Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:11]=[CH:10][N:9]([CH2:12][CH2:13][NH:14]C(=O)OC(C)(C)C)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:22]>O1CCOCC1>[ClH:22].[ClH:22].[C:1]1([C:7]2[N:11]=[CH:10][N:9]([CH2:12][CH2:13][NH2:14])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NCCn1cnc(-c2ccccc2)n1
Agent: Cl
Solvent: C1COCCO1
Product: NCCn1cnc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.3 %

Procedure:
To a solution of tert-butyl 2-(3-phenyl-1H-1,2,4-triazol-1-yl)ethylcarbamate (34 mg, 118 μmol) in dioxane (1 mL) was added hydrochloric acid (4M in dioxane, 590 μl, 2.36 mmol). The reaction mixture was stirred at RT for 18 h. All volatiles were removed in vacuo and the product was dried to yield a white solid (38 mg, 116 μmol, 98.7%) that was used without additional purification. MS: =189.3 M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:18]1([C:24]([C:26]2[S:30][C:29]([C:31]([NH:33][NH2:34])=[O:32])=[CH:28][CH:27]=2)=[O:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15](=[N:34][NH:33][C:31]([C:29]3[S:30][C:26]([C:24]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[O:25])=[CH:27][CH:28]=3)=[O:32])[CH3:17])[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NNC(=O)c1ccc(C(=O)N2CCOCC2)s1
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Solvent: CC(C)O
Product: CC(=NNC(=O)c1ccc(C(=O)N2CCOCC2)s1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 25 °C
Yield: 86 %

Procedure:
28 mg of 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene and 26 mg of 5-(morpholine-4-carbonyl)thiophene-2-carbohydrazide prepared in Reference Synthetic Example 2 were heated in isopropyl alcohol with 3 mg of p-tosylic acid monohydrate at 105° C. for 18 hours and cooled to room temperature. The precipitated solid was recovered by filtration and washed with 1 mL of isopropyl alcohol, and the resulting crystals were dried to give the desired product (yield 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:15])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[O:26][CH2:25][CH:24]1[C:31](O)=[O:32])=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[C@H:24]([C:31](=[O:32])[NH:15][C:13]2[CH:14]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:12]=2[NH:11][C:10]2[CH:9]=[N:8][CH:7]=[CH:6][C:5]3=2)[CH2:25][O:26][C:27]([CH3:30])([CH3:29])[CH2:28]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: Nc1cc(Cl)cc2c1[nH]c1cnccc12
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)OCC1C(=O)O
Product: CC(C)(C)OC(=O)N1CC(C)(C)OC[C@H]1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Yield: 87 %

Procedure:
The desired compound was prepared according to Method C from 6-chloro-9H-β-carboline-8-ylamine and 6,6-dimethyl-morpholine-3,4-dicarboxylic acid 4-tert-butyl ester in 87% yield.
Reaction SMILES: CN(C)CCOCCN(C)C.C([Mg]Cl)(C)C.[CH3:17][O:18][C:19](=[O:37])[C:20]1[CH:25]=[CH:24][C:23](I)=[C:22]([O:27][CH2:28][CH2:29][C:30]2[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=2)[CH:21]=1.[B:38](OC)([O:41]C)[O:39]C.Cl>C1COCC1>[CH3:17][O:18][C:19](=[O:37])[C:20]1[CH:25]=[CH:24][C:23]([B:38]([OH:41])[OH:39])=[C:22]([O:27][CH2:28][CH2:29][C:30]2[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=2)[CH:21]=1
Reactant: COB(OC)OC
Reactant: COC(=O)c1ccc(I)c(OCCc2cccc(C)c2)c1
Agent: CC(C)[Mg]Cl
Agent: CN(C)CCOCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(B(O)O)c(OCCc2cccc(C)c2)c1
Temperature: 15 °C
Reaction time: 0.33 h
Yield: 56.4 %

Procedure:
2.3 g of bis(2-dimethylaminoethyl)ether were dissolved in 50 ml of anhydrous THF and 7.1 ml of a 2 M solution of isopropylmagnesium chloride added at 15° C. The mixture was stirred for 20 min at 15° C. Then a solution of 4.7 g of 4-iodo-3-(2-m-tolyl-ethoxy)-benzoic acid methyl ester in 20 ml of anhydrous THF was added at room temperature. The mixture was stirred for 10 min at 20° C., and then 2.4 g of trimethyl borate were added dropwise at 0° C. and the mixture stirred for 20 min at 0° C. 100 ml of 0.1 N hydrochloric acid were added, and the mixture was extracted three times with 100 ml of EA. The combined organic layers were washed with 100 ml of water, dried with magnesium sulfate and evaporated. Silica gel chromatography (EA/HEP 1:5) of the residue yielded 2.1 g of the title compound.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:9][C:10]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: Oc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(c2ccc(C(F)(F)F)cc2)Oc2ccccc2O1

