Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([CH2:18][NH:19][C:20]4[CH:21]=[CH:22][N:23]=[C:24]5[C:29]=4[N:28]=[CH:27][C:26]([C:30]4([OH:43])[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]4)=[CH:25]5)=[N:16][N:17]=3)[N:14]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.CC1C=C(C2C=CC3N(C(CN)=NN=3)N=2)SN=1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([CH2:18][NH:19][C:20]4[CH:21]=[CH:22][N:23]=[C:24]5[C:29]=4[N:28]=[CH:27][C:26]([C:30]4([OH:43])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[CH:25]5)=[N:16][N:17]=3)[N:14]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cnc3c(NCc4nnc5ccc(-c6cc(F)cc(F)c6)nn45)ccnc3c2)CC1
Agent: Cc1cc(-c2ccc3nnc(CN)n3n2)sn1
Product: OC1(c2cnc3c(NCc4nnc5ccc(-c6cc(F)cc(F)c6)nn45)ccnc3c2)CCNCC1

Procedure:
Deprotection of tert-butyl 4-(8-((6-(3,5-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamino)-1,5-naphthyridin-3-yl)-4-hydroxypiperidine-1-carboxylate using the method described for (6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanamine. M/Z=489.2 [M+H], calc 488.19 for C25H22F2N8O.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([F:28])[CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(O)C.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>[NH2:20][C:4]1[N:3]=[C:2]([C:24]2[CH:23]=[C:22]([F:21])[CH:27]=[C:26]([F:28])[CH:25]=2)[N:19]=[C:18]2[C:5]=1[N:6]=[CH:7][N:8]2[C@H:9]1[C@H:10]([OH:11])[C@H:12]([OH:13])[C@@H:14]([CH2:15][OH:16])[O:17]1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: OB(O)c1cc(F)cc(F)c1
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: Cc1ccccc1
Solvent: CCO
Product: Nc1nc(-c2cc(F)cc(F)c2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 8.7 %

Procedure:
A solution of 2-iodo adenosine (200 mg, 0.51 mmol), 3,5-difluorophenylboronic acid (150 mg, 0.95 mmol), cesium carbonate (364 mg, 1.12 mmol) and Pd(PPh3)4 (59 mg, 0.051 mmol) in toluene (1.2 mL) and ethanol (2.4 mL) was heated in a Biotage microwave (120° C., absorption high, pre-stirring 15 s) for 40 min. The solvents were then removed in vacuo and the residue dissolved in EtOAc (20 mL) and washed with sat. aq. NaHCO3 (20 mL×2) and brine (20 mL) and dried over MgSO4. Purification by reverse phase prep HPLC in 2 batches (Phenomenex Synergi, RP-Hydro 150×10 mm, 10%, 20 mL per min, gradient 5-100% acetonitrile in water over 10 min, product eluted in 35% acetonitrile) and (Phenomenex Synergi, RP-Hydro 150×10 mm, 10μ, 20 mL per min, gradient 5-100% acetonitrile in water over 10 min, product eluted in 40% acetonitrile), combination of the purer fractions from both columns, concentration in vacuo to ˜20 mL and filtration of the resulting white precipitate gave (2R,3R,4S,5R)-2-{6-amino-2-(3,5-difluorophenyl)-9H-purin-9-yl}-5-(hydroxymethyl)tetrahydrofuran-3,4-diol 10 as a white solid (16.8 mg, 9%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([OH:14])=O.[CH3:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH2:21][CH2:20][CH2:19]2>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([N:22]1[C:23]2[C:18](=[CH:17][C:16]([CH3:15])=[CH:25][CH:24]=2)[CH2:19][CH2:20][CH2:21]1)=[O:14]
Reactant: Cc1ccc2c(c1)CCCN2
Reactant: O=C(O)CSc1nc2ccccc2s1
Product: Cc1ccc2c(c1)CCCN2C(=O)CSc1nc2ccccc2s1
Yield: 85 %

Procedure:
The title compound was synthesized according to General Procedure B using 2-(benzo[d]thiazol-2-ylthio)acetic acid and 6-methyl-1,2,3,4-tetrahydroquinoline to yield 38 (450.5 mg, 85%): MS (APCI): m/z 355 [M+H]+. Anal. Calcd. for C19H18N2OS2: C, 64.39; H, 5.12; N, 7.90. Found: C, 64.55; H, 5.01; N, 7.88.
