Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9](=[O:17])[CH2:8][C:7]1=[O:18].[BrH:19].C(O)(=O)C>O>[Br:19][CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9](=[O:17])[CH2:8][C:7]1=[O:18]
Reactant: Br
Reactant: COCCCN1C(=O)CC(=O)Nc2ccccc21
Solvent: O
Solvent: CC(=O)O
Product: O=C1CC(=O)N(CCCBr)c2ccccc2N1
Temperature: 60 °C
Reaction time: 4.7 h

Procedure:
To 4.9 g of the compound of Example 208, 25 ml of 30% hydrobromic acid-acetic acid solution is added and the resulting mixture is stirred at 60° C. for 4.7 hours. The resulting mixture is poured into water and the resultant is subjected to extraction with ethyl acetate. The organic layer is washed with aqueous sodium carbonate solution and brine and dried. The resultant is purified by silica gel column chromatography (ethyl acetate) to obtain 3.3 g of (209).
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:13][C:14](=[O:33])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)[CH:16]=2)[CH2:10][CH2:9][CH:8]([CH2:11]O)[CH2:7][CH2:6]1)=[O:4].C(N(S(F)(F)[F:40])CC)C>C(Cl)Cl>[F:40][CH2:11][CH:8]1[CH2:9][CH2:10][C:5]([NH:13][C:14](=[O:33])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)[CH:16]=2)([C:3]([OH:2])=[O:4])[CH2:6][CH2:7]1
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(C)c3)c2)CCC(CO)CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C(=O)NC2(C(=O)O)CCC(CF)CC2)cc1OCCc1cccc(C)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The compound of step 1 of example 58 (100 mg, 0.220 mmol) was dissolved in DCM (2 ml), diethylaminosulfur trifluoride (35 mg, 0.22 mmol) was added and the mixture was stirred at room temperature for 72 h. The mixture was partitioned between EA and aqueous sodium hydrogencarbonate solution. The aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography (HEP/EA gradient) and hydrolyzed in analogy to step 4 of example 1 to yield the title compound.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].Br[CH2:10][C:11]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:12]=1[C:13]#[N:14].O>CN(C)C=O>[F:19][C:17]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([CH2:10][O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[CH:18]=1
Reactant: N#Cc1ccc(F)cc1CBr
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(F)cc1COCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
336 μl 2,2,2-Trifluoroethanol were dissolved in 10 ml dimethylformamide. 243 mg sodium hydride were added and the mixture stirred at room temperature for one hour. Then 1.0 g 2-Bromomethyl-4-fluoro-benzonitrile were added in one portion and the reaction mixture was stirred at room temperature for three hours. The reaction mixture was poured on 50 ml water and extracted five times with portion of 25 ml ethyl acetate. The combined organic layers were dried over MgSO4, the solvent removed in vacuo and the resulting residue purified on silica gel with the eluent heptane=>n-heptane:ethyl acetate=4:1 to obtain 750 mg 4-Fluoro-2-(2,2,2-trifluoro-ethoxymethyl)-benzonitrile.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH:17]1[CH2:19][CH2:18]1)[C:9]([N:11]1[CH2:14][CH:13]([C:15]#[N:16])[CH2:12]1)=[O:10])(C)(C)C.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>ClCCl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[NH2:7][C@H:8]([CH:17]1[CH2:19][CH2:18]1)[C:9]([N:11]1[CH2:12][CH:13]([C:15]#[N:16])[CH2:14]1)=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CC(C#N)C1)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1CN(C(=O)[C@H](N)C2CC2)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-carbamic acid tert-butyl ester (190 mg, 0.69 mmol) in dichloromethane (4 ml) was added trifluoroacetic acid (1.8 ml, 23.4 mmol). The reaction mixture was stirred at room temperature for 2.5 h then concentrated to afford 1-((R)-2-amino-2-cyclopropyl-acetyl)-azetidine-3-carbonitrile trifluoroacetate as a light yellow oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=2)[CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=1)[C:8]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=2)[CH:17]=1)=[O:9]
Reactant: O=C(Cl)c1ccnc(Cl)c1
Reactant: COC(=O)c1ccc(-c2cc(N)ccc2C)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2cc(NC(=O)c3ccnc(Cl)c3)ccc2C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 60.6 %