Procedure:
A solution of catechol (5.5 g) and 4-(trifluoromethyl)acetophenone (10.3 g) in toluene (150 ml) containing a catalytic amount (0.2 g) of p-toluenesulphonic acid monohydrate was heated under reflux for 3 days. Water produced in the condensation was separated by means of a Dean-Stark trap. After removal of the solvent under reduced pressure, the residue was purified by chromatography on silica gel using methylene chloride as eluant. Pure 2-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-benzodioxole was obtained as a colourless oil (10.8 g, 77%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:19]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:22]2[CH2:21][CH2:20][N:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23]2)=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(C=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(CCO[Si](C)(C)C(C)(C)C)cc2)CC1
Yield: 83.4 %

Procedure:
To a 1,2-dichloroethane (15 mL) solution of 4-(2-{[tert-butyl(dimethyl)silyl]-oxy}ethyl)benzaldehyde (0.70 g) and tert-butyl piperazine-1-carboxylate (0.52 g) was added NaBH(OAc)3 (0.83 g) at 0° C. The resultant mixture was stirred at room temperature for 66 hours. To the reaction mixture was added saturated aqueous NaHCO3, and extracted with CH2Cl2. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=9/1 to 2/1) to afford tert-butyl 4-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)benzyl]piperazine-1-carboxylate (0.96 g) as a colorless oil.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[CH:6]1)[C:2]#[C:3][CH3:4].[Cl:17]N1C(=O)CCC1=O.O>CN(C)C=O>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[C:6]1[Cl:17])[C:2]#[C:3][CH3:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC#CCn1cnc2c1c(=O)[nH]c(=O)n2C
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.2 %

Procedure:
7-(2-Butynyl)-3-methyl-3,7-dihydropurine-2,6-dione (112 g) was dissolved in N,N-dimethylformamide (2200 mL), then N-chlorosuccinimide (75.3 g) was added to this mixture, and the reaction solution was stirred at room temperature for five hours. After completion of the reaction, water (2200 mL) was added to the reaction solution, this was stirred at room temperature for 1.5 hours. A white precipitate was then collected by filtration. The white solid obtained was washed with water and t-butyl methyl ether to give the title compound (117 g).
Reaction SMILES: [Cl:1][C:2]1[C:47]([F:48])=[CH:46][CH:45]=[CH:44][C:3]=1[CH2:4][NH:5][C:6](=[O:43])[N:7]([C@H:9]([CH2:27][O:28][C:29](=[O:42])[NH:30][C:31]1[N:32]=[CH:33][C:34]2[C:39]([CH:40]=1)=[CH:38][C:37]([F:41])=[CH:36][CH:35]=2)[CH2:10][CH2:11][C:12]([N:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1)=[O:13])[CH3:8].Cl>CO>[F:41][C:37]1[CH:38]=[C:39]2[C:34](=[CH:35][CH:36]=1)[CH:33]=[N:32][C:31]([NH:30][C:29](=[O:42])[O:28][CH2:27][C@@H:9]([N:7]([CH3:8])[C:6]([NH:5][CH2:4][C:3]1[CH:44]=[CH:45][CH:46]=[C:47]([F:48])[C:2]=1[Cl:1])=[O:43])[CH2:10][CH2:11][C:12](=[O:13])[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[CH:40]2
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1)COC(=O)Nc1cc2cc(F)ccc2cn1
Agent: Cl
Solvent: CO
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)N1CCNCC1)COC(=O)Nc1cc2cc(F)ccc2cn1
Reaction time: 8 h
Yield: 73.4 %

