Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.F[B-](F)(F)F.[O:18]=[N+:19]=[O:20].O>C(#N)C>[CH3:1][O:2][C:3]1[C:4]([N+:19]([O-:20])=[O:18])=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=[N+]=O
Reactant: COc1cccc(NC(C)=O)c1
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CC#N
Product: COc1cccc(NC(C)=O)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
N-(3-methoxyphenyl)acetamide (14.23 g, 0.086 mol) was dissolved in acetonitrile (200 mL) and cooled to 0° C. Solid nitronium tetrafluoroborate (14.79 g, 0.106 mol) was added in four portions. The temperature rose to about 5° C. during each addition and was allowed to cool down to 0°0 C. between additions. After the last addition of nitronium tetrafluoroborate, water (200 mL) was added to the reaction mixture and the mixture was concentrated under reduced pressure to give approximately 200 mL of a dark oil. The dark oil was dissolved in dichloromethane (200 mL) and washed with water (6×150 mL). The organic layer was concentrated under reduced pressure and dried to obtain 16.1 g of a dark red oil. The red oil was purified by flash chromatography (silica gel, 25% ethyl acetate/hexane) to give 4.53 g (27%) of the crude product. The crude product was triturated with 25% ethyl acetate/hexane to give 3.0 g (17%) of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[F:30][C:31]1([F:39])[CH2:34][N:33]([CH:35]2[CH2:38][NH:37][CH2:36]2)[CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:30][C:31]1([F:39])[CH2:34][N:33]([CH:35]2[CH2:38][N:37]([CH2:18][C:13]3[N:14]([CH3:17])[C:15]4[C:11]([N:12]=3)=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:9]=[C:8]([N:7]3[C:6]5[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=5[N:4]=[C:3]3[CH2:1][CH3:2])[N:16]=4)[CH2:36]2)[CH2:32]1
Reactant: FC1(F)CN(C2CNC2)C1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CC(F)(F)C4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 79.6 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.0725 g, 0.18 mmol), 3,3-difluoro-[1,3′]biazetidinyl (0.033 g, 0.22 mmol) and 4 Å molecular sieves (0.2 g) in DCE (5 mL). The reaction mixture was stirred for 7 h at room temperature. Sodium triacetoxyborohydride (0.079 g, 0.37 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:EtOAc, gradient 0:100 to 40:60) to give 562 as a yellow solid (0.075 g, 78%). LCMS (Method I): RT=2.66 min, [M+H]+ 524.2 1H NMR (400 MHz, DMSO-d6): δ 8.03-7.98 (m, 1 H), 7.65-7.60 (m, 1 H), 7.27-7.20 (m, 2 H), 4.50-3.96 (m, 4 H), 3.88 (s, 2 H), 3.86-3.67 (m, 7 H), 3.71-3.55 (m, 4 H), 3.48-3.39 (m, 1 H), 3.37-3.35 (m, 2 H), 3.26 (q, J=7.5 Hz, 2 H), 3.06 (dd, J=7.5, 5.3 Hz, 2 H), 1.33 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.[C:34]([OH:40])([C:36](F)(F)F)=[O:35].C(Cl)Cl>>[OH:3][C:2]([C:4]([F:7])([F:6])[F:5])=[O:1].[CH:29]([N:25]1[C:24]([C:18]2[S:19][C:20]3[CH2:21][CH2:22][O:23][C:14]4[CH:13]=[C:12]([CH:10]5[CH2:11][N:8]([CH2:36][C:34]([OH:40])=[O:35])[CH2:9]5)[CH:33]=[CH:32][C:15]=4[C:16]=3[N:17]=2)=[N:28][CH:27]=[N:26]1)([CH3:31])[CH3:30]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(=O)O)C3)ccc1-2

