Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH:60]([CH3:62])[CH3:61].FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH:60]([CH3:62])[CH3:61])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: CC(C)OC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC(C)C)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (110 mg in 1.5 ml 33% methylene chloride in cyclohexane), isopropyl trichloroacetimidate (52 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 3 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×5 ml). The combined organic were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate:hexane (1:1)+1% methanol) gave the title compounds (15 mg 4"-ether; 16 mg 3"-ether).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:17][C:16](=[O:18])[C:9]3([CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)[N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:25]=1.[H-].[Na+].CI.Cl.[CH2:31](OCC)C.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:17]([CH3:31])[C:16](=[O:18])[C:9]3([CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)[N:8]=[C:7]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:6]=2[CH:25]=1
Reactant: CN1CCC2(CC1)N=C(c1ccccc1)c1cc(Cl)ccc1NC2=O
Reactant: CCOCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCC2(CC1)N=C(c1ccccc1)c1cc(Cl)ccc1N(C)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.6 g (0.0016 mole) of 7-chloro-5-phenyl-1'-methyl-spiro[1H-1,4-benzodiazepine-3,4'-piperidin]-2(3H)-one are dissolved in 15 ml of absolute dimethylformamide and reacted with 0.1 g of sodium hydride (55-60% strength dispersion) at 70° C. After 30 minutes, the mixture is cooled to 25° C., 0.22 g (0.0016 mole) of methyl iodide in 10 ml of absolute dimethylformamide is added and the mixture is stirred for 2 hours. After the solvent has been distilled off, the residue is taken up in water and the mixture is extracted with methylene chloride. For purification, the product is chromatographed on aluminum oxide 90 (Merck), activity level II-III, with a cyclohexane/methylene chloride/methanol mixture (6:3:1), and the base thus obtained is converted into the hydrochloride by treatment with diethyl ether/HCl.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[N+:10]([CH:13](C(OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])([O-])=[O:11]>CCCCCCCCCCCC>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]2[O:11][N:10]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:7]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1
Reactant: CCOC(=O)C(C(=O)OCC)[N+](=O)[O-]
Solvent: CCCCCCCCCCCC
Product: CCOC(=O)c1noc(-c2ccc(Cl)cc2)n1
Temperature: 150 °C

Procedure:
This product was prepared by a modification of the general procedure described in Shimizu, T. et al. Bull.Chem.Soc.Jpn. 1985, 58, 2519. A mixture of 4-chlorobenzonitrile (1.7 g, 12.2 mmol), and diethyl nitromalonate (2.5 g, 12.2 mmol) in dodecane (20 mL) was heated at 150° C. for 15 h. After the reaction was complete, the mixture was allowed to cool to room temperature and was then concentrated in vacuo. The residue was purified by flash chromatography to yield ethyl 5-(4-chlorophenyl)-1,2,4-oxadiazole-3-carboxylate as a light brown solid: mp 88°-89° C.; 1H NMR (300 MHz, CDCl3) δ (TMS) 8.15 (dt, Jt =2.3, Jd =8.7, 2H, arom), 7.54 (dt, Jt =2.3, Jd =8.7, 2H, arom), 4.55 (q, J=7.1, 2H, OCH2), 1.47 (t, J=7.1, 3H, OCH2CH3).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[CH3:15]OS(OC)(=O)=O>>[Cl:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH3:15])[C:6]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2o1
Reactant: COS(=O)(=O)OC
Product: Cn1c(=O)oc2cc([N+](=O)[O-])c(Cl)cc21

Procedure:
5-Chloro-3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one was prepared by the procedure described in Example 2, step 2 starting from 5-chloro-6-nitrobenzo[d]oxazol-2(3H)-one (1.75 g, 8.1 mmol) substituting iodomethane for dimethylsulfate. The crude product was recrystallised from methanol to afford an orange solid (0.6 g, 32%), which was taken through to the next step with no further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[CH:20]=[C:13]2[CH:14]=[N+:15]([O-])[CH:16]=[C:17]([F:18])[C:12]2=[N:11]1.P(Br)(Br)([Br:23])=O>ClCCCl.C(Cl)Cl>[Br:23][C:14]1[C:13]2=[CH:20][N:10]([C:3]3[C:2]([Cl:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=3[Cl:9])[N:11]=[C:12]2[C:17]([F:18])=[CH:16][N:15]=1
Reactant: O=P(Br)(Br)Br
Reactant: [O-][n+]1cc(F)c2nn(-c3c(Cl)cc(F)cc3Cl)cc2c1
Solvent: ClCCCl
Solvent: ClCCl
Product: Fc1cc(Cl)c(-n2cc3c(Br)ncc(F)c3n2)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 28.4 %

