Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH2:11][CH2:10][C:9]=2[C:13]2[CH:18]=[CH:17][C:16](SC)=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.O[O:22][S:23]([O-:25])=O.[K+].OS([O-])(=O)=O.[K+].[CH3:33]O>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][CH2:11][CH2:10][C:9]=2[C:13]2[CH:14]=[CH:15][C:16]([S:23]([CH3:33])(=[O:25])=[O:22])=[CH:17][CH:18]=2)=[CH:6][CH:7]=1
Reactant: O=S([O-])OO
Reactant: CSc1ccc(C2=C(c3ccc(F)cc3)CCC2)cc1
Reactant: CO
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1ccc(C2=C(c3ccc(F)cc3)CCC2)cc1
Reaction time: 4 h
Yield: 54 %

Procedure:
A solution of 1.5 g (5. mmol) of 1-[2-(4-fluorophenyl) cyclopenten-1-yl]-4-(methylthio)benzene (Step 3) in 46 mL of methanol/thf (1:1) was slowly treated with 5.2 g (8.4 mmol) of Oxone® [2 KHSO5.KHSO4.K2SO4 ] in 23 mL of water. After stirring for 4 h, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and washed with water and brine, dried (MgSO4), and reconcentrated. Recrystallization from ethyl acetate/hexane provided 960 mg (54%) of 1-[2-(4-fluorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene (41 in Synthetic Scheme X when R5 =SO2CH3, R10 =F, and R1, R2, R3, R4, R6, R7, R8, R9, R11, and R12 =H) as a colorless solid: mp 138°-139° C.; NMR (CDCl3) d 2.09 (m, J=7 Hz, 2H), 2.91 (t, J=7 Hz, 4H), 3.04 (s, 3H), 6.88-6.96 (m, 2H), 7.06-7.14 (m, 2H), 7.32 (d, J=8 Hz, 2H), 7.76 (d, J=8 Hz, 2H). MS (EI) m/e (rel intensity) 316 (100), 237 (41), 161 (13); HRMS. Calc'd for C18H17FO2S: 316.0933. Found: 316.0943. Anal. Calc'd for C18H17FO2S: C, 68.33; H, 5.42; F, 6.00; S, 10.13. Found: C, 68.08; H, 5.45; F, 6.42; S, 9.98.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][C:22]1[S:26][C:25]([C:27]#[N:28])=[C:24]([CH3:29])[CH:23]=1.[Br:30]C(Br)(Br)Br>O1CCCC1>[Br:30][CH2:21][C:22]1[S:26][C:25]([C:27]#[N:28])=[C:24]([CH3:29])[CH:23]=1
Reactant: Cc1cc(CO)sc1C#N
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(CBr)sc1C#N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
44 g (167 mmol) of triphenylphosphine were added to a solution of 24 g (152 mmol) of 5-hydroxymethyl-3-methylthiophene-2-carbonitrile in 180 ml of tetrahydrofuran. Then, a solution of 55 g (167 mmol) of tetrabromomethane in 100 ml of tetrahydrofuran was added. The mixture was stirred for 90 minutes at room temperature. The reaction mixture was concentrated on a rotary evaporator under a water pump vacuum, and the residue was purified by column chromatography (eluant hexane:ethyl acetate 8:2). This gave 34 g of the title compound which still contained a small amount of solvent. 1H NMR (270 MHz, DMSO-d6): δ=2.4 (s, 3H), 5.0 (s, 2H), 7.3 (s, 1H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].I[C:13]([F:56])([F:55])[C:14]([F:54])([F:53])[O:15][C:16]([F:52])([F:51])[C:17]([F:50])([F:49])[O:18][C:19]([F:48])([F:47])[C:20]([F:46])([F:45])[O:21][C:22]([F:44])([F:43])[C:23]([F:42])([F:41])[C:24]([F:40])([F:39])[C:25]([F:38])([F:37])[C:26]([F:36])([F:35])[O:27][C:28]([F:34])([F:33])[C:29]([F:32])([F:31])I.[C:57]([O:60][C:61](=O)[CH3:62])(=[O:59])[CH3:58]>[Cu].CCOCC>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:13]([F:56])([F:55])[C:14]([F:54])([F:53])[O:15][C:16]([F:52])([F:51])[C:17]([F:50])([F:49])[O:18][C:19]([F:48])([F:47])[C:20]([F:46])([F:45])[O:21][C:22]([F:44])([F:43])[C:23]([F:42])([F:41])[C:24]([F:40])([F:39])[C:25]([F:38])([F:37])[C:26]([F:36])([F:35])[O:27][C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[C:5]2[CH:10]=[CH:62][C:61]([O:60][C:57](=[O:59])[CH3:58])=[CH:7][CH:6]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(I)cc1