Procedure:
Following a similar procedure to 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 using {3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-acetic acid tert-butyl ester and TFA:DCM (1:2), {3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-acetic acid TFA salt was isolated as a white solid (75 mg, 90%). 1H NMR δ (ppm) (DMSO-d6): 8.35 (1H, d, J=8.20 Hz), 8.11 (1H, d, J=0.75 Hz), 7.29 (1H, d, J=8.33 Hz), 7.21 (1H, s), 5.85-5.77 (1H, m), 4.48-4.39 (2H, m), 4.41-4.35 (2H, m), 4.36-4.22 (3H, m), 3.48-3.42 (2H, m), 1.55 (6H, d, J=6.59 Hz) plus 2 protons obscured by the water peak and 2 exchangeable protons not observed.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4]([CH:16]1[CH2:20][C:19](=[O:21])[N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[O:31][CH3:32])[C:17]1=[O:33])[NH:5]C(OCC1C=CC=CC=1)=O.[H][H]>CO.C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:34])[CH:4]([CH:16]1[CH2:20][C:19](=[O:21])[N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[O:31][CH3:32])[C:17]1=[O:33])[NH2:5]
Reactant: [H][H]
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)C1CC(=O)N(Cc2ccc(OC)cc2OC)C1=O
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C(N)C1CC(=O)N(Cc2ccc(OC)cc2OC)C1=O

Procedure:
In a mixture of 50 ml of methanol and 5 ml of acetic acid was dissolved 3 g of benzyloxycarbonyl-2-[1-(2,4-dimethoxybenzyl)-2,5-dioxopyrrolidin-3-yl]glycine methyl ester and after addition of 500 mg of palladium black, the mixture was stirred in a stream of hydrogen at room temperature for 2.5 hours. The catalyst was filtered off and the filtrate was concentrated to dryness under reduced pressure. The concentrate was chromatographed on a silica gel column and eluted with toluene-acetone (4:1). The eluate was concentrated under reduced pressure and to the residue was added 100 ml of ethyl ether-petroleum ether (1:5). The mixture was allowed to stand in a refrigerator overnight and the resulting precipitate was collected by filtration and dried. Yield 1.4 g.
Reaction SMILES: C(O[C@H](C)[C@H](NC(C1(CC2C=CC=CC=2)CCCN1)=O)C(OC)=O)(=O)C.C([O-])([O-])=O.[Na+].[Na+].[CH2:33]([O:40][C:41]([N:43]1[CH2:47][CH2:46][CH2:45][C@H:44]1[C:48]([OH:50])=O)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O=S(Cl)[Cl:53]>C(Cl)Cl.O>[Cl:53][C:48]([C@@H:44]1[CH2:45][CH2:46][CH2:47][N:43]1[C:41]([O:40][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:42])=[O:50]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: COC(=O)[C@@H](NC(=O)C1(Cc2ccccc2)CCCN1)[C@@H](C)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(Cl)[C@@H]1CCCN1C(=O)OCc1ccccc1

Procedure:
To a stirred solution of compound 6 (1 g, 2.76 mmol) and Na2CO3 (732 mg, 6.90 mmol) in CH2Cl2:H2O (20 mL, 1:1) was added a solution of acid chloride [To a solution of (S)-1-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid (825 mg, 3.31 mmol) in CH2Cl2 (20 mL) was added SOCl2 (0.60 mL) drop wise at 0° C. and was refluxed for 2 h. The volatiles were removed under reduced pressure to yield (S)-benzyl 2-(chlorocarbonyl)pyrrolidine-1-carboxylate] in CH2Cl2 and the reaction mixture was stirred at RT for 2 h. The volatiles were evaporated under reduced pressure. The residue was diluted with CH2Cl2 (100 mL), filtered and the filtrate was concentrated under vacuum. The crude residue was purified by column chromatography using 60% EtOAc/Hexane as eluent to afford compound 7 (750 mg, 45%).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[S:15][C:14]([C:16]3[CH:17]=[CH:18][C:19]4[CH2:26][CH:25]5[C:27]6([CH2:31][N:30]([CH2:32][C:33]([F:36])([F:35])[F:34])[S:29](=[O:38])(=[O:37])[NH:28]6)[CH:22]([CH2:23][CH2:24]5)[CH2:21][C:20]=4[CH:39]=3)=[N:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[H][H]>[Pd].C(OCC)(=O)C>[F:41][C:2]([F:1])([F:40])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[S:15][C:14]([C:16]3[CH:17]=[CH:18][C:19]4[CH2:26][CH:25]5[C:27]6([CH2:31][N:30]([CH2:32][C:33]([F:36])([F:35])[F:34])[S:29](=[O:37])(=[O:38])[NH:28]6)[CH:22]([CH2:23][CH2:24]5)[CH2:21][C:20]=4[CH:39]=3)=[N:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(N1CC=C(c2cnc(-c3ccc4c(c3)CC3CCC(C4)C34CN(CC(F)(F)F)S(=O)(=O)N4)s2)CC1)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(N1CCC(c2cnc(-c3ccc4c(c3)CC3CCC(C4)C34CN(CC(F)(F)F)S(=O)(=O)N4)s2)CC1)C(F)(F)F
Yield: 99.7 %

