Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]#[C:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18].Cl[C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([I:40])[CH:38]=2)[N:33]=[CH:32][N:31]=1>C(O)(C)C>[F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([I:40])[CH:38]=3)[N:33]=[CH:32][N:31]=2)=[CH:9][C:8]=1[C:14]#[C:15][Si:16]([CH:17]([CH3:18])[CH3:19])([CH:20]([CH3:21])[CH3:22])[CH:23]([CH3:25])[CH3:24]
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: CC(C)[Si](C#Cc1cc(N)ccc1OCc1cccc(F)c1)(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)[Si](C#Cc1cc(Nc2ncnc3ccc(I)cc23)ccc1OCc1cccc(F)c1)(C(C)C)C(C)C

Procedure:
4-(3-fluorobenzyloxy)-3-(2-(triisopropylsilyl)ethynyl)benzenamine (900 mg, 2.27 mmol) and 4-chloro-6-iodo-quinazoline (657 mg, 2.27 mmol) were dissolved in isopropanol (50 ml). The reaction mixture was refluxed for 12 hours. The solid product was collected by filtration, washed with cold isopropanol (10 mL) and ether (20 mL), and air dried to afford the clean desired material.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:27][CH2:26][CH2:25][C@H:6]1[C:7]([N:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])(O)=[O:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:43]12([CH2:53][NH2:54])[CH2:52][CH:47]3[CH2:48][CH:49]([CH2:51][CH:45]([CH2:46]3)[CH2:44]1)[CH2:50]2>C(#N)C>[C:43]12([CH2:53][NH:54][C:1]([CH2:4][N:5]3[CH2:27][CH2:26][CH2:25][C@H:6]3[C:7]([N:9]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])=[O:2])[CH2:50][CH:49]3[CH2:48][CH:47]([CH2:46][CH:45]([CH2:51]3)[CH2:44]1)[CH2:52]2
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)NCC12CC3CC(CC(C3)C1)C2
Yield: 10.2 %

Procedure:
Using the procedure described previously, a solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (106 mg, 0.28 mmol), triethylamine (158 uL, 1.13 mmol, 4 eq) in acetonitrile (1.5 mL, was cooled to 0° C. and treated with isobutyl chloroformate (40.5 uL, 0.31 mmol, 1.1 eq) followed by 1-adamantanemethylamine (100 uL, 0.57 mmol, 2 eq). After TLC indicated the reaction was complete, the mixture was purified by HPLC to provide 15 mg (10%) of L-isoleucine, N-[1-(adamant-1-ylmethylcarbamoylmethyl)-L-prolyl] benzylamide.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([NH:21][C:22](=[O:35])[CH:23]([NH:27]C(=O)OC(C)(C)C)[CH:24]([CH3:26])[CH3:25])[CH2:17][CH2:16]1)=[N:11][C:10]([C:36]1[CH:41]=[C:40]([F:42])[C:39]([OH:43])=[C:38]([Cl:44])[CH:37]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:64].Cl>>[ClH:44].[ClH:64].[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([NH:21][C:22](=[O:35])[CH:23]([NH2:27])[CH:24]([CH3:26])[CH3:25])[CH2:17][CH2:16]1)=[N:11][C:10]([C:36]1[CH:41]=[C:40]([F:42])[C:39]([OH:43])=[C:38]([Cl:44])[CH:37]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@H](NC(=O)C(NC(=O)OC(C)(C)C)C(C)C)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@H](NC(=O)C(N)C(C)C)CC1