Reaction SMILES: Cl[C:2]1N=C2C(N=CN2C2CC(N3C=C(CC)N=N3)C(O)C2O)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)[N:3]=1.FC(F)(F)C(O)=O.[C:47]1([CH:53]([C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=2)[CH2:54][NH:55][C:56]2[N:64]=[C:63](NCCN3CCCCC3)[N:62]=[C:61]3[C:57]=2[N:58]=[CH:59][N:60]3[C@@H:74]2[CH2:78][C@H:77]([N:79]3C=[C:82]([CH2:84]O)[CH:81]=[N:80]3)[C@@H:76]([OH:86])[C@H:75]2[OH:87])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.[C:94]([O:98][C:99](=[O:106])[NH:100][C@@H:101]1[CH2:105][CH2:104][NH:103][CH2:102]1)([CH3:97])([CH3:96])[CH3:95]>>[C:94]([O:98][C:99](=[O:106])[NH:100][C@@H:101]1[CH2:105][CH2:104][N:103]([C:63]2[N:62]=[C:61]3[C:57]([N:58]=[CH:59][N:60]3[C@@H:74]3[CH2:78][C@H:77]([N:79]4[N:80]=[C:81]([CH2:82][CH3:84])[CH:2]=[N:3]4)[C@@H:76]([OH:86])[C@H:75]3[OH:87])=[C:56]([NH:55][CH2:54][CH:53]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:88]3[CH:89]=[CH:90][CH:91]=[CH:92][CH:93]=3)[N:64]=2)[CH2:102]1)([CH3:97])([CH3:95])[CH3:96]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: CCc1cn(C2CC(n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)C(O)C2O)nn1
Reactant: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1
Solvent: O=C(O)C(F)(F)F
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)OC(C)(C)C)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from 3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-ethyl-[1,2,3]triazol-1-yl)-cyclopentane-1,2-diol (Intermediate BA9) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoroacetate (Example 46) by replacing trans-1,4-diaminocyclohexane with (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:33])[C:13]2[O:19][C:18]3[C:20]([Cl:29])=[CH:21][C:22]([NH:24][C:25](=[O:28])[CH2:26]Cl)=[CH:23][C:17]=3[CH2:16][S:15](=[O:31])(=[O:30])[C:14]=2[CH:32]=1)=[O:9]>CN(C=O)C>[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:33])[C:13]2[O:19][C:18]3[C:20]([Cl:29])=[CH:21][C:22]([NH:24][C:25](=[O:28])[CH2:26][N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)=[CH:23][C:17]=3[CH2:16][S:15](=[O:31])(=[O:30])[C:14]=2[CH:32]=1)=[O:9]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CCl)cc(Cl)c1O2
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)Cn3ccnc3)cc(Cl)c1O2
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
Imidazole (0.215 g, 3.16 mmol) was added to a solution of Example 133 (0.7 g, 1.58 mmol) in DMF (15 mL) and the reaction mixture was stirred at 120° C. for 2.5 h. It was concentrated, treated with water and the solid that precipitated was filtered, washed with water and purified using flash chromatography (silica gel, 4% methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.4 g, (53.33%); 1H NMR (DMSO-d6): δ 2.66 (s, 3H, CH3), 3.9 (s, 3H, OCH3), 4.97 (s, 2H, CH2), 5.4 (s, 2H, CH2), 6.9 (s, 1H, Ar), 7.2 (s, 1H, Ar), 7.64 (s, 1H, Ar), 7.7 (d, 1H, Ar), 7.9 (d, 1H, Ar), 8.12 (s, 1H, Ar), 8.2 (s, 1H, Ar), 10.72 (bs, 1H, NH); MS: m/e (ES+) 476 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].CCN(CC)CC.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:16]1([S:22]([NH:5][C:4]2[CH:3]=[C:2]([I:1])[CH:8]=[CH:7][CH:6]=2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cccc(I)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1cccc(I)c1)c1ccccc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
