Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:28]1[CH:33]=[C:32]([F:34])[C:31]([Si:35]([CH3:38])([CH3:37])[CH3:36])=[C:30]([F:39])[CH:29]=1.C([Mg]Cl)(C)C.[Cl-].[Li+].BrBr.[Mg]>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([C@H:24]([C:28]3[CH:29]=[C:30]([F:39])[C:31]([Si:35]([CH3:37])([CH3:36])[CH3:38])=[C:32]([F:34])[CH:33]=3)[OH:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reactant: C[Si](C)(C)c1c(F)cc(Br)cc1F
Agent: BrBr
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Product: CC(C)c1nc2c(c(I)c1[C@@H](O)c1cc(F)c([Si](C)(C)C)c(F)c1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and (4-bromo-2,6-difluorophenyl)trimethylsilane. Isopropylmagnesiumchloride-lithium chloride-complex (1.3 M in tetrahydrofurane) is used instead of isopropylmagnesium chloride. The bromine-magnesium exchange is performed at room temperature for 18 hours and at 40° C. for 4 hours.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[CH:26](O)[CH3:27].CCOC(/N=N/C(OCC)=O)=O.O1CCCCC1[N:47]1[C:55]2[C:50](=[CH:51][C:52]([C:56]3[N:60]=[CH:59][N:58](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:57]=3)=[CH:53][CH:54]=2)[C:49]([C:80]2[CH:81]=[C:82]([OH:86])[CH:83]=[CH:84][CH:85]=2)=[N:48]1.Cl>O1CCCC1>[NH:57]1[C:56]([C:52]2[CH:51]=[C:50]3[C:55](=[CH:54][CH:53]=2)[NH:47][N:48]=[C:49]3[C:80]2[CH:85]=[CH:84][CH:83]=[C:82]([O:86][CH2:27][CH2:26][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][NH:20]3)[CH:81]=2)=[N:60][CH:59]=[N:58]1
Reactant: Oc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: CC(O)C1CCCCN1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc(OCCC2CCCCN2)cc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 48.2 %

