Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([Si:7]([CH2:10]Cl)([CH3:9])[CH3:8])=[CH:3][CH:2]=1.[Na].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1.C(OCC)(=O)C>CN(C)C=O.O>[C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([Si:7]([CH3:9])([CH3:8])[CH2:10][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)=[CH:3][CH:2]=1
Reactant: c1c[nH]cn1
Reactant: C[Si](C)(CCl)c1ccc(-c2ccccc2)cc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[Si](C)(Cn1ccnc1)c1ccc(-c2ccccc2)cc1
Yield: 28.7 %

Procedure:
A mixture of 2.6 g (0.010 mol) of (1,1'-biphenyl-4-yl)chloromethyldimethylsilane and 1.1 g (0.012 mol) of imidazole sodium salt in 5 ml of dimethylformamide was warmed to 80°-90° for 2 hours, cooled, diluted with water, and extracted with ether. The ether solution was washed with water and brine, dried over magnesium sulfate, and evaporated to leave 2.0 g of a viscous, pale yellow oil. Trituration of a small sample with hexanes gave a solid. The bulk of the crude product was then taken up in a hot mixture of 20 ml of hexanes and 3 ml of ethyl acetate, the solution was cooled slowly, and seed crystals were added when cloudiness was observed. The resulting crystals were collected and dried to give 0.84 g (29%) of the title compound as colorless flakes: m.p. 51°-53°; ir (NujolR) 1235, 1215, 1105, 1065, 900, 830, 785, 750, 730, 685 cm-1 ; nmr (CDCl3) 0.4 (6 H, s), 3.7 (2H, s), 6.7 (1H, broad s), 7.0 (1H, broad s), 7.1-7.8 (10H, m); analysis for C18H20N2Si (mw 292.45):
Reaction SMILES: C([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[CH:8]=1)(=O)CCC.[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[C:7]([C:12]1[C:11]([CH3:13])=[CH:10][C:9]([CH3:14])=[CH:8][C:7]=1[OH:6])(=[O:6])[CH2:8][CH2:9][CH3:10]
Reactant: CCCC(=O)Oc1cc(C)cc(C)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCC(=O)c1c(C)cc(C)cc1O
Temperature: 70 °C
Reaction time: 4 h

Procedure:
180 g. of 1-butyryloxy-3,5-dimethyl-benzene are treated at room temperature with 340 g. of aluminium chloride. The mixture is stirred for 4 hours at 90°-95° C., then cooled at 70° C., poured onto ice and 3 n aqueous hydrochloric acid and extracted with ether. The ether extract is washed with water to neutral reaction, dried over sodium sulfate and evaporated. There is obtained 2-butyryl-3,5-dimethyl-phenol, which melts at 48°-52° C. after recrystalization from petroleum ether.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.Cl.[C@H:14]12[CH2:20][C@H:17]([O:18][CH2:19]1)[CH2:16][NH:15]2.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].C(N(CC)CC)C>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH2:16][C@@H:17]3[CH2:20][C@H:14]2[CH2:19][O:18]3)=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: COc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc(N2C[C@@H]3C[C@H]2CO3)cc1[N+](=O)[O-]
Yield: 65.7 %

Procedure:
To a stirred solution of 7.34 g (31.0 mmol) 4-bromo-2-nitro-anisole in 125 ml dioxane were added 5.25 g (37.2 mmol) (1S,4S)-(+)-2-aza-5-oxabicyclo[2,2,1]heptane hydrochloride, 1.109 g (3.10 mmol) 2-(dicyclohexylphosphino)biphenyl, 14.2 g (43.4 mmol) cesium carbonate, 696 mg (3.10 mmol) palladium (II) acetate and 5.65 ml (40.3 mmol) triethylamine. The mixture was heated at reflux for 24 h and then poured onto water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/99 methanol/dichloromethane) afforded 5.10 g (66%) (1S,4S)-5-(4-methoxy-3-nitro-phenyl)-2-oxa-5-aza-bicyclo[2.2.1]heptane as an orange oil. ES-MS m/e (%): 251 (M+H+, 100).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([N:12]3[CH2:18][C:17]4([CH3:20])[CH2:19][CH:13]3[CH2:14][C:15]([CH3:22])([CH3:21])[CH2:16]4)=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Br[CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>CN(C=O)C>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][CH2:32][N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([N:12]3[CH2:18][C:17]4([CH3:20])[CH2:19][CH:13]3[CH2:14][C:15]([CH3:22])([CH3:21])[CH2:16]4)=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH3:31]
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2ccc3[nH]ccc3c2)C1
Reactant: CCOC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1ccc2cc(C(=O)N3CC4(C)CC3CC(C)(C)C4)ccc21
Temperature: 60 °C
Reaction time: 16 h
Yield: 37.5 %

