C:4]([B:9]2[O:10][CH2:17][CH2:16][NH:12][CH2:13][CH2:14][O:11]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: OCCNCCO
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: Clc1cc(Cl)cc(B2OCCNCCO2)c1
Yield: 94 %

Procedure:
The title compound (94%, crystals) was prepared from 3,5-dichlorophenylboronic acid and diethanolamin.
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[C:24]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1)#[CH:25]>>[C:26]1([C:24]2[N:3]=[N:2][N:1]([CH:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[CH:25]=2)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Reactant: C#Cc1cccc2ccccc12
Product: O=C(O)Cc1c2n(c3ccccc13)CC(n1cc(-c3cccc4ccccc34)nn1)CC2

Procedure:
The title compound was prepared using procedures described in EXAMPLE 1 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and 1-ethynylnaphthalene. MS (+ESI) m/z: 423.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:14]=1[NH2:15]>>[F:12][C:13]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1ccc(F)cc1F
Product: O=C(O)Cc1ccccc1Nc1ccc(F)cc1F

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid was condensed with 2,4-difluoroaniline to yield 2-[(2,4-difluorophenyl)amino]phenylacetic acid.
Reaction SMILES: O[CH:2]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2)[CH2:3][CH2:4]Cl.[C:17]1([C:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:17]1([C:23]2[CH2:28][CH2:27][N:26]([CH2:4][CH:3]=[CH:2][C:6]3[CH:7]=[C:8]4[C:13](=[CH:14][CH:15]=3)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]4)[CH2:25][CH:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: O=C1CCc2cc(C(O)CCCl)ccc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1CCc2cc(C=CCN3CC=C(c4ccccc4)CC3)ccc2N1

Procedure:
2.5 Grams of 6-[1-hydroxy-3-chloropropyl]-3,4-dihydrocarbostyril and 3.0 g of 4-phenyl-1,2,5,6-tetrahydropyridine were mixed in 50 ml of toluene and the mixture was refluxed by heating for 5 hours, then toluene was removed by distillation. To the residue thus obtained was added 50 ml of 5%-sodium hydrogencarbonate aqueous solution and was extracted with chloroform. The chloroform layer was washed with water and dried, then chloroform was removed by distillation. The residue thus obtained was recrystallized from ethanol to obtain 2.1 of 6-[3-(4-phenyl-1,2,5,6-tetrahydropyridyl)-1-propenyl]-3,4-dihydrocarbostyril in light yellow plate-like crystals. Melting point: 182°-183° C. (decomposed).
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:5][CH:4]=[C:3]1[C:21]([O:23]CC)=[O:22].[I-].[Li+]>N1C=CC=CC=1>[O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[N:5][CH:4]=[C:3]1[C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)c1cnc(-c2ccccc2)n(Cc2ccccc2)c1=O
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: O=C(O)c1cnc(-c2ccccc2)n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of ethyl 1,6-dihydro-6-oxo-2-phenyl-1-(phenylmethyl)-5-pyrimidinecarboxylate (i.e. the product from Step B) (2.9 g, 8.6 mmol) in pyridine (15 mL) was added lithium iodide (3.01 g, 21.7 mmol). The reaction mixture was heated to reflux for 4 h, cooled, and then stirred at room temperature for 72 h. The reaction mixture was concentrated under reduced pressure. To the resulting residue was added water (10 mL), followed by 1 N hydrochloric acid until the pH was 7. The solution was filtered through Celite® diatomaceous filter aid, and the filtrate was acidified with 1 N hydrochloric acid until the pH was 1. The mixture was extracted with dichloromethane, and the organic layer was dried (MgSO4) and concentrated under reduced pressure to afford a solid, which was washed with diethyl ether and dried under reduced pressure to afford the title product as a white solid (2.2 g).
Reaction SMILES: [H-].[Na+].[C:3]([OH:5])#N.[CH2:6](Br)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C>[CH2:6]([O:5][CH2:3][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: BrCc1ccccc1
Reactant: N#CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a slurry of 1.1 g of sodium hydride (21 mmole, 50% oil dispersion) in 25 ml of dry DMF at 0° C. was added a solution of 3.34 g of Example 1 Part G cyanoalcohol (20 mmole) in 10 ml of DMF over a period of 10 minutes. After stirring for an additional b 15 minutes, 3.6 g of benzyl bromide was added dropwise. The reaction mixture was stirred for 30 minutes at 0° C. and 3 hours at 25° C. then quenched with a saturated ammonium chloride solution, and diluted with ether. The organic layer was washed with brine. The combined aqueous layer was re-extracted with ether. The combined organic layer was dried over anhydrous MgSO4 and concentrated to leave an oil. The crude oil was chromatographed on a silica gel column, eluting with 10-20% ethyl acetate in hexanes to give 4.43 g of the title A benzyl ether.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.O>N1C=CC=CC=1>[S:33]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:17]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:14][CH2:15]2)=[CH:8][CH:9]=1)([C:30]1[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=1)(=[O:35])=[O:34]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(NC1CCN(c2ccc(CCO)cc2)CC1)OCc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(N3CCC(NC(=O)OCc4ccccc4)CC3)cc2)cc1
Reaction time: 4 h