Procedure:
Following general procedure IV-2, tert-butyl [1-(trans-4-{[3-acetyl-6-(3-chloro-5-fluoro-4-hydroxyphenyl)-1,5-naphthyridin-4-yl]amino}cyclohexylamino)-3-methyl-1-oxobutan-2-yl]carbamate (0.19 mmol) was reacted with TFA (2 mL) followed by formation of the dihydrochloride salt to afford the desired product (35 mg, 30% over two steps) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 9.14 (s, 1H), 8.44 (d, J=9.0 Hz, 1H), 8.33 (d, J=9.0 Hz, 1H), 8.00 (s, 1H), 7.87 (dd, J=11.4, 2.2 Hz, 1H), 5.63-5.57 (m, 1H), 3.88-3.83 (m, 1H), 3.62 (d, J=6.0 Hz, 1H), 2.76 (s, 3H), 2.51-2.40 (m, 2H), 2.10-2.12 (m, 3H), 1.81-1.53 (m, 4H), 1.08 (t, J=7.4 Hz, 6H); ESI MS m/z 528 [M+H]+; HPLC 98.9% (AUC), tR=9.99 min.
Reaction SMILES: C([O:8][C:9]1[C:10]([O:32][CH2:33][O:34][P:35]([O:45]CC2C=CC=CC=2)([O:37]CC2C=CC=CC=2)=[O:36])=[C:11]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:12]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:13]=1[C:14](=[O:18])[N:15]([CH3:17])[CH3:16])C1C=CC=CC=1>CO.[Pd]>[CH3:17][N:15]([CH3:16])[C:14]([C:13]1[N:12]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:11]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:10]([O:32][CH2:33][O:34][P:35]([OH:37])([OH:45])=[O:36])[C:9]=1[OH:8])=[O:18]
Reactant: CCOC(=O)c1c(OCOP(=O)(OCc2ccccc2)OCc2ccccc2)c(OCc2ccccc2)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1c(OCOP(=O)(O)O)c(O)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Yield: 95.1 %

Procedure:
A solution of ethyl 4-(benzyloxy)-3-(((bis(benzyloxy)phosphoryl)oxy)methoxy)-5-(dimethylcarbamoyl)-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (61) (102 mg, 0.14 mmol) in MeOH (5 mL) was passed through a Thales ‘H-cube’ cartridge (10% Pd/C) at a flow rate of 1 mL/min at 45° C. under H2 (full H2 mode). The output was concentrated in vacuo to afford ethyl 5-(dimethylcarbamoyl)-4-hydroxy-1-(4-methoxyphenyl)-3-((phosphonooxy)methoxy)-1H-pyrrole-2-carboxylate (UL1-115) (61 mg, 93%) as a white solid: m/z 459 (M+H)+ (ES+); 457 (M−H)− (ES−), 1H NMR (400 MHz, DMSO-d6) δ: 7.11-7.05 (m, 2H), 6.91-6.84 (m, 2H), 5.45 (d, J=16 Hz, 2H), 3.98 (q, J=7.1 Hz, 2H), 3.77 (s, 3H), 2.98 (br s, 3H) 2.74 (br s, 3H), 1.01 (t, J=7.0 Hz, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN1CCCCC1=O.O>C(OCC)(=O)C>[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: CN1CCCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(F)ccc1NC1CCN(Cc2ccccc2)CC1
Yield: 86.9 %

Procedure:
21.5 g 2,5-difluoro-nitrobenzene, 52.3 g 1-benzyl-4-amino-piperidine and 100 ml N-methyl-piperidone were stirred at 100° C. for 3 h. After cooling the mixture was treated distributed between water and ethyl acetate and the aqeous layer was extracted 2× with ethyl acteate. The combined organic layers were extracted 5× with water, and the solvent was removed by evaporation. The target compound was crystallized from methanol to yield 38.7 g orange crystals (mp. 86–87° C.).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]2[C:28]3[CH:29]=[CH:30][C:31]([C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][C:27]=3[S:26][C:25]2=[O:41])=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11].C(N(CC)CC)C.[C:49](Cl)(=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C(OCC)(=O)C>[C:49]([NH:8][CH:9]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][N:24]2[C:28]3[CH:29]=[CH:30][C:31]([C:33](=[O:40])[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:32][C:27]=3[S:26][C:25]2=[O:41])=[CH:19][CH:20]=1)[C:10]([O:12][CH3:13])=[O:11])(=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)C(N)Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)NC(=O)c1ccccc1
Reaction time: 8 h

