Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([NH:17][S:18]([C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.Cl>[OH-].[Na+]>[NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([NH:17][S:18]([C:21]4[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Nc2ccc3ccc4nc(N)[nH]c(=O)c4c3c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc2ccc3ccc(NS(=O)(=O)c4ccc(C(=O)O)cc4)cc3c2c(=O)[nH]1

Procedure:
A solution of methyl 4-(((3-Amino-1,2-dihydro-1-oxobenzo[f]quinazolin-9-yl)amino)sulfonyl)benzoate (0.54 g, 1.2 mmoles) in 0.1N NaOH (30 ml) was stirred at room temperature under a nitrogen atmosphere for 19 hrs. After this time, the solution was acidified (pH 4) with 1N HCl to cause precipitation of the product which was filtered and dried to give 4-(((3-amino-1,2-dihydro-1-oxobenzo[f]quinazolin-9-yl)amino)sulfonyl)benzoic acid as a light brown solid. (0.46 g, 86%) 1HNMR(DMSO-d6, 200 MHz) δ: 7.28(d, J=8.9 Hz, 1H, Ar); 7.30(dd, J=8.3, 2 Hz, 1H, Ar); 7.37(br s, 2H, NH2); 7.82(d, J=8.6 Hz, 1H, Ar); 7.95-8.06(m, 5H, Ar); 9.38(d, J=2 Hz, 1H, Ar); 10.85(s, 1H, NH). Anal. Calculated for C19H14N4O5.4/5 HCl.11 /10H2O: C, 49.68; H, 3.73; N, 12.20. Found: C, 49.61; H, 3.78; N, 12.30.
Reaction SMILES: [CH2:1]([C:3]1[N:15]2[C:6]([C:7](=[O:26])[NH:8][C:9]3[C:10]([CH2:23][CH2:24][CH3:25])=[N:11][C:12]([N:16]4[CH:20]=[CH:19][N:18]=[C:17]4CC)=[N:13][C:14]=32)=[CH:5][N:4]=1)[CH3:2].N1C=CN=C1>>[CH2:1]([C:3]1[N:15]2[C:6]([C:7](=[O:26])[NH:8][C:9]3[C:10]([CH2:23][CH2:24][CH3:25])=[N:11][C:12]([N:16]4[CH:20]=[CH:19][N:18]=[CH:17]4)=[N:13][C:14]=32)=[CH:5][N:4]=1)[CH3:2]
Reactant: CCCc1nc(-n2ccnc2CC)nc2c1[nH]c(=O)c1cnc(CC)n12
Agent: c1c[nH]cn1
Product: CCCc1nc(-n2ccnc2)nc2c1[nH]c(=O)c1cnc(CC)n12

Procedure:
Prepared by treatment of the product of Example 8 with excess imidazole at 200° C.
Reaction SMILES: [C:1]1(=O)[O:5][CH2:4][CH2:3][CH2:2]1.[NH2:7][CH2:8][CH2:9][OH:10]>O>[OH:10][CH2:9][CH2:8][N:7]1[CH2:1][CH2:2][CH2:3][C:4]1=[O:5]
Reactant: O=C1CCCO1
Reactant: NCCO
Solvent: O
Product: O=C1CCCN1CCO

Procedure:
A reactor was charged with γ-butyrolactone, 2-aminoethanol and water, to produce N-(2-hydroxyethyl)-2-pyrrolidone. The molar ratio of the 2-aminoethanol/γ-butyrolactone was 1.0, and that of the γ-butyrolactone/water was 1.1. The reaction temperature was 250° C. and the reaction time was 2 hours.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19](=[C:24]([F:26])[F:25])[CH2:20][C:21](Cl)=[O:22]>ClCCl.O>[F:18][C:19](=[C:24]([F:26])[F:25])[CH2:20][C:21]([NH:1][C:2]1[N:3]=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[N:7]=1)=[O:22]
Reactant: COc1cc(OC)nc(N)n1
Reactant: O=C(Cl)CC(F)=C(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COc1cc(OC)nc(NC(=O)CC(F)=C(F)F)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 10.7 %