To a solution of 3iodoaniline (5 g, 22.8 mmol), in CH2Cl2 (100 mL), were added at room temperature Et3N (6.97 mL) followed by benzenesulfonyl chloride (5.84 mL). The mixture was stirred 4 h then a white precipitate was formed. A saturated aqueous solution of NaHCO3 was added and the phases were separated. The aqueous layer was extracted several times with CH2Cl2 and the combined extracts were dried over (MgSO4) then evaporated. The crude mixture was dissolved in MeOH (100 mL) and NaOMe (6 g), was added and the mixture was heated 1 h at 60° C. The solution became clear with time and HCl (1N) was added. The solvent was evaporated under reduced pressure then the aqueous phase was extracted several times with CH2Cl2. The combined organic extracts were dried over (MgSO4) and evaporated. The crude material was purified by flash chromatography using (100% CH2Cl2) as solvent yielding the title compound 21 (7.68g, 94%) as yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][OH:27]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][OH:27])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: OCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 63.9 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (10.0 g, 45 mmol), K2CO3 (10.0 g), 3-bromo-1-propanol (7.3 g, 46 mmol) and acetonitrile (200 ml) was refluxed for 3 hours. The reaction was poured into H2 and 7.1 g of a beige solid was collected. The filtrate was extracted with dichloromethane, and after concentration an additional 6.7 g of crude solid was harvested. The solids were combined and triturated with refluxing ethyl acetate to afford 8.0 g of 6-fluoro-3-[1-(3-hydroxypropyl)-4-piperidinyl]-1,2-benzisoxazole as an off-white solid. A sample (4.0 g) was recrystallized from ethanol-water (with charcoal treatment) to yield 2.4 g (40%) of the alcohol as a white solid, m.p.=140-142° C.
Reaction SMILES: [CH2:1]([CH:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:39][N:40]([CH:42]([CH2:46][CH3:47])C(O)=O)[CH3:41].C(N(C(C)C)CC)(C)C.[CH3:57][OH:58]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14]/[CH:13]=[CH:12]\[CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH:19]([O:20][C:57](=[O:58])[CH2:47][CH2:46][CH2:42][N:40]([CH3:39])[CH3:41])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCC(C(=O)O)N(C)C
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(O)CCCCCCCC/C=C\C/C=C\CCCCC
Reactant: CO
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(CCCCCCCC/C=C\C/C=C\CCCCC)OC(=O)CCCN(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91 %

Procedure:
The dilinoleyl methanol 6 (144 g, 272 mmol) was dissolved in 1 L of dichloromethane and to it the hydrochloride salt of dimethylaminobutyric acid 7 (55 g, 328 mmol) was added followed by diisopropylethylamine (70 mL) and DMAP (4 g). After stirring for 5 min. at ambient temperature, MC1 (80 g, 417 mmol) was added and the reaction mixture was stirred at room temperature overnight after which the TLC (silica gel, 5% MeOH in CH2Cl2) analysis showed complete disappearance of the starting alcohol. The reaction