Procedure:
500 mg of the compound obtained in Step A of Example 12 are dissolved in 10 ml of ethyl acetate; 0.353 ml of triethylamine is then added and the temperature is lowered to 0° C. 0.197 ml of benzoyl chloride is added and the mixture is allowed to return to ambient temperature and is stirred overnight.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH3:14])[O:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:13][C:12]1[O:11][C:10]([CH3:14])=[N:9][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(-c2ccc(Cl)cc2)c(C)o1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nc(-c2ccc(Cl)cc2)c(CBr)o1
Reaction time: 0.25 h

Procedure:
A solution of 4-(4-chlorophenyl)-2,5-dimethyloxazole (6.21 g), N-bromosuccinimide (5.34 g) and azobisisobutyronitrile (0.25 g) in carbon tetrachloride (90 ml) was refluxed with stirring for 15 minutes, then washed with water, saturated aqueous sodium hydrogen carbonate and water in that order, and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residue was crystallized from cold ethanol to give 5-bromomethyl-4-(4-chlorophenyl)-2-methyloxazole, yield 6.73 g (78.4%). Recrystallization from ethanol gave needles, melting at 75°-76° C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([N:23]1[C:31]2[N:30]=[CH:29][NH:28][C:27]=2[C:26](=[O:32])[NH:25]/[C:24]/1=[N:33]\[NH2:34])[CH2:19][CH2:20][CH2:21][CH3:22].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[O:32]=[C:26]1[NH:25]/[C:24](=[N:33]\[NH:34][C:15](=[O:17])[CH2:14][CH2:13][CH2:12][N:10]2[CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=[N:9]2)/[N:23]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:31]2[N:30]=[CH:29][NH:28][C:27]1=2
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]cnc21
Reactant: O=C(O)CCCn1cc(-c2ccccc2)cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCn1/c(=N/NC(=O)CCCn2cc(-c3ccccc3)cn2)[nH]c(=O)c2[nH]cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
A mixture of 4-(4-phenyl-1H-pyrazol-1-yl)butanoic acid (190 mg, 0.825 mmol), (2E)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (195.0 mg, 0.825 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (401 mg, 0.908 mmol) and triethyl amine (0.23 ml, 1.65 mmol) in DMF (10 ml) was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with water and then brine. The organic phase was dried over Na2SO4, filtered and concentrated to yield the desired product (369 mg, 99.7% yield) as yellowish oil. LCMS calculated for C23H29N8O2 (M+H): 449.2. found: 449.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][NH:13][C:12](=[O:16])[CH:11]=2)=[N:6][CH:7]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[C:22]3[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:23]=3[N:24]([CH3:27])[C:25]=2[CH:26]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:18]3[CH:19]=[CH:20][C:21]4[C:22]5[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:23]=5[N:24]([CH3:27])[C:25]=4[CH:26]=3)[C:12](=[O:16])[CH:11]=2)=[N:6][CH:7]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(OCc2ccc(F)cn2)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cn5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 66.6 %

Procedure:
4-((5-Fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (275 mg, 1.25 mmol) and tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (456 mg, 1.25 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (420 mg, 66%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.15 (d, J=2.1 Hz, 1H), 7.50 (m, 3H), 7.36 (d, J=7.8 Hz, 1H), 7.31 (d, J=1.6 Hz, 1H), 7.01 (d, J=8.9 Hz, 1H), 6.11-6.08 (m, 2H), 5.18 (s, 2H), 4.65 (s, 2H), 3.87 (t, J=5.3 Hz, 2H), 3.65 (s, 3H), 2.84 (t, J=4.2 Hz, 2H), 1.60 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:21]=1)[CH2:7][O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.C([O-])(=O)C.[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10]3[C:9](=[C:18]4[CH:17]=[CH:16][C:15]([O:19][CH3:20])=[CH:14][C:13]4=[CH:12][CH:11]=3)[O:8][CH2:7][C:6]=2[CH:21]=1
Reactant: COc1ccc2c(OCc3cc(Br)ccc3I)cccc2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c3c(ccc2c1)-c1ccc(Br)cc1CO3
Temperature: 110 °C
Yield: 35.3 %