Procedure:
To an ice-cooled stirred suspension of 2-amino-4,6-dimethoxypyrimidine (1.55 g, 10 mmol) in dichloromethane (50 mL) and potassium carbonate (2.76 g, 20 mmol) in water (20 mL) was added 3,4,4-trifluoro-3-butenoyl chloride (3.17 g, 20 mmol). The reaction mixture was stirred in cold for 10 min and at r.t. for 15 min. The organic layer was washed with 3N HCl (2×25 mL), saturated sodium bicarbonate (25 mL) and brine, and dried. Evaporation of the solvent gave 0.296 g (10%) of the title compound as a white solid. m.p. 127°-130° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[I:15](O)(O)(O)(O)(O)=O.II.S(=O)(=O)(O)O>O.C(O)(=O)C>[I:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: [O-][I+](O)(O)(O)(O)O
Reactant: CCc1ccc(-c2ccccc2)cc1
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CCc1ccc(-c2ccc(I)cc2)cc1
Temperature: 70 °C

Procedure:
25.0 g (137 mmol) of 4-ethylbiphenyl, 7.23 g (27.4 mmol) of orthoperiodic acid, 13.9 g (54.9 mmol) of iodine, 133 ml of acetic acid, 27 ml of water and 4.1 ml of sulfuric acid were placed in a 500 ml three-necked flask with a mechanical stirrer and bulb-shaped cooler. This was heated to 70° C. in a water bath, and subjected to the reaction for 2 hours. The product was cooled down to the ambient temperature. To this was added 300 ml of water, which was subjected to the extraction with chloroform. The resultant chloroform phase was washed with sodium thiosulfate and water in this order. To this was added sodium sulfate, and the dehydration was carried out. After the filtration was carried out, the chloroform was distilled away in an evaporator to obtain a light yellow solid. The resultant solid was recrystallized in the presence of ethanol to obtain a white crystal. The yield of the compound was 71%. Its melting point was 145-149° C. The IR chart is shown in FIG. 24.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:14]#[N:15])[N:6]([CH3:13])[CH2:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[CH3:2].[C:17]1([Mg]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCOCC>[CH2:1]([O:3][C:4](=[O:16])[C:5]([N:6]([CH3:13])[CH2:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)=[C:14]([NH2:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:2]
Reactant: CCOC(=O)C(C#N)N(C)Cc1cccs1
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C(=C(N)c1ccccc1)N(C)Cc1cccs1

Procedure:
Ethyl-2-[methyl(thienylmethyl)amino]-cyanoacetate (0.014 mol, 3.4 g) was dissolved in 100 mL of ether and added to 9.5 mL of 3M PhMgBr, and the resulting mixture was refluxed for 18 h. The reaction was cooled, quenched with sat. NH4Cl solution and extracted with ether. The organics were dried, concentrated, and chromatographed using 1:1 hexanes:ethyl acetate to give 1.4 g of product. 1H NMR (300 MHz) CDCl3: 7.58 (d, 2H), 7.4 (m, 3H), 7.21 (d, 1H), 6.89 (m, 2H), 5.0 (s, 1H), 4.28 (t, 2H), 3.85 (s, 2H), 2.75 (t, 2H), 2.38 (s, 3H).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH3:9][C:10]1([CH3:16])[CH2:14][CH2:13][CH2:12][C:11]1=[O:15]>>[CH3:6][N:4]([CH:3]=[C:12]1[CH2:13][CH2:14][C:10]([CH3:16])([CH3:9])[C:11]1=[O:15])[CH3:5]
Reactant: COC(OC)N(C)C
Reactant: CC1(C)CCCC1=O
Product: CN(C)C=C1CCC(C)(C)C1=O
Temperature: 25 °C
Yield: 83 %