Procedure:
2-Chloropyridine-4-carbonyl chloride (1.58 g, 9.0 mmol) in DCM (10 ml) was added dropwise to a solution of methyl 5′-amino-2′-methyl-1,1′-biphenyl-4-carboxylate (1.81 g, 7.5 mmol) and triethylamine (3.13 ml, 22.5 mmol) in DCM (10 ml) at 0° C. The reaction was stirred at room temperature for 20 h, the solvent evaporated under vacuum and the residue partitioned between ethyl acetate (50 ml) and saturated aqueous sodium bicarbonate (50 ml). The aqueous was extracted with ethyl acetate (50 ml) and the combined organic phases washed with brine (50 ml), dried (magnesium sulphate) and the solvent evaporated under vacuum. The residue was purified by flash column chromatography on silica eluting with DCM/ethanol/ammonia (300:8:1). The solvents were evaporated under vacuum to give methyl 5′-[(2-chloroisonicotinoyl)amino]-2′-methyl-1,1′-biphenyl-4-carboxylate (1.73 g, 61%).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][C@H:55]([C:57]([O:59][CH:60]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[O:58])[CH3:56])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37]Cl)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:73][C:74]1[S:75][C:76]2[CH:77]=[N:78][CH:79]=[CH:80][C:81]=2[N:82]=1.SC1SC2C=CN=CC=2N=1>>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][C@H:55]([C:57]([O:59][CH:60]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[O:58])[CH3:56])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37][S:73][C:74]4[S:75][C:76]5[CH:77]=[N:78][CH:79]=[CH:80][C:81]=5[N:82]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Sc1nc2ccncc2s1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(NC(=O)/C(=N\O[C@@H](C)C(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Agent: Sc1nc2cnccc2s1
Product: COc1ccc(COC(=O)C2=C(CSc3nc4ccncc4s3)CS[C@@H]3C(NC(=O)/C(=N\O[C@@H](C)C(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Yield: 63.3 %

Procedure:
Using 305 mg of p-methoxybenzyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-{(S)-1-diphenylmethoxycarbonylethoxyimino}acetamido]-3-chloromethyl-3-cephem-4-carboxylate and 60 mg of 2-mercaptothiazolo[5,4-c]pyridine in place of p-methoxybenzyl 7-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido}-3-chloromethyl-3-cephem-4-carboxylate and 2-mercaptothiazolo[4,5-c]pyridine, respectively, the reaction and purification were carried out in the same manner as in Example 1(a) to obtain 218 mg of the title compound in a yield of 63%.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[N:31]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[C:32]=[O:33]>C1COCC1>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:32]([NH:31][CH2:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: O=C=NCCc1ccccc1
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCCc1ccccc1)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 31.5 mg (0.21 mmol) of (2-isocyanatoethyl)benzene. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 32 mg (61.8% of theory) of the title compound are obtained.
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[N:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]>CC(O)=O>[NH2:3][C:4]1[N:13]=[CH:12][C:11]([Br:1])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccnc1N
Reactant: BrBr
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
Bromine (0.7 mL, 14 mmole) was added dropwise to a stirred solution of methyl 2-aminonicotinate (2.0 g, 13 mmole) in HOAc (50 mL). A suspension formed within 30 min. The reaction was allowed to stir at room temperature for 2 h, then was concentrated under vacuum. The residue was triturated with 1.0 N Na2CO3 (50 mL) and the solid was collected by suction filtration. The solid was washed with H2O (50 mL) and dried under vacuum to give the title compound (2.95 g, 98%) as a pale yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J=2.5 Hz, 1 H), 8.23 (d, J=2.5 Hz, 1 H), 6.40 (br s, 2 H), 3.90 (s,3 H).
Reaction SMILES: [CH2:1]([N:4]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)[CH:5]1[CH2:13][CH2:12][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1)[CH2:2][CH3:3].Cl.[CH2:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH:26]1[NH2:34].OCCCCNC(=O)C1C=CC=CC=1>>[CH2:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH:26]1[NH:34][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:15]([CH2:14][N:4]([CH2:1][CH2:2][CH3:3])[CH:5]2[CH2:13][CH2:12][C:8]3[N:9]=[CH:10][S:11][C:7]=3[CH2:6]2)=[CH:16][CH:17]=1
Reactant: NC1Cc2ccccc2C1
Reactant: CCCN(Cc1ccc(C(=O)Cl)cc1)C1CCc2ncsc2C1
Agent: Cl
Agent: O=C(NCCCCO)c1ccccc1
Product: CCCN(Cc1ccc(C(=O)NC2Cc3ccccc3C2)cc1)C1CCc2ncsc2C1
Yield: 58 %