Procedure:
Triphenylphosphine (0.694 g, 2.65 mmol), tetrahydrofuran (2.12 mL), 2-piperidylethanol (0.352 mL, 2.65 mmol) and diethylazodicarboxylate (0.418 mL, 2.65 mmol) were added to 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenol (0.400 g, 0.662 mmol). The mixture was stirred at ambient temperature for 23 h and poured into aqueous 6 N hydrochloric acid (30 mL). After stirring at ambient temperature for 4 h, the mixture was extracted with ether (3×). The aqueous fraction was added to aqueous 6 N sodium hydroxide (30 mL) and the pH adjusted to 11. The solution was extracted with ethyl acetate (3×) and the organic fractions were combined and dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica pretreated with 2% triethylamine/ethyl acetate elution followed by 0-20% methanol/ethyl acetate. The desired fractions were concentrated, dissolved in ethyl acetate, washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated which gave the title compound (0.124 g, 48% yield). 1H NMR (CD3OD) δ 8.72 (m, 1H), 8.34 (s, 1H), 8.10 (dd, 1H), 7.67 (dd, 1H), 7.62 (dt, 1H), 7.58 (m, 1H), 7.47 (t, 1H), 7.04 (m, 1H), 4.27 (t, 2H), 2.89 (t, 2H), 2.63 (m, 4H), 1.68 (m, 4H), 1.51 (m, 2H). ES-MS (m/z) 389 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][O:15][C:16](=[O:25])[CH:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[CH3:14][O:15][C:16](=[O:25])[CH:17]([NH:24][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:13])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)C(N)c1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1ccccn1
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To (S)-2-tert-Butoxycarbonylamino-propionic acid (1.54 g, 8.12 mmol), Amino-pyridin-2-yl-acetic acid methyl ester (1.35 g, 8.12 mmol) and HATU (3.1 g, 8.12 mmol) was added the DMF (20 mL) and Et3N (2.26 ml, 16.20 mmol) and the solution was stirred for 2 h. The mixture was concentrated to remove most of the DMF was removed. The resulting oil was dissolved in EtOAc, washed with water, 0.1 N HCl aq., 1 N NaHCO3 aq., followed by Brine. The combined organics were dried over MgSO4, filtered, and concentrated in vacuo to provide ((S)-2-tert-Butoxycarbonylamino-propionylamino)-pyridin-2-yl-acetic acid methyl ester (2.7 g, 98%) as a yellow oil, m/z 338.61 [M+1]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32]CC)=[O:31])=[CH:25][C:24]=2[O:35][CH3:36])=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16]([CH3:38])[N:17]2[CH3:37])(=[O:11])=[O:10].[OH-].[Li+].Cl>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[CH:25][C:24]=2[O:35][CH3:36])=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16]([CH3:38])[N:17]2[CH3:37])(=[O:11])=[O:10]
Reactant: CCOC(=O)Cc1ccc(Oc2ccc3c(cc(C)n3C)c2NS(=O)(=O)c2ccc(Cl)cc2Cl)c(OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(CC(=O)O)ccc1Oc1ccc2c(cc(C)n2C)c1NS(=O)(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a room temperature solution of 3.4 (25 mg, 0.043 mmol) dissolved in a mixture of tetrahydrofuran (2 mL) and methanol (1 mL) was added a solution of lithium hydroxide (50 mg, 2.1 mmol) dissolved in water (1 mL). The reaction was stirred at room temperature for 1 h then poured into aqueous 1N hydrochloric acid solution. The aqueous mixture was extracted twice with ethyl acetate. The combined organic extracts were washed twice with water then brine, stirred over magnesium sulfate, filtered and the filtrate concentrated in vacuo on a rotary evaporator to afford a colorless solid. LC-MS ESI (neg.) m/z: 547.0 (M−H). 1H NMR (400 MHz) (d6-DMSO) δ 12.30 (br s, 1H); 9.80 (br s, 1H); 7.63 (d, J=8.8 Hz, 1H); 7.53 (d, J=2.0 Hz, 1H); 7.31 (dd, J=2.4 & 8.8 Hz, 1H); 7.22 (d, J=8.8 Hz, 1H); 6.89 (d, J=1.6 Hz, 1H); 6.59 (d, J=1.6 Hz, 1H); 6.39 (d, J=8.8 Hz, 1H); 6.23 (dd, J=3.6 & 3.6 Hz, 1H); 3.70 (s, 3H); 3.63 (s, 3H); 3.52 (s, 2H): 2.41 (s, 3H) ppm.
Reaction SMILES: [CH:1]([NH:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][C:13]([CH:18]=[CH:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:12][C:11]=3[N:10]=[C:9]([NH2:26])[C:8]=2[N:7]=[C:6]1[CH2:27][CH2:28][CH3:29])([CH3:3])[CH3:2]>CCO.CO.[Pd]>[CH:1]([NH:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][C:13]([CH2:18][CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:12][C:11]=3[N:10]=[C:9]([NH2:26])[C:8]=2[N:7]=[C:6]1[CH2:27][CH2:28][CH3:29])([CH3:3])[CH3:2]
Reactant: CCCc1nc2c(N)nc3cc(C=Cc4cccnc4)ccc3c2n1NC(C)C
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CCCc1nc2c(N)nc3cc(CCc4cccnc4)ccc3c2n1NC(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 23.1 %