Procedure:
A mixture of N,N-dimethylformamide dimethyl acetal (67 mL, 503 mmol) and 2,2-dimethylcyclopentanone (10 g, 90 mmol) was heated at reflux for 2 days. The reaction mixture was then cooled down to room temperature and concentrated. Water (˜380 mL) was added to the residue, and the resulting solution was extracted with methylene chloride. The organic layer was separated, dried over MgSO4 and concentrated to give the title compound (12.5 g) as a yellow-orange oil.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1.S(=O)(=O)(O)O.[CH:18](OC)(OC)OC>CO>[C:1]([O:12][CH3:18])(=[O:11])[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1
Reactant: COC(OC)OC
Reactant: O=C(O)c1cc(O)c(O)c(O)c1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cc(O)c(O)c(O)c1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
To a solution in which gallic acid (5.0 g, 29.39 mmol) was dissolved in methanol (25 mL), concentrated sulfuric acid (0.5 mL) and trimethyl orthoformate (3.21 mL, 88.17 mmol) were added consecutively at room temperature. The reaction mixture was heated under reflux for 10 hours, cooled to room temperature, and methanol was removed by vacuum distillation. To the residue obtained as above, distilled water (10 mL) was added, and the precipitated solid was filtered to give methyl gallate (5.15 g, 95%). 1H NMR (500 MHz, DMSO-D6) δ 9.29 (s, 2H), 8.96 (s, 1H), 6.92 (s, 2H), 3.73 (s, 3H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][S:13][C:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])=[CH:20][CH:21]=2)[N:16]([C:31]2[N:36]=[CH:35][C:34]([C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)=[CH:33][N:32]=2)[CH:15]=1>ClCCl>[CH3:12][S:13]([C:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])=[CH:20][CH:21]=2)[N:16]([C:31]2[N:32]=[CH:33][C:34]([C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)=[CH:35][N:36]=2)[CH:15]=1)=[O:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cn(-c2ncc(-c3cccnc3)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Solvent: ClCCl
Product: CS(=O)c1cn(-c2ncc(-c3cccnc3)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
m-Chloroperoxybenzoic acid (48 mg, 0.21 mmol) was added at 0° C. to a solution of 49a) (0.18 g, 0.25 mmol) in dichloromethane (20 mL) and the resulting mixture was stirred at room temperature for 4 h. The reaction was quenched with saturated sodium sulfite solution (20 mL) and stirred for further 5 min. The organic layer was separated, washed with saturated sodium hydrogen carbonate solution (2×20 mL) and brine (1×20 mL), dried over sodium sulphate and concentrated. The residue was purified by flash column chromatography [methanol/dichloromethane=1:25]. White solid. Yield: 0.06 g (53% of theory)
Reaction SMILES: O[CH:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]3[CH2:22][CH2:23][C:24]4[NH:25][C:26](=[O:29])[CH:27]=[CH:28][C:19]([C:20]=43)=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(Cl)([Cl:32])=O>>[Cl:32][CH:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]3[CH2:22][CH2:23][C:24]4[NH:25][C:26](=[O:29])[CH:27]=[CH:28][C:19]([C:20]=43)=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1C=CC2=CN=C(c3ccc(C(O)Cc4ccccc4)cc3)N3CCC(=C23)N1
Product: O=C1C=CC2=CN=C(c3ccc(C(Cl)Cc4ccccc4)cc3)N3CCC(=C23)N1

Procedure:
This compound was prepared from intermediate 247a and thionyl chloride according to the procedure used in Example 171. Received 3.53 g (75%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[F:11][C:12]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:13]=1[NH2:14].[OH-].[K+]>O>[F:11][C:12]1[CH:18]=[C:17]([O:19][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[NH:8][CH:9]=[CH:10][C:3]=23)[CH:16]=[CH:15][C:13]=1[NH2:14]
Reactant: Clc1ccnc2[nH]ccc12
Reactant: Nc1ccc(O)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(Oc2ccnc3[nH]ccc23)cc1F
Temperature: 25 °C