Procedure:
Compound 44 is prepared from 42C and indan-2-ylamine hydrochloride as described for 1D.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11].[CH2:12]=[O:13]>C(O)(C)(C)C.CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][CH2:12][OH:13]
Reactant: Cc1c(Br)cccc1[N+](=O)[O-]
Reactant: C=O
Solvent: CS(C)=O
Solvent: CC(C)(C)O
Product: O=[N+]([O-])c1cccc(Br)c1CCO
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A solution of potassium tertiary-butylate (90 mg, 0.8 mmol) in tert-butanol (1 ml, synthesis quality, 99%) was added to 2-bromo-6-nitrotoluene (1.08 g, 5 mmol) and paraformaldehyde (150 mg, 5 mmol in DMSO (2.5 ml, synthesis quality, additionally dried for 2 d over molecular sieve 4 Å). After the addition of the potassium tertiary-butylate solution, a color change from yellow to deep violet occurred. It was stirred for 5 min at room temperature and for 30 min at 70° C. (oil bath temperature). The mixture was then allowed to cool to room temperature and neutralized with a few drops of conc. HCl. The mixture was diluted with EtOAc (30 ml) and washed with H2O (20 ml). The aqueous phase was post-extracted with EtOAc (2×20 ml). Drying of the organic phases over Na2 SO4, filtering and evaporating the solvent under reduced pressure yielded the crude product (1.49 g) which was purified by column chromatography (20 g SiO2, 20×2 cm, solvent: PE 45 ml, PE/EtAOc 10:1 110 ml, 8:1 180 ml, 7.5:1 340 ml, 6:1 140 ml). 2-(2-bromo-6-nitrophenyl)ethanol (867 mg, 70%) was obtained as a yellow solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[S:6][CH:7]=[CH:8][C:2]1=2.[Cl:9][CH2:10][C:11](Cl)=[O:12].O.Cl>C(Cl)Cl>[Cl:9][CH2:10][C:11]([C:5]1[S:1][C:2]2[CH:8]=[CH:7][S:6][C:3]=2[CH:4]=1)=[O:12]
Reactant: O=C(Cl)CCl
Reactant: c1cc2sccc2s1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(CCl)c1cc2sccc2s1
Temperature: 0 °C
Reaction time: 5 h
Yield: 43 %

Procedure:
Thieno[3,2-b]-thiophene (38.5 mmol) was solubilized in anhydrous DCM (77 mL) and the chloroacetylchloride (39.66 mmol) was added. The reaction mixture was cooled down to 0° C. and A1Cl3 (43.12 mmol) solubilized in DCM (385 mL) was added slowly. The mixture was stirred at room temperature during 5 hrs. The reaction mixture was cooled again to 0° C. and water and 2N HCl were added until pH=1. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give intermediate E71 as a yellow solid in 43% yield. MS (ESI, EI+) m/z=216.8 (MH+).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11].[CH3:16]O>>[CH3:16][O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([CH2:6][Cl:5])[CH:8]=1
Reactant: O=C(O)c1cccc(CCl)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
650 μl (8.8 mmol) of thionyl chloride was added dropwise to a stirred solution of 1 g (5.8 mmol) of 3-(chloromethyl)benzoic acid in 40 ml of methanol at 0° C. under a nitrogen atmosphere, then stirred at room temperature overnight. The solvent was evaporated, the residue dissolved in dichloromethane (30 ml), washed with saturated aqueous sodium bicarbonate (2×40 ml), brine (40 ml), dried over magnesium sulfate, filtered and evaporated to give 0.94 g (88%) of methyl-3-(chloromethyl)benzoate as a colorless mobile liquid.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][NH:13][C:12](=[O:15])[CH:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[CH2:34]([N:13]1[CH2:14][CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10][CH:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]1=[O:15])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)NC1CC(O[Si](C)(C)C(C)(C)C)CNC1=O
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CC(O[Si](C)(C)C(C)(C)C)CN(Cc2ccccc2)C1=O
Reaction time: 0.08 h
Yield: 77.5 %