Procedure:
A mixture of the tetrahydropyridine from Example 41 (0.018 g, 0.029 mmol), palladium on carbon (0.01 g) and ethyl acetate (2 mL) was stirred under 1 atmosphere of hydrogen for 16 hours. The catalyst was removed by filtration through a glass fibre pad and the solvent removed in vacuo to give the title compound (0.018 g, quant.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][CH3:24])=[C:6]([C:8]2[NH:9][C:10](=[O:21])[C:11]3[N:16]([CH3:17])[N:15]=[C:14]([CH2:18][CH2:19][CH3:20])[C:12]=3[N:13]=2)[CH:7]=1.[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35])[CH2:27][CH2:26]1>>[CH2:23]([O:22][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:34]([CH2:33][CH2:32][CH2:31][N:28]2[CH2:29][CH2:30][O:25][CH2:26][CH2:27]2)(=[O:36])=[O:35])=[CH:7][C:6]=1[C:8]1[NH:9][C:10](=[O:21])[C:11]2[N:16]([CH3:17])[N:15]=[C:14]([CH2:18][CH2:19][CH3:20])[C:12]=2[N:13]=1)[CH3:24]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(N)ccc3OCC)nc12
Reactant: O=S(=O)(Cl)CCCN1CCOCC1
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(NS(=O)(=O)CCCN4CCOCC4)ccc3OCC)nc12

Procedure:
The title compound was prepared from 5-(5-amino-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one and 3-morpholinopropylsulphonyl chloride, following the procedure of Example 41, and was obtained as brown crystals (14%), m.p. 157°-159° C. Found: C,55.42; H,6.53; N,16.01. C24H34N6O5S requires C,55.58; H,6.61; N,16.21%.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([Cl:15])=[N:12][O:13][CH3:14])(=[O:4])=[O:3].C1([O:22][C:23](=O)[NH:24][C:25]2[N:30]=[C:29]([O:31][CH3:32])[N:28]=[C:27]([CH3:33])[N:26]=2)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>>[CH3:14][O:13][N:12]=[C:11]([Cl:15])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[S:2]([NH:1][C:23]([NH:24][C:25]1[N:30]=[C:29]([O:31][CH3:32])[N:28]=[C:27]([CH3:33])[N:26]=1)=[O:22])(=[O:3])=[O:4]
Reactant: CON=C(Cl)c1ccccc1S(N)(=O)=O
Reactant: COc1nc(C)nc(NC(=O)Oc2ccccc2)n1
Solvent: C1CCC2=NCCCN2CC1
Product: CON=C(Cl)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1
Yield: 67.4 %

Procedure:
By the procedure of Example 5, 0.4 g of the product of Example 4 was reacted with 0.46 g of phenyl(4-methoxy-6-methyl-1,3,5-triazin-2-yl)carbamate and 0.25 g of DBU. The resulting suspension was acidified, without prior filtration, with concentrated hydrochloric acid and filtered. The residue was washed with excess water and suction-dried to yield 0.45 g of the subject compound, m.p. 182° to 184° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11]1C[O:14][CH2:13][CH2:12]1.C(O)CCO.CC1C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]1[O:14][CH2:13][CH2:12][CH2:11][O:5]1
Reactant: O=Cc1cc(O)ccc1Br
Reactant: C1CCOC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: OCCCO
Product: Oc1ccc(Br)c(C2OCCCO2)c1

