Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@:8]23[CH2:16][N:15]([C:17]4[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:9]3)[CH:5]=[CH:6][CH:7]=1.[C:33]([C:35]1[CH:36]=[CH:37][C:38]([C:41](O)=[O:42])=[N:39][CH:40]=1)#[N:34].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>ClCCl>[C:25]([NH:24][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:14][N:15]([C:17]3[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=3)[CH2:16][C@:8]2([C:4]2[CH:3]=[C:2]([NH:1][C:41]([C:38]3[CH:37]=[CH:36][C:35]([C:33]#[N:34])=[CH:40][N:39]=3)=[O:42])[CH:7]=[CH:6][CH:5]=2)[N:9]=1)(=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: Nc1cccc([C@]23CN(c4ncc(F)cn4)C[C@H]2CSC(NC(=O)c2ccccc2)=N3)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(C(=O)Nc2cccc([C@]34CN(c5ncc(F)cn5)C[C@H]3CSC(NC(=O)c3ccccc3)=N4)c2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
N-[(4aR,7aS)-7a-(3-Aminophenyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (0.30 g, 0.67 mmol) is dissolved in dichloromethane (10 mL) and 5-cyanopyridine-2-carboxylic acid (129 mg, 0.87 mmol), 1-hydroxybenzotriazole (185 mg, 1.34 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (169 mg, 0.87 mmol) are added. Diisopropylethyamine (0.35 mL, 2 mmol) is added and the reaction is stirred at room temperature overnight. The material is purified directly with silica gel chromatography eluting with a 0-100% ethyl acetate/hexanes gradient to give the title compound (360 mg, 88%). ES/MS (m/e): 579 (M+H).
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14](N)[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4](O)[C@H:2]1O.[OH2:20]>CO>[C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([OH:20])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[CH2:4][CH2:2]1
Reactant: O
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: CO
Product: OC[C@@H]1CC[C@H](n2cnc3c(O)ncnc32)O1
Temperature: 20 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
This mixture of anomers (1.66 g) was treated with 170 mL of methanol saturated with ammonia. This was tightly stoppered and stirred at 18° C. for 48 hrs. TLC indicated that reaction was incomplete. The solvent was evaporated and replaced with 170 mL of fresh ammonia solution in methanol. TLC after an additional 48 hr implied the reaction was complete. Hence, the solvent was evaporated and ethanol was added (5 mL). This yielded colorless crystals which were collected and washed with (5 mL) of 95% ethanol to yield 1.20 g (95%) of 2', 3'-dideoxyadenosine 5a together with its α anomer 5b in a 1:1 ratio by 1H-NMR. The α+β2',3'-dideoxyadenosine mixture was dissolved in 50 mL of deionized water and to this solution was added 10 mg of adenosine deaminase (type II, from Sigma; 9 units/mg→.9 μmole/min). The solution was stirred at 20° C. and reaction monitored by HPLC. After 2 hrs 30 min another 10 mg of adenosine deaminase was added. HPLC showed the reaction was nearly complete after 3 hrs. The reaction was then concentrated (1-2 mL) at 35° C. to give an oil. The oil was scratched and slowly diluted with 2×1.5 mL portions of methanol which produced white crystals. After 15 min the material was filtered and the colorless crystals washed with 2×1.5 mL portions of methanol to yield 2', 3'-dideoxyinosine (120 mg, 48%). The mother liquor was treated as above to yield an additional 29 mg (12%) of good quality product, which was characterized by 1H-NMR. The nuclear magnetic resonance spectrum was consistent with the structure.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:23][O:24][CH3:25])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:15]CC1C=CC=CC=1)[CH:9]=2)=[O:5])[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:23][O:24][CH3:25])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([OH:15])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(OCc3ccccc3)cc2n1COC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc2ccc(O)cc2n1COC
Temperature: 50 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