Reactant: FC(F)(I)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)I
Reactant: CC(=O)OC(C)=O
Agent: [Cu]
Solvent: CCOCC
Product: CC(=O)Oc1ccc(C(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)c2ccc(OC(C)=O)cc2)cc1

Procedure:
4-Iodophenyl acetate (7.86 g, 0.030 mole), 1,17-diiodoperfluoro-3,6,9,15-tetraoxaheptadecane (9.68 g, 0.010 mole), and copper bronze (5.08 g, 0.080 g atom) were stirred together under nitrogen at 113°-117° C for 48 hours. The cooled reaction mixture was added to 200 ml of ether. The cuprous salts and excess copper were filtered off and washed on the frit with ether. The ethereal solution was washed several times with water to remove the reaction solvent, dried over anhydrous magnesium sulfate, and reduced in volume under reduced pressure to yield a brown oil. The oil was refluxed with 10 ml of acetic anhydride for 20 minutes and the excess acetic anhydride then distilled off under reduced pressure. Distillation of the residue yielded 4.53 g of 1,17-bis (4-acetoxyphenyl)perfluoro-3,6,9,15-tetraoxaheptadecane, b.p. 184°-189° C/0.10 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:32]2[CH:37]=[CH:36][C:35]([C:38](O)=[O:39])=[CH:34][CH:33]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[C:10]1=[O:31].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[F:54][C:55]1([F:61])[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([N:58]3[CH2:59][CH2:60][C:55]([F:61])([F:54])[CH2:56][CH2:57]3)=[O:39])=[CH:34][CH:33]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:15][CH2:16][CH:17]([O:20][Si:21]([CH:25]([CH3:27])[CH3:26])([CH:28]([CH3:29])[CH3:30])[CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:19]2)[C:10]1=[O:31]
Reactant: FC1(F)CCNCC1
Reactant: CC(C)[Si](OC1CCN(N2CCC(Cc3ccc(-c4ccc(C(=O)O)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3ccc(-c4ccc(C(=O)N5CCC(F)(F)CC5)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
Treat a solution of 3′-chloro-4′-[2-oxo-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid (0.2 g, 0.34 mmol) in CH2Cl2 (15 mL) with 1,1′-carbonyldiimidazole (0.11 g, 0.68 mmol) and stir for 1 hour at room temperature. Treat the reaction with 4,4-difluoropiperidine hydrochloride (0.08 g, 0.51 mmol) and diisopropylethylamine (0.07 g, 0.51 mmol) and stir for 12 hours at room temperature. Load the mixture on silica gel column, flash with 0% to 50% ethyl acetate in hexanes to afford 0.15 g (64%) of the title compound. MS (m/z): 688 (M+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.[NH2:13][C@H:14]([C:18]([NH:20][C@H:21]([C@@H:29]([OH:48])[C@H:30]([OH:47])[C@@H:31]([NH:39][C:40](=[O:46])[C@H:41]([CH:43]([CH3:45])[CH3:44])[NH2:42])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:19])[CH:15]([CH3:17])[CH3:16].N=[C:50]=[NH:51]>>[NH:51]1[C:50]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:13][C@H:14]([C:18]([NH:20][C@H:21]([C@@H:29]([OH:48])[C@H:30]([OH:47])[C@@H:31]([NH:39][C:40](=[O:46])[C@H:41]([CH:43]([CH3:44])[CH3:45])[NH:42][C:10]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:12])[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12]
Reactant: N=C=N
Reactant: CC(C)[C@H](N)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)C(C)C
Reactant: O=C(O)c1cc2ccccc2[nH]1
Product: CC(C)[C@H](NC(=O)c1cc2ccccc2[nH]1)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)c1cc2ccccc2[nH]1)C(C)C