mixture was diluted with CH2Cl2 (500 mL) and washed with saturated NaHCO3 (400 mL), water (400 mL) and brine (500 mL). The combined organic layers were dried over anhyd. Na2SO4 and solvents were removed in vacuo. The crude product (180 g) thus obtained was purified by Flash column chromatography [2.5 Kg silica gel, Using the following eluents i) column packed with 6 L of 0.1% NEt3 in DCM; after loading ii) 4 L of 0.1% NEt3 in DCM; iii) 16 L of 2% MeOH—98% of 0.1% NEt3 in DCM; iv) 4 L of 2.5% MeOH—97.5% of 0.1% NEt3 in DCM; v) 12 L of 3% MeOH—97% of 0.1% NEt3 in DCM] to isolate the pure product 8 (MC3, 159 g, 91%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 5.46-5.23 (m, 8H), 4.93-4.77 (m, 1H), 2.83-2.66 (m, 4H), 2.37-2.22 (m, 4H), 2.20 (s, 6H), 2.10-1.96 (m, 9H), 1.85-1.69 (m, 2H), 1.49 (d, J=5.4, 4H), 1.39-1.15 (m, 39H), 0.95-0.75 (m, 6H). 13C NMR (101 MHz, CDCl3): δ 173.56, 130.38, 130.33, 128.17, 128.14, 7754, 77.22, 76.90, 74.44, 59.17, 45.64, 34.36, 32.69, 31.73, 29.87, 29.76, 29.74, 29.70, 29.56, 29.50, 27.44, 27.41, 25.84, 25.55, 23.38, 22.78, 14.27. EI-MS (+ve): MW calc. for C43H79NO2 (M+H)+: 642.6. found: 642.6.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.[CH2:36]([NH:38][CH3:39])[CH3:37].O>C1COCC1>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:26]2[S:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=4)[C:7]([C:8]#[N:9])=[C:2]([N:38]([CH2:36][CH3:37])[CH3:39])[N:3]=3)[N:25]=2)=[CH:34][CH:33]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: CCNC
Solvent: O
Solvent: C1CCOC1
Product: CCN(C)c1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N

Procedure:
At RT, 60 mg (0.11 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 0.019 ml (0.22 mmol) of N-ethylmethylamine were stirred in 1.5 ml of THF for 30 min. About 15 ml of water were added to the reaction mixture, and the aqueous phase was extracted 3× with ethyl acetate. The combined organic phases were washed once with sodium chloride solution, dried over sodium sulfate, concentrated by evaporation and dried under high vacuum. This gave 63 mg (99% of theory) of the desired target compound.
Reaction SMILES: C([O:4][CH:5]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:21]=1)[CH2:6][NH:7][C:8]1[N:12]([CH3:13])[N:11]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[N:9]=1)(=[O:3])C.[OH-].[K+]>C(O)C>[OH2:3].[OH:4][CH:5]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[CH:21]=1)[CH2:6][NH:7][C:8]1[N:12]([CH3:13])[N:11]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[N:9]=1.[OH:4][CH:5]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[CH:21]=1)[CH2:6][NH:7][C:8]1[N:12]([CH3:13])[N:11]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[N:9]=1
Reactant: CC(=O)Nc1nc(NCC(COc2cccc(CN3CCCCC3)c2)OC(C)=O)n(C)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)Nc1nc(NCC(O)COc2cccc(CN3CCCCC3)c2)n(C)n1
Product: O
Yield: 84.4 %

Procedure:
A solution of 1-[[3-(acetylamino)-1-methyl-1H-1,2,4-triazol-5-yl]amino]-3-[3-(1-piperidinylmethyl)phenoxy]-2-propanol acetate (ester) (0.32 g) and 0.9M aqueous potassium hydroxide (1.0 ml) in ethanol (25 ml) was stirred for 0.5 h at 23°. The ethanol was evaporated, and the residue was suspended in sodium carbonate solution. This solution was extracted with methyl acetate. The extract was dried, and evaporated to give a gum, which was chromatographed using system A to give the title compound (0.25 g) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C([Li])CCC.CN(C)[C:24](=[O:26])[CH3:25].Cl>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][C:9]([C:24](=[O:26])[CH3:25])=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Reactant: CC(=O)N(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine 4, Example 2) (1.0 eq) dissolved in THF (0.1M) at −78° C. was added a solution of n-butyllithium (1.3 eq, 1.6M in hexanes) following General Procedure D. The reaction mixture was stirred at −40° C. for 30 minutes. N,N-dimethylacetamide (4.0 eq) was added and reaction mixture was allowed to slowly warm up to 0° C. and stirred for 2 hours. Reaction mixture was poured in a cold solution of 0.25M HCl, and extracted with dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated. The crude reaction mixture was purified by flash chromatography to yield 1-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)ethanone.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][N:17]3[C:21]=2[CH2:20][CH2:19][CH2:18]3)=[CH:10][CH:9]=1.NN.[OH-:30].[K+]>C1COCC1.O.C(O)COCCO>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[C:16]([CH2:2][C:1]([OH:5])=[O:30])[N:17]3[C:21]=2[CH2:20][CH2:19][CH2:18]3)=[CH:12][CH:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: [OH-]
Reactant: Clc1ccc(-c2c(-c3ccccc3)cn3c2CCC3)cc1
Agent: NN
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: OCCOCCO
Product: O=C(O)Cc1c(-c2ccccc2)c(-c2ccc(Cl)cc2)c2n1CCC2
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
Oxalyl dichloride (5.6 g, 0.044 mol) is added dropwise at 0-10° C. to an ice-cold solution of 7-(4-chlorophenyl)-6-phenyl-2,3-dihydro-1H-pyrrolizine (9.2 g, 0.031 mol) in THF (100 ml). After addition is complete, the mixture is stirred for 15 min and the excess of acid chloride is then cautiously decomposed (gas and foam formation!) with ice water (12 ml). Hydrazine (18 ml, 80%, about 0.3 mol) is added dropwise, the mixture is stirred for 30 min and diethylene glycol (36 ml) is poured in. THF and water are distilled off under atmospheric pressure at a bath temperature of 100-110° C. (foam formation at 105° C.!). The mixture is cooled to 60° C. and potassium hydroxide (15.7 g of KOH 85%, 0.238 mol) is added in portions and the temperature in the bottom is increased to 140° C. (foam formation!), and water, hydrazine and residual solvents are distilled off. This temperature is maintained in the bottom for 1 h and the mixture is allowed to cool. The mixture cooled to 60° C. is treated with water (200 ml) and acidified to pH 2-3 with conc. HCl in an ice bath (temp. <10° C.). The depositing carboxylic acid is extracted with ethyl acetate (300 ml), and the EA extract is washed with water until neutral, dried using Na2SO4 sicc. and concentrated in the presence of heat (45° C.) until the start of crystallization and placed in the cold. The crystal mass deposited at 5° C. is filtered off with suction and washed with cold ethyl acetate and dried.