Procedure:
To a solution of (S)-tert-butyl 4-(4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-(6-fluoroisoquinolin-3-ylcarbamoyloxy)pentanoyl)piperazine-1-carboxylate (56 mg, 0.081 mmol, 1.0 equiv.) in MeOH (1 mL) was added HCl (4 M in 1,4-dioxane, 1 mL). The mixture was stirred overnight and concentrated. The resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O. The fractions containing the product were combined and concentrated. The resulting solid was dissolved in EtOAc. The organic solution was washed with saturated NaHCO3. HCl (4 N) was added into the organic solution. The solution was then concentrated to give (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-oxo-5-(piperazin-1-yl)pentyl 6-fluoroisoquinolin-3-ylcarbamate (35 mg, 65%) as a HCl salt. LRMS (M+H+) m/z 589.2.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([O-:14])=[O:13].[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[NH:45][C:39]3[N:40]=[CH:41][N:42]=[C:43](Cl)[C:38]=3[CH:37]=2)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[NH:45][C:39]3[N:40]=[CH:41][N:42]=[C:43]([O:21][C:18]4[CH:19]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=4)[C:38]=3[CH:37]=2)=[CH:32][CH:31]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Clc1ncnc2[nH]c(-c3ccc(OCc4ccccc4)cc3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ncnc3[nH]c(-c4ccc(OCc5ccccc5)cc4)cc23)cc1
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 36.9 %

Procedure:
After adding 2.97 of potassium carbonate and 30 ml of dimethylformamide to 3.09 g of 4-nitrophenol and stirring the mixture at 130° C. for 10 minutes, 2.49 g of 6-(4-benzyloxyphenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine was added and the mixture was further stirred at 130° C. for 5 hours and at 135° C. overnight. After returning the mixture to room temperature, water was added, the precipitated solid was filtered out and subjected to NH silica gel column chromatography (ethyl acetate) and silica gel column chromatography (ethyl acetate), and then ether and ethyl acetate were added prior to sonication. The solid was filtered out to obtain 1.2 g of the title compound.
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[F:29][C:3]([F:2])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][N:12]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:11][C@H:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: CS(=O)(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Yield: 57 %

Procedure:
The compound (0.15 g) obtained in Example 1 and methylsulfonyl chloride (0.040 ml) were reacted and treated in the same manner as in the method described in Example 2 to obtain the title compound as colorless oil (0.093 g, 57%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1)=[O:17].C(N(CC)CC)C>C(Cl)Cl.O>[O:11]=[CH:12][CH2:13][CH2:14][NH:15][C:16]([C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1)=[O:17]
Reactant: O=C(NCCCO)c1ccc[nH]1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CCCNC(=O)c1ccc[nH]1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 70.8 %

Procedure:
Method A. A mixture of 6 (2.85 g, 13.6 mmol) and p-toluenesulfonic acid monohydrate (1.3 g, 6.84 mmol) in 80 mL of acetone/water (1:1, v/v) was refluxed for 6 h. After cooling, the reaction mixture was extracted with CH2Cl2 (3×100 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The resulting solid was recrystallized from acetone/CH2Cl2 to afford 7 (1.81 g, 80%) as a colorless solid: mp 88-90° C.; 1H NMR (CDCl3) d 2.77 (t, 2H, J=5.8), 3.66 (q, 2H, J=5.8), 6.16 (m, 1H), 6.38 (br, 1H), 6.50 (m, 1H), 6.87 (m, 1H), 9.69 (br, 1H), 9.78 (bs, 1H); 13C NMR (CD3COCD3) d 33.7 (e), 44.6 (e), 109.6 (o), 110.0 (o), 122.1 (o), 127.1 (e), 162.0 (e), 201.9 (o); IR (nujol) 1715, 1622, 1565, 1409, 1328 cm−1; MS m/z (relative intensity) 167 (M++1, 100), 138 (15) , 123 (28), 94 (50); Anal. Calcd for C8H10N2O2: C, 57.82; H, 6.07; N, 16.86; Found: C, 57.68; H, 5.17; N, 16.79. Method B. To a stirred solution of oxalyl chloride (0.12 mL, 1.31 mmol) in 3 mL of CH2Cl2 at −78° C. was added DMSO (0.21 mL, 2.9 mmol) in 0.6 mL of CH2Cl2 under argon. After 2 min, a solution of 5 (0.2 g, 1.19 mmol) in 40 mL of CH2Cl2 was added to the mixture and allowed to stir for 15 min. Next, triethylamine (830 mL, 5.92 mmol) was added and the reaction mixture was allowed to warm to room temperature. After 15 min, the mixture was poured into 10 mL of water and the organic layer was separated and washed successively with 10% citric acid (20 mL), saturated NaHCO3 (20 mL), and saturated NaCl (20 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (CH2Cl2/MeOH 19:1) to afford 7 (0.14 g, 70%) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:20]CC3C=CC=CC=3)[C:14]=2[O:18][CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:20])[C:14]=2[O:18][CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(OCc2ccccc2)ccc2c1CCN(C(=O)OC(C)(C)C)C2
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1c(O)ccc2c1CCN(C(=O)OC(C)(C)C)C2