Procedure:
A mixture of 1-(5-bromo-2-iodobenzyloxy)-6-methoxynaphthalene (5.0 g, 10.7 mmol) and sodium acetate (2.64 g, 32.1 mmol) in dimethylformamide (100 mL) was degassed with a stream of argon for 15 minutes. PdCl2(PPh3)2 was added and the reaction was heated to 110° C. After 16 hours the reaction was diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and concentrated. The resulting residue was purified by flash column chromatography to yield 8-bromo-2-methoxy-6H-dibenzo[c,h]chromene (1.29 g, 35%).
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[Cl:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32](O)=[O:33])[CH:27]=[CH:28][C:29]=1[F:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32]([N:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[C:20]5[C:15](=[N:16][CH:17]=[N:18][C:19]=5[NH2:21])[N:14]([CH3:22])[N:13]=4)=[CH:9][CH:10]=3)[CH2:5][CH2:4]2)=[O:33])[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: O=C(O)Cc1ccc(F)c(Cl)c1
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1nc(-c2ccc3c(c2)CCN3C(=O)Cc2ccc(F)c(Cl)c2)c2c(N)ncnc21
Reaction time: 8 h

Procedure:
In a 20 mL vial with cap, to the solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 2HCl (64.6 mg, 0.190 mmol), (3-chloro-4-fluorophenyl)acetic acid (35.9 mg, 0.190 mmol), HATU (72.4 mg, 0.190 mmol) in DMF (2 mL) was added Hunig's base (0.133 mL, 0.762 mmol). The mixture was stirred overnight. The reaction was poured into water, and an off-white solid formed. The solid was filtered to give the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.22-3.30 (m, 2H), 3.94 (s, 5H), 4.26 (t, J=8.46 Hz, 2H), 7.33 (dd, J=4.93, 2.15 Hz, 1H), 7.37-7.40 (m, 1H), 7.41-7.47 (m, 1H), 7.51-7.58 (m, 2H), 8.18 (d, J=8.59 Hz, 1H), 8.25 (s, 1H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH2:15])=[N+:2]=[N-:3].C(N(CC)CC)C.[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[C:32]([Cl:34])[CH:33]=1)[CH2:30][N:29]([CH3:35])[CH2:28][CH:27]2[C:36]1[CH:37]=[C:38]([S:42](Cl)(=[O:44])=[O:43])[CH:39]=[CH:40][CH:41]=1>C(Cl)Cl>[N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][S:42]([C:38]1[CH:39]=[CH:40][CH:41]=[C:36]([CH:27]2[C:26]3[C:31](=[C:32]([Cl:34])[CH:33]=[C:24]([Cl:23])[CH:25]=3)[CH2:30][N:29]([CH3:35])[CH2:28]2)[CH:37]=1)(=[O:44])=[O:43])=[N+:2]=[N-:3]
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)Cl)c2)C1
Reactant: [N-]=[N+]=NCCOCCOCCOCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN=[N+]=[N-])c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethanamine (1.5 g, 6.87 mmol, 1.79 equiv) in DCM (20 mL) was added triethylamine (1.5 g, 14.82 mmol, 3.86 equiv) and 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzene-1-sulfonyl chloride (1.5 g, 3.84 mmol, 1.00 equiv). The reaction was stirred overnight at room temperature at which time the resulting mixture was concentrated under vacuum. The residue was dissolved in 100 mL of ethyl acetate and then was washed with 2×20 mL of water, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.8 g (85%) of N-(2-(2-(2-(2-azido ethoxy)ethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide as yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21].OS(O)(=O)=O.O>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([O:18][CH3:19])=[CH:11][C:12]([C:15](=[O:17])[CH3:16])=[C:13]([N+:20]([O-:22])=[O:21])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C(C)=O)ccc1OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(C)=O)c([N+](=O)[O-])cc1OCc1ccccc1
Yield: 61 %

