Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:35](=[O:36])[O:37][CH2:38][CH3:39])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CCOC(=O)Cl
Agent: Cl
Product: CCOC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f13) and commercially ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [OH-:1].[Na+].OO.[Br:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C@H:13]([C:15]2[N:16]([CH3:32])[C:17]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=3[C:28]([F:31])([F:30])[F:29])=[N:18][N:19]=2)[CH3:14])=[N:10][CH:11]=1.O>C(O)C>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C@H:13]([C:15]2[N:16]([CH3:32])[C:17]([C:20]3[CH:27]=[CH:26][C:23]([C:24]([NH2:25])=[O:1])=[CH:22][C:21]=3[C:28]([F:31])([F:29])[F:30])=[N:18][N:19]=2)[CH3:14])=[N:10][CH:11]=1
Reactant: C[C@H](Oc1ccc(Br)cn1)c1nnc(-c2ccc(C#N)cc2C(F)(F)F)n1C
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@H](Oc1ccc(Br)cn1)c1nnc(-c2ccc(C(N)=O)cc2C(F)(F)F)n1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1M aqueous sodium hydroxide solution (0.73 ml) and a 30% hydrogen peroxide solution (0.1 ml) were added to a solution of 4-(5-{(1S)-1-[(5-bromopyridin-2-yl)oxy]ethyl}-4-methyl-4H-1,2,4-triazol-3-yl)-3-(trifluoromethyl)benzonitrile (50 mg) in ethanol (3 ml) in an ice bath, followed by stirring at room temperature for 3 hours, and a 1M aqueous sodium hydroxide solution (0.42 ml) was added thereto, followed by stirring overnight. Water was added to the reaction solution, followed by extraction with ethyl acetate twice. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Ethyl acetate (1 ml) was added to the residue and the precipitated solid was washed with ethyl acetate and then diethylether to obtain, as a white solid 4-(5-{(1S)-1-[(5-bromopyridin-2-yl)oxy]ethyl}-4-methyl-4H-1,2,4-triazol-3-yl)-3-(trifluoromethyl)benzamide (29.2 mg).
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[F:23][C:24]1[CH:25]=[C:26]2[C:31](=[C:32]([F:34])[CH:33]=1)[C:30]([CH3:36])([CH3:35])[C:29](=O)[CH2:28][CH2:27]2>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][CH:29]2[CH2:28][CH2:27][C:26]3[C:31](=[C:32]([F:34])[CH:33]=[C:24]([F:23])[CH:25]=3)[C:30]2([CH3:36])[CH3:35])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CC1(C)C(=O)CCc2cc(F)cc(F)c21
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1(C)C)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was reacted with 6,8-Difluoro-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.3, 19.4, 19.7, 22.5, 23.0, 24.3, 24.8, 26.3, 26.6, 27.4, 27.5, 29.7, 36.4, 37.1, 38.0, 45.8, 47.6, 56.0, 59.2, 60.7, 62.5, 63.0, 65.5, 67.3, 104.7, 104.8, 111.0, 110.2, 112.5, 131.1, 131.2, 137.2, 172.2; MS m/z 502.3. (M+1).
Reaction SMILES: [CH3:1][NH2:2].Br[C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10]>C(O)C.O>[CH3:1][NH:2][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CN
Solvent: CCO
Solvent: O
Product: CNc1cncc(C(=O)O)c1

Procedure:
The intermediate methyl 5-methylamino-nicotinate has been obtained as follows: reaction of methylamine (40% in water) with 5-bromo-nicotinic acid in autoclave at 140° C. for seven hours gives 5-methylamino-nicotinic acid, m.p. 239°-242° C. from ethanol/water; this acid reacts with SOCl in methanol under reflux for seven hours to afford the ester (methyl 5-methylaminonicotinate; m.p. 113°-115° C., from petroleum ether.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[C:22]([O:23][CH2:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])=[CH:21][N:20]=[C:19]([CH:31]([NH2:33])[CH3:32])[CH:18]=1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:33]([CH:31]([C:19]3[CH:18]=[C:17]([CH3:16])[C:22]([O:23][CH2:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])=[CH:21][N:20]=3)[CH3:32])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(C(C)N)ncc1OCC(F)(F)C(F)F
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)ncc1OCC(F)(F)C(F)F
Yield: 71 %