Procedure:
To a cooled (0° C.) suspension of 2-(2,6-dichloro-4-fluorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine-5-oxide (2.95 g, 9.3 mmol) in DCE (50 mL) was added phosphorus oxybromide (8.0 g, 28 mmol). The reaction mixture was stirred at 0° C. for 1 hour, warmed to room temperature, and stirred for a further 3 hours. The reaction mixture was diluted with DCM and washed with sodium carbonate (sat. aq.). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-20% ethyl acetate in cyclohexane) to afford the title compound as a white solid (1.0 g, 28% yield). LCMS (Method D): RT=3.82 min, m/z: 380 [M+H+].
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[C:11](Cl)=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9].CO.C(S)[CH2:40][S:41]([O-])(=O)=O.[Na+]>C1COCC1.O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[C:11]([S:41][CH3:40])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9]
Reactant: O=S(=O)([O-])CCS
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1c(Cl)nc2ccccc2c1-c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CSc1nc2ccccc2c(-c2ccccc2)c1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
To a solution of the compound obtained in Example 269 (100 mg) in THF (6 ml)-methanol (2 ml) was added 15% MeSNa in water (4 ml), and the mixture was stirred for 8 hours with heating under reflux. The solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed with water, dried and evaporated to yield the title compound as colorless crystals (55 mg).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])[CH3:4].[NH:17]([C:24]1([C:30]#[N:31])[CH2:29]CNC[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[O:16]=[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH2:15][CH:6]1[CH2:5][N:3]1[CH2:2][CH2:25][C:24]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:30]#[N:31])[CH2:29][CH2:4]1
Reactant: CN(C)CC1CCc2ccccc2C1=O
Reactant: N#CC1(Nc2ccccc2)CCNCC1
Agent: Cl
Solvent: CCO
Product: N#CC1(Nc2ccccc2)CCN(CC2CCc3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-[(Dimethylamino)methyl]-3,4-dihydro-1(2H)-naphthalenone, hydrochloride (10.0 g) and 4-anilino isonipecotonitrile (10.2 g) are dissolved in absolute ethanol (150 ml) by brief heating. The reaction mixture is stirred at room temperature under nitrogen for 16 hours. The resulting precipitate is collected by filtration, washed with additional absolute ethanol, and dried in vacuo to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]23[CH2:18][C:15]([NH:19]C(=O)OCC4C=CC=CC=4)([CH2:16][CH2:17]2)[CH2:14][CH2:13][CH2:12]3)=[O:10])[CH:5]=[CH:4][N:3]=1>Br.CC(O)=O>[NH2:19][C:15]12[CH2:18][C:11]([C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[N:7]=3)=[O:10])([CH2:17][CH2:16]1)[CH2:12][CH2:13][CH2:14]2
Reactant: Cc1nccc(NC(=O)C23CCCC(NC(=O)OCc4ccccc4)(CC2)C3)n1
Agent: Br
Solvent: CC(=O)O
Product: Cc1nccc(NC(=O)C23CCCC(N)(CC2)C3)n1
Yield: 53.8 %