Procedure:
To a solution of 1-(4-(benzyloxy)-3-methoxyphenyl)ethanone (5.0 g, 19.5 mmol, Alfa Aesar Company) in dichloromethane (75 mL) at ice bath temp. was added slowly HNO3 (1.5 mL of 90% nitric acid) followed by conc H2SO4 (1.8 mL of 96.2% acid) at 0° C. with stirring. After 1 h at 0° C. additional HNO3 (0.5 mL) was added and the reaction mixture was stirred for 20 minutes at 0° C. To the reaction mixture was added dichloromethane (25 mL) and the mixture was poured into water (60 mL), the organic layer was separated which was washed with water (2×60 mL) followed by aq NaHCO3 (2×60 mL), dried over Na2SO4 and concentrated in vacuo. The residue was mixed with DMF (˜3 mL) and ether (70 mL), stirred for a while and the solid was filtered, washed with a small amount of ether and dried to obtain the desired product (3.6 g, 61%) as a yellow solid. 1H NMR (CDCl3) δ 7.64 (s, 1H), 7.42-7.35 (m, 5H), 6.76 (s, 1H), 5.21 (s, 2H), 3.93 (s, 3H), 2.48 (s, 3H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(OC([N:18]1[C:22]([NH2:23])=[CH:21][C:20]([CH2:24][CH2:25][C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=2)=[N:19]1)=O)(C)(C)C.[NH2:36][CH:37]([CH3:49])[CH2:38][C:39]1[CH:48]=[CH:47][C:42]([C:43](OC)=[O:44])=[CH:41][CH:40]=1>C1COCC1>[NH2:36][CH:37]([CH3:49])[CH2:38][C:39]1[CH:48]=[CH:47][C:42]([C:43]([NH:23][C:22]2[CH:21]=[C:20]([CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=3)[NH:19][N:18]=2)=[O:44])=[CH:41][CH:40]=1
Reactant: COC(=O)c1ccc(CC(C)N)cc1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(CC(C)N)cc3)n[nH]2)cc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.2 %

Procedure:
A solution of NaHMDS in THF (1 M, 0.86 ml, 0.86 mmol, 1.5 eq) was added dropwise at ambient temperature to a mixture of tert-butyl-5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]pyrazole-1-carboxylate (200 mg, 0.58 mmol, 1 eq) and methyl 4-(2-aminopropyl)benzoate (133 mg, 0.69 mmol, 1.2 eq) in THF (1 ml). The reaction mixture was stirred at ambient temperature for 2 h. It was then concentrated and the crude product was purified by reverse-phase prep. HPLC (basic) using a gradient of acetonitrile in water containing 1% ammonium hydroxide solution. The clean fractions were taken and evaporated to afford the title compound as a pale yellow gum (10 mg, 4% yield); 1H NMR (399.902 MHz, DMSO) δ 0.89 (3H, d), 2.53-2.47 (2H, m), 2.80 (4H, s), 3.01-2.93 (1H, m), 3.65 (6H, s), 6.25-6.24 (1H, m), 6.34 (2H, d), 6.40 (1H, s), 7.21 (2H, d), 7.84 (2H, d), 10.47 (1H, br.s), 12.06 (1H, br.s). MS: m/z 409 (MH+)
Reaction SMILES: C([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[F:13])(=O)CC.[Cl-].[Cl-].[Cl-].[Al+3].Cl>ClC1C=CC=CC=1Cl.ClCCl>[F:13][C:7]1[C:6]([OH:5])=[C:11]([C:6](=[O:5])[CH2:7][CH3:8])[CH:10]=[CH:9][C:8]=1[F:12]
Reactant: CCC(=O)Oc1cccc(F)c1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: Clc1ccccc1Cl
Product: CCC(=O)c1ccc(F)c(F)c1O
Temperature: 100 °C
Reaction time: 6 h
Yield: 143.5 %