Procedure:
The title compound is prepared in 71% yield (490 mg, yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (460 mg, 1.65 mmol, Step-1 of Intermediate-1) and 1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethanamine hydrochloride (500 mg, 1.65 mmol, Amine-72, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.[C:18]1([N:24]2[C:32]3[CH:31]=[CH:30][N:29]=[CH:28][C:27]=3[N:26]=[C:25]2[CH:33](O)[CH3:34])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[N:15]([CH:33]([C:25]1[N:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:32]2[CH:31]=[CH:30][N:29]=[CH:28][C:27]=2[N:26]=1)[CH3:34])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(O)c1nc2cnccc2n1-c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(N=[N+]=[N-])c1nc2cnccc2n1-c1ccccc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 151.4 %

Procedure:
Diphenylphosphoryl azide (0.50 g, 1.81 mmol) and diisopropyl azadicarboxylate (0.61 g, 3.01 mmol) were added to a stirred solution of 1-(1-phenyl-1H-imidazo[4,5-c]pyridin-2-yl)ethanol (0.36 g, 1.50 mmol) and triphenylphosphine (0.79 g, 3.01 mmol) in dioxane (15 mL) at 0° C. under nitrogen. After addition the mixture was stirred at 20° C. for 16 h. Additional diphenyl phosphoryl azide (0.25 g, 0.91 mmol), triphenylphosphine (0.40 g, 1.53 mmol) and diisopropyl azadicarboxylate (0.30 g, 1.48 mmol) were added and the resultant mixture stirred at 20° C. for 30 minutes. The reaction mixture was concentrated in vacuo and the residue purified by chromatography (SiO2 0-10% (2M ammonia in methanol) in DCM) to give the title compound as an oil (0.60 g, contaminated with triphenylphosphine oxide). LCMS (method H): Rt 1.86 min, [M+H]+ 265
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)=[O:4].C(N(C(C)C)CC)(C)C.[CH:26]1[CH:31]=[CH:30][C:29]([C@H:32]([NH2:35])[CH2:33][OH:34])=[CH:28][CH:27]=1>CN(C=O)C>[OH:16][C:8]1[CH:7]=[CH:6][C:5]([C@@H:3]([OH:4])[CH2:2][NH:35][C@@H:32]([C:29]2[CH:30]=[CH:31][CH:26]=[CH:27][CH:28]=2)[CH2:33][OH:34])=[CH:10][C:9]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Nc1cc(C(=O)CBr)ccc1O
Reactant: N[C@H](CO)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CN[C@H](CO)c2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 6.7 %

Procedure:
A solution of N-[5-(bromoacetyl)-2-hydroxyphenyl]methanesulfonamide (J. Med. Chem. 1967, 10, 462-72) (1.15 g) in dry DMF (30 mL) was treated with diisopropylethylamine (1.06 mL) and (S)-phenylglycinol (474 mg) and the reaction mixture stirred at room temperature for 4 h. The reaction mixture was concentrated in vacuo and the residue re-suspended in methanol (50 mL). The reaction mixture was cooled to 0° C. and treated with CaCl2 (1.27 g). The reaction mixture was stirred at 0° C. for 30 min prior to portionwise addition of NaBH4 (218 mg) ensuring that the temperature did not rise above 10° C. After complete addition the reaction mixture was allowed to warm to room temperature and stirred for a further 74 h. The reaction mixture was concentrated in vacuo and the residue partitioned between EtOAc and water. The organic phase was dried and concentrated in vacuo. The mixture was purified by chromatography (SPE, gradient from DCM to DCM-MeOH—NH3(aq) 100:10:1) afforded the title compound (85 mg). LCMS RT=2.48 min
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:17][CH2:18][N:19]([C:33](=[O:34])[NH:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[O:25][CH3:24])[CH2:20][CH2:21]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1
Reactant: COc1ccccc1N=C=O
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Solvent: O
Solvent: ClCCl
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)Nc3ccccc3OC)CC2)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.4 %