Procedure:
A solution of N1-isopropyl-2-propyl-7-(2-pyridin-3-yl-vinyl)-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.97 g, 2.5 mmol) in 15 mL of EtOH and 15 mL of MeOH was treated with palladium on carbon (0.10 g, 0.050 mmol, 5% w/w). The mixture was placed under an atmosphere of hydrogen (3.8×105 Pa) and shaken at ambient temperature. After 3 d, the reaction mixture was filtered through a pad of CELITE filter agent and rinsed with a 1:1 MeOH:EtOH until the filtrate ran clear. The filtrate was concentrated under reduced pressure to yield a light green solid. The solid was purified by chromatography (SiO2, 10–50% (80:18:2 CHCl3:MeOH:NH4OH) in CHCl3) to yield a clear oil. The oil was twice crystallized from MeCN to give N1-isopropyl-2-propyl-7-(2-pyridin-3-ylethyl)-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.224 g) as white crystals. mp 100–103° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.43 (d, J=1.6 Hz, 1H), 8.37 (dd, J=3.8, 1.6 Hz, 1H), 8.32 (d, J=8.4 Hz, 1H), 7.68–7.64 (m, 1H), 7.37 (d, J=1.5 Hz, 1H), 7.31–7.26 (m, 1H), 7.12 (dd, J=8.4, 1.7 Hz, 1H), 6.93 (d, J=1.4 Hz, 1H), 6.39 (s, 2H), 3.52–3.44 (m, 1H), 3.00 (s, 4H), 2.89 (bs, 2H), 1.91–1.79 (m, 2H), 1.04–1.00 (m, 9H); 13C NMR (125 MHz, DMSO-d6) δ 154.2, 152.0, 150.1, 147.5, 145.0, 139.6, 137.2, 136.3, 132.8, 125.4, 123.9, 123.7, 122.0, 121.1, 113.1, 51.2, 37.0, 34.1, 28.2, 21.1, 20.6, 14.3; MS (APCI) m/z 389 (M+H)+; Anal. Calcd for C23H28N6: C, 71.10; H, 7.26; N, 21.63; Found: C, 70.87; H, 7.54; N, 21.58.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][C@@H:6]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[N:7]1[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][CH2:14][CH2:15][C:16](=O)[CH3:17])[C:8]1=[O:19])[CH3:2].[NH2:28][C:29]1[C:34]([CH:35]=O)=[CH:33][CH:32]=[CH:31][N:30]=1.N1CCC[C@H]1C(O)=O>C(O)C>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][C@@H:6]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[N:7]1[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:35][C:34]3[C:29](=[N:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)[C:8]1=[O:19])[CH3:2]
Reactant: Nc1ncccc1C=O
Reactant: CCOC(=O)C[C@@H](c1cccc(F)c1)N1CCCC(CCCC(C)=O)C1=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C[C@@H](c1cccc(F)c1)N1CCCC(CCCc2ccc3cccnc3n2)C1=O

Procedure:
A mixture of 2-7 (450 mg, 1.2 mmol), 2-amino-3-formylpyridine (145 mg, 1.2 mmol; for prep., see JOC 1983,48, 3401) and proline (137 mg, 1.2 mmol) in absolute ethanol (20 mL) was heated at reflux for 12 h. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 50% ethyl acetate/chloroform to 70:25:5 chloroform/ethyl acetate/MeOH) to give 2-8 as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:9]=[CH:10][C:5]2=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH2:24]([CH2:26][NH2:27])[OH:25]>CN1C(=O)CCC1>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:4]1[N:3]=[C:2]([NH:27][CH2:26][CH2:24][OH:25])[N:7]=[C:6]2[N:8]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:9]=[CH:10][C:5]=12
Reactant: Clc1nc(-c2ccco2)c2cnn(CCc3ccccc3)c2n1
Reactant: NCCO
Solvent: CN1CCCC1=O
Product: OCCNc1nc(-c2ccco2)c2cnn(CCc3ccccc3)c2n1
Temperature: 100 °C
Yield: 57.2 %

Procedure:
A solution of 6-chloro-4-(2-furyl)-1-(2-phenylethyl)-1H-pyrazolo[3,4-d]pyrimidine (162 mg, 0.5 mmol) in NMP (1 mL) was treated with ethanolamine (60 μL, 1 mmol), heated at 100° C. for 16 h, cooled and purified by chromatography (EtOAc:Heptane, 2:1). The resulting colourless oil was crystallised (MeOH/water) and filtered to give the title compound (100 mg, 57%) as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([N+:26]([O-])=O)[CH:22]=[CH:23][CH:24]=3)[C:19]([CH:29]3[CH2:31][CH2:30]3)=[N:18]2)=[N:13][C:14]=1[CH3:15])C1C=CC=CC=1>CCO.[Pd]>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:20]=1[C:19]([CH:29]1[CH2:31][CH2:30]1)=[N:18][N:17]2[CH2:16][C:12]1[N:13]=[C:14]([CH3:15])[C:9]([OH:8])=[CH:10][CH:11]=1
Reactant: Cc1nc(Cn2nc(C3CC3)c3c([N+](=O)[O-])cccc32)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Cc1nc(Cn2nc(C3CC3)c3c(N)cccc32)ccc1O
Reaction time: 3 h
Yield: 86 %