To a solution of 6-benzyloxy-1-methoxymethyl-1H-indole-2-carboxylic acid ethyl ester (3.45 g, 10 mmol) in EtOH (35 ml) was added 10% Pd/C (0.35 g) and the mixture was stirred under a hydrogen atmosphere (1 atm) for 2 hours at 50° C. The catalyst was filtered off and the filtrate was evaporated. The residue was purified by silica gel column chromatography (n-hexane:AcOEt=4:1) to give 2.0 g of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=2[CH:10]=[C:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])[CH2:4][CH2:3]1.C([O-])=O.[NH4+]>[Pd].C(O)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=2[CH2:10][CH:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccccc2C=C2CCNC2=O)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CN1CCN(c2ccccc2CC2CCNC2=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A round bottom flask under N2 was charged with 10% Pd/C (0.99 g) and ethyl alcohol (50 mL) followed by 3-[2-(4-methylpiperazin-1-yl)-benzylidene]-pyrrolidin-2-one (3.00 g, 11.1 mmol) and ammonium formate (6.97 g, 110.6 mmol). The reaction mixture was stirred at room temperature for 1 hour then heated to 50° C. for 3 hours. The reaction mixture was cooled to room temperature and filtered through Celite™ under N2. The Celite™ pad was washed with ethyl alcohol (25 mL) and water (10 mL). The filtrate was evaporated to give white solids which were partitioned between ethyl acetate (25 mL) and H2O (10 mL). The aqueous layer was extracted with additional ethyl acetate (2×25 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated to a white solid (2.90 g, 96%). The material could be used crude or triturated with ethyl acetate (5 vol) to give 80% recovery of improved purity of the title compound. 13C NMR (100 MHz, CDCl3) d 180.6, 152.1, 135.5, 130.4, 127.5, 124.5, 120.8, 55.9, 52.9, 46.4, 42.4, 40.6, 31.8, 27.3; MS (AP/Cl) 274.3 (M+H)+.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[C:11]2[CH:12]=[C:13]([C:16]([OH:18])=O)[CH:14]=[CH:15][C:10]=2[O:9][CH:8]=1)(=[O:3])[CH3:2].S(Cl)([Cl:21])=O>>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[C:11]2[CH:12]=[C:13]([C:16]([Cl:21])=[O:18])[CH:14]=[CH:15][C:10]=2[O:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCCc1coc2ccc(C(=O)O)cc12
Reactant: O=S(Cl)Cl
Product: CC(=O)NCCc1coc2ccc(C(=O)Cl)cc12
Reaction time: 1 h

Procedure:
5 mmol of the product obtained in Step E are dissolved in 40 ml of thionyl chloride. After stirring under an inert atmosphere for 1 hour, the thionyl chloride is removed by evaporation under reduced pressure to yield the title product.
Reaction SMILES: P(O[C:18]([CH3:49])=[C:19]([N:33]1[C:39](=[O:40])[CH:38]2[CH:34]1[S:35][C:36]([CH2:41][O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[N:37]2)[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:21])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1.O>C(OCC)(=O)C>[O:42]([CH2:41][C:36]1[S:35][CH:34]2[CH:38]([C:39](=[O:40])[N:33]2[C:19](=[C:18]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)[CH3:49])[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[N:37]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CC(OP(=O)(Oc1ccccc1)Oc1ccccc1)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Reactant: C1COCCN1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21)N1CCOCC1
Reaction time: 2 h

Procedure:
To a solution of diphenyl 1-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-1-(p-nitrobenzyloxycarbonyl)-prop-1-en-2-yl phosphate (7.02 g) in ethyl acetate (70 ml) at 0°-5° C. was added morpholine (1.83 ml) dropwise and the reaction mixture stirred at this temperature for 2 hours. Water (30 ml) was added and the organic layer was separated, washed with water (30 ml) and saturated sodium chloride solution (30 ml), dried with magnesium sulphate, filtered and evaporated to give the title compound as a yellow foam in almost quantitative yield. TLC (silica) Rf 0.57 (ethyl acetate). The product was a mixture of geometric isomers (ca. 1:1.4) about the enamine double bond. NMRδCDCl3 1.93 (s), +2.43 (s) (3H), 3.17-3.93 (m, 8H), 4.90 (s, 2H), 5.25 (s, 2H), 5.68-6.13 (m, 2H) and 6.87-7.7+8.1-8.4 (m, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:20]([CH3:21])=[CH:19][C:5]2[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.C(O)C>[C].[Pd].O1CCCC1>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:6]2[C:5]3[CH:19]=[C:20]([CH3:21])[C:2]([CH3:1])=[CH:3][C:4]=3[N:8]=[CH:7]2)=[CH:11][CH:12]=1
Reactant: Cc1cc2ncn(Cc3ccc([N+](=O)[O-])cc3)c2cc1C
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc2ncn(Cc3ccc(N)cc3)c2cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.2 %

Procedure:
A mixture of 5,6-dimethyl-1-(4-nitrobenzyl)-1H-benzimidazole (2.5 g), 10% palladium carbon (300 mg), ethanol (150 ml) and tetrahydrofuran (150 ml) was stirred under a hydrogen atmosphere at room temperature for 4 hrs. Palladium carbon was removed from the reaction mixture by filtration, and the filtrate was concentrated. Recrystallization of the residue from ethyl acetate-methanol gave 1-(4-aminobenzyl)-5,6-dimethyl-1H-benzimidazole (1.88 g, 84%) as colorless prism crystals. melting point: 238-239° C.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH2:8][C@H:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[CH:19][C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[CH3:10].C([O:34][N+:35]([O-])=[O:36])(C)C>C(O)(C)(C)C>[OH:7][CH2:8][C@H:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[C:19]([N+:35]([O-:36])=[O:34])[C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[CH3:10]
Reactant: CC(C)O[N+](=O)[O-]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C([N+](=O)[O-])C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
Potassium tert-butoxide (1.70 g, 15 mM) and (20S)-20-hydroxymethylpregn-4-en-3-one (1.65 g, 5 mM) are mixed together in tert-butanol (25 mL), and heated at reflux temperature under argon atmosphere for 75 minutes. Isopropylnitrate (0.51 mL, 5mM) is then added to the refluxing reaction mixture, resulting in an exothermic reaction. After one minute, the reaction vessel is removed from heat and allowed to cool to room temperature. The cooled mixture is then made acidic by addition of acetic acid (5mL), and stirred overnight. The mixture is then diluted with dichloromethane so as to form a separate phase sufficient to solubilize the synthesized product. Subsequently, the solids are removed by filtration and washed with dichloromethane. The materials in both the filtrate and wash(es) are combined together and concentrated. The residue is then redissolved in dichloromethane, then purified by flash chromatagraphy on silica gel to give (20S)-20-hydroxymethyl-4-nitropregn-4-en-3-one. The crystallization of this material from aqueous acetone gives white needles (m.p. 166-168° C.).
Reaction SMILES: O=[C:2]1[C:7]([O:8]B(O)O)=[CH:6][CH2:5][CH2:4][CH2:3]1.Br[C:13]1[N:17]([CH3:18])[CH:16]=[N:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>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.O>[CH3:18][N:17]1[C:13]([C:2]2[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH:3]=2)=[CH:14][N:15]=[CH:16]1
Reactant: O=C1CCCC=C1OB(O)O
Reactant: Cn1cncc1Br
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cncc1C1=CCCCC1=O
Yield: 8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 39a by using (6-oxocyclohex-1-en-1-yl)boric acid (J. Org. Chem. 2011, 76, 3946-3959; 790 mg, 5.65 mmol), 5-bromo-1-methyl-1H-imidazole (910 mg, 5.65 mmol), tetrakis(triphenylphosphine)palladium (0) (326 mg, 0.282 mmol), cesium carbonate (4.00 g, 12.3 mmol), 1,4-dioxane (10 mL) and water (5 mL), to yield the title compound (80 mg, 8%) as a brown oil.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].Cl.Cl[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[N:16]1[CH:17]=[CH:18][C:13]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])=[CH:14][CH:15]=1
Reactant: Clc1ccncc1
Reactant: Nc1ccccc1C(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)c1ccccc1Nc1ccncc1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A suspension of 274.5 g (2.0 moles) of anthranilic acid, 300 g (2.0 moles) of 4-chloropyridine hydrochloride and 180 g (2.19 moles) of anhydrous sodium acetate in 855 ml of glacial acetic acid was stirred at reflux for three hours. The mixture was cooled to room temperature and the precipitated solid was filtered. The product was washed with a small amount of cold acetic acid followed by cold ether. It was dried at 75° C., in vacuo to give 428 g (85.6%) of 2-(4-pyridinylamino)benzoic acid as the hydrochloride salt, m.p. 275°-280° C.(decompn.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].O>CN(C=O)C.CCOC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-nitrophenol (3.00 g, 21.6 mmol) and K2CO3 (6.00 g, 43.4 mmol) in DMF (50 mL), t-butyl bromoacetate (2.90 mL, 19.6 mmol) was added. The mixture was stirred at room temperature for 5 h. Water and EtOAc were added. The organic phase was separated, washed with water, then with aq. 1N NaOH and brine. It was dried over Na2SO4, concentrated in vacuo to give tert-butyl 2-(4-nitrophenoxy)acetate as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.BrBr>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(c2ccc(Br)cc2)=NN1