Procedure:
30.1 g (161 mmol) of 2,3-difluorophenyl propionate in 16 ml of 1,2-dichlorobenzene are added dropwise to 21.5 g (161 mmol) of aluminum trichloride in 16 ml of 1,2-dichlorobenzene and the mixture is subsequently stirred at 100° C. for 6 hours. It is cooled, diluted with dichloromethane and poured cautiously onto a mixture of 2 M hydrochloric acid and ice. The phases are separated, extraction is carried out with dichloromethane and the extracts are washed with saturated sodium chloride solution and dried over sodium sulphate. The crude product is purified by column chromatography on silica gel (hexane/ethyl acetate 10-20%) to give 21.5 g of 1-(3,4-difluoro-2-hydroxyphenyl)propan-1-one. 21.4 g (115 mmol) of 1-(3,4-difluoro-2-hydroxyphenyl)propan-1-one are dissolved in 170 ml of acetone, and the solution is admixed with 29.5 g of potassium carbonate and 13 ml (209 mmol) of methyl iodide. The mixture is boiled under reflux for 4 hours and stirred at room temperature for 12 hours and then the solvent is largely removed. The residue is poured into water and subjected to extraction with diethyl ether. The extracts are washed with water, dried over sodium sulphate and, following the removal of the solvent in vacuo, give 21.2 g of 1-(3,4-difluoro-2-methoxyphenyl)propan-1-one.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CN([CH2:19][C:20]1[C:28]2[C:23](=[N:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)C>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[N:10]1[CH2:15][CH2:14][N:13]([CH2:19][C:20]2[C:28]3[C:23](=[N:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[CH2:12][CH2:11]1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Reactant: c1ccc2sc(N3CCNCC3)cc2c1
Product: c1ccc2sc(N3CCN(Cc4c[nH]c5ncccc45)CC3)cc2c1
Yield: 53.6 %

Procedure:
The title compound was prepared in an analogous manner to Example 6, Step 3 using 1-(benzothiophen-2-yl)piperazine (180 mg, 0.83 mmol) and 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (145 mg, 0.83 mmol). Recrystallisation from ethyl acetatehexane afforded the title compound (155mg, 54%), m.p. 269° C. (dec.); (Found: C, 69.10; H, 5.85; N, 16.08. C20H20N4S requires C, 68.94; H, 5.79; N, 16.08%); δH (DMSO-d6) 2.55 (4H, t, J 5 Hz, 2×piperazinyl CH2), 3.18 (4H, t, J 5 Hz, 2×piperazinyl CH2), 3.70 (2H, s, indole-CH2N), 6.26 (1H, s, 3-H-benzothiophene), 7.04 (2H, m, 2×ArH), 7.19 (1H, m, ArH), 7.05 (2H, m, 2× ArH), 7.63 (1H, d, 8 Hz, ArH), 8.06 (1H, d, 8 Hz, ArH), 8.20 (1H, d, 3 Hz, ArH), and 11.46 (1H, br s, NH); m/z (CI+, NH3) 349 (M+1)+.
Reaction SMILES: CS(O[C@H:6]([CH3:28])[CH2:7][O:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)=O.Cl.[F:30][C@@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[F:30][C@@H:31]1[CH2:35][CH2:34][N:33]([C@@H:6]([CH3:28])[CH2:7][O:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:32]1
Reactant: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)OS(C)(=O)=O
Reactant: F[C@@H]1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)N1CC[C@@H](F)C1
Temperature: 25 °C
Yield: 59.1 %

Procedure:
A mixture of (R)-1-(trityloxy)propan-2-yl methanesulfonate (1.25 g, 3.15 mmol), (R)-3-fluoropyrrolidine hydrochloride (480 mg, 3.52 mmol), and K2CO3 (1.31 g, 9.48 mmol) in acetonitrile (40 mL) was heated at reflux for 4 days. The reaction was cooled to room temperature, concentrated under reduced pressure, and diluted with DCM (100 mL). The solution was washed (50 mL sat'd NaHCO3), dried (Naz SO4), and concentrated under reduced pressure. The crude material was purified on a silica gel column to yield (R)-3-fluoro-1-((S)-1-(trityloxy)propan-2-yl)pyrrolidine (725 mg) as a pale brown oil. 1H NMR (CDCl3): δ 7.60-7.20 (m, 15H), 5.40-4.95 (m, 1H), 3.30 (m, 1H), 3.05-2.50 (m, 5H), 2.29 (m, 1H), 2.06-1.70 (m, 2H), 1.07 (d, 3H).