Procedure:
To a solution of (1H-indol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)methanone (250 mg, 0.84 mmol) in dry DMF (5 mL) at room temperature under an inert atmosphere of nitrogen was added sodium hydride (30 mg, 1.26 mmol, 60% dispersion in oil), and after stirring for 30 min ethyl bromopropionate (168 mg, 0.93 mmol) was added, and the reaction mixture was stirred for 16 h at 60° C. The reaction was quenched by the addition of water (20 mL) followed by extraction with DCM (3×100 mL). The combined organic phases were dried (MgSO4), filtered and evaporated in vacuo. The resulting solid was purified by silica gel chromatography using a mixture of ethyl acetate and heptane (1:1) as eluent. Pure fractions were collected, the solvent evaporated in vacuo and dried in vacuo at 50° C. affording 125 mg (37%) of the title compound as a solid. MS-ESI m/z 397; 1H NMR (400 MHz, CDCl3) δ 0.95 (d, 3H), 1.03 (d, 3H), 1.13-1.22 (m, 7H), 1.25-1.43 (m, 2H), 1.45 (s, 1H), 1.62-1.68 (m, 1H), 1.76-1.80 (m, 1H), 2.29-2.33 (m, 1H), 2.82 (t, 2H), 3.28-3.35 (m) and 3.63 (d), 1H), 4.12-4.14 and 4.64-4.66 (m, 1H), 4.11 (q, 2H), 4.47 (t, 2H), 6.52 (d, 1H), 7.18 (d, 1H), 7.32-7.39 (m, 2H), 7.74 (d, 1H).
Reaction SMILES: [CH2:1](N1CCCC(CCN2C(OC)=NC3C2=NC(O[C@@H](C)CCC)=NC=3N)C1)[CH3:2].[CH3:29][C@H:30]([O:34][C:35]1[N:43]=[C:42]2[C:38]([N:39]=[C:40]([O:52][CH3:53])[N:41]2[CH2:44][CH2:45][CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[C:37]([NH2:54])[N:36]=1)[CH2:31][CH2:32][CH3:33].ICC>>[CH2:1]([N:49]1[CH2:48][CH2:47][CH:46]([CH2:45][CH2:44][N:41]2[C:40]([O:52][CH3:53])=[N:39][C:38]3[C:42]2=[N:43][C:35]([O:34][C@@H:30]([CH3:29])[CH2:31][CH2:32][CH3:33])=[N:36][C:37]=3[NH2:54])[CH2:51][CH2:50]1)[CH3:2]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCN(CC)C3)c2n1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCNCC3)c2n1
Solvent: CCI
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCN(CC)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 46 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9-[2-(4-piperidinyl)ethyl]-9H-purin-6-amine and 2-iodoethane. LCMS (System B): tRET=1.28 min; MH+ 391
Reaction SMILES: I[CH2:2][CH2:3][S:4][C:5]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:6]=1[NH2:7].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[N+:12]([C:9]1[CH:10]=[CH:11][C:5]2[S:4][CH2:3][CH2:2][NH:7][C:6]=2[CH:8]=1)([O-:14])=[O:13]
Reactant: Nc1cc([N+](=O)[O-])ccc1SCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)NCCS2
Temperature: 90 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a stirred solution of 2-(2-iodoethylthio)-5-nitroaniline (1.18 g, 3.64 mmol) in DMF (10 mL) was added potassium carbonate (1.006 g, 7.28 mmol). The resulting mixture was then stirred at 90° C. for 1 hour. The mixture was then cooled to room temperature and diluted with water (40 mL). The resulting red precipitate was collected by vacuum filtration, giving the title compound (625 mg, 87%). 1H NMR (DMSO-d6) δ 7.38 (s, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.12 (d, J=8.7 Hz, 6.78 (brs, 1H), 3.56-3.49 (m, 2H), 3.08-3.03 (m, 2H); ELMS (m/z, %): 196 (M+, 100), 181 (45), 122 (73).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl.O>[CH3:25][S:26]([O:17][CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:5]2[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)=[CH:14][CH:13]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccc(Nc2ncc(Br)cn2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCCc1ccc(Nc2ncc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(4-(5-bromopyrimidin-2-ylamino)phenyl)ethanol 18 (6.22 mmol) in DCM (30 mL) is added triethylamine (9.33 mmol) and methanesulfonyl chloride (7.47 mmol). The reaction mixture is stirred at rt for 1.5 h. The reaction is diluted with H2O (10 mL) and washed with Na2CO3 solution (3×10 mL). The organic layer is washed with brine, dried over MgSO4 and concentrated to afford 4-(5-bromopyrimidin-2-ylamino)phenethyl methanesulfonate 19. 1H NMR (400 MHz, CD2Cl2) δ 8.36 (s, 2H), 7.65 (bs, 1H), 7.49 (d, J=8.8 Hz, 2H), 7.14 (d, J=8.4 Hz, 2H), 4.31 (t, J=6.8 Hz, 2H), 2.95 (t, J=6.8 Hz, 2H), 2.79 (s, 3H). MS (m/z) (M+1)+: 372.0, 374.0.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]3[C:19](=O)[C:18]([CH2:26][CH2:27][F:28])([CH2:21][CH2:22][C:23](=[O:25])[CH3:24])[CH2:17][C:14]=32)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCCC1.C(O)(=O)C>C1(C)C=CC=CC=1.CCCCCCC.ClCCl>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]3[C:19]4[C:18]([CH2:26][CH2:27][F:28])([CH2:21][CH2:22][C:23](=[O:25])[CH:24]=4)[CH2:17][C:14]=32)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CCC1(CCF)Cc2c(ccc3nn(Cc4ccccc4)cc23)C1=O
Solvent: C1CCNC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=C1C=C2c3ccc4nn(Cc5ccccc5)cc4c3CC2(CCF)CC1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
To a solution of 2-benzyl-7-(2-fluoroethyl)-7-(3-oxobutyl)-7,8-dihydrocyclopenta[e]indazol-6(2H)-one (10.8 g, 28.6 mmol) in 300 mL of toluene were added pyrrolidine (2.4 mL, 28.6 mmol) and acetic acid (1.64 mL, 28.6 mmol) and the solution was heated at 90° C. under nitrogen. After 15 hours, the solution was cooled to room temperature and partitioned between EtOAc and water. The organic phase was washed with 5% aqueous NaHCO3 and brine and dried over MgSO4. Evaporation of the solvent under vacuum gave a brown oil which was purified by chromatography on silica gel (1:2 to 1:1 EtOAc/hexanes) to give a sticky orange solid. The solid was dissolved in heptane-dichloromethane and then most of the dichloromethane was evaporated under reduced pressure. The resulting precipitated solid was isolated by filtration to give 2-benzyl-9a-(2-fluoroethyl)-8,9,9a,10-tetrahydroindeno[2,1-e]indazol-7(2H) -one.
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6](=O)[CH2:7][Br:8])#[N:2].[N-:10]=[N+:11]=[N-:12].[Na+].FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Br:8][CH2:7][C:6]1[N:5]([CH2:4][CH2:3][C:1]#[N:2])[N:12]=[N:11][N:10]=1
Reactant: N#CCCNC(=O)CBr
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#CCCn1nnnc1CBr