Procedure:
To a stirred solution of compound 1D (0.403 g, 1.17 mmol) in 5 mL of THF at room temperature under argon was added (in one portion) 1.20 mL (in THF, 1.2 mmol) of 1M lithium bis(trimethylsilyl)amide and, after 5 min, 153 μL of benzyl bromide (1.29 mmol). After 15 h, additional portions of the base and alkylating agent were added as before. After 1 h more, the reaction mixture was quenched with saturated NaCl and extracted twice with EtOAc. The combined organic extracts were dried over MgSO4, filtered and evaporated under reduced pressure. Purification by silica gel chromatography (7:33 EtOAc/CH2Cl2) provided the title compound (394 mg, 77%) as a colorless oil and a 61:39 mixture of diastereomers of unknown assignment. MS [M+H]+: found 435.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[H-].[Na+].Cl.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16]Cl>CN(C=O)C>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCn1ccc2cccnc21
Reaction time: 16 h
Yield: 81 %

Procedure:
A stirred solution of 1H-pyrrolo[2,3-b]pyridine (5.00 g, 42.3 mmol) in DMF at ambient temperature is treated with 95% sodium hydride in oil (3.78 g, 150 mmol). After gas evolution subsides, the reaction mixture is treated with 2-(dimethylamino)-ethyl chloride hydrochloride (6.40 g, 44.4 mmol), stirred for 16 h and concentrated in vacuo. The resultant residue is partitioned between EtOAc and water. The organic phase is separated, dried over MgSO4 and concentrated in vacuo to afford the title compound as an oil, 6.50 g (81% yield), identified by HNMR and mass spectral analyses.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[C:12](Br)[CH:13]=[CH:14][CH:15]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1>>[CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[C:12]([C:32]3[CH:31]=[N:30][C:29]([O:28][CH3:27])=[N:34][CH:33]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ncc(B(O)O)cn1
Reactant: Brc1cccc2c1C[C@@H](N(Cc1ccccc1)Cc1ccccc1)CC2
Product: COc1ncc(-c2cccc3c2C[C@@H](N(Cc2ccccc2)Cc2ccccc2)CC3)cn1
Yield: 80 %

Procedure:
The title compound was synthesized as described for Intermediate example I-4 in 80% yield starting from (S)-N,N-dibenzyl-8-bromo-1,2,3,4-tetrahydronaphthalen-2-amine and 2-methoxypyrimidine-5-boronic acid (1.9 equiv) and. The reaction mixture was irradiated in a microwave under an atmosphere of argon at 140° C. for 1 h; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.59 (s, 2 H), 7.22-7.32 (m, 8 H), 7.09-7.20 (m, 4 H), 7.00-7.04 (m, 1 H), 4.00 (s, 3 H), 3.53-3.70 (m, 4 H), 2.87-3.00 (m, 2 H), 2.64-2.85 (m, 2 H), 2.45-2.54 (m, 1 H, obscured by DMSO), 2.05-2.14 (m, 1 H), 1.62-1.78 (m, 1 H); MS (ESI) m/z 436[M+H+].
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]([O:10][CH2:11]C)=[O:9])=[CH:5][CH:4]=1.[CH3:13][O-:14].[Na+].Cl>CO>[CH3:13][O:14][CH2:2][C:3]1[O:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=1
Reactant: C[O-]
Reactant: CCOC(=O)c1ccc(CCl)o1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCc1ccc(C(=O)OC)o1
Temperature: 25 °C
Reaction time: 17 h
Yield: 82.7 %