Procedure:
Indole-2-carboxylic acid was coupled to the resultant compound of Example 173 using the carbodiimide coupling procedure of Example 55 to provide the desired compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[C:8]([NH:16][C:17](=[O:45])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:26]=[N:27][C:28]([O:34]CC5C=CC(OC)=CC=5)=[C:29]([O:31][CH2:32][CH3:33])[CH:30]=4)=[CH:21][C:20]=3[F:44])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=2)[CH:3]=[N:2]1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:54]>>[ClH:54].[NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[C:8]([NH:16][C:17](=[O:45])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH2:32][CH3:33])[C:28](=[O:34])[NH:27][CH:26]=4)=[CH:21][C:20]=3[F:44])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=2)[CH:3]=[N:2]1
Reactant: ClCCl
Reactant: CCOc1cc(-c2ccc(CC(=O)Nc3cc(-c4cn[nH]c4)cc(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(-c4cn[nH]c4)cc(C(F)(F)F)c3)c(F)c2)c[nH]c1=O
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.9 %

Procedure:
To a mixture of N-(3-(1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (50 mg, 0.081 mmol) in DCM (10 mL) was added TFA (1 mL, 12.98 mmol). The mixture was stirred at 25° C. for 2 h. The mixture was concentrated and NH4OH (0.5 mL) was added. Then the reaction residue was concentrated and purified by preparative HPLC (Column: ASB C18 150*25 mm; Mobile phase A: Water+0.1% HCl; Mobile phaseB: MeCN; Flowrate: 25 mL/min; Gradient Profile Description: 40-70 (B %)) to yield an off-white solid of N-(3-(1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide hydrochloride (6.95 mg, 0.013 mmol, 15.9% yield): 1H NMR (400 MHz, CD3OD) δ 8.16 (s, 2H), 8.06 (s, 1H), 7.82 (s, 1H), 7.62 (s, 1H), 7.48-7.42 (m, 1H), 7.41-7.34 (m, 3H), 7.33 (s, 1H), 4.15 (q, J=7.2 Hz, 2H), 3.84 (s, 2H), 1.46 (t, J=7.2 Hz, 3H). ES-LCMS m/z 501.2 (M+H). TLC (DCM/MeOH=10:1, Rf=0.2)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[C:26]([S:31][CH:32]([CH3:34])[CH3:33])=[N:27][CH:28]=[CH:29][CH:30]=1>>[F:1][C:2]1[CH:7]=[C:6]([C:25]2[C:26]([S:31][CH:32]([CH3:34])[CH3:33])=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: CC(C)Sc1ncccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: CC(C)Sc1ncccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 3-bromo-2-(isopropylthio)pyridine. MS (ESI): mass calcd. for C18H17FN4S, 340.12; m/z found, 341.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.62-8.57 (m, 1H), 8.49-8.43 (m, 1H), 8.12 (d, J=1.5, 1H), 8.04-7.93 (m, 1H), 7.45-7.39 (m, 1H), 7.34-7.30 (m, 1H), 7.29-7.22 (m, 1H), 7.11-7.03 (m, 1H), 4.69 (s, 2H), 4.17-4.00 (m, 1H), 1.37 (d, J=6.8, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([N:15]3[CH2:20][CH2:19][N:18](CC4C=CC=CC=4)[CH2:17][CH2:16]3)[C:8]=2[CH:7]=1)=[O:5])[CH3:2].[Cl:28]C(OC(Cl)C)=O>ClCCCl>[ClH:28].[N:15]1([C:14]2[C:8]3[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[S:10][C:9]=3[CH:11]=[CH:12][CH:13]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)c1cc2c(N3CCN(Cc4ccccc4)CC3)cccc2s1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: CCOC(=O)c1cc2c(N3CCNCC3)cccc2s1
Product: Cl
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