Procedure:
1.50 g (7.85 mmol) of bromoacetic acid-(2-cyanoethyl)-amide are dissolved in 50 ml of methylene chloride and mixed with 508 mg (7.85 mmol) of sodium azide. At 0° C. a solution of 2.20 g (7.85 mmol) of trifluoroacetic acid anhydride in 5 ml of methylene chloride is added dropwise. After 22 hours at ambient temperature saturated sodium hydrogen carbonate solution is added and the resulting mixture is extracted 3 x with methylene chloride. The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The crude product is chromatographed on silica gel, eluting first with methylene chloride, later with methylene chloride/ethanol (50:1). The desired fractions are combined and concentrated by evaporation.
Reaction SMILES: [Na].[CH2:2]([O:4][CH:5]([O:14][CH2:15][CH3:16])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)[CH3:3].[CH2:17]1[S:19][CH2:18]1.[Cl-].[NH4+]>N>[N:11]1[CH:12]=[CH:13][C:8]([CH:7]([CH2:6][CH:5]([O:4][CH2:2][CH3:3])[O:14][CH2:15][CH3:16])[CH2:17][CH2:18][SH:19])=[CH:9][CH:10]=1
Reactant: C1CS1
Reactant: CCOC(CCc1ccncc1)OCC
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Product: CCOC(CC(CCS)c1ccncc1)OCC
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To stirred liquid ammonia (2 liters) was added ferric nitrate (0.1 gm) followed by sodium metal (2.3 gms) in small pieces. The mixture was allowed to stand for 30 minutes and 3-(4-pyridyl)-propionaldehyde diethyl acetal (20.0 gms) was then added. A deep yellow colour was allowed to develop over a period of 2 hours, after which time ethylene sulphide (6.0 gms) was added quickly. A vigorous reaction occurred and the mixture was stirred for a further 5 hours. Ammonium chloride (7 gms) was added and the solvent was allowed to evaporate overnight. The residual tacky solid was extracted into pyridine and filtered and the solvent was evaporated from the filtrate. Distillation of the residual oil yielded 3-(4-pyridyl)-5,5-diethoxy-pentane-1-thiol (17 gms, 63% conversion) b.p. 167°-172° C/1 mm Hg, characterised by the following spectra:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH:20]=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)([OH:24])N.[O-]Cl=O.[Na+]>O1CCOCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([OH:24])=[O:21])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NS(=O)(=O)O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2C=O)CC1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2C(=O)O)CC1
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
4-(2-Formyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.50 g, 1.72 mmol) is dissolved in 80 mL of dioxane and 20 mL of H2O. The mixture is cooled to 4° C. and then sulfamic acid (1.36 g, 14.00 mmol) is added in one portion. The mixture is stirred for an additional 30 min and then 3 mL of a solution of NaClO2 (0.343 g, 3.80 mmol) is added in a drop-wise portion. The reaction is quenched by the addition of 50 mL of H2O and 50 mL of brine. The resulting mixture is extracted with 3×100 mL of CH2Cl2. The combined organic phase is washed with 2×50 mL of brine, dried with MgSO4, filtered and concentrated to give 500 mg of 4-(2-carboxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=O)[CH2:13][CH2:14][C:5]=3[C:4]=2[CH:3]=1.[NH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>C(#N)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:11][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][C:4]=2[C:5]2[CH2:14][CH2:13][C:12](=[N:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:6]1=2
Reactant: NCCN1CCOCC1
Reactant: Cn1c2c(c3cc(O)ccc31)CCC2=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CC#N
Product: Cn1c2c(c3cc(O)ccc31)CCC2=NCCN1CCOCC1
Reaction time: 2 h
Yield: 9.6 %

