Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:24]=[CH:25][CH:26]=2)[CH2:11][N:12]([CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[CH:4][N:3]=1.[NH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>>[OH:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][NH:27][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[C:10]([CH:24]=[CH:25][CH:26]=3)[CH2:11][N:12]([CH2:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[CH:4][N:3]=2)=[CH:31][CH:32]=1
Reactant: CS(=O)(=O)N(Cc1ccncc1)Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1ccc(O)cc1
Product: CS(=O)(=O)N(Cc1ccncc1)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 15 was coupled with tyramine following procedure F. LC-MS showed the product had the expected M+H+ of 490. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.4 (d, 2H) 8.2 (d, 1H) 7.9 (m, 2H) 7.4 (m, 2H) 7.2 (d, 2H) 7.0 (d, 2H) 6.9 (d, 1H) 6.7 (d, 2H) 4.4 (s, 2H) 4.3 (s, 2H) 3.6 (m, 2H) 2.9 (m, 5H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=[O:21])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:50][CH2:51][CH2:52][NH:53][C:54](=[O:60])[O:55][C:56]([CH3:59])([CH3:58])[CH3:57].CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1>[C:56]([O:55][C:54]([NH:53][CH2:52][CH2:51][CH2:50][O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=[O:21])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29])=[O:60])([CH3:59])([CH3:58])[CH3:57]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCOc1ccc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 99.1 %

Procedure:
In a similar manner to Step 1 of Example 149, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (150 mg, 0.382 mmol) was dissolved in THF (7.5 mL), and the solution was treated with triphenylphosphine (200 mg, 0.764 mmol), tert-butyl N-(3-hydroxypropyl)carbamate (134 mg, 0.764 mmol) and 40% DEAD-toluene solution (0.348 mL), followed by purification by flash column chromatography (chloroform/methanol=100/0 to 95/5) to obtain 4-[3-(tert-butoxycarbonylamino)propoxy]-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (208 mg, yield 99%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2>CO.C(O)(=O)C.[Pd]>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH2:24])[CH:18]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2
Reactant: N#Cc1cccc(-c2ccc(C(=O)N[C@H]3CN4CCC3CC4)s2)c1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: NCc1cccc(-c2ccc(C(=O)N[C@H]3CN4CCC3CC4)s2)c1
Reaction time: 36 h
Yield: 7.3 %

Procedure:
To the solution of (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(3-cyanophenyl)thiophene-2-carboxamide) (311 mg) in methanol and acetic acid (1:1, 10 mL) a catalytic amount of 10% Pd—C was added and the mixture was hydrogenated at 50 p.s.i. for 36 hr. The mixture was filtered through a pad of celite. The residue was purified first by flash chromatography using 5-20% 3.5M methanolic ammonia/chloroform mixtures as the eluent and then by reverse phase HPLC on a Waters Bondapak® C18 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The free base was prepared by basification of the product-containing fractions and extraction into chloroform followed by evaporation to gave the title compound (23 mg); MS (ES+) 342 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:15]=3[N:16]=2)[C:5]([NH:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=1.[CH:22]1[C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]2[C:31]([O:33][C:34](=O)[C:24]=2[CH:23]=1)=[O:32]>>[CH3:21][C:17]1[C:15]2[N:16]=[C:12]([C:4]3[CH:3]=[C:2]([N:1]4[C:31](=[O:32])[C:25]5[C:24](=[CH:23][CH:22]=[C:27]([C:28]([OH:30])=[O:29])[CH:26]=5)[C:34]4=[O:33])[CH:7]=[CH:6][C:5]=3[NH:8][CH2:9][CH2:10][CH3:11])[O:13][C:14]=2[CH:20]=[CH:19][CH:18]=1
Reactant: CCCNc1ccc(N)cc1-c1nc2c(C)cccc2o1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: CCCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2c(C)cccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-propylaminophenyl)-4-methylbenzoxazole (112 mg, 0.4 mmol) and 1,2,4-benzenetricarboxylic anhydride (96 mg, 0.5 mmol) the title compound was obtained (110 mg, 60%). 1H NMR (DMSO) δ 8.46(t, 1H), 8.41(dd, 1H), 8.03(s, 1H), 8.06(m, 2H), 7.61(m, 2H), 7.44(dd, 1H), 7.22(d, 1H), 7.00(d, 1H), 3.34(m, 2H), 2.44(s, 3H), 1.74(m, 2H), 1.06(t, 3H). MS 453.9 m/z (M−H)−.
Reaction SMILES: S(O[CH2:12][C@@H:13]1[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)(C1C=CC(C)=CC=1)(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C)C=O>[N:26]([CH2:12][C@@H:13]1[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](CN=[N+]=[N-])C1

