Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][C:4]1([C:13]([F:16])([F:15])[F:14])[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5]1.[Br:19]Br>C(Cl)(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Br:19][C:11]1[CH:10]=[CH:9][C:7]2[O:8][C:4]([CH2:3][C:2]([F:1])([F:17])[F:18])([C:13]([F:15])([F:14])[F:16])[O:5][C:6]=2[CH:12]=1
Reactant: BrBr
Reactant: FC(F)(F)CC1(C(F)(F)F)Oc2ccccc2O1
Agent: Cl[Fe](Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)CC1(C(F)(F)F)Oc2ccc(Br)cc2O1

Procedure:
54.4 g of 2-(2,2,2-trifluoroethyl)-2-trifluoromethyl-1,3-benzodioxole were dissolved in 300 ml of carbon tetrachloride, and 0.4 g of anhydrous iron(III) chloride was added. 32 g of bromine were then added dropwise at the reflux temperature and the mixture was subsequently stirred until conversion was complete (monitoring by gas chromatography). The reaction mixture was then left to cool, washed with 10% by weight aqueous sodium hydrogen-sulphite solution and water, dried over magnesium sulphate and concentrated. The residue was distilled under vacuum. The yield was 58 g (83% of theory) and the boiling point was 80° C. at 14 mbar. The characteristic absorptions in the NMR spectra were as follows: 19F NMR: -59.2 and -84.9 ppm. 1H NMR: 3.02 ppm.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH:5]([CH2:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:6]([O:8]CC)=[O:7])C.[OH-].[K+]>C(O)C.O>[CH2:15]([CH:12]([CH2:13][CH3:14])[CH2:11][CH:5]([C:6]([OH:8])=[O:7])[C:4]([OH:17])=[O:3])[CH3:16]
Reactant: CCOC(=O)C(CC(CC)CC)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC(CC)CC(C(=O)O)C(=O)O
Temperature: 105 °C
Yield: 96.7 %

Procedure:
A solution of 2-(2-ethyl-butyl)-malonic acid diethyl ester (4.78 g, 19.5 mmol) in ethanol (43.5 mL) was treated with a solution of potassium hydroxide (3.3 g, 58.7 mmol) in water (10.9 mL). The reaction was then heated to 105° C. for 6 h. After this time, the reaction was concentrated in vacuo. The residue was diluted with water (50 mL) which was then acidified with a 2N aqueous hydrochloric acid solution and then extracted with a 90/10 methylene chloride/methanol solution (3×50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-(2-ethyl-butyl)-malonic acid (3.55 g, 96%) as an off-white solid, which was used without further purification; EI+-HRMS m/e calcd for C9H16O4 [M+Na]+ 211.0941, found 211.0941. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.79 (t, J=7.4 Hz, 6H) 1.09-1.39 (m, 5H) 1.65 (t, J=7.1 Hz, 2H) 3.22 (t, J=7.5 Hz, 1H) 12.65 (br. s., 2H).
Reaction SMILES: [C:1]([C:4]1[C:5]([Cl:12])=[N:6][C:7]([Cl:11])=[N:8][C:9]=1Cl)([OH:3])=[O:2].[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:17][NH2:18].C(N(CC)CC)C>CN(C)C=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:17][NH:18][C:9]1[C:4]([C:1]([OH:3])=[O:2])=[C:5]([Cl:12])[N:6]=[C:7]([Cl:11])[N:8]=1
Reactant: O=C(O)c1c(Cl)nc(Cl)nc1Cl
Reactant: COc1ccc(CN)cc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nc(Cl)nc(Cl)c2C(=O)O)cc1Cl
Reaction time: 1 h

Procedure:
To a solution of 5-carboxy-2,4,6-trichloropyrimidine 10.0 g in dimethylformamide 45 ml is added a suspension of 3-chloro-4-methoxybenzylamine 4.82 g and triethylamine 6.98 ml in dimethylformamide 40 ml over a period of 20 minutes on ice bath, and the mixture is stirred for 1 hour. The reaction mixture is diluted with a 10% aqueous citric acid solution and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo to give 4-(3-chloro-4-methoxybenzylamino)-5-carboxy-2,6-dichloropyrimidine as a pale brown solid, 17.59 g. mp 150-151° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=3)[C:9]([S:17][CH3:18])=[C:8]2[CH:19]([CH3:25])[C:20]([O:22]CC)=[O:21])=[CH:4][CH:3]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=3)[C:9]([S:17][CH3:18])=[C:8]2[CH:19]([CH3:25])[C:20]([OH:22])=[O:21])=[CH:26][CH:27]=1
Reactant: CCOC(=O)C(C)c1c(SC)c2cc(F)ccc2n1Cc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