Agent: BrBr
Solvent: CC(=O)O
Product: O=c1ccc(-c2ccc(Br)cc2)n[nH]1

Procedure:
An 86.3 g. sample of 6-(p-bromophenyl)-4,5-dihydro-3(2H)-pyridazinone (prepared as in U.S. Pat. No. 3,689,652, Example 4) is dissolved in 500 ml. of glacial acetic acid by heating to 80° C. with continuous stirring. A solution of 60 g. of bromine in 80 ml. of acetic acid is added dropwise at 75°-80° C. over a one hour period. A solid is separated near the end of the addition. The reaction mixture is heated with stirring on the steam bath for half an hour more, then is poured into 3 liters of cracked ice-water. The white solid formed is collected by filtration and is air dried. The product is then recrystallized from ethyl alcohol to afford 6-(p-bromophenyl)-3(2H)-pyridazinone.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10](=[O:32])[CH:11]([OH:31])[CH2:12][CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:19]=2)(=[O:16])=[O:15])[CH2:3][CH2:2]1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>C(Cl)Cl>[CH3:33][S:34]([O:31][CH:11]([C:10]([NH:9][CH2:8][CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:32])[CH2:12][CH2:13][S:14]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1)(=[O:16])=[O:15])(=[O:36])=[O:35]
Reactant: O=C(NCCN1CCOCC1)C(O)CCS(=O)(=O)Cc1cccc(Oc2ccccc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC(CCS(=O)(=O)Cc1cccc(Oc2ccccc2)c1)C(=O)NCCN1CCOCC1
Reaction time: 1 h
Yield: 92.5 %

Procedure:
Part H: A cooled solution of 2.1 g (5 mmol) of N1-(2-morpholinoethyl)-2--hydroxy-4-[(3-phenoxybenzyl)sulfonyl]butanamide from Part G in 55 mL of anhydrous CH2Cl2 was treated with 0.5 mL (0.8 g, 7 mM) of methanesulfonyl chloride, followed by 1.0 mL (0.7 g, 7 mM) of triethylamine. After 1 hour, the reaction was concentrated in vacuo, and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted with ethyl acetate (1×). The organic layers were combined and washed with brine, dried (MgSO4) and concentrated to yield 2.5 g of 1-[(2-morpholinoethyl)amino]carbonyl-3-[(3-phenoxybenzyl)sulfonyl]propyl methanesulfonate suitable for the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:18]=[C:17]4[C:13]([NH:14][C:15](=[S:30])[N:16]4[C@H:19]4[C:28]5[C:23](=[C:24]([F:29])[CH:25]=[CH:26][CH:27]=5)[O:22][CH2:21][CH2:20]4)=[CH:12][N:11]=3)[C:6]=2[CH:31]=1.[CH3:32]CN(P1(N(C)CCCN1)=NC(C)(C)C)CC.IC>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:18]=[C:17]4[C:13]([NH:14][CH:15]([S:30][CH3:32])[N:16]4[C@H:19]4[C:28]5[C:23](=[C:24]([F:29])[CH:25]=[CH:26][CH:27]=5)[O:22][CH2:21][CH2:20]4)=[CH:12][N:11]=3)[C:6]=2[CH:31]=1
Reactant: Fc1ccc2ncn(-c3ncc4[nH]c(=S)n([C@@H]5CCOc6c(F)cccc65)c4n3)c2c1
Reactant: CCN(CC)P1(=NC(C)(C)C)NCCCN1C
Solvent: CC#N
Solvent: CI
Product: CSC1Nc2cnc(-n3cnc4ccc(F)cc43)nc2N1[C@@H]1CCOc2c(F)cccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
2-(6-Fluoro-1H-benzo[d]imidazol-1-yl)-9-((R)-8-fluorochroman-4-yl)-7H-purine-8(9H)-thione (4 mg, 0.009 mmol) was dissolved in 1 mL anhydrous acetonitrile, add 25 mg (0.054 mmol) 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polystyrene (Fluka), then 3 microliter iodomethane. The mixture was stirred at room temperature for 30 minutes. After concentration in vacuo, the residue was purified by silica gel column chromatography eluting with 2% MeOH in DCM and EtOAc to yield 2.1 mg (52%) the titled compound as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[N:12]3[CH2:13][CH2:14][CH2:15][CH:16]([C:17]([O:19]C(C)C)=[O:18])[C:11]3=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[N:12]3[CH2:13][CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:11]3=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)OC(=O)C1CCCn2c(C(=O)c3ccc(F)cc3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(c1ccc(F)cc1)c1ccc2n1CCCC2C(=O)O
Temperature: 25 °C

Procedure:
A solution of isopropyl 3-p-fluorobenzoyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylate in methanol is treated under an atmosphere of nitrogen with a solution of sodium hydroxide in water, maintaining the reaction mixture at room temperature for 1.5 hours. The methanol is then removed under reduced pressure and the basic solution which remains is diluted with water and extracted with ether to remove any unsaponifiable product. The aqueous solution is acidified with 10% hydrochloric acid and extracted three times with ethyl acetate. The combined extracts are dried and evaporated to dryness under reduced pressure, and the residue crystallized from ethyl acetate-hexane, to give 3-p-fluorobenzoyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylic acid, identical to the product obtained in Example 8.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][CH2:11][C:5]=2[C:4]([C:16]([OH:18])=O)=[CH:3][CH:2]=1.S(Cl)([Cl:21])=O>>[CH:1]1[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][CH2:11][C:5]=2[C:4]([C:16]([Cl:21])=[O:18])=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc2c1CCCc1ccccc1-2
Product: O=C(Cl)c1cccc2c1CCCc1ccccc1-2

Procedure:
Under a dry nitrogen atmosphere a stirred solution of 6,7-dihydro-5H-dibenzo[a,c]cycloheptene-4-carboxylic acid (3.4 grams, 0.0142 mole) in thionyl chloride (10 ml) was heated at reflux for 1.5 hours. The excess thionyl chloride was removed by distillation under reduced pressure. Benzene (10 ml) was added and then removed by distillation under reduced pressure to leave 6,7-dihydro-5H-dibenzo[a,c]cycloheptene-4-carbonyl chloride as a residue.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[C:4]([NH2:16])[C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][C:7]=1[CH3:8].Cl.N1C=CC=[CH:33][CH:32]=1.C(OCC)(OCC)(OCC)C>C1(C)C=CC=CC=1>[CH3:32][C:33]1[N:17]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[C:3]2[C:2]([CH3:1])=[C:7]([CH3:8])[N:6]=[C:5]([O:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:4]=2[N:16]=1
Reactant: c1ccncc1
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCCOCCCc2cccnc2)c1C
Agent: CCOC(C)(OCC)OCC
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1nc(Oc2ccccc2)c2nc(C)n(CCOCCCc3cccnc3)c2c1C
Temperature: 99 °C

Procedure:
A solution of 5,6-dimethyl-2-phenoxy-N4-[2-(3-pyridin-3-ylpropoxy)ethyl]pyridine-3,4-diamine (12 g) in toluene (300 ml) from Part C was combined with pyridine HCl (0.08 g) and triethyl orthoacetate (8.4 ml). Under a nitrogen atmosphere, the reaction mixture was heated to reflux (99° C.) for 1.5 hours. TLC and HPLC analysis indicated that the reaction was complete. The solvent was removed under reduced pressure. The resulting yellow oil was dissolved in dichloromethane and washed once with saturated potassium carbonate, 3 times with water, and 3 times with brine. The combined organic layers were dried with magnesium sulfate and concentrated under reduced pressure. The resulting yellow oil darkened slightly after being dried under vacuum at 70° C. overnight. The product was purified by column chromatography over silica using 95/5 ethyl acetate/methanol as the eluant. The product was dried and then triturated with diethyl ether to yield a white solid that was dried under vacuum at 80° C. overnight. NMR analysis of the dried solid indicated a pure product.
Reaction SMILES: [CH3:1][O:2][C@H:3]([CH3:7])[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:32][C:33]([F:57])([F:56])[O:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]2[CH2:46][NH:45][CH2:44][CH:43]([NH:47][C:48](=[O:55])[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH2:42]2)=[CH:37][CH:36]=1>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:1][O:2][C@H:3]([CH3:7])[C:4]([N:45]1[CH2:46][CH:41]([C:38]2[CH:39]=[CH:40][C:35]([O:34][C:33]([F:57])([F:32])[F:56])=[CH:36][CH:37]=2)[CH2:42][CH:43]([NH:47][C:48]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)=[O:55])[CH2:44]1)=[O:6]
Reactant: CO[C@H](C)C(=O)O
Reactant: O=C(NC1CNCC(c2ccc(OC(F)(F)F)cc2)C1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CO[C@H](C)C(=O)N1CC(NC(=O)c2ccccc2)CC(c2ccc(OC(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
44 mg (0.41 mmol) of (2R)-2-methoxypropanoic acid together with 157 mg (0.41 mmol) of HATU and 67 mg (0.55 mmol) of 4-dimethylaminopyridine were initially charged in 2 ml of DMF, and 100 mg (0.27 mmol) of N-{5-[4-(trifluoromethoxy)phenyl]piperidin-3-yl}benzamide were added. The reaction mixture was stirred overnight at RT and then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 116 mg (94% of theory)