Procedure:
To the solution of 2-bromo-5-methoxy-benzaldehyde (10 g, 46.5 mmol) at −78° C. is added BBr3 (25 g, 93.75 mmol) and allowed to warm to room temperature. After 2 h, the reaction is quenched with water and extracted with ethyl acetate. The combined organic layers are washed with water, brine, dried over MgSO4, concentrated and purified by column chromatography to afford 3.6 g of 2-bromo-5-hydroxy-benzaldehyde. To the solution of 2-bromo-5-hydroxy-benzaldehyde (1.45 g, 7.2 mmol in benzene (30 ml) and THF (6 ml) is added 1,3-propanediol (2.74 g, 36 mmol) and TsOH (37 mg, 0.22 mmol). The mixture is refluxed for 24. After cooling down, the solvent is evaporated. The residue is loaded on silica and purified by column chromatography to afford the titled compound (2.3 g) as brown oil.
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]12([CH2:29][CH2:30][C:31](Cl)=[O:32])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2>>[C:19]12([CH2:29][CH2:30][C:31]([NH:1][N:2]3[C:11](=[O:12])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]=[C:3]3[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:32])[CH2:26][CH:25]3[CH2:24][CH:23]([CH2:22][CH:21]([CH2:27]3)[CH2:20]1)[CH2:28]2
Reactant: O=C(Cl)CCC12CC3CC(CC(C3)C1)C2
Reactant: Nn1c(-c2ccccc2)nc2ccccc2c1=O
Product: O=C(CCC12CC3CC(CC(C3)C1)C2)Nn1c(-c2ccccc2)nc2ccccc2c1=O

Procedure:
3-Amino-2-phenyl-4(3H)-quinazolinone and the product of Example 13A were reacted as described in Example 5 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93-1.13 (m, 2H), 1.23-1.33 (m, 6H), 1.51-1.65 (m, 6H), 1.85-1.89 (m, 3H), 1.96-2.08 (m, 2H), 7.44-7.55 (m, 3H), 7.58-7.64 (m, 3H), 7.75 (d, J=7.8 Hz, 1H), 7.89-7.94 (m, 1H), 8.18 (dd, J=8.0, 1.2 Hz, 1H), 11.06 (s, 1H) ppm; MS (DCI/NH3) m/z 428 (M+H)+; Elemental Analysis: Calculated for C27H29N3O2: C, 75.85; H, 6.84; N, 9.83. Found: C, 75.75; H, 6.97; N, 9.84.
Reaction SMILES: I[C:2]1[C:10]2[O:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:13][O:12][C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[CH2:8][O:9][C:10]=2[C:2]=1[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=1
Reactant: COc1ccc2c(c1I)OCC2=O
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2c(c1C1=CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 47.2 %