Procedure:
To 1-((5-(benzyloxy)-6-methylpyridin-2-yl)methyl)-3-cyclopropyl-4-nitro-1H-indazole (5.1 g, 12.3 mmol) in EtOH (100 mL) was carefully added Pd/C (10%, 1.5 g, 1.41 mmol). The reaction mixture was evacuated with N2 and H2 (three times each), and stirred under a H2 balloon for 3 hours. The reaction mixture was then evacuated with N2, filtered through Celite® and washed with MeOH. The filtrate was concentrated to give the desired product (86%) which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[CH2:9][N:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=O)=[O:12])[C:4]=2[CH:3]=1.CN1CCOCC1.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1>>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[CH2:9][N:10]([C:11]([NH:13][CH2:14][C:15]([NH:31][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[O:17])=[O:12])[C:4]=2[CH:3]=1
Reactant: O=C(O)CNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: NCCc1ccccn1
Solvent: CN1CCOCC1
Product: O=C(CNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21)NCCc1ccccn1
Yield: 55.2 %

Procedure:
By the method described in Example 5, the title compound of Example 4 (0.5 g, 1.5 mmol) in 20 mL of CH2CL2 was converted to its mixed anhydride with NMM (0.16 mL, 1.5 mmol) and IBCF (0.2 mL, 1.5 mmol) and coupled to 2-(2-aminoethyl)pyridine (0.18 mL, 1.5 mmol). This procedure gave 362 mg of the title compound after Chromatotron® chromatography eluting with 5% ethanol (EtOH)/CH2CL2 containing 1% ammonium hydroxide (NH4OH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:28])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[C@H:29]1([CH2:37]O)[CH2:34][CH2:33][C@H:32]([CH2:35][OH:36])[CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:28][CH2:37][CH:29]3[CH2:34][CH2:33][CH:32]([CH2:35][OH:36])[CH2:31][CH2:30]3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: OC[C@H]1CC[C@H](CO)CC1
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Product: O=C1c2ccccc2C(OCC2CCC(CO)CC2)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Yield: 71.1 %

Procedure:
The named compound was synthesised from 3-(4-Chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (400 mg, 1.01 mmol, 1 equiv.) and trans-cyclohexane-1,4-dimethanol (728 mg, 5.05 mmol, 5 equiv.) using General Procedure A and obtained as a yellow solid (374 mg, 71%). 1H NMR (300 MHz, CDCl3): 8.05-7.92 (m, 3H, O2N—C—CH and C(O)═C═CH), 7.56-7.53 (m, 2H, Ar—H), 7.38-7.10 (m, 7H, Ar—H), 4.59 and 4.35 (d: AB, J=15.0 Hz, 2H, N—CH2), 3.44 (d, J=6.3 Hz, 2H, HO—CH2), 2.65-2.53 (m, 2H, OCH2), 1.81-1.74 (m, 3H, OH and CH), 1.44-1.32 (m, 2H), 0.93-0.79 (m, 5H). 13C NMR (75 MHz, CDCl3): 168.26, 145.41, 144.82, 137.42, 134.84, 132.93, 130.01, 128.63, 128.01, 123.80, 123.24, 123.18, 94.67, 68.41, 68.26, 42.41, 40.59, 38.04, 29.68, 29.31, 28.90. m/z (ES): 521 [M+H]+. Anal.: calc. for C29H29ClN2O5+0.2 H2O: C, 66.38; H, 5.66; N, 5.34. Found: C, 66.23; H, 5.79; N, 4.99.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:10])[C:5](=[CH:7][C:8]=1[Cl:9])[OH:6].[C:11](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][C:5]([OH:6])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(Cl)c(Cl)cc1O
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(Cl)cc1O
Temperature: 130 °C
Reaction time: 20 h
Yield: 45.2 %