Procedure:
A solution of EXAMPLE 442A (1.66 g, 4.47 mmol) and sodium azide (0.581 g, 8.94 mmol) in anhydrous N,N-dimethylformamide (10 mL) was stirred at 90° C. for 4 hours. The mixture was cooled and concentrated to dryness. The residue was taken up in 5% aqueous sodium carbonate solution and extracted with methylene chloride. The combined organic layers was dried (MgSO4), filtered and concentrated to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:11][C@H:12]([CH3:15])[CH2:13]I)[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[CH:18](=[C:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21]>CCCCCCC.CCOC(C)=O>[CH:18](=[C:22]1[CH2:27][CH2:26][N:25]([CH2:13][C@@H:12]([CH3:15])[CH2:11][N:6]2[C:5]3[CH:16]=[CH:17][C:2]([F:1])=[CH:3][C:4]=3[O:9][CH2:8][C:7]2=[O:10])[CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21]
Reactant: C[C@H](CI)CN1C(=O)COc2cc(F)ccc21
Reactant: CCCC=C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCC=C1CCN(C[C@@H](C)CN2C(=O)COc3cc(F)ccc32)CC1
Yield: 74.2 %

Procedure:
The compound (S)-7-Fluoro-4-(3-iodo-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one (111MF20)(0.515 g, 1.47 mmol) and 4-butylidenepiperidine (0.205 g, 1.47 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (111MF29) (0.393 g, 73%). 1H NMR (CDCl3) δ 7.17-7.12 (m, 1H), 6.74-6.69 (m, 2H), 5.15-5.11 (t, J=7.2 Hz, 1H), 4.61 (q, J=15.2 Hz, 2H), 4.04-3.92 (m, 2H), 2.48-2.40 (m, 2H), 2.32-2.13 (m, 9H), 1.96 (q, J=7.2 Hz, 2H), 1.38-1.30 (m, 2H), 0.91-0.86 (m, 6H); 13C NMR (CDCl3) δ 164.1, 158.9 (d, J=243.4 Hz), 146.5 (d, J=11.9 Hz), 136.1, 125.2 (d, J=3.0 Hz), 128.9, 116.2 (d, J=22.7 Hz), 109.0 (d, J=22.7 Hz), 105.2 (d, J=26.2 Hz), 67.8, 63.7, 56.5, 55.7, 54.6, 36.3, 29.3, 28.5, 23.3, 17.1, 13.9.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([OH:17])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1C2N=NNC=2C=CC=1.[NH2:28][C@@H:29]([CH2:53][C:54]1[CH:59]=[CH:58][C:57]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[CH:56][CH:55]=1)[C:30]([N:32]([C@@H:44]([CH3:52])[CH:45]([O:49][CH2:50][CH3:51])[O:46][CH2:47][CH3:48])[CH2:33][C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1)=[O:31]>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([NH:28][C@@H:29]([CH2:53][C:54]1[CH:59]=[CH:58][C:57]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[CH:56][CH:55]=1)[C:30]([N:32]([C@@H:44]([CH3:52])[CH:45]([O:49][CH2:50][CH3:51])[O:46][CH2:47][CH3:48])[CH2:33][C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1)=[O:31])=[O:17])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CN(C)NC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To the solution of 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-3) 182 mg (0.77 mmol), hydroxybenzotriazole 104 mg (0.77 mmol) and 1-ethyl-3-(3-s dimethylaminopropyl)carbodiimide 148 mg (0.77 mmol) in dichloromethane 3 ml, a solution of (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-2) 260 mg (0.51 mmol) and 4-dimethylaminopyridine 31 mg (0.26 mmol) in dichloromethane 3 ml was added and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate 50 ml and washed with saturated sodium bicarbonate 50 ml, water 50 ml and brine 50 ml. The organic phase was dried with magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified on Buch silica gel column chromatography (chloroform:methanol=95:5) to obtain the title compound 333 mg (90%).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([OH:11])(=[O:10])[CH:8]=[CH2:9].[C:12](=[O:21])([O:18][CH2:19]Cl)[O:13][CH2:14][CH2:15][CH2:16][CH3:17].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C>[C:12](=[O:21])([O:18][CH2:19][O:10][C:7](=[O:11])[CH:8]=[CH2:9])[O:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCOC(=O)OCCl
Reactant: C=CC(=O)O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CC(=O)OCOC(=O)OCCCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.2 %