Procedure:
7.8 g (21 mmol) 6-Benzyloxy-5-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (example XV) in 150 mL THF are hydrogenated (3 bar, r.t.) using 250 mg Pd/C (10%). The reaction mixture is filtered, the solvent is removed in vacuo and the residue is purified by HPLC (ACN/H2O/NH3). After HPLC, ACN is removed in vacuo and the aq. layer is extracted with EtOAc. The organic layer is dried over MgSO4, filtered and the solvent is removed in vacuo.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH:16]=[CH2:17])=[N:5][CH:4]=[C:3]1[C:18]([O:20]CC)=O.[NH3:23]>>[O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH:16]=[CH2:17])=[N:5][CH:4]=[C:3]1[C:18]([NH2:23])=[O:20]
Reactant: C=CCOc1ccccc1-c1ncc(C(=O)OCC)c(=O)[nH]1
Reactant: N
Product: C=CCOc1ccccc1-c1ncc(C(N)=O)c(=O)[nH]1
Reaction time: 18 h

Procedure:
A mixture of ethyl 1,6-dihydro-6-oxo-2-(2-allyloxyphenyl)-pyrimidine-5-carboxylate (5.0 g.) and liquid ammonia (50 ml.) in a steel bomb was kept at 25° for 18 hours and then heated on a steam bath for 2.5 hours. The ammonia was removed. The residue was dissolved in water and the solution acidified with acetic acid. The precipitated title compound (4.4 g., 97%), m.p. 202-204° with resolodification and remelting at 275°-280° , was recrystallized from ethanol to give analytical material, m.p. 205°-207° .
Reaction SMILES: [C:1](=[O:17])([O:15][CH3:16])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([F:12])=[CH:5][C:4]=1[CH2:13][CH3:14]>CO.[Pd]>[C:1](=[O:17])([O:15][CH3:16])[O:2][C:3]1[CH:8]=[C:7]([NH2:9])[C:6]([F:12])=[CH:5][C:4]=1[CH2:13][CH3:14]
Reactant: CCc1cc(F)c([N+](=O)[O-])cc1OC(=O)OC
Agent: [Pd]
Solvent: CO
Product: CCc1cc(F)c(N)cc1OC(=O)OC
Reaction time: 8 h
Yield: 94 %

Procedure:
To a flask charged with 10% Pd/C (170 mg) under inert atmosphere was added a solution of 2-ethyl-4-fluoro-5-nitrophenyl methyl carbonate (1.7 g, 6.99 mmol) in methanol (17 mL). The mixture was stirred overnight under an atmosphere of H2. The reaction was filtered and concentrated in vacuo to provide 5-amino-2-ethyl-4-fluorophenyl methyl carbonate (1.400 g, 6.57 mmol). NMR (400.0 MHz, DMSO-d6) δ 6.92 (d, J=12.0 Hz, 1H), 6.52 (d, J=8.1 Hz, 1H), 5.16 (s, 2H), 3.81 (s, 3H), 2.33 (q, J=7.5 Hz, 2H), 1.05 (t, J=7.5 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@@H:16]3[O:17]C(C)(C)[O:19][C@@H:15]3[C@@H:14]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])[O:13]2)=[C:5]([NH:27][CH2:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:4]=1.C(N(CC)CC)C.[C:49]1([CH2:55][S:56](Cl)(=[O:58])=[O:57])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>ClCCl>[CH2:55]([S:56]([NH:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@@H:12]2[O:13][C@H:14]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])[C@@H:15]([OH:19])[C@H:16]2[OH:17])=[C:5]([NH:27][CH2:28][CH:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:4]=1)(=[O:58])=[O:57])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNS(=O)(=O)Cc4ccccc4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
A solution of (3aS,4S,6R,6aR)-6-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide (Preparation 10) (120 mg, 0.21 mmol) and triethylamine (0.04 ml, 0.29 mmol) in anhydrous dichloromethane (2 ml) was treated with phenylmethylsulphonyl chloride (45 mg, 0.24 mmol). The mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue dissolved in ethanol (1 ml). Hydrochloric acid (1M, 1 ml) was added to the solution and the mixture was heated at 60° C. for 8 hours. The solvent was removed under reduced pressure and the residue was azeotroped with ethanol (×2). The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane methanol (95:5 by volume) gradually changing to dichloromethane: methanol (90:10 by volume) to give a solid which was triturated with diethyl ether, diluted with pentane, filtered and dried to afford the title compound as a white solid (92 mg).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:13]O.Cl>O1CCOCC1>[N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1
Reactant: CO
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc[nH]c2c1
Reaction time: 4 h