Procedure:
A solution of 7-iodo-6-methoxybenzofuran-3(2H)-one (0.100 g, 0.345 mmol) synthesized in Example B46, Step 2 in 1,4-dioxane (6 mL) was added with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.107 g, 0.345 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.0252 g, 0.0345 mmol) and 2 M aqueous sodium carbonate (0.515 mL, 1.03 mmol), and the mixture was stirred at 150° C. for 30 minutes under irradiation of microwaves. The reaction mixture was poured into water, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated, and the resulting residue was subjected to silica gel column chromatography (hexane/ethyl acetate). The resulting crude product was purified again by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl 4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.0562 g, 47%).
Reaction SMILES: Br[C:2]1[C:14]([CH3:15])=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][S:10][CH2:9][CH2:8]2)=[CH:4][C:3]=1[CH3:16].CCCCCC.C([Li])CCC.[B:28](OC(C)C)([O:33]C(C)C)[O:29]C(C)C.Cl>O1CCCC1>[CH3:16][C:3]1[CH:4]=[C:5]([O:6][CH:7]2[CH2:12][CH2:11][S:10][CH2:9][CH2:8]2)[CH:13]=[C:14]([CH3:15])[C:2]=1[B:28]([OH:33])[OH:29]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cc(OC2CCSCC2)cc(C)c1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(OC2CCSCC2)cc(C)c1B(O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
To a solution of 4-(4-bromo-3,5-dimethylphenoxy)tetrahydro-2H-thiopyran (3.01 g, 10.0 mmol) in tetrahydrofuran (50 mL) was added dropwise n-butyllithium hexane solution (1.6 M, 6.57 mL, 10.5 mmol) at −78° C., and the reaction mixture was stirred for 1.5 hr at the same temperature. Triisopropyl borate (6.92 mL, 30.0 mmol) was added, and the mixture was stirred overnight, during which the mixture was allowed to warm to room temperature. The reaction mixture was ice-cooled, 2 M hydrochloric acid (50 mL) was added, and the mixture was stirred for 2.5 hr. The aqueous layer and the organic layer were separated, and the organic layer was washed with saturated brine and saturated aqueous sodium hydrogencarbonate while simultaneously adjusting to neutral. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with cool hexane to give the title compound (1.89 g, yield 71%) as colorless crystals.
Reaction SMILES: [C:1]([Si:5]([CH3:22])([CH3:21])[O:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[C:23]([O:27][C:28](=[O:47])/[CH:29]=[CH:30]/[C:31]1[CH:35]=[CH:34][N:33]([S:36]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45]Br)=[CH:41][CH:40]=2)(=[O:38])=[O:37])[CH:32]=1)([CH3:26])([CH3:25])[CH3:24]>C(O)C>[C:23]([O:27][C:28](=[O:47])/[CH:29]=[CH:30]/[C:31]1[CH:35]=[CH:34][N:33]([S:36]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45][N:9]([CH2:8][CH2:7][O:6][Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([CH3:22])[CH3:21])[CH2:10][CH2:11][C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:14][CH:13]=3)=[CH:41][CH:40]=2)(=[O:38])=[O:37])[CH:32]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(CBr)cc2)c1
Reactant: CC(C)(C)[Si](C)(C)OCCNCCc1c[nH]c2ccccc12
Solvent: CCO
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(CN(CCO[Si](C)(C)C(C)(C)C)CCc3c[nH]c4ccccc34)cc2)c1
Reaction time: 43 h

Procedure:
[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-[2-(1H-Indol-3yl)-ethyl]-amine (compound E2) (830 mg, 2.60 mmol) is dissolved in ethanol (200 ml). (E)-3-[1-(4-bromomethyl-benzenesulfonyl)-1H-pyrrol-3yl]-acrylic acid tert-butyl ester (compound D4) (1.01 g, 2.37 mmol) is added and the mixture is stirred for 43 hours and evaporated. The residue is purified by a silica gel flash chromatograph using petrol ether-ether eluent.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:11](Br)[CH:12]=[CH2:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:13]([O:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1)[CH:12]=[CH2:11]
Reactant: C=CCBr
Reactant: N#Cc1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOc1ccc(C#N)c(F)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-Fluoro-4-hydroxybenzonitrile (5.00 g, 36.5 mmoles) and allyl bromide (3.47 mL, 40.1 mmoles) in anhydrous DMF (40 mL) were treated with K2CO3 (10.0 g, 72.9 mmoles) and stirred overnight at 80° C. Reaction mixture cooled and diluted with ethyl acetate, washed with H2O (2×) and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to provide the title compound with no further purification.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:27])=[N:14][C:15]2[N:16]([N:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=2)[C:17]=1I)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]1[CH:30]=[C:31](B2OC(C)(C)C(C)(C)O2)[C:32]([CH3:39])=[C:33]2[C:38]=1[O:37][CH2:36][CH2:35][CH2:34]2.C([O-])([O-])=O.[Na+].[Na+].O>CN(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>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:27])=[N:14][C:15]2[N:16]([N:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=2)[C:17]=1[C:31]1[C:32]([CH3:39])=[C:33]2[C:38](=[C:29]([F:28])[CH:30]=1)[O:37][CH2:36][CH2:35][CH2:34]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cc(F)c2c1CCCO2
Reactant: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(I)n2n1
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: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(-c3cc(F)c4c(c3C)CCCO4)n2n1
Temperature: 100 °C
Yield: 82.4 %