Procedure:
100 mg (660 μmol) of 4-chloro-1H-pyrrolo[2,3-b]pyridine (from example XVIII), 166 mg (1.31 mmol) of 2-fluoro-4-hydroxyaniline and 73.5 mg (1.31 mmol) of powdered potassium hydroxide are heated at 260° C. for 8 hours. For work-up, the mixture is cooled to room temperature, diluted with water and extracted three times with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated using a rotary evaporator. The residue is purified by preparative HPLC.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][S:4](Cl)(=[O:6])=[O:5].[CH3:10][O:11][CH:12]([O:29][CH3:30])[C:13]1[CH:17]=[C:16]([C:18]2[CH:19]=[C:20]([C:24]([NH2:27])([CH3:26])[CH3:25])[CH:21]=[CH:22][CH:23]=2)[N:15]([CH3:28])[N:14]=1.CCN(CC)CC>C(Cl)Cl>[CH3:30][O:29][CH:12]([O:11][CH3:10])[C:13]1[CH:17]=[C:16]([C:18]2[CH:19]=[C:20]([C:24]([NH:27][S:4]([CH2:3][C:2]([F:9])([F:8])[F:1])(=[O:6])=[O:5])([CH3:26])[CH3:25])[CH:21]=[CH:22][CH:23]=2)[N:15]([CH3:28])[N:14]=1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: COC(OC)c1cc(-c2cccc(C(C)(C)N)c2)n(C)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(OC)c1cc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)n(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
2,2,2-Trifluoroethylsulfonyl chloride (253 mg, 1.4 mmol) was added dropwise to a stirred solution of the amine from Step 2 (267 mg, 0.92 mmol) and Et3N (193 □L, 1.4 mmol) in CH2Cl2 (25 mL) at RT under N2. The mixture was stirred at RT for 30 min and then diluted with CH2Cl2 (25 mL), washed with NaHCO3 solution (20 mL) and concentrated under reduced pressure to yield the crude sulfonamide (213 mg, 53%). 1H NMR (CDCl3, 360 MHz) δ 7.60-7.53 (2H, m), 7.49 (1H, t, J=7.6 Hz), 7.37 (1H, d, J=7.6 Hz), 6.38 (1H, s), 5.50 (1H, s), 5.02 (1H, s), 3.88 (3H, s), 3.47 (2H, q, J=8.8 Hz), 3.44 (6H, s), 1.81 (6H, s). MS (ES+) C18H24F3N3O4S requires: 435, found: 404 (M-OCH3+, 100%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5](I)=[CH:4][N:3]=1.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1B(O)O>>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:15]2[S:14][CH:18]=[CH:17][CH:16]=2)=[CH:4][N:3]=1
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1I
Reactant: OB(O)c1cccs1
Product: C[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Yield: 70 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-iodopyrimidine-4-ylamino)propan-1-ol (400 mg, 1.3 mmol) with thiophen-2-boronic acid (e. g.: Aldrich, Acros, Apin) (179 mg, 1.4 mmol) according to procedure 3, the desired product is obtained in 70% yield (240 mg) after chromatographic purification (silica gel, ethyl acetate/hexane (0%-100% ethyl acetate)).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].S(=O)(=O)(O)O.[N+:20]([O-])([OH:22])=[O:21]>O>[OH:1][C:2]1[C:3]([N+:20]([O-:22])=[O:21])=[C:4]([C:11]([O:13][CH3:14])=[O:12])[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(O)c(C(=O)OC)s1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1sc(C(=O)OC)c([N+](=O)[O-])c1O
Reaction time: 1 h
Yield: 19.9 %

Procedure:
Methyl 4-hydroxy-5-(methoxycarbonyl)thiophene-2-carboxylate (5 g, 23.14 mmol) was added slowly for 15 min at 0 to −5° C. to concentrated sulfuric acid (25 mL). Then concentrated nitric acid (3.2 mL, 70%, 34.7 mmol) was added to the above reaction mixture for 10 min and stirred at the same temperature for 1 h. The mixture was poured into ice cooled water and extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (95:5) as eluents to give the product as a yellow color semi-solid (1.2 g, 20%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.C(N)(=[S:21])C.Cl>CN(C)C=O>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([C:15](=[S:21])[NH2:16])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: CC(N)=S
Reactant: N#Cc1ccc(-c2cn3cc(I)ccc3n2)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: NC(=S)c1ccc(-c2cn3cc(I)ccc3n2)cc1
Temperature: 80 °C
Yield: 71 %