Procedure:
To a solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester (which may be prepared as described above; 83.6 mg, 0.265 mmol) in methylene chloride (8.0 mL) was added 2-methoxyphenyl isocyanate (71 μL, 0.53 mmol) at room temperature under nitrogen. The resulting light brown solution was stirred at room temperature for 10 minutes. The reaction mixture was diluted with water (˜25 mL) and the resulting mixture was extracted with methylene chloride (2×30 mL). The combined organic layers were washed with saturated aqueous NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated to a light yellow film. Flash chromatography (0-60% ethyl acetate in hexanes) provided {6-fluoro-4-[1-(2-methoxy-phenylcarbamoyl)-piperidin-4-yl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (107.6 mg, 87%) as a colorless film. MS cald. for C27H30FN2O4 [(M+H)+]: 465, obsd. 465.3.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:12][C:13]2[N:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[O:4][CH2:3]1.[C:20]([O:24][C:25]([NH:27][C@:28]([CH3:34])([CH2:32][CH3:33])[C:29](O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:34][C@:28]([NH:27][C:25](=[O:26])[O:24][C:20]([CH3:23])([CH3:22])[CH3:21])([C:29](=[O:30])[NH:19][C:16]1[CH:17]=[N:18][C:13]([O:12][C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[CH2:11][CH:2]([CH3:1])[CH2:3][O:4]3)=[CH:14][CH:15]=1)[CH2:32][CH3:33]
Reactant: CC[C@@](C)(NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC1COc2cccc(Oc3ccc(N)cn3)c2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@@](C)(NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2cccc3c2CC(C)CO3)nc1
Temperature: 25 °C
Yield: 401.6 %

Procedure:
In a 8 mL 6-[(3-methyl-3,4-dihydro-2H-chromen-5-yl)oxy]-3-pyridinamine (Intermediate 119, 82.4 mg, 0.0305 mmol), (2R)-2-(tert-butoxycarbonylamino)-2-methyl-butanoic acid (59.7 mg, 0.275 mmol) and DIPEA (0.080 mL, 0.458 mmol) were dissolved in N,N-Dimethylformamide (DMF) (2 mL) to give a pale yellow solution. HATU (151 mg, 0.397 mmol) was added. The reaction mixture was stirred at room temperature over week-end. The reaction mixture was evaporated in vacuo and the residue was purified by flash chromatography on silica gel using a column SNAP 25 g and cyclohexane/ethyl acetate from 3:1 to 1:2 as eluents affording the title compound (55.8 mg) as white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:24])[C:9]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH3:12])[CH3:11])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Cl)=[CH:35][CH:34]=1>O1CCOCC1.O>[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:24])[C:9]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:10]([CH3:12])[CH3:11])[CH2:5][CH2:6]2)=[CH:35][CH:34]=1
Reactant: CCCCOC(C(=O)NC1CCNCC1)(c1ccccc1)C(C)C
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCCCOC(C(=O)NC1CCN(Cc2ccc(OC)cc2)CC1)(c1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-(4-Piperidinyl)-2-butoxy-3-methyl-2-phenylbutanamide (invention compound, Compound No. 27) (4.5 g) was dissolved in dioxane (25 ml) and water (25 ml). To the resulting solution, potassium carbonate (0.7 g) and 4-methoxybenzyl chloride (0.8 g) were added, followed by stirring at room temperature for 2 days. To the reaction mixture, was added water (40 ml). The resulting mixture was extracted with an ethyl acetate. The extract was then dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by a silica gel column to obtain the invention compound (Compound No. 29, 0.60 g, 26.4%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C@@H]1N2C=NC=C2C(=O)C1)C#N.[O:19]=[C:20]1[CH2:25][CH2:24][C@H:23]([C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=2)[N:22]2[CH:34]=[N:35][CH:36]=[C:21]12>>[F:1][C:2]1[CH:3]=[CH:4][C:7]([C:20]2([OH:19])[CH2:25][CH2:24][C@H:23]([C:26]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=3)[N:22]3[CH:34]=[N:35][CH:36]=[C:21]23)=[CH:8][CH:9]=1
Reactant: N#Cc1ccc([C@H]2CCC(=O)c3cncn32)cc1
Reactant: N#Cc1ccc([C@H]2CC(=O)c3cncn32)c(F)c1
Product: N#Cc1ccc([C@H]2CCC(O)(c3ccc(F)cc3)c3cncn32)cc1