Procedure:
The N-(4-(2-hydroxyethyl)phenyl)-4-benzyloxycarbonylaminopiperidine (1.38 g, 3.89 mmol) obtained in Example 7 (4) was dissolved in pyridine (7.5 ml), and p-toluenesulfonyl chloride (960 mg, 5.04 mmol) was added thereto under ice-cooling, followed by stirring for 4 hours. Water was added to the reaction mixture, and the precipitate was collected by filtration, thereby obtaining N-(4-(2-tosyloxyethyl)phenyl)-4-benzyloxycarbonylaminopiperidine (1.35 g, 68%) as a yellow solid.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10]1[CH:11]=[N:12][C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:23]([C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[C:20]([F:19])([F:30])[F:31])=[O:24])[CH2:3][CH2:2]2)=[CH:8][CH:9]=1
Reactant: c1ccc(-c2ccc(N3CCNCC3)nc2)nc1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(-c3ccccn3)cn2)CC1
Yield: 20 %

Procedure:
Following the procedure as described in Example 5, making variations only as required to use 6′-piperazin-1-yl-[2,3′]bipyridine in place of 3-piperazin-1-yl-6-pyridin-2-ylpyridazine to react with 2-trifluoromethylbenzoyl chloride, the title compound was obtained as a white solid in 20% yield (0.102 g). 1H NMR (300 MHz, CDCl3) δ 8.75 (m, 1H), 8.62 (m, 1H), 8.19 (m, 1H), 7.73-7.67 (m, 2H), 7.63-7.58 (m, 2H), 7.53 (t, J=7.4 Hz, 7.39, 1H), 7.35 (d, J=7.4 Hz, 1H), 7.16 (m, 1H), 6.73 (d, J=8.9 Hz, 1H), 4.01-3.85 (m, 2H), 3.73-3.69 (m, 2H), 3.59-3.56 (m, 2H), 3.31-3.28 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 167.5, 158.9, 155.1, 149.7, 146.6, 136.7, 136.3, 132.2, 129.3, 127.3, 126.8, 126.7, 125.3, 121.5, 119.2, 106.9, 134.6, 46.7, 45.0, 44.9, 41.4. MS (ES+) m/z 413.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH2:10][C:11]#[N:12].[CH:13](OCC)=[O:14].[O-]CC.[Na+].O>C(O)C>[OH:14][CH:13]=[C:10]([C:3]1[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])[C:11]#[N:12]
Reactant: Cc1cc(C)c(CC#N)c(C)c1
Reactant: CCOC=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c(C(C#N)=CO)c(C)c1
Temperature: 60 °C
Yield: 52.2 %

Procedure:
A solution of 2,4,6-trimethylphenylacetonitrile (75 g) and ethyl formate (67 g) in 225 ml absolute ethanol was treated with solid sodium ethoxide (36 g) in small portions over 10 minutes, with good stirring. The mixture was heated to 60° C. under nitrogen for 16 hours and allowed to cool to room temperature. The reaction mixture was poured into 1.2 liters of water, extracted with diethyl ether (3×200 ml). The aqueous phase was acidified with 6 M HCl to pH=1 and extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried over MgSO4 and concentrated, yielding 46 g (98%) of 3-hydroxy-2-(2,4,6-trimethylphenyl)acrylonitrile (intermediate 1).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[F:12][C:13]1([F:24])[CH2:18][CH2:17][CH:16]([CH2:19][NH:20][CH2:21][CH2:22][OH:23])[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:5]([O:4][C:2](=[O:3])[N:20]([CH2:19][CH:16]1[CH2:15][CH2:14][C:13]([F:12])([F:24])[CH2:18][CH2:17]1)[CH2:21][CH2:22][OH:23])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCCNCC1CCC(F)(F)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N(CCO)CC1CCC(F)(F)CC1
Reaction time: 1 h
Yield: 83.7 %