Procedure:
A suspension of 4,5-dichlorocatechol (1 g, 5.62 mmol), potassium carbonate (780 mg, 5.62 mmol), and methyl iodide (0.34 mL, 5.62 mmol) in N,N-dimethylformamide (20 mL) was stirred rapidly at 130° C. for 20 hours, under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature before diluting with ethyl acetate (50 mL). The mixture was washed with water (50 mL), saturated aqueous sodium bicarbonate (50 mL), and saturated brine solution (50 mL). The organic layer was separated and dried over sodium sulphate, and evaporated under reduced pressure to a deep brown solid. The crude material was purified by flash chromatography (eluting with 1:1 heptane/dichloromethane) to afford 4,5-dichloro-2-methoxyphenol as a white solid (490 mg, 45%).
Reaction SMILES: [CH2:1]([O:3][CH:4]1[CH:8]([NH:9][C:10]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17](=[O:35])[CH:18]([NH:20][C:21](=[O:34])[C:22]2[CH:27]=[C:26]([Cl:28])[C:25]([O:29]CC=C)=[C:24]([Cl:33])[CH:23]=2)[CH3:19])=[O:11])[CH2:7][C:6](=[O:36])[O:5]1)[CH3:2].CC1C2C(=CC=CC=2)C(C)=C2C=1C=CC1C2=CC=CC=1.C(Cl)Cl.CO>C(Cl)Cl.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>[CH2:1]([O:3][CH:4]1[CH:8]([NH:9][C:10]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17](=[O:35])[CH:18]([NH:20][C:21](=[O:34])[C:22]2[CH:23]=[C:24]([Cl:33])[C:25]([OH:29])=[C:26]([Cl:28])[CH:27]=2)[CH3:19])=[O:11])[CH2:7][C:6](=[O:36])[O:5]1)[CH3:2]
Reactant: C=CCOc1c(Cl)cc(C(=O)NC(C)C(=O)N2CCCC2C(=O)NC2CC(=O)OC2OCC)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1c2ccccc2c(C)c2c1ccc1ccccc12
Solvent: ClCCl
Solvent: CO
Product: CCOC1OC(=O)CC1NC(=O)C1CCCN1C(=O)C(C)NC(=O)c1cc(Cl)c(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
To a solution of 110 (194 mg, 0.36 mmol) in CH2Cl2 (5 ml) was added DMBA (70.7 mg, 0.45 mmol) and Pd(PPh3)4 (50.3 mg, 0.044 mmol) at 0° C. The solution was warmed to room temperature after 15 mins, stirred for 2 hours, diluted with CH2Cl2 then washed with water (2×) and brine. The organic layer was dried over anhydrous Na2SO4 and evaporated to give the crude product. Flash chromatography using CH2Cl2/MeOH (99/1 to 95/5%) afforded the title compound (138.6 mg, 77% yield). 1H-NMR (500 MHz, CD3OD) δ 1.13-1.31 (m, 3H), 1.35-1.49 (m, 3H), 1.84-2.35 (m, 4H), 2.43-3.05 (m, 2H), 3.48-3.93 (m, 4H), 4.22-4.80 (m, 3H), 5.38 (d, 0.4H), 5.46 (s, 0.1H), 5.55-5.61 (m, 0.5H), 7.76-7.94 (m, 2H). Analytical HPLC 8.70 min. LC-MS (ES+) m/e=502.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[Br:12].[H-].[Na+].Cl[CH2:16][C:17]1[CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH:21]=1.O>CN(C)C=O>[Br:12][C:3]1[CH:4]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:6]=[CH:7][C:2]=1[NH:1][CH2:16][C:17]1[CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH:21]=1
Reactant: Nc1ccc(C(F)(F)F)cc1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(CCl)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(CNc2ccc(C(F)(F)F)cc2Br)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.5 %

Procedure:
4-Amino-3-bromobenzotrifluoride (15.0 g, 62.5 mmol) was dissolved in N,N-dimethylformamide (400 mL). Thereafter, sodium hydride (5.0 g, 126 mmol) was added to the above obtained solution under cooling on ice, and the thus obtained mixture was then stirred at room temperature for 2 hours. Thereafter, an N,N-dimethylformamide (30 mL) solution of the tert-butyl 3-(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (9.20 g, 42.0 mmol) synthesized by a method described in the known methods (European Journal of Organic Chemistry, 4264-4276; 2008 etc.) or a method similar thereto was further added to the reaction solution under cooling on ice, and the thus obtained mixture was then stirred at room temperature for 3 hours. Subsequently, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (hexane ethyl acetate=3:1) to obtain tert-butyl 3-(((2-bromo-4-(trifluoromethyl)phenyl)amino)methyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (6.46 g, 37%) in the form of a colorless amorphous product.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6]C=C[C:3]=1[S:8]([N:11]1[C:19]2[C:14](=[C:15]([CH:20]=[CH2:21])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)(=[O:10])=[O:9].BrC1C=CC=C2C=1C=CN2[S:32](C1SC=CC=1)(=O)=O.C([Sn](CCCC)(CCCC)C=C)CCC>>[S:32]1[CH:6]=[CH:7][CH:2]=[C:3]1[S:8]([N:11]1[C:19]2[C:14](=[C:15]([CH:20]=[CH2:21])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)(=[O:10])=[O:9]
Reactant: O=S(=O)(c1cccs1)n1ccc2c(Br)cccc21
Reactant: C=Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1C
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Product: C=Cc1cccc2c1ccn2S(=O)(=O)c1cccs1
Yield: 79 %