Procedure:
Potassium tert. butoxide (5.84 g, 0.052 mol ) was added to a solution of acrylic acid (4.47 g, 0.045 mol) in DMF (220 ml). Butyl chloromethyl carbonate (Example 1i, 6.5 g, 0.052 mol) in DMF (150 ml) was added to the resulting suspension. 18-crown-6 (0.6 g) was then added and the reaction mixture was left with stirring at room temperature for 2 days. The reaction mixture was filtered and the solvent was removed under reduced pressure. The residue was dissolved in chloroform (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (50 ml) and water (50 ml). The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. Flash chromatography gave 4.57 g of the title product.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([N:11]2[CH2:10][CH2:9][N:8]=[C:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:14][CH:15]=1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Reactant: COc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(N2CCN=C2c2ccccc2)cc1
Yield: 25 %

Procedure:
A mixture of 28.8 parts of 2-phenyl-1H-imidazole, 37.4 parts of 1-bromo-4-methoxybenzene, 20 of potassium carbonate and 180 parts of N,N-dimethylacetamide is stirred for one week at reflux temperature. The reaction mixture is cooled, poured onto water and the product is extracted twice with 2,2'-oxybispropane. The combined extracts are dried, filtered and evaporated, yielding 10 parts (25%) of 1-(4-methoxyphenyl)-2-phenyl-4H-imidazole as a residue.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[N+:10]([C:13]1[CH:14]=[C:15]([C:19]2[C:23](C#N)=[C:22]([N:26]=[CH:27][N:28]([CH3:30])C)[NH:21][N:20]=2)[CH:16]=[CH:17][CH:18]=1)([O-:12])=[O:11]>CO>[Cl:2][C:3]1[CH:4]=[C:5]([NH:6][C:30]2[N:28]=[CH:27][N:26]=[C:22]3[NH:21][N:20]=[C:19]([C:15]4[CH:16]=[CH:17][CH:18]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=4)[C:23]=23)[CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)C=Nc1[nH]nc(-c2cccc([N+](=O)[O-])c2)c1C#N
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Solvent: CO
Product: O=[N+]([O-])c1cccc(-c2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1

Procedure:
With the exclusion of air, 172.2 mg (1.05 mmol) of 3-chloro-aniline hydrochloride (see Step 14.4) are added to 199 mg (0.70 mmol) of N'-[3-(3-nitro-phenyl)-4-cyano-1H-pyrazol-5-yl]-N,N-dimethylformamidine in 2 ml of methanol and the reaction mixture is boiled under reflux for 19 hours. Cooling, filtering and washing with isopropanol and hexane yield 4-(3-chloro-phenylamino)-3-(3-nitro-phenyl)-1H-pyrazolo[3,4-d]pyrimidine; TLC: Rt=0.55 (methylene chloride:methanol=10:1); HPLC: TRet (Grad20-100)=14.2; 1H-NMR: (DMSO-d6) 9.05 (s, HN), 8.54 (s, 2H), 8.32 (dd, J=8, 2, 1H), 8.22 (d, J=8, 1H), 7.8 (m, 2H), 7.49 (d, J=8, 1H), 7.33 (t, J=8, 1H), 7.10 (dd, J=8, 2, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[C:11]2[S:13][CH:14]=[CH:15][C:10]2=[CH:9][C:8]=1[CH:16]([NH2:18])[CH3:17].Cl[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[NH:22][CH:23]=[N:24]2.C(N(C(C)C)CC)(C)C>C(O)CCC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[C:11]2[S:13][CH:14]=[CH:15][C:10]2=[CH:9][C:8]=1[CH:16]([NH:18][C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][NH:24]2)[CH3:17]
Reactant: Clc1ncnc2nc[nH]c12
Reactant: CC(N)c1cc2ccsc2nc1-c1ccccn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1cc2ccsc2nc1-c1ccccn1
Temperature: 110 °C