Procedure:
To a stirred solution of 7-hydroxy-4-methyl-1,4-dihydrocyclopent[b]indol-3-one (8.00 g) in acetonitrile (125 ml) under nitrogen were added 4-(2-aminoethyl)morpholine (10.35 g) and titanium isopropoxide (22.60 g). The reaction was monitored by TLC and after two hours additional equivalents of 4-(2-aminoethyl)morpholine (5.17 g) and titanium isopropoxide (1 1.30 g) were added. Fourteen hours later the reaction was quenched with water (200 ml). EtOAc (200 ml) was added and the mixture stirred for fifteen minutes and filtered. The layers were separated, the aqueous layer was extracted with ethyl acetate, and the combined organics were dried (Na2SO4) and concentrated in vacuo. The resulting yellow solid was dried yielding 6.65 g. of product. A 2 g sample of the solid was further purified by crystallization from CH2Cl2 /hexane to afford 1.2 g of 4-methyl-3-[2-(4-morpholinyl)ethyl]imino-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH2:10].C(N(CC)CC)C.[Cl:18][C:19]([Cl:24])([Cl:23])[C:20](Cl)=[O:21]>C(Cl)Cl>[NH2:10][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([NH:8][C:20](=[O:21])[C:19]([Cl:24])([Cl:23])[Cl:18])=[CH:5][C:4]=1[Cl:9]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Nc1cc(Cl)c(N)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1c(Cl)cc(NC(=O)C(Cl)(Cl)Cl)cc1Cl
Temperature: 5 °C
Yield: 113.6 %