Procedure:
The experimental for Intermediate 15 was followed using 4-bromo-1-(2-thienylsulfonyl)-1H-indole (500 mg, 1.46 mmol; Intermediate 20), tributyl(vinyl)stannane (tot 0.864 mL, 2.92 mmol) and Pd(PPh3)2OAc2 (tot 55 mg, 0.073 mmol). The title compound (333 mg, 79%) was obtained as a colorless solid. MS (ESI+) for C14H11NO2S2 m/z 290 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:34][C:20]3[N:21]=[CH:22][N:23]=[C:24]([NH:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=4)[C:19]=3[CH:18]=2)=[CH:13][CH:12]=1)C.C1COCC1.O.[OH-].[Na+]>C1COCC1.O>[Cl:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[CH2:26][NH:25][C:24]1[C:19]2[CH:18]=[C:17]([C:14]3[CH:13]=[CH:12][C:11]([CH2:10][OH:9])=[CH:16][CH:15]=3)[NH:34][C:20]=2[N:21]=[CH:22][N:23]=1
Reactant: CCOC(=O)c1ccc(-c2cc3c(NCc4cccc(Cl)c4)ncnc3[nH]2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(-c2cc3c(NCc4cccc(Cl)c4)ncnc3[nH]2)cc1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
2.236 g (0.059 mol) lithium aluminum hydride are suspended in 600 ml dry THF at RT. 4-[4-(3-Chloro-benzylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoic acid ethyl ester (4.8 g, 0.0118 mol) is added in portions over 5 min and the resulting mixture is heated to 60° C. for 1 h. The mixture is cooled in an ice bath to about 10° C. and treated sequentially with THF/water 1:1 (2.24 ml), 15% sodium hydroxide solution (4.48 ml) and water (6.72 ml). The solid aluminum complex is removed by filtration (Hyflo Super Cel®; Fluka, Buchs, Switzerland) and washed thoroughly with THF. The filtrate is concentrated to about 50 ml and the resulting suspension treated with water/ethanol 9:1 (50 ml). After stirring for 10 min the crystals were collected by filtration and dried under reduced pressure to give the title compound; m.p. 296-298° C.; MS-ES+: (M+H)+=365.
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:12][C:13]1[C:18]([F:19])=[CH:17][N:16]=[C:15]([Cl:20])[N:14]=1)[C:8]([CH3:11])([CH3:10])[CH3:9])(=O)=O.[N-:21]=[N+:22]=[N-:23].[Na+].O>CN(C=O)C>[N:21]([CH2:6][C@@H:7]([NH:12][C:13]1[C:18]([F:19])=[CH:17][N:16]=[C:15]([Cl:20])[N:14]=1)[C:8]([CH3:11])([CH3:10])[CH3:9])=[N+:22]=[N-:23]
Reactant: CC(C)(C)[C@@H](COS(C)(=O)=O)Nc1nc(Cl)ncc1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[C@@H](CN=[N+]=[N-])Nc1nc(Cl)ncc1F
Temperature: 70 °C

Procedure:
A mixture of (S)-2-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3,3-dimethylbutyl methanesulfonate, 75a, (2.37 g, 7.26 mmol) and sodium azide (1.89 g, 29.07 mmol) in DMF (50 mL) was heated at 70° C. for 6 hours. The reaction mixture was cooled to room temperature and poured into water. The aqueous phase was extracted with EtOAc (2×25 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified via silica gel chromatography (0-20% EtOAc/Hexanes gradient) to afford 1.2 g of the desired product as a white crystalline solid: 1H NMR (400 MHz, CDCl3) δ 7.86 (dd, J=2.6, 1.1 Hz, 1H), 5.07 (m, 1H), 4.32-4.09 (m, 1H), 3.60 (dd, J=12.8, 3.9 Hz, 1H), 3.34 (dd, J=12.8, 7.6 Hz, 1H), 0.96 (m, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=3.28 minutes (M+H) 273.14.