Procedure:
4-(6-Iodoimidazo[1,2-a]pyridin-2-yl)benzonitrile (345 mg) and thioacetamide (150 mg) were added to a saturated solution (5 mL) of hydrogen chloride in dimethylformamide. The mixture was heated at 80° C. for 4 hours, and the solvent was evaporated. Saturated sodium hydrogencarbonate was added to the residue, followed by recovering the solid through filtration and drying, to thereby yield the title compound (269 mg).
Reaction SMILES: C(OC([NH:8][C@@:9]([CH2:27][CH2:28][N:29]1[C@H:38]([CH2:39][OH:40])[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30]1)([CH2:14][CH2:15][CH2:16][CH2:17][B:18]1[O:22]C(C)(C)C(C)(C)[O:19]1)[C:10]([O:12]C)=[O:11])=O)(C)(C)C.[ClH:41]>O>[ClH:41].[ClH:41].[NH2:8][C@@:9]([CH2:27][CH2:28][N:29]1[C@H:38]([CH2:39][OH:40])[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30]1)([CH2:14][CH2:15][CH2:16][CH2:17][B:18]([OH:22])[OH:19])[C:10]([OH:12])=[O:11]
Reactant: COC(=O)[C@@](CCCCB1OC(C)(C)C(C)(C)O1)(CCN1Cc2ccccc2C[C@H]1CO)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: O
Product: N[C@](CCCCB(O)O)(CCN1Cc2ccccc2C[C@H]1CO)C(=O)O
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of (R)-methyl 2-(tert-butoxycarbonylamino)-2-(2-((S)-3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (0.187 g, 0.334 mmol) in 6 N HCl (5 mL) was heated to a gentle reflux for 16 h. After cooling to room temperature, the reaction mixture was transferred to a separatory funnel, diluted with deionized water (5 mL) and washed with dichloromethane (3×5 mL). The aqueous layer was frozen in liquid nitrogen and lyophilized to give (R)-2-amino-6-borono-2-(2-((S)-3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)hexanoic acid dihydrochloride as an off-white foam (0.122 g, 89%). 1H NMR (D2O, 300 MHz) δ 7.26-7.08 (m, 4H), 3.89-375 (m, 1H), 3.78-3.65 (m, 1H), 3.61-3.50 (m, 1H), 3.41-3.18 (m, 1H), 3.10-3.00 (m, 1H), 2.99-2.75 (m, 2H), 2.35-2.20 (m, 2H), 1.84-1.60 (m, 2H), 1.31-1.16 (m, 2H), 1.15-1.00 (m, 2H), 0.66-0.50 (m, 2H); ESI-LCMS m/z calcd for C18H29BN2O5: expected 364.2. found 365.2 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][Cl:37]>CN(C=O)C>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][Cl:37])=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: ClCCCCCBr
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
2-(Butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate salt (for example, as prepared for Intermediate 6) (2 g, 5.69 mmol) and potassium carbonate (1.967 g, 14.23 mmol) were suspended in DMF (20 mL) and heated to 50° C., under nitrogen for 1 hour. The mixture was cooled to room temperature, 1-bromo-5-chloropentane (commercially available, for example, from Aldrich) (0.75 mL, 5.69 mmol) was added and stirring was continued at room temperature for 18 hours. The reaction mixture was partitioned between DCM (40 mL) and water (40 mL) and the layers were separated using a hydrophobic frit. The aqueous layer was extracted again with DCM (10 mL) and the combined organics were washed with saturated lithium chloride solution, separated (hydrophobic frit) and concentrated in vacuo to give the title compound as a yellow oil (1.946 g).
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([S:11][CH3:12])[C:3]=1[C:13]#[N:14].CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([S:11][CH3:12])[C:3]=1[C:13]#[N:14]
Reactant: CSc1nc2ccnn2c(O)c1C#N
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CSc1nc2ccnn2c(Cl)c1C#N
Temperature: 25 °C