Procedure:
In 20 ml of dry methanol was dissolved 5.0 g (26.5 mmol) of ethyl 5-chloromethyl-2-furancarboxylate, followed by addition of 20 ml of a 28% solution of sodium methoxide in methanol. The mixture was stirred at room temperature for 17 hours, at the end of which time it was neutralized with 1N-hydrochloric acid. The resulting precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform and the solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure to give 3.73 g (82.7%) of methyl 5-methoxymethyl-2-furancarboxylate (Compound c) as light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25]C(=O)C)[C@@H:17]([O:18]C(=O)C)[C@H:12]2[O:13]C(=O)C)=[C:4](Cl)[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:36]([CH:38]([NH2:41])[CH2:39][CH3:40])[CH3:37]>C(O)(C)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:41][CH:38]([CH2:39][CH3:40])[CH2:36][CH3:37])[C:5]2[N:6]=[CH:7][N:8]([C:9]=2[N:10]=1)[C@@H:11]1[O:23][C@H:22]([CH2:24][OH:25])[C@@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: CCC(N)CC
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CCC(CC)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 54 °C
Reaction time: 24 h

Procedure:
A mixture of 2,6-dichloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-9H-purine ** (10.1 g, 22.6 mM), iso-propanol (300 ml), K2CO3 (5 g) and 1-ethylpropylamine (2.17 g, 24.84 mM) was stirred at 20 C. for 24 hrs. The reaction mixture was heated at 54° C. for 73 hrs. Solvent was removed in vacuo, water (50 ml) was added, extracted with ethyl acetate (3×80 ml), the combined extracts were dried (MgSO4) affording the title compound as a creamy light brown foam (9.44 g). LC/MS system A Rt=2.66 min, m/z=372 MH+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([S:9][C:10]#N)[CH:6]=[CH:5][C:3]=1[NH2:4].O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].[CH2:24](I)C>C(O)C.O>[Cl:1][C:2]1[CH:8]=[C:7]([S:9][CH2:10][CH3:24])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: CCI
Reactant: N#CSc1ccc(N)c(Cl)c1
Agent: [Na+]
Agent: [S-2]
Solvent: CCO
Solvent: O
Product: CCSc1ccc(N)c(Cl)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of 2-chloro-4-thiocyanoaniline (40 g., 0.22 mole) in ethanol (250 ml.) is added to a stirred solution of sodium sulfide nonahydrate (58.5 g., 0.22 mole) in water (110 ml.) and the mixture is warmed (50° C.) for 45 minutes. Ethyl iodide (36.6 g., 0.22 mole) is added and stirring is continued for 2 hours at 50° C. and then at room temperature overnight. The reaction is poured into water (3 liters) and the product extracted with either. The combined extracts are washed with water and dried (CaSO4). Removal of the drying agent and solvent gives 2-chloro-4-ethylthioaniline, an oil.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[C:5]([Cl:10])=[C:4]([Cl:11])[C:3]=1[Cl:12].C([Li])CCC.[F:18][C:19]([F:31])([O:23][C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[C:20](F)=[O:21].C(OCCOCC)(=O)C>C(OCC)C>[F:18][C:19]([C:20]([C:2]1[C:3]([Cl:12])=[C:4]([Cl:11])[C:5]([Cl:10])=[C:6]([Cl:9])[C:7]=1[Cl:8])=[O:21])([F:31])[O:23][C:24]([F:29])([F:30])[C:25]([F:26])([F:28])[F:27]
Reactant: Clc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: O=C(F)C(F)(F)OC(F)(F)C(F)(F)F
Agent: [Li]CCCC
Solvent: CCOCCOC(C)=O
Solvent: CCOCC
Product: O=C(c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)C(F)(F)OC(F)(F)C(F)(F)F
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Hexachlorobenzene (35 g) was slurried in 160 ml of anhydrous ethyl ether at -40° C. A 2.5 M hexanes solution of n-butyllithium (54.1 mL) was added, and the reaction was stirred for 30 minutes at -40° C. Perfluoro-2-ethoxyacetylfluoride (40 g, 72% pure, prepared from 2-ethoxyethyl acetate by the method described in Example I of U.S. Pat. No. 5,326,919, incorporated herein by reference) was added to the -40° C. reaction mixture which was then allowed to warm slowly to room temperature. The reaction mixture was quenched with 200 mL of cold 5% aqueous HCl. The aqueous mixture was extracted with ethyl ether and the extracts were dried over MgSO4 and rotary evaporated to give pentachlorophenyl perfluoroethoxymethyl ketone (49% crude yield). Vacuum distillation (105-109° C., 240 Pa) using a 15 cm Vigreux column gave 19.7 g of a colorless liquid which slowly crystallized on standing.