Procedure:
A solution of benzyl 5-(2-methylpyrimidin-4-ylcarbamoyl)bicyclo[3.2.1]octan-1-ylcarbamate (1 g, 2.5 mmol) in HBr/HOAc (33% solution, 8 mL) was stirred at room temperature for an hour and then concentrated under reduced pressure. The resulting residue was dissolved in aq. HCl (6N, 10 mL) and extracted with ethyl acetate (10 mL) to remove the organic impurities. The aqueous phase was basified with aq. NaOH (6N, 4 mL), and then extracted with DCM (4×20 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 350 mg (66%) of 5-amino-N-(2-methylpyrimidin-4-yl)bicyclo[3.2.1]octane-1-carboxamide as a white solid ESI-MS m/z: 261 (M+H)+.
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].C([Li])CCC.[O:13]=[C:14]1[N:21]2[CH:16]([CH2:17][CH2:18][O:19][C:20]2([CH3:23])[CH3:22])[CH2:15]1.C(I)(C)C>CCCCCC.C1COCC1.CCOC(C)=O.CN(C)P(N(C)C)(N(C)C)=O>[O:13]=[C:14]1[N:21]2[CH:16]([CH2:17][CH2:18][O:19][C:20]2([CH3:23])[CH3:22])[CH:15]1[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)NC(C)C
Reactant: CC1(C)OCCC2CC(=O)N21
Agent: [Li]CCCC
Solvent: CC(C)I
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)C1C(=O)N2C1CCOC2(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
THF, 20 ml is placed under N2, treated with 1.54 ml diisopropylamine and cooled to -78° C. A solution of n-butyl lithium 1.97 M in hexane 5.6 ml is added dropwise over 5 min. The reaction mixture is stirred at -78° C. for 10 min. and then treated with 8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]octane 1.55 g in 15 ml THF added dropwise over 5 min. After another 10 min. hexamethylphosphoramide 1.97 ml is added. The mixture is stirred another 10 min., then treated with 2 ml of isopropyl iodide. The reaction mixture is stirred at -78° C. for 15 min. and allowed to warm to 25° C. and stirred for 15 min. The reaction mixture is diluted with EtOAc, washed once with pH 7 phosphate buffer then dried and evaporated. The residue is chromatographed on silica gel using 25% EtOAc/C6H6 as eluant to give 8-oxo-2,2-dimethyl-7α-isopropyl-3-oxa-1-azabicyclo[4.2.0]-octane. μ i.r.: 5.7 (β-lactam). n.m.r. δ: 0.96d, 1.06d ##STR15## 1.4S, 1.76S (gem dimethyl);
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[C:19]([C:26]([NH2:28])=[O:27])=[N:20][C:21](Cl)=[C:22]([NH2:24])[N:23]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.C(O)C.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>[NH2:17][C:18]1[C:19]([C:26]([NH2:28])=[O:27])=[N:20][C:21]([C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)=[C:22]([NH2:24])[N:23]=1
Reactant: NC(=O)c1nc(Cl)c(N)nc1N
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: NC(=O)c1nc(-c2ccc(Oc3ccccc3)cc2)c(N)nc1N
Temperature: 25 °C
Yield: 27.4 %

Procedure:
To a mixture of 4-phenoxyphenylboronic acid (0.22 g, 1.02 mmol), 3,5-diamino-6-chloropyrazine-2-carboxamide (0.176 g, 0.919 mmol), sodium carbonate (0.33 g, 2.06 mmol) in toluene (14 mL), ethanol (3.5 mL), and water (3.5 mL) was added tetrakis(triphenylphosphine)palladium (60 mg). The mixture was refluxed overnight. The reaction was allowed to cool to room temperature, then partitioned between water and ethyl acetate. The aqueous layer was extracted one more time with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give the crude product as a solid. Flash chromatography (Silica gel; 6:4 ethyl acetate/dichloromethane to 7:3 ethyl acetate/dichloromethane) and subsequent recrystalization from chloroform afforded 81 mg (27%) of the desired product as white solid. 1H NMR (CDCl3): δ 7.58 (d, J=9.0 Hz, 2H), 7.37 (t, J=7.8 Hz, 2H), 7.38 (bs, 1H), 7.15 (t, J=8.4 Hz, 1H), 7.10-7.05 (m, 4H), 5.26 (bs, 1H), 4.97 (s, 4H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11](CC3C=CC=CC=3)[CH2:10][CH2:9]2)=[N:6][C:5]([CH3:21])=[CH:4][N:3]=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][C:5]([CH3:21])=[CH:4][N:3]=1
Reactant: Cc1cnc(C)c(N2CCN(Cc3ccccc3)CC2)n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cnc(C)c(N2CCNCC2)n1

Procedure:
To a solution of 2,5-dimethyl-3-[4-(phenylmethyl)piperazin-1-yl]pyrazine (Preparation 17, 1.14 g, 4.04 mmol) in methanol (80 ml) was added ammonium formate (1.27 g, 20.2 mmol) followed by palladium (10% w/w on carbon, 0.17 g) under a nitrogen atmosphere. The reaction mixture was heated under reflux, after 2.5 h, more ammonium formate (0.64 g, 10.1 mmol) and palladium (0.06 g) were added. The reaction mixture was filtered through Celite® washed with methanol and concentrated in vacuo. The crude product was purified by flash chromatography using silica gel eluting with methanol:dichloromethane (8:92 and then 10:90) and then methanol:dichloromethane:0.88 ammonia solution (10:90:1). The title compound was obtained as a white solid (0.35 g, 45%).
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17](Cl)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH:20]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CS(C)=O>[N:1]1([C:10]2[N:18]=[C:17]([NH:26][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: NC1CCCCC1
Reactant: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Solvent: CS(C)=O
Product: c1ccc2c(c1)ncn2-c1nc(NC2CCCCC2)nc2[nH]cnc12
Temperature: 110 °C