Procedure:
Benzyl chloroformate (4.8 mL, 33.2 mmol) was added to a solution of 2-[(4,4-difluoro-cyclohexylmethyl)-amino]-ethanol (6.41 g, 33.2 mmol) and DIPEA (5.8 mL) in DCM (200 mL) and the reaction mixture was stirred for 1 h. The reaction mixture was washed with 0.1 N HCl (150 mL) and then with water (100 mL). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title product as a clear oil (9.1 g) which partially crystallized overnight.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10](N(OC)C)=[O:11])=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10](=[O:11])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)C[C@H](c1ccc(Br)cc1)c1ccccc1C
Reactant: Cc1ccccn1
Product: Cc1ccccc1[C@H](CC(=O)Cc1ccccn1)c1ccc(Br)cc1

Procedure:
In analogy to example 261, step 1, from (R)-3-(4-bromophenyl)-N-methoxy-N-methyl-3-o-tolylpropanamide (example 142, step 1) and 2-methyl-pyridine was prepared the title compound as a yellow oil, MS (ESI+): m/z=394.0 ([M+H]+, 1Br).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[OH:6][C:7]1[C:15]2[N:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[N:12]([CH2:25][CH2:26][CH2:27][CH:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]3)[C:11]=2[CH:10]=[CH:9][CH:8]=1>CN(C)C=O>[Br:1][CH2:2][CH2:3][CH2:4][O:6][C:7]1[C:15]2[N:14]=[C:13]([CH2:16][O:17][C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[N:12]([CH2:25][CH2:26][CH2:27][CH:28]3[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:33]3)[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(O)cccc32)CC1
Reactant: BrCCCBr
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(OCCCBr)cccc32)CC1
Yield: 80 %

Procedure:
A solution of 1,3-dibromopropane (41.3 mg, 0.3 mmol, 1.5 eq) in anhydrous N,N-dimethylformamide (2 ml) was treated with a solution of 4-hydroxy-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole (100 mg, 0.2 mmol, 1 eq) in anhydrous N,N-dimethylformamide (1 ml). The resulting mixture was stirred for twelve hours. The reaction was quenched by the addition of water (10 ml). The aqueous fraction was extracted with diethyl ether (3×10 ml). The organic fractions were combined, washed with water (3×10 ml), and brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The residue was subjected to column chromatography to yield the desired title product as a white crystalline product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[N+:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20])([O-:15])=[O:14]>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][CH:24]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: COCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCNC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2-methoxyethylamine (0.9 ml) in dichloromethane (20 ml) was added triethylamine (2.1 ml), and the mixture was cooled in an ice-cooling bath. A solution of 3-nitrobenzoyl chloride (1.8 g) in dichloromethane (10 ml) was dropwise added thereto and the resulting mixture was stirred for 1.5 hours at the same temperature. The mixture was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate. After filtration, the solvent was removed in vacuo to afford N-(2-methoxyethyl)-3-nitrobenzamide (2.7 g) as a yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:42])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[O:40][N:39]=[C:38]([CH3:41])[CH:37]=2)[CH:31]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:41][C:38]1[CH:37]=[C:36]([C:32]2[CH:31]=[C:30]([C:28]3[CH2:27][C:26](=[O:42])[NH:19][C:9]4[CH:10]=[C:11]([N:14]5[CH:18]=[CH:17][CH:16]=[CH:15]5)[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)[O:40][N:39]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (2-amino-4-pyrrol-1-yl-phenyl)-carbamic acid tert.-butyl ester (Example J2) (191 mg) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example K4) (211 mg) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (92 mg).
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:18]=[CH:17][C:15]([NH2:16])=[N:14][C:12]2=[O:13])[CH2:5]1)=[N+]=[N-].N>[Pd]>[NH2:1][C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:18]=[CH:17][C:15]([NH2:16])=[N:14][C:12]2=[O:13])[CH2:5]1
Reactant: [N-]=[N+]=N[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1CO
Agent: [Pd]
Agent: N
Product: Nc1ccn([C@H]2C[C@H](N)[C@@H](CO)O2)c(=O)n1