Procedure:
2,6-Dichloro-1,4-benzenediamine (225 g., 1.27 mol) is suspended in methylene chloride (1.3 liters) containing triethylamine (245 mL, 1.7 mol). After the mixture is cooled to 5° C., trichloroacetylchloride (169 mL, 1.5 mol, Aldrich Chemical Co.) is added dropwise with stirring at a rate to maintain 5° C. Upon complete addition, the stirred reaction is allowed to reach room temperature. After 24 hours the mixture is filtered and the collected solid is washed with methylene chloride (700 mL). The filtrate is evaporated to a small volume. A solid is collected and washed with methylene chloride (250 mL) to yield 465 grams of N-(4-amino-3,5-dichlorophenyl)-trichloroacetamide. The product exhibits a mass spectral analysis of m/e+. 320 for C8H5Cl5N2O. 3. N-(3,5-Dichloro-4-formamidophenyl)-trichloroacetamide may be prepared from N-(4-amino-3,5-dichlorophenyl)-trichloroacetamide as follows:
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:14][N:13](C(OCC3C=CC=CC=3)=O)[CH2:12][CH2:11][C:4]=2[N:5]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:7]=1.[CH2:25]([Mg]Br)[CH3:26]>>[CH:8]1([C:6]2[N:7]=[C:2]([CH2:25][CH3:26])[C:3]3[CH2:14][NH:13][CH2:12][CH2:11][C:4]=3[N:5]=2)[CH2:9][CH2:10]1
Reactant: CC[Mg]Br
Reactant: O=C(OCc1ccccc1)N1CCc2nc(C3CC3)nc(Cl)c2C1
Product: CCc1nc(C2CC2)nc2c1CNCC2

Procedure:
Benzyl 4-chloro-2-cyclopropyl-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate, which was made using the general route described in footnote 14, was reacted with ethylmagnesium bromide under [1,2-bis(diphenylphosphino)ethane]dichloronickel(II) catalysis. Upon deprotection, the requisite 2-cyclopropyl-4-ethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine was isolated.
Reaction SMILES: [C:1]1([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][N:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H][H]>C1(C)C=CC=CC=1>[C:1]1([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][N:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccc(Oc2cccc3ccccc23)nc1
Reactant: [H][H]
Solvent: Cc1ccccc1
Product: Nc1ccc(Oc2cccc3ccccc23)nc1

Procedure:
To a solution of 13.11 g. (0.049 mol.) of 2-(1-naphthoxy)-5-nitropyridine in 250 ml. of toluene was added 1.31 g. of 5% paladium in carbon. The resulting mixture was placed in a 500 ml. Rocking Parr pressure vessel under 100 psig of hydrogen at r.t. for 3 hours. The mixture was filtered through celite and the filtrate was concentrated to give 11.5 g. (0.048 mol., 99.4%) of a yellow solid; mp. 82.2°-83.7°
Reaction SMILES: [Na].[CH2:2]([C:5]1[N:6]([C:10]2[N:18]=[CH:17][N:16]=[C:15]3[C:11]=2[NH:12][CH:13]=[N:14]3)[CH:7]=[CH:8][N:9]=1)[CH2:3][CH3:4].[C:19]1([CH3:45])[CH:24]=[CH:23][C:22]([C:25]([O:27][C@@H:28]2[C@@H:32]([CH2:33][O:34][C:35]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)=[O:36])[O:31][C@H:30](Cl)[CH2:29]2)=[O:26])=[CH:21][CH:20]=1>CC#N.C1(C)C=CC=CC=1>[C:19]1([CH3:45])[CH:20]=[CH:21][C:22]([C:25]([O:27][C@@H:28]2[C@@H:32]([CH2:33][O:34][C:35]([C:37]3[CH:38]=[CH:39][C:40]([CH3:43])=[CH:41][CH:42]=3)=[O:36])[O:31][C@@H:30]([N:14]3[CH:13]=[N:12][C:11]4[C:15]3=[N:16][CH:17]=[N:18][C:10]=4[N:6]3[CH:7]=[CH:8][N:9]=[C:5]3[CH2:2][CH2:3][CH3:4])[CH2:29]2)=[O:26])=[CH:23][CH:24]=1
Reactant: CCCc1nccn1-c1ncnc2nc[nH]c12
Reactant: Cc1ccc(C(=O)OC[C@H]2O[C@H](Cl)C[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Agent: [Na]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CCCc1nccn1-c1ncnc2c1ncn2[C@H]1C[C@H](OC(=O)c2ccc(C)cc2)[C@@H](COC(=O)c2ccc(C)cc2)O1
Yield: 49.3 %