Procedure:
A mixture of (S)-ethyl 6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (4.5 g, 9.20 mmol), 2-(8-fluoro-5-methylchroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.22 g, 11.04 mmol) and 2N Na2CO3 (9.20 mL, 18.39 mmol) in DMF (100 mL) was degassed and flushed with N2 for 30 min. Tetrakis(triphenylphosphine)palladium(0) (0.744 g, 0.644 mmol) was then added and the reaction was flushed with N2 for another 15 min. The mixture was then heated at 100° C. for 16 h. At this point LCMS indicated completion of reaction and appearance of desired product. After cooling to rt, water was added (50 mL) and the mixture was extracted with ether (2×200 mL). The organic phase was washed with brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was then purified by silica gel chromatography (5-60% EtOAc/hexane) to afford ethyl 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (4 g, 7.58 mmol, 82% yield) as mixture of atrope isomers (approx 10% of minor atrope isomer was present). 1H NMR (500 MHz, CDCl3) δ 7.10 (s, 1H), 6.87 (d, J=10.7 Hz, 1H), 5.00 (s, 1H), 4.41 (qd, J=7.1, 3.1 Hz, 2H), 4.35 (dd, J=5.2, 4.0 Hz, 2H), 4.14 (q, J=7.2 Hz, 2H), 2.80 (s, 3H), 2.79-2.73 (m, 2H), 2.23-2.15 (m, 2H), 1.82 (s, 3H), 1.41 (t, J=7.2 Hz, 3H), 1.22-1.19 (m, 4H), 1.18 (s, 9H). LCMS (M+H)=528.4.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH2:11])[CH2:4][CH2:3]1.CN1CCNCC1.C(#N)C=C.[C:23](Cl)(=[O:37])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(Cl)(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH:11][C:23](=[O:37])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:4][CH2:3]1
Reactant: CCCCCCCCCCCCCC(=O)Cl
Reactant: CN1CCN(CCCN)CC1
Agent: CN1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: C=CC#N
Product: CCCCCCCCCCCCCC(=O)NCCCN1CCN(C)CC1

Procedure:
4.7 g. (0.03 mol) of N-methyl-N'-(3-aminopropyl)-piperazine (prepared from N-methyl piperazine and acrylonitrile and subsequent reduction to the primary amine) in 200 mL chloroform was cooled down in an ice bath. To this was added 7.3 g. (0.03 mol) of myristoyl chloride dropwise for two hours. The reaction mixture was brought to room temperature and then allowed to react for another four hours. The reaction mixture was treated with 10 g. of sodium bicarbonate in 100 mL water and the separated chloroform layer was washed with water (2×200 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Crystallization from acetonitrile afforded 8 g. (72.3%) of the subject product.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[S:7]([C:11]1[N:12]([CH2:16][C:17]([OH:19])=O)[CH:13]=[CH:14][N:15]=1)([CH3:10])(=[O:9])=[O:8].CN(C)C=O>C(Cl)Cl>[S:7]([C:11]1[N:12]([CH2:16][C:17]([Cl:2])=[O:19])[CH:13]=[CH:14][N:15]=1)([CH3:10])(=[O:9])=[O:8]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CS(=O)(=O)c1nccn1CC(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1nccn1CC(=O)Cl
Temperature: 10 °C
Yield: 92.5 %

Procedure:
Phosphorus pentachloride (22.5 g.) dissolved in methylene chloride (150 cc.) is added dropwise and whilst cooling to 5° C., to a suspension of (2-mesyl-imidazol-1-yl)-acetic acid (12.3 g.) in methylene chloride (50 cc.). Dimethylformamide (2 cc.) is added thereafter and the mixture is then heated under reflux for 4 hours. The mixture is cooled to 10° C., the resulting solid is filtered off and washed with methylene chloride (15 ac.) to give (2-mesyl-imidazol- 1 -yl)-acetyl chloride (12.4 g.), m.p. 132°-133° C.