Procedure:
To a reaction flask containing 1-(6-(pyridin-2-yl)thieno[2,3-b]pyridin-5-yl)ethanamine (134 mg, 0.525 mmol), 6-chloropurine (97 mg, 0.63 mmol, 1.2 eq) and diisopropylethylamine (137 μL, 0.79 mmol, 1.5 eq) was added 5 mL of n-butanol. The reaction was heated to 110° C. for 24 h, then cooled to rt and concentrated in vacuo. The residue was dissolved in ethyl acetate (˜50 mL) with heat and sonication, then washed with 5 mL water and 5 mL brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by column chromatography using 0-80% gradient of (90:9:1 DCM:MeOH:NH4OH) in dichloromethane afforded racemic N-(1-(6-(pyridin-2-yl)thieno[2,3-b]pyridin-5-yl)ethyl)-9H-purin-6-amine. The room temperature NMR spectrum in CDCl3 exists as a roughly 3:1 mixture of isomers. 1H NMR (400 MHz, CDCl3) δ 8.80 (br d, J=4.3 Hz, 0.75 H), 8.73 (br d, J=3.1 Hz, 0.25 H), 8.55 (s, 0.25 H), 8.36-8.26 (series of m, 1.75 H), 8.15-8.03 (series of m, 1.5 H), 7.93 (br s, 0.75 H), 7.88 (m, 1.4 H), 7.56 (m, 0.5 H), 7.55 (d, J=5.9 Hz, 0.75 H), 7.37 (dd, J=6.6, 5.1 Hz, 0.75 H), 7.26 (d, J=5.9 Hz, 0.75 H), 7.20 (d, J=5.9 Hz, 0.25 H), 6.65 (m, 0.25 H), 6.35 (m, 0.25 H), 6.15 (br s, 0.75 H), 1.55 (d, J=7.0 Hz, 2.25 H), 1.35 (d, J=6.3 Hz, 0.75 H) ppm. LC/MS (M+1, found=374.0). Chiral SFC separation of the racemate afforded the individual enantiomers, (S)—N-(1-(6-(pyridin-2-yl)thieno[2,3-b]pyridin-5-yl)ethyl)-9H-purin-6-amine and (R)—N-(1-(6-(pyridin-2-yl)thieno[2,3-b]pyridin-5-yl)ethyl)-9H-purin-6-amine.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:13].[N:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]>ClCCl>[OH:22][N:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:12](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:13]
Reactant: CCOC(=O)/C=C/C=O
Reactant: O=Nc1ccccc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)/C=C/C(=O)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DBU (7.5 mg, 0.05 mmol) was added under argon to a solution of (E)-ethyl 3-formylacrylate (128 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (18.2 mg, 0.05 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([OH:28])=[O:27])=[C:24]([CH:29]([OH:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[N:23]=[C:22]2[CH2:35][CH2:36][CH3:37])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:39]1[C:43](=[O:44])[CH2:42][CH2:41][C:40]1=[O:45]>>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([O:28][N:39]3[C:43](=[O:44])[CH2:42][CH2:41][C:40]3=[O:45])=[O:27])=[C:24]([CH:29]([OH:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[N:23]=[C:22]2[CH2:35][CH2:36][CH3:37])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1nc(C(O)C(C)(C)C)c(C(=O)O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1O
Product: CCCc1nc(C(O)C(C)(C)C)c(C(=O)ON2C(=O)CCC2=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 89.8 %

Procedure:
Following a procedure similar to that described in Example 52(a), but using 300 mg of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-4-(1-hydroxy-2,2-dimethylpropyl)-2-propylimidazole-5-carboxylic acid [prepared as described in step (e) above], 110 mg of N-hydroxysuccinimide and 130 mg of N,N-dicyclohexylcarbodiimide, 321 mg of the title compound were obtained as an amorphous solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[Cl:10].[C:11]([O-])(=[O:13])[CH3:12].[Na+].O.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[C:11]([NH:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[Cl:10])(=[O:13])[CH3:12]
Reactant: Nc1ccc(O)cc1Cl
Reactant: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(O)cc1Cl
Yield: 84.2 %

Procedure:
Part E. A solution of 4-amino-3-chlorophenol hydrochloride (18.6 g, 103 mmol) and sodium acetate (18.6 g, 227 mmol) in glacial acetic acid (200 mL) was heated to gentle reflux for 12 hours, then cooled and poured into 4 volumes water. This was neutralized with portionwise addition of sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate (2×500 mL). The extracts were washed with brine, combined, dried over magnesium sulfate, filtered and evaporated. The resulting solid was triturated with warm ether; filtration and vacuum drying gave 4-acetamido-3-chlorophenol (16.1 g, 86.7 mmol, 84%). m.p. 128-129° C. TLC RF 0.14 (50:50 ethyl acetate-hexane). 1H NMR (300 MHz, 4:1 CDCl3.CD3OD): d 7.66 (1H, d, J=8.8 Hz), 6.88 (1H, d, J=1.7 m z Hz), 6.74 (1H, dd, J=8.8, 1.7 Hz), 2.19 (3H, s). MS(H2O-GC/MS): m/e 186 (100).
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].[N:12]1([C:18]([S-:20])=[S:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[NH2+]1CCCCC1.C(=S)=S>CO>[N:12]1([C:18]([S:20][CH:5]([CH2:4][N+:1]([O-:3])=[O:2])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[S:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: S=C([S-])N1CCCCC1
Reactant: O=[N+]([O-])C=Cc1ccccc1
Agent: C1CC[NH2+]CC1
Solvent: CO
Solvent: S=C=S
Product: O=[N+]([O-])CC(SC(=S)N1CCCCC1)c1ccccc1
Temperature: 8 °C