Procedure:
The sodium salt of 6-(2-propylimidazol-1-yl)purine (55 mg, 0.24 mmol) in dried CH3CN (5 mL) was treated with 2-deoxy-3,5-di-O-(p-toluoyl)-α-D-erythro-pentofuranosyl chloride (0.15 g, 0.39 mmol) in toluene (5 mL) by general method 1. The residue was chromatographed (25 g silica gel, MeOH/CH2Cl2, 1:12) to give the two diastereomers [quantitative, containing traces of α-anomer (α/β ˜1:34)]. Recrystallization (EtOAc) gave 9-[2-deoxy-3,5-di-O-(p-toluoyl)-β-D-erythro-pentofuranosyl]-6-(2-propylimidazol-1-yl)purine (68.7 mg, 53%): mp 197-197.5° C.; UV (MeOH) max 242, 276 nm (∈ 31200, 12 500), min 223, 263 nm (∈ 16 400, 9700); 1H NMR (500 MHz, CDCl3) δ 8.80 (s, 1H), 8.41 (s, 1H), 8.28 (s, 1H), 8.00 (d, J=8.3 Hz, 2H), 7.89 (d, J=8.3 Hz, 2H), 7.31 (d, J=8.3 Hz, 2H), 7.21 (d, J=8.3 Hz, 2H), 7.12 (s, 1H) 6.65 (dd, J=6.2, 8.1 Hz, 1H), 5.85-5.87 (m, 1H), 4.68-4.83 (m, 3H), 3.30 (t, J=7.3 Hz, 2H), 3.17-3.23 (m, 1H), 2.91-2.95 (m, 1H), 2.47 (s, 3H), 2.39 (s, 3H), 1.85 (sext, J=7.5 Hz, 2H), 1.03 (t, J=7.3 Hz, 3H); NOE difference: irradiation at H1′ gave enhancement of the H4′ (small), H8 and H2′,2″ signals; 13C NMR (125 MHz, CDCl3) δ 166.4, 166.2, 153.1, 152.1, 151.0, 148.1, 144.9, 144.6, 142.4, 130.1, 129.8, 129.6, 129.5, 128.8, 126.8, 126.5, 124.6, 120.8, 85.5, 83.6, 75.2, 64.1, 38.3, 32.8, 22.0, 21.9, 21.5, 14.3; HRMS m/z 603.2347 (MNa+ [C32H32N6O5Na]=603.2332); Anal. Calcd for C32H32N6O5: C, 66.20; H, 5.56; N, 14.47. Found: C, 66.59; H, 5.67; N, 14.62.
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](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.Cl.[F:62][C@H:63]1[CH2:67][CH2:66][NH:65][CH2:64]1>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:26])([F:28])[F:27])=[N:20][C:21]([C:22]([N:65]3[CH2:66][CH2:67][C@H:63]([F:62])[CH2:64]3)=[O:23])=[C:15]2[CH2:14]1)=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: F[C@H]1CCNC1
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: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CC[C@H](F)C3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 89.4 %

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 (0.15 g, 0.27 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.140 g, 0.54 mmol), triethylamine (0.4 mL, 2.6 mmol) and (S)-3-fluoropyrrolidine hydrochloride (68 mg, 0.54 mmol) were dissolved in 10 mL of dichloromethane under stirring. 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-((S)-3-fluoro-pyrrolidine-1-carbonyl)-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 26a (0.15 g, yield 89%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: OB(O)c1ccccc1F
Product: COc1ccc2c(-c3ccccc3F)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 2-fluoro-phenylboronic acid to give [1-(2-fluoro-phenyl)-6-methoxy-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 335(MH+).