Reaction SMILES: C(OC([NH:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:26]2[CH:27]=[CH:28][C:29]([O:40]S(C(F)(F)F)(=O)=O)=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[CH:31]=2)([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:10]=1)=O)(C)(C)C.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>ClCCl>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[NH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:26]2[CH:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[C:29]([OH:40])=[CH:28][CH:27]=2)([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[N:10]=1
Reactant: COc1ccc(C2(c3ccc(OS(=O)(=O)C(F)(F)F)c(-c4cccc(OC)c4)c3)N=C(NC(=O)OC(C)(C)C)c3ccccc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2(c3ccc(O)c(-c4cccc(OC)c4)c3)N=C(N)c3ccccc32)cc1
Reaction time: 1 h

Procedure:
To [3-(6-hydroxy-3′-methoxy-biphenyl-3-yl)-3-(4-methoxy-phenyl)-3H-isoindol-1-yl]-carbamic acid tert-butyl ester (Scheme #2, F) (10.0 mg, 18.6 umol) was added trifluoroacetic acid in dichloromethane (10%, 1-2 mL) and reaction stirred 60 minutes. The solvents were removed under reduced pressure and the resulting gum put under high vacuum at 50° C. over night to give the title compound as a waxy solid (10.4 mg). 1H NMR (300 MHz, DMSO-d6) δ 8.26 (d, J=7.8 Hz, 1 H), 7.85-7.67 (m, 3 H), 7.32-7.18 (m, 4 H), 7.03-6.85 (m, 8 H), 3.74 (d, J=2.7 Hz, 6 H); MS (APCI+) m/z 437 [M+1]+; tR=2.14 min.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:19][N:18]=1.[Si:28]([O:35][C:36]1([CH2:40][CH:41]=[O:42])[CH2:39][CH2:38][CH2:37]1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>C1COCC1.O>[Si:28]([O:35][C:36]1([CH2:40][CH:41]([C:22]2[C:17]([F:16])=[N:18][CH:19]=[C:20]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:21]=2)[OH:42])[CH2:37][CH2:38][CH2:39]1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)OC1(CC=O)CCC1
Reactant: CC(C)(C)Cc1ccc(F)nc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)Cc1cnc(F)c(C(O)CC2(O[Si](C)(C)C(C)(C)C)CCC2)c1
Temperature: -78 °C
Reaction time: 0.05 h

Procedure:
2,2,6,6-tetramethylpiperidine (13.0 ml, 76.5 mmol) was dissolved in 500 ml THF and cooled to −78° C. Butyllithium (26.8 ml, 67.0 mmol) was added over the period of 10 min and the reaction was allowed to warm up to 0° C. and kept there for 3 min. The mixture was cooled back to −78° C. and a solution of 2-fluoro-5-neopentylpyridine (8.000 g, 47.8 mmol) in 10 ml THF was added over the period of 30 min. The mixture was stirred for 20 min at the same temperature and a solution of 2-(1-(tert-butyldimethylsilyloxy)cyclobutyl) acetaldehyde (19.7 g, 86.1 mmol) in 25 ml THF was added over the period of 20 min. The reaction was stirred for 15 min at the same temperature and hydrolyzed with 200 ml of H2O. The mixture was allowed to warm up to room temp and extracted 2 times with 1 L EtOAc (each). The combined organic extracts were dried over MgSO4 and evaporated. The crude material was used without further purification. MS found 396.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:18])[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:11].S(=O)(=O)(O)O.[OH-:24].[Na+].[C:26]1([CH3:32])C=CC=CC=1>C(Cl)Cl.C(O)CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:10]1([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[O:24][CH2:26][CH2:32][O:11]1)[CH3:18]
Reactant: [OH-]
Reactant: CC(C(=O)c1cccnc1)c1ccc(Cl)cc1Cl
Reactant: Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: OCCO
Solvent: ClCCl
Product: CC(c1ccc(Cl)cc1Cl)C1(c2cccnc2)OCCO1
Reaction time: 15 h

Procedure:
2 g of 2-(2,4-dichlorophenyl)-1-(3-pyridyl)-1-propanone are dissolved in 80 ml of toluene. After the addition of 1.05 g of concentrated sulfuric acid and 1.02 g of ethylene glycol, the mixture is heated at reflux. The water which is formed in the course of the reaction is separated using a water separator. After a reaction period of 4, 7 and 12 hours, an additional 1.5 g of ethylene glycol are added each time. After 15 hours, the mixture is cooled, the toluene phase is discarded, the lower viscous phase is diluted with 50 ml of methylene chloride and subsequently poured into 37.5 ml of 1N sodium hydroxide. Then it is back-extracted with methylene chloride and the organic phase is washed and dried over anhydrous sodium sulfate. After removal of the solvent, 3-[2-(2,4-dichloro-α-methyl-benzyl)-1,3-dioxolan-2-yl]pyridine is obtained as a brownish, highly viscous oil.