Dissolve ethyl-4-[4-(phenylmethyl)-1-piperazinyl]-benzo[b]thiophene-2-carboxylate (2.00 g, 5.26 mmol, prepared in example 1) in 1,2-dichloroethane (40 mL) under an atmosphere of nitrogen and cool the solution with an ice bath. Add 1-chloroethyl chloroformate (1.40 mL, 13.1 mmol) and warm the reaction to room temperature (20° C.). Stir for 30 minutes and then heat the reaction to reflux for 4.5 hours. After cooling, concentrate under vacuum, add ethanol (40 mL) to the residue, reflux for 1.5 hours under nitrogen and then stir at room temperature for 15 hours. Concentrate under vacuum and recrystallize the residue from warm ethanol (50 mL). Collect the product by suction filtration and wash with ether to provide the title compound (1.14 g) as a white solid, mp 238°-240° C.; 1H NMR (DMSO-d6) δ 9.43 (2H, bs), 8.13 (1H, s), 7.75 (1H, d, J=8.2 Hz), 7.49 (1H, t, J=7.9 Hz), 7.06 (1H, d, J=7.5 Hz), 4.37 (2H, q, J=7.1 Hz), 3.34 (8H, bs), 1.35 (3H, t, J=7.1 Hz); 13C NMR (DMSO-d6) δ 161.90, 148.81, 142.84, 132.69, 131.91, 128.35, 128.01, 117.91, 113.64, 61.50, 48.88, 43.01, 14.17; IR (KBr) 1711, 1281, 1246, 756 cm-1 ; EI/MS (70eV) 290(55%), 248(100%). IC50 =89 nM (5HT1ABinding Affinity) IC50 =47 nM (5HT1DBinding Affinity)
Reaction SMILES: C(O[C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([O:14]CC)=O)C.[NH2:18][CH2:19][CH2:20][OH:21]>>[OH:21][CH2:20][CH2:19][N:18]1[C:4](=[O:17])[C:5]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:11][C:12]1=[O:14]
Reactant: NCCO
Reactant: CCOC(=O)Nc1ccccc1C(=O)OCC
Product: O=c1[nH]c2ccccc2c(=O)n1CCO
Temperature: 25 °C
Yield: 71.3 %

Procedure:
A mixture of 2-[(ethoxycarbonyl)amino]benzoic acid ethyl ester (65.75 g, 0.277 mol) and 2-aminoethanol (16.9 g, 0.277 mol) was refluxed for 2.5 days in 350 mL of xylenes. The reaction was cooled to room temperature and xylene was removed. Chloroform was added to the residue and a brown solid crystallized. The brown solid was filtered from the solution. The chloroform layer was extracted with water, dried (Na2SO4), filtered and the solvent was removed. The residue was placed in the freezer in isopropyl alcohol. The brown solid was triturated with isopropyl alcohol. Both produced a crystalline white solid which was dried in vacuo overnight at 80° C. This gave a total of 40.70 g (71.3% yield) of white crystalline solid, mp 250°-252° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH:11]2[CH2:20][CH2:19]C3(OCCO3)[CH2:13][CH2:12]2)[CH:3]=1.OC1N2N=CC=C2N=C(C2CC[N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])CC2)C=1.O1C2(CCC(C3C=C(O)N4N=CC=C4N=3)CC2)OCC1>>[Cl:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH:11]2[CH2:12][CH2:13][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:19][CH2:20]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(O)n3nccc3n2)CC1
Reactant: Clc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Agent: Oc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Product: CC(C)(C)OC(=O)N1CCC(c2cc(Cl)n3nccc3n2)CC1

Procedure:
tert-Butyl 4-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate was synthesized in a manner similar to the synthesis of 7-chloro-5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidine, but with tert-butyl 4-(7-hydroxypyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate substituted for 5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidin-7-ol.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1[Br:22])(=[O:3])[CH3:2].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>N1C=CC=CC=1>[C:23]([O:21][C@@H:8]1[C@H:7]([Br:22])[C@@H:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[O:10][C@H:9]1[N:11]1[C:20]2[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=2[N:13]=[CH:12]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1Br