Procedure:
Following compounds are prepared using similar procedure as example 1-1 through example 1-7 using either 3-fluoro-4-((R)-7-oxo-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-benzonitrile or (R)-4-(8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile with appropriate reagents and conditions: Note when possible, separation of diastereomers were individually achieved with preparation plates, flash chromatography, prep-LCMS, HPLC, and or using HPLC CHIRALPAK® HPLC columns (such as AD, OJ, OD, etc.) which are purchased from Daicel.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1C(=C)C(=O)NC2C=CC(OC)=CC=2C1=O.FC1C=CC2NC(=O)CCC(=O)C=2C=1.[CH3:34][C:35]1[CH:36]=[CH:37][C:38]2[C:44](=[O:45])[CH2:43][CH2:42][C:41](=[O:46])[NH:40][C:39]=2[CH:47]=1>>[CH3:1][N:2]([CH:19]=[C:43]1[CH2:42][C:41](=[O:46])[NH:40][C:39]2[CH:47]=[C:35]([CH3:34])[CH:36]=[CH:37][C:38]=2[C:44]1=[O:45])[CH3:3]
Reactant: Cc1ccc2c(c1)NC(=O)CCC2=O
Reactant: C=C1C(=O)Nc2ccc(OC)cc2C(=O)C1N(C)C
Agent: O=C1CCC(=O)c2cc(F)ccc2N1
Product: Cc1ccc2c(c1)NC(=O)CC(=CN(C)C)C2=O

Procedure:
In a manner similar to that described above for 4-dimethylamino-methylene-7-methoxy-3,4-dihydro-1H-benzo[b]azepine-2,5-dione, 7-fluoro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione, 0.64 g of 8-methyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione was converted to v-g (87%): MS m/z═245 (M+H).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2[CH2:12][CH2:13][C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19](CC)CC)[CH3:18].C(Cl)(=O)OCC.C(N)C>O.O1CCCC1>[CH2:17]([NH:19][C:14](=[O:16])[CH2:13][CH2:12][C:8]1[CH:9]=[N:10][O:11][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:18]
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Reactant: CCN(CC)CC
Agent: CCN
Agent: CCOC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)CCc1cnoc1-c1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a mixture of 3-(5-phenyl-4-isoxazolyl)propionic acid (1.00 g), triethylamine (1.0 ml) and tetrahydrofuran (50 ml) was added ethyl chlorocarbonate (0.5 ml) at −30° C. and the mixture was stirred at −20° C. for 1 hr. To the obtained mixture was added aqueous ethylamine solution (10 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated to give N-ethyl-3-(5-phenyl-4-isoxazolyl)propionamide (0.93 g, yield 83%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 75–76° C.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:13]2[C:8](=[C:9]([F:14])[CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1.[CH3:15][CH:16]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:26])=[CH:20][CH:19]=1)[CH3:17]>CN(C=O)C.O>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[N:7]=[CH:6][CH:5]=[C:4]2[O:26][CH2:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([CH:16]([CH3:17])[CH3:15])=[CH:19][CH:20]=1
Reactant: Fc1cccc2c(Cl)ccnc12
Reactant: CC(C)c1ccc(CCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1ccc(CCOc2ccnc3c(F)cccc23)cc1
Reaction time: 8 h
Yield: 40.8 %