Procedure:
A mixture comprising 2.15 g of 7-hydroxy-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile (compound No. 49), 1.3 g of N,N-dimethylaniline and 5 ml of phosphorus oxychloride was stirred under reflux with heating for about 3 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, and poured into ice water, followed by stirring. The precipitated crystals were collected by filtration, washed with water and dried to obtain crude crystals. The crude crystals were purified by silica gel column chromatography to obtain 2.17 g of 7-chloro-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile (compound No. 62) having a melting point of from 201 to 202° C.
Reaction SMILES: [CH2:1]([C:3]1([CH3:14])[CH:8]([CH3:9])[CH:7]([OH:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)[CH3:2].[H-].[Na+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[CH2:17]([O:10][CH:7]1[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4][C:3]([CH2:1][CH3:2])([CH3:14])[CH:8]1[CH3:9])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCC1(C)CC(O)C(C)C(C)(CC)N1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC1(C)CC(OCc2ccccc2)C(C)C(C)(CC)N1
Yield: 48.3 %

Procedure:
To a solution of 3.0 g of 2,6-diethyl-2,3,6-trimethyl-4-piperidinol (Compound 1) in 30 ml of dry toluene was added, at 0° - 5° C, 0.65 g of sodium hydride (purity 52.9%). The mixture was refluxed by heating for 6 hours. After cooling the mixture, 1.9 g of benzyl chloride were added dropwise at 0° - 5° C and the resulting mixture was refluxed by heating for 4 hours. The reaction mixture was then washed with water and dried over anhydrous magnesium sulphate; the solvent was then distilled off. The residue was purified by column chromatography on silica gel using benzene as eluent, followed by distillation under reduced pressure. There were obtained 2.1 g of Compound 95 as a pale yellow oil (bp 120° - 124° C/0.2 mmHg).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]1[S:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][C:6]=1[N+:14]([O-])=O.C(O)(=O)C>O1CCCC1.[Pd]>[S:9]1[C:5]2[CH:4]=[CH:3][NH:14][C:6]=2[CH:7]=[C:8]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(/C=C/N(C)C)s1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1cc2[nH]ccc2s1
Yield: 84.9 %

Procedure:
A solution of methyl (E)-5-(2-dimethylaminovinyl)-4-nitrothiophene-2-carboxylate (20 g, 78 mmol), 5% palladium/carbon (2 g) and acetic acid (20 ml) in tetrahydrofuran (300 ml) was stirred under hydrogen atmosphere (3.5 atm) at room temperature for 16 hr. The reaction mixture was filtered through celite and concentrated under reduced pressure. Diethyl ether (300 ml) was added to the residue. The mixture was washed successively with 1N hydrochloric acid (100 ml×2), water (100 ml), saturated aqueous sodium hydrogen carbonate solution (100 ml×2) and saturated brine (100 ml), and dried over magnesium sulfate. Filtration and concentration under reduced pressure gave methyl 4H-thieno[3,2-b]pyrrole-2-carboxylate (12 g, yield 87%).
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][N:4]=1.[CH3:13][OH:14]>>[CH3:13][O:14][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][N:4]=1
Reactant: CO
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: [Na]
Product: COc1cc(C)c([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a stirred solution of sodium (2.30 g, 100mmol, 3.8 eq) in absolute methanol (75 ml) at 0° C., a solution of 2-chloro-4-methyl-5-nitropyridine (4.50 g, 26.07 mmol) in absolute methanol (15 ml) was added dropwise rapidly. The resulting dark colored solution was stirred at room temperature for 30 minutes, and then it was concentrated to a solid via evaporation under reduced pressure. This solidwas placed in water (25 ml), the pH of which was adjusted to 6 with concentrated HCl, and this aqueous mixture was extracted with ethyl acetate (2×25 ml). These extracts were combined, dried (MgSO4),and evaporated under reduced pressure to yield 2-methoxy-4-methyl-5-nitropyridine (4.30 g, 25.57 mmol, 98%) as an orange solid: mp, 70°-72° C.; 1H NMR (DMSO-d6) δ 8.94 (s, 1H), 6.97 (s, 1H), 3.99 (s, 3H), 2.58 (s, 3H); LRMS (m/z relativeintensity) 168 (M+, 98), 167 (100), 151 (34), 138 (24), 80 (17).