Procedure:
200 mg of product obtained in stage 1 above are mixed with 2 ml of DMSO and 0.42 ml of cyclohexylamine, and the mixture is then heated at 110° C. for approximately 48 hours. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with a CH2Cl2-MeOH—NH4OH: 90-9-1 mixture for eluent. 84.7 mg of expected product are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[C:7]#[N:8].CO[CH:13]1[CH2:17][CH2:16][CH:15](OC)O1>C(OC(=O)C)(=O)C>[Cl:10][C:5]1[N:4]=[CH:3][C:2]([N:1]2[CH:13]=[CH:17][CH:16]=[CH:15]2)=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: COC1CCC(OC)O1
Reactant: N#Cc1cc(N)cnc1Cl
Solvent: CC(=O)OC(C)=O
Product: N#Cc1cc(-n2cccc2)cnc1Cl
Reaction time: 2 h
Yield: 78.4 %

Procedure:
A solution of 5-amino-2-chloronicotinonitrile (5.0 g, 0.033 m), 2,5-dimethoxytetrahydrofuran (11 g, 0.085 m) and acetic anhydride (20 ml) was heated at reflux with stirring. After two hours, the solution was concentrated to dryness under reduced pressure (20 mm). The residue was triturated with CCl4 and filtered to yield 5.2 g (78% yield) of 2-chloro-5-(1-pyrrolyl)nicotinonitrile, m.p.=144°-146°.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[CH:7]/[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:9])=[CH:2]1>C1COCC1.[Pd]>[NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:9])=[CH:2]1
Reactant: CCCCOC(=O)/C=C/c1cc[nH]c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCOC(=O)CCc1cc[nH]c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.5 %

Procedure:
To a solution of (E)-butyl 3-(1H-pyrrol-3-yl)acrylate (2.0 g, 10.4 mmol) in 50 mL of THF was added Pd (10% on activated carbon; 0.50 g). The solution was deoxygenated under vacuum, and H2 was introduced to the reaction flask from a balloon. The process was repeated three times, and the reaction mixture was stirred for 4 h at room temperature. The mixture was filtered through celite, and the filtrate was evaporated under reduced pressure to yield butyl 3-(1H-pyrrol-3-yl)propionate (2.0 g, 99%) as a light-yellow oil. LC-MS (ESI) m/z 196 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[C:20]([O:19][C:17]([NH:16][C@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:24])[CH:30]=2)=[CH:3][CH:4]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CCOC(=O)C[C@@H](Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)OC(C)(C)C
Temperature: 95 °C
Reaction time: 3 h
Yield: 62.9 %