Procedure:
To a suspension of 0.96 g of sodium hydride in 10 mL of dry DMF was added 3.6 g of 4-chloro-8-fluoroquinoline. The mixture was cooled in an ice/water bath, and 3.3 g of 2-[4-(1-methylethyl)phenyl]ethyl alcohol was added. The mixture was stirred overnight, then diluted with ice and water. The pH was adjusted to 7, then the product was extracted into CH2Cl2. The CH2Cl2 layer was separated, filtered, and evaporated in vacuo. An azeotrope with xylene was formed to facilitate removal of residual DMF. The residue was chromatographically purified on a silica gel column, eluting with CH2Cl2, →5% EtOAc/CH2Cl2 →10% EtOAc/CH2Cl2. The fractions containing product were combined and evaporated to give an oil, which crystallized on adding ether. Recrystallization yielded 2.5 g of title product. M.P. 56°-60° C.
Reaction SMILES: [CH3:1][N:2]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15]Br)=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:3]1=[O:4].[C:17]([C:20]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)(=[O:19])[CH3:18].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:1][N:2]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15][N:23]3[CH2:24][CH2:25][C:20]([C:17](=[O:19])[CH3:18])([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:21][CH2:22]3)=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:3]1=[O:4]
Reactant: CC(=O)C1(c2ccccc2)CCNCC1
Reactant: CN1C(=O)CCc2cc(OCCBr)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)C1(c2ccccc2)CCN(CCOc2ccc3c(c2)CCC(=O)N3C)CC1

Procedure:
1.43 Grams of 1-methyl-6-(2-bromoethoxy)-3,4-dihydrocarbostyril, 1.3 g of 4-acetyl-4-phenylpiperidine and 1 g of triethylamine were mixed with 30 ml of dimethylformamide and the mixture was heated at 60°-70° C. for 5 hours. The reaction mixture thus obtained was concentrated under a reduced pressure to dryness, and to the residue thus obtained was added 5% sodium hydrogencarbonate aqueous solution and stirred. The insoluble matters were collected by filtration, washed with water then dried and recrystallized from ethanol-water to obtain 1.3 g of 1-methyl-6-[2-(4-acetyl-4-phenyl-1-piperidyl)ethoxy]-3,4-dihydrocarbostyril as in the form of colorless prism-like crystals. Melting point: 101°-103° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][C:6]([C:10](=[O:12])[CH3:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:13]N1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O>[Cl:13][C:3]1[C:4]2=[N:5][C:6]([C:10](=[O:12])[CH3:11])=[CH:7][CH:8]=[C:9]2[NH:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)c1ccc2[nH]ccc2n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2[nH]cc(Cl)c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To 1-(1H-pyrrolo[3,2-b]pyridin-5-yl)ethanone (2.80 g, 17.48 mmol) in anhydrous DMF (27 mL) at 0° C. was added a solution of N-chlorosuccinimide (2.50 g, 18.36 mmol) dissolved in anhydrous DMF (54 mL). The reaction mixture was stirred at 0° C. for 1 h and then at RT for 18 h. The reaction mixture was diluted with EtOAc, and the organic layer was washed with sat'd. aq. NaHCO3 solution, water and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by SiO2 chromatography eluting with EtOAc/heptane. Trituration with DCM/heptane afforded 3.35 g (98.59%) of 1-(3-chloro-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanone as a white solid. 1H NMR (400 MHz, DMSO) δ 11.96 (br s, 1H), 8.01 (d, J=2.9 Hz, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.88 (d, J=8.6 Hz, 1H), 2.71 (s, 3H); MS (ESI) m/z: 195.2 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:12]2[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:4](N)[N:3]=1.NC1N=C2C(N=CN2[C@@H]2O[C@H](CO)[C@@H](OCCCCCCCCC)[C@H]2[OH:42])=C(N)N=1.CS(C)=O.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1O>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[CH2:14]([O:13][C@@H:12]1[C@H:23]([OH:24])[C@@H:25]([CH2:27][OH:28])[O:26][C@H:11]1[N:8]1[C:9]2[N:10]=[C:2]([NH2:1])[NH:3][C:4](=[O:42])[C:5]=2[N:6]=[CH:7]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)nc(N)nc21
Reactant: CCCCCCCCCO[C@H]1[C@@H](O)[C@H](n2cnc3c(N)nc(N)nc32)O[C@@H]1CO
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21