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](OC(=O)c2ccccc2)[C@@H]1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
After 1 g (2.7 mmols) of 5'-O-acetyl-3'-deoxy-3'-bromoadenosine was added to 10 ml of pyridine, 418 mg (1.1 eq.) of benzoyl chloride was added to the mixture. The mixture was stirred at room temperature for 2 hours and pyridine was distilled off under reduced pressure. The residue was added to 30 ml of water followed by extraction twice with 30 ml of chloroform. After the organic solvent was washed with water and then dried over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to give 1.18 g (yield, 92%) of 2'-O-benzoyl-5'-O-acetyl-3'-deoxy-3'-bromoadenosine.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([CH:13]([F:15])[F:14])[CH:10]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[N:8]=2)[CH:6]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[F:14][CH:13]([F:15])[C:11]1[CH:10]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([NH2:26])=[N:28][CH:29]=3)[N:3]=[CH:4]2)[N:12]=1
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(Br)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-difluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.7) (0.21 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.64 mmol) according to the general procedure VI. Obtained as a yellow solid (0.031 g, 7%). MS (ISP) 433.3 [(M+H)+]; mp 253.5° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2N=[C:21]([C:23]#[N:24])[C:20]3[N:25]=[N:26][N:27]([CH3:28])[C:19]=3[CH:18]=2)=[CH:13][C:12]=1[C:29]([F:32])([F:31])[F:30].[CH:33](N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:33]=[C:21]([C:23]#[N:24])[C:20]3[N:25]=[N:26][N:27]([CH3:28])[C:19]=3[CH:18]=2)=[CH:13][C:12]=1[C:29]([F:30])([F:32])[F:31])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(OCCCO)c(C(F)(F)F)c3)cc21
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nnc2c(C#N)cc(-c3ccc(OCCCOS(C)(=O)=O)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methanesulphonyl chloride (6.29 g) was added dropwise to a solution of 6-(4-(3-hydroxypropoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]-pyridine-4-carbonitrile (10.34 g) and diisopropylethylamine (22.7 ml) in DCM (300 ml) at 0° C. The mixture was stirred at room temperature for 2 hours. The DCM was removed under reduced pressure, MeOH and water were added to the residue and the solid was collected by filtration to give the expected product (11.56 g). 1H NMR (DMSO) δ: 8.96 (s, 1H), 8.49 (d, 1H), 8.46 (s, 1H), 7.51 (d, 1H), 4.46 (s, 3H), 4.39 (t, 2H), 4.34 (t, 2H), 3.18 (s, 3H), 2.21 (quin, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C(=O)([O-])[O-].[K+].[K+].CC1C=CC([C:26]2[C:27]([F:37])=[C:28]([CH:32]=[C:33]([Cl:36])[C:34]=2F)[C:29]([O-:31])=[O:30])=CC=1>CS(C)=O>[Cl:36][C:33]1[C:34]([O:12][C:4]2[CH:5]=[CH:6][C:7]([C:8]([F:10])([F:11])[F:9])=[C:2]([Cl:1])[CH:3]=2)=[CH:26][C:27]([F:37])=[C:28]([CH:32]=1)[C:29]([O:31][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:2][CH:3]=1)=[O:30]
Reactant: Oc1ccc(C(F)(F)F)c(Cl)c1
Reactant: Cc1ccc(-c2c(F)c(Cl)cc(C(=O)[O-])c2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc(OC(=O)c2cc(Cl)c(Oc3ccc(C(F)(F)F)c(Cl)c3)cc2F)cc1
Reaction time: 0.08 h
Yield: 92.7 %

Procedure:
To a solution of 3-chloro-4-(trifluoromethyl)phenol (Preparation 16, 100 mg, 0.470 mmol) in DMSO (1 mL) was added potassium carbonate (0.84 mg, 0.611 mmol) and the mixture stirred for 5 minutes. 4-methylphenyl-5-chloro-2,4-difluorobenzoate (Preparation 10, 0.133 mg, 0.470 mmol) was then added and the reaction stirred under nitrogen for 3 hours. The reaction was quenched by the addition of water (2 mL) and ethyl acetate (3 ml). The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo to afford a white solid that was purified using silica gel column chromatography eluting with ethyl acetate:heptane 3:97 to furnish the title compound (100 mg, 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:24])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]21.[CH:25](=O)[CH3:26].[C:28](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:29].[Na+]>CO.C(O)(=O)C>[Cl:1][C:2]1[C:3]([CH2:25][CH3:26])=[C:4]([CH2:28][CH3:29])[C:5]([NH2:24])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC=O
Reactant: Nc1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(Cl)cc1Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCc1c(CC)c(N)c2c(nc3n2CCCCN3c2ccc(Cl)cc2Cl)c1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 24 %

Procedure:
To a solution of 10-chloro-1-(2,4-dichlorophenyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazol-7-amine (29 mg, 0.075 mmol) in methanol (5.0 mL) and acetic acid (1.0 mL) was added acetaldehyde (0.05 mL, 0.84 mmol) at 0° C. The resultant mixture was stirred at 0° C. for 30 min. To the reaction mixture was added sodium triacetoxyborohydride (173 mg, 0.84 mmol) at 0° C. After stirring at room temperature for 5 h, the mixture was con concentrated in vacuo, diluted with water, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on a silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound (8 mg, 0.018 mmol, 24%) as a white amorphous.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]([OH:21])=O)=[CH:11]2)[C:4]=1[CH3:22].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(N(CC)CC)C.[CH:48]1([CH2:51][NH2:52])[CH2:50][CH2:49]1>C(Cl)Cl.O>[CH:48]1([CH2:51][NH:52][C:19]([C:12]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:18]3[N:10]([CH2:9][C:5]3[C:4]([CH3:22])=[C:3]([O:2][CH3:1])[N:8]=[CH:7][N:6]=3)[CH:11]=2)=[O:21])[CH2:50][CH2:49]1
Reactant: NCC1CC1
Reactant: COc1ncnc(Cn2cc(C(=O)O)c3ncccc32)c1C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ncnc(Cn2cc(C(=O)NCC3CC3)c3ncccc32)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
See FIG. 16(b). 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (200 mg, 0.67 mmol) was taken in DCM (10 mL). Added 1-Propanephosphonic acid cyclic anhydride (427 mg, 1.34 mmol) followed by the addition of Triethyl amine (339 mg, 3.35 mmol) and cyclopropylmethanamine (95 mg, 1.34 mmol). The reaction mass was stirred at RT for overnight. After the completion of the reaction added water and extracted with DCM. The organic layer was washed with water and brine solution. The organic layer was separated, dried over sodium sulphate. Evaporated the organic layer to get the residue, which was purified by column chromatography to get the pure compound. Yield-74%. ES+MS m/z: 352.38 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.02 (q, J=4.58 Hz, 2 H ) 0.18-0.31 (m, 2 H ) 0.83 (t, J=6.88 Hz, 1 H ) 2.00 (s, 3 H ) 2.98-3.11 (m, 3 H ) 3.69 (s, 3 H ) 5.43 (s, 2 H ) 7.00 (dd, J=8.29, 4.71 Hz, 1 H ) 7.68 (dd, J=8.29, 1.13 Hz, 1 H ) 7.98 (s, 1 H ) 8.17 (s, 1 H) 8.24 (dd, J=4.71, 1.13 Hz, 1 H ) 8.55 (t, J=5.75 Hz, 1 H ).