Procedure:
The synthesis of several new 3 -azido and 3'-amino nucleosides is outlined above. Tritylation of 2'-deoxyuridine (I) with trityl chloride in pyridine gives the corresponding 5'-0-trityl derivative, (II), which is then converted to the 3'-0-methanesulfonyl analog, (III), with methanesulfonyl chloride in pyridine. The replacement of the mesyloxy group at the 3'-position in (III) with net inversion to yield 1-(2'-deoxy-5'-0-trityl-β-D-lyxosyl)uracil (V), is accomplished by refluxing compound (III) with excess sodium hydroxide solution. Mesylation of compound (V) affords the sulfonate (VI). This compound is then treated with lithium azide in N,N-dimethylformamide followed by detritylation by refluxing with 80% aqueous acetic acid to yield 3'-azido-2',3'-dideoxyuridine (VIII). Catalytic hydrogenation of compound (VIII) in the presence of 10% palladium on charcoal in ethanol gives 3'-amino-2',3'-dideoxyuridine (IX). Acetylation of compound (VIII) with acetic anhydride in pyridine at 4° C. yields 5'-0-acetyl-3'-azido-2',3'-dideoxyuridine (X). Reaction of compound (X) with thionyl chloride and N,N-dimethylformamide in absolute chloroform at reflux temperature for 6 hours affords the corresponding 4-chloro derivative (XI) which is then converted to 3'-azido-2',3'-dideoxycytidine (XII) by treatment with saturated methanolic ammonia at room temperature for 6 days. Hydrogenation of compound (XII) using 10% palladium on charcoal as a catalyst gives 3'-amino-2',3'-dideoxycytidine (XIII). Compounds (VIII) and (IX) are key intermediates for the synthesis of various 5-substituted 3'-azido and 3' -amino nucleoside analogs.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:24][C:25]3[CH:36]=[CH:35][C:28]([O:29][CH2:30][C:31]([O:33]C)=[O:32])=[CH:27][CH:26]=3)[C:19]([CH3:37])=[C:18]4[CH3:38])=[O:14])[CH3:11])[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:24][C:25]3[CH:36]=[CH:35][C:28]([O:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:27][CH:26]=3)[C:19]([CH3:37])=[C:18]4[CH3:38])=[O:14])[CH3:11])[CH:7]=[CH:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)COc1ccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C5CC5)c4)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C)n(Cc2ccc(OCC(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(C4CC4)c3)cc12
Temperature: 50 °C

Procedure:
To a solution of the (S)-methyl 2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate in methanol (1 mL) was added a 5N NaOH solution (1 mL). The resulting solution was heated at 50° C. for 4 h, and then quenched carefully by addition of a 6N HCl solution (1 mL). The mixture was diluted with ethyl acetate, washed with a 0.5 N HCl solution and brine, dried on MgSO4, and concentrated. The resulting oil was purified by preparative HPLC to afford a white powder (46 mg). ESI-MS (m/z): 497 [MH]+
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[O-]CC.[Na+].Cl>C(O)C>[F:19][C:14]1[CH:13]=[C:12]([C:7]2[C:6]([C:4]([OH:3])=[O:5])=[C:10](/[CH:11]=[CH:20]/[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:9][N:8]=2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)c1c(-c2ccc(F)c(F)c2)noc1C
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1c(-c2ccc(F)c(F)c2)noc1/C=C/c1ccccc1
Yield: 87.4 %

Procedure:
To a stirred solution of 3-(3,4-difluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (50 g, 187 mmol) and benzaldehyde (19.1 mL, 187 mmol) in ethanol (280 mL) was added sodium ethoxide (2.71 M, 75.8 mL, 206 mmol) and the reaction was stirred at reflux for 1 h. Hydrochloric acid (1 N, 225 mL) was added and the resulting mixture was then triturated with dichloromethane and filtered to afford the title compound (53.5 g, 87%) as a light yellow solid. MS: m/e=328.3 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C:9]1=[O:17].[CH3:18][Si:19]([CH3:22])([CH3:21])Cl>O1CCCC1>[CH3:18][Si:19]([CH3:22])([CH3:21])[O:17][C:9]1[CH2:10][C:11]2[C:16]([CH:8]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: C[Si](C)(C)Cl
Reactant: O=C1Cc2ccccc2C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)OC1=Cc2ccccc2C1
Reaction time: 3 h
Yield: 71 %

Procedure:
Methyl alpha-2-[2'-(3"-cyclopropylisoxazol-5"-yl)-ethen-1'-yl]-phenyl-β-methoxyacrylate ##STR10## a) 30.3 g (0.30 mole) of triethylamine are added to a solution of 36.5 g (0.28 mole) of 2-indanone and 32.4 g (0.30 mole) of trimethylchlorosilane in 300 ml of tetrahydrofuran at room temperature while stirring. Stirring is continued for a further 3 hours at room temperature (20° C.), the precipitate which has separated out is filtered off under suction and the filtrate is evaporated down. The residue is purified by distillation (53° C., 0.3 mbar). 40.6 g (72%) of 2-trimethylsilyloxy-1H-indene are obtained as a colorless liquid in this manner.