Procedure:
A mixture of (R)-ethyl 4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoate (4.89 g, 12.66 mmol), 3-chlorophenylboronic acid (2.97 g, 18.99 mmol), Pd(PPh3)4 (1.463 g, 1.266 mmol) and 2 M aqueous Na2CO3 (12.66 ml, 25.3 mmol) in 1,2-dimethoxyethane (100 ml) is allowed to stir at 95° C. under nitrogen for 3 hours. The reaction mixture is cooled to room temperature and quenched with brine. The two phases are separated. The mixture is extracted twice with ethyl acetate from the aqueous layer. The combined organic layer is washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by silica gel flash column chromatography (heptane/EtOAc=100:0 to 70:30) to give (R)-ethyl 3-(tert-butoxycarbonylamino)-4-(3′-chlorobiphenyl-4-yl)butanoate (3.33 g); HPLC retention time=1.44 minutes (condition B); MS (ES+)=318.26 (m-BOC+2; 100%); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (t, J=7.2 Hz, 3 H) 1.41 (s, 9 H) 2.47 (A of ABX, Jab=15.8 Hz, Jax=5.9 Hz, 1 H) 2.52 (B of ABX, Jab=15.8 Hz, Jbx=5.4 Hz, 1 H) 2.83-2.89 (m, 1 H) 2.95-3.00 (m, 1 H) 4.17 (q, J=7.2 Hz, 2 H) 4.18 (br s, 1 H) 5.07 (br s, 1 H) 7.26-7.37 (m, 4 H) 7.43-7.51 (m, 3 H) 7.55 (br t, J=1.8 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22](O)=[O:23])=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:25]1([S:31]([C:34]2[CH:35]=[C:36]([NH2:40])[CH:37]=[CH:38][CH:39]=2)(=[O:33])=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[N:25]1([S:31]([C:34]2[CH:35]=[C:36]([NH:40][C:22]([C:21]3[CH:20]=[N:19][N:12]4[C:13]([C:15]([F:16])([F:17])[F:18])=[CH:14][C:9]([C:4]5[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=5)=[N:10][C:11]=34)=[O:23])[CH:37]=[CH:38][CH:39]=2)(=[O:33])=[O:32])[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Reactant: Nc1cccc(S(=O)(=O)N2CCOCC2)c1
Product: O=C(Nc1cccc(S(=O)(=O)N2CCOCC2)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.9) and 3-(morpholine-4-sulfonyl)-phenylamine [CAS 22184-97-0; commercially available] according to general procedure II. Yellow solid. MS (ISP) 601.3 [(M+H)+]; mp 239° C.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([CH2:23][O:24][CH3:25])[O:17]2)=[C:9]([NH:26][CH2:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]=1)(=O)=O.[NH2:41][CH2:42][C:43]([N:45]([CH:49]([CH3:51])[CH3:50])[CH:46]([CH3:48])[CH3:47])=[O:44].C(N(C(C)C)C(C)C)C>>[OH:21][C@@H:20]1[C@H:19]([OH:22])[C@@H:18]([CH2:23][O:24][CH3:25])[O:17][C@H:16]1[N:13]1[CH:12]=[N:11][C:10]2[C:14]1=[N:15][C:7]([CH2:6][NH:41][CH2:42][C:43]([N:45]([CH:46]([CH3:48])[CH3:47])[CH:49]([CH3:50])[CH3:51])=[O:44])=[N:8][C:9]=2[NH:26][CH2:27][CH:28]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COS(C)(=O)=O)nc32)[C@H](O)[C@@H]1O
Reactant: CC(C)N(C(=O)CN)C(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNCC(=O)N(C(C)C)C(C)C)nc32)[C@H](O)[C@@H]1O
Yield: 11.3 %

Procedure:
The title compound was prepared by a similar method to example 40 using {9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl methanesulfonate (preparation 25) (374 mg, 0.66 mmol), 2-amino-N,N-diisopropylacetamide (520 mg, 3.3 mmol) (preparation 22) and N-ethyl-N-isopropyl-2-propanamine (170 mg, 1.32 mmol). The compound was purified by column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol:ammonia (95:5:0.5) increasing in polarity to (90:10:1). The solvent was removed under reduced pressure to give a residue which was triturated with diethyl ether to give the title compound (47 mg) as a solid. MS: 632 (MH+).
Reaction SMILES: [CH2:1]([N:8](C)[C:9]12[CH2:17][CH2:16][CH:13]([CH2:14][CH2:15]1)[CH2:12][N:11]1[C:18](=[O:34])[C:19]([OH:33])=[C:20]([C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[O:23])[N:21]=[C:10]21)C1C=CC=CC=1>CO.[Pd]>[F:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][NH:24][C:22]([C:20]2[N:21]=[C:10]3[C:9]4([NH:8][CH3:1])[CH2:17][CH2:16][CH:13]([CH2:14][CH2:15]4)[CH2:12][N:11]3[C:18](=[O:34])[C:19]=2[OH:33])=[O:23])=[CH:31][CH:30]=1
Reactant: CN(Cc1ccccc1)C12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Agent: [Pd]
Solvent: CO
Product: CNC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Reaction time: 1 h
Yield: 119.8 %

Procedure:
To a solution of 10-(benzyl(methyl)amino)-N-(4-fluorobenzyl)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamide (255 mg, 0.432 mmol) in methanol (2 mL) was added Pd/C (32.2 mg, 0.030 mmol) and the mixture was stirred under hydrogen atmosphere (balloon) for 1 h. The catalyst was then filtered off, and the filtrate was evaporated under reduced pressure to afford the title compound as a white solid (200 mg, 93% yield). 1H NMR (300 MHz, DMSO-d6) δ: 12.3 (1 H, s), 9.5 (1 H, s), 7.3-7.4 (2 H, m), 7.2-7.2 (2 H, m), 4.5 (2 H, d, J=6.22 Hz), 4.0 (2 H, d, J=3.29 Hz), 2.6 (3 H, brs), 2.0-2.1 (4 H, m), 1.7-1.9 (5 H, m). LCMS (M+H)=387.17.