Procedure:
A mixture of 10 g of 5-benzimidazolecarboxylic acid, 150 ml of methanol and 100 ml of a 4N solution of hydrogen chloride in 1,4-dioxane was agitated ultrasonically for 4 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, after which 300 ml of methanol and 3.5 g of lithium borohydride were added to the residue and the mixture was stirred for 1 hour. The solvent was then removed by evaporation under reduced pressure and the residue was mixed with an aqueous solution of sodium chloride, after which it was extracted with ethyl acetate. The solvent was removed by distillation under reduced pressure, to give 5.44 g of the title compound, melting at 136°-138° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[C:6]([O:13][CH3:14])[CH:5]=1)([OH:3])=O.[CH2:15]([CH2:17][NH2:18])[OH:16]>>[OH:16][CH2:15][CH2:17][NH:18][C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[C:6]([O:13][CH3:14])[CH:5]=1)=[O:3]
Reactant: COc1cc(C(=O)O)ccc1B(O)O
Reactant: NCCO
Product: COc1cc(C(=O)NCCO)ccc1B(O)O

Procedure:
The title compound was prepared in analogy to the procedure described for Intermediate K from 4-carboxy-2-methoxyphenyl boronic acid and ethanolamine. The solvent was removed and then water and EtOAc were added. The phases were separated and the aqueous one was extracted twice with EtOAc. The organics extracts were combined and dried (Na2SO4), and concentrated. The residue was triturated in acetonitrile to give the title compound. tR: 0.42 min (LC-MS 2); ESI-MS: 240.1 [M+H]+ (LC-MS 2).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[As](=O)(O)(O)O.S(=O)(=O)(O)O.N.O[CH2:26][CH:27]([CH2:29]O)O>C(O)(=O)C.O>[C:4]([C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[C:10]2[C:2]=1[N:1]=[CH:29][CH:27]=[CH:26]2)([OH:6])=[O:5]
Reactant: OCC(O)CO
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: N
Agent: O=S(=O)(O)O
Agent: O=[As](O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc([N+](=O)[O-])cc2cccnc12
Yield: 83.5 %

Procedure:
A mixture of 2-amino-5-nitrobenzoic acid (4 g, 22 mM), glycerol (8 g), arsenic acid (80% in water) (20 g), and sulphuric acid (65%) (36 ml) was heated at reflux for 3.5 hours. After addition of water (100 ml), the pH was adjusted to 8 with concentrated ammonia and then to 3.5 with acetic acid. The resulting precipitate was filtered and dried to give 8-carboxy-6-nitroquinoline (4 g; 83%).
Reaction SMILES: C[Mg+].[Br-].[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[Cl:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=1>ClCCCl>[Cl:13][C:14]1[N:19]=[C:18]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4][CH:5]=2)[CH:17]=[CH:16][N:15]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Clc1ccnc(Cl)n1
Agent: C[Mg+]
Agent: [Br-]
Solvent: ClCCCl
Product: Clc1nccc(-c2c[nH]c3ccccc23)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.9 %

Procedure:
CH3MgBr (3M in diethyl ether, 22.68 mL, 68.03 mmol) was added dropwise over a period of 10 minutes to a stirred solution of 1H-indole (7.97 g, 68.03 mmol) in 1,2-dichloroethane (250 mL) at 0° C. under an atmosphere of N2. The resulting solution was stirred for 15 minutes and then 2,4-dichloropyrimidine (15.00 g, 100.69 mmol) was added in one portion. The resulting solution was allowed to warm to r.t. and was stirred for a further 16 h. The reaction was quenched by the addition of CH3OH (25 mL) then the mixture was concentrated in vacuo and absorbed onto silica. Purification by FCC, eluting with 0-20% CH3OH in CH2Cl2 gave the title compound (7.17 g, 46%) as a yellow solid; 1H NMR: 7.20-7.28 (2H, m), 7.49-7.53 (1H, m), 7.91 (1H, d), 8.42 (1H, dd), 8.50 (1H, d), 8.53 (1H, d), 12.06 (1H, s); m/z: ES+ MH+ 230.