Procedure:
β-Nitrostyrene (14.9 grams, 0.10 mole) was added in portions to a stirred mixture of piperidinium 1-piperidinecarbodithioate (24.6 grams, 0.10 mole), and carbon disulfide (7.6 grams, 0.10 mole) in methanol (200 ml.). During the addition, the reaction temperature was 25° C.-29° C. After the addition of β-nitrostyrene, the reaction mixture was cooled to 8° C., and the precipitated product was filtered off, washed with water, and dried in air. The yield of product melting at 85° C.-87° C. (prior sintering) was 29.0 grams (93%). Repeated recrystallizations without heating from methylene chloride-hexane and methylene chloride-methanol solutions gave pure α-(nitromethyl)benzyl 1-piperidinecarbodithioate melting at 86° C.-90.5° C. (prior sintering).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].CC(C)([O-])C.[K+].CC1C=CC([C:19]2[C:20]([F:41])=[C:21]([CH:25]=[C:26]([Cl:40])[C:27]=2[S:28][C:29]2[CH:30]=[N:31][C:32]([O:36][CH:37]([CH3:39])[CH3:38])=[C:33]([Cl:35])[CH:34]=2)[C:22]([O-])=[O:23])=CC=1>C1COCC1>[Cl:40][C:26]1[C:27]([S:28][C:29]2[CH:30]=[N:31][C:32]([O:36][CH:37]([CH3:39])[CH3:38])=[C:33]([Cl:35])[CH:34]=2)=[CH:19][C:20]([F:41])=[C:21]([CH:25]=1)[C:22]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:23]
Reactant: CS(N)(=O)=O
Reactant: Cc1ccc(-c2c(F)c(C(=O)[O-])cc(Cl)c2Sc2cnc(OC(C)C)c(Cl)c2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)Oc1ncc(Sc2cc(F)c(C(=O)NS(C)(=O)=O)cc2Cl)cc1Cl
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 13.2 %

Procedure:
To a suspension of methanesulfonamide (93.4 mg, 0.98 mmol) in THF (2 mL) at room temperature was added potassium tert-butoxide (119 mg, 1.06 mmol) in one portion with stirring under nitrogen for 15 minutes. 4-Methylphenyl-5-chloro-4-[(5-chloro-6-isopropoxypyridin-3-yl)thio]-2-fluorobenzoate (Preparation 224, 352 mg, 0.75 mmol) was added as a solution in THF (2 mL). The mixture was then heated at 60° C. for 3 hours and then left at room temperature for 18 hours. The solvent was concentrated in vacuo and the residue was partitioned between EtOAc (10 mL) and water (5 mL). The organic layer was separated and then washed with 1M NaOH (5 mL), 2M HCl (5 mL), saturated aqueous brine (5 mL), dried over MgSO4 filtered and evaporated. The residue was triturated with acetone/heptane (1:9) to afford a white solid which was filtered and washed with heptane to yield the title compound (45 mg, 13%) as a white solid.
Reaction SMILES: [CH:1]([CH:14]1[CH2:16][O: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.S(O[CH2:22][CH2:23][NH2:24])(O)(=O)=O>C(O)(C)C.[OH-].[Na+]>[CH:1]([CH:14]1[O:15][CH2:22][CH2:23][NH:24][CH2:16]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NCCOS(=O)(=O)O
Reactant: c1ccc(C(c2ccccc2)C2CO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: c1ccc(C(c2ccccc2)C2CNCCO2)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 13.4 %

Procedure:
A solution of 2-benzhydryloxirane (631 mg) in isopropyl alcohol (4 ml) was added portionwise to a stirred solution of 2-aminoethyl hydrogensulfate (2.12 g) in a mixture of 20% sodium hydroxide solution (3 ml) at 50° C. The whole was stirred at 100° C. for 6 hours and thereto 40% sodium hydroxide solution (6 ml) was added at 100° C. After being stirred for 18 hours at the same temperature, the mixture was partitioned between ethyl acetate and 2N sodium hydroxide. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (20:1) to give 2-benzhydrylmorpholine (102 mg) as a colorless powder.