Procedure:
A mixture of 2,6-diamino-9-(2′-O-nonyl-β-D-ribofuranosyl)purine and 2,6-diamino-9-(3′-O-nonyl-β-D-ribofuranosyl)purine (≈80:20 mixture, 29 g) in 0.1 M sodium phosphate buffer (50 ml, pH 7.4), 0.1 M tris buffer (1800 ml, pH 7.4) and DMSO (1080 ml) was treated with adenosine deaminase (1.6 g) as per the procedure of Example 3 to yield 60 g of product as an oil. An analytical product was purified by silica gel chromatography and recrystallized from EtOAc. m.p. 258-259° C. 1H NMR (DMSO-d6) δ 0.96 (t, 3, CH3, J=7 Hz); 1.17 [m, 12, O—CH2—CH2—(CH2)6]; 1.42 [m, 2, O—CH2CH2(CH2)6]; 3.27-3.61 (m, 4, H-5′, O—CH2(CH2)7]; 3.95 (m, 1, H-4′), 4.10-4.13 (m, 2, H-2′, H-3′); 5.13-6.06 (m, 2, 3′—OH 5′—OH); 5.80 (d, 1, H-1′, J=6.4 Hz); 6.47 (s, 2, 2—NH2); 7.98 (s, 1, 8-H) and 10.64 (s, 1, N1 amide). Anal. Calcd. for C19H31N5O5: C, 55.73; H, 7.63; N, 17.10. Found: C, 55.67; H, 7.66; N, 17.02.
Reaction SMILES: C([C:4]1[C:8]([CH3:9])=[C:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[O:11])[N:6]([CH3:19])[C:5]=1[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(O)=O.N1C2C(=CC=CC=2)C=CC=1>[Cr]([O-])([O-])=O.[Cu+2]>[CH3:19][N:6]1[C:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[O:11])=[C:8]([CH3:9])[CH:4]=[C:5]1[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)Cc1c(C(=O)O)c(C)c(C(=O)c2ccc(C)cc2)n1C
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Solvent: c1ccc2ncccc2c1
Product: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(C)cc2)n1C
Reaction time: 0.5 h

Procedure:
A solution of 33.0 g. (0.096 mole) of ethyl 3-carboxy-1,4-dimethyl-5-(p-toluoyl)-pyrrole-2-acetate in 200 ml. of quinoline with 0.1 g. copper chromite added is heated under nitrogen for 6 hr. at 200° C., then for 30 min. at 220° C. The quinoline is distilled off in vacuo. The residue is dissolved in ether and washed successively with dilute hydrochloric acid, dilute sodium hydroxide, and brine; dried over magnesium sulfate; and the solvent evaporated in vacuo to give a brown oily residue which crystallizes. It is recrystallized from methanol, sublimed at 150° C. (0.025 mm/Hg) and recrystallized from hexane to give ethyl 1,4-dimethyl-5-(p-toluoyl)-pyrrole-2-acetate as a white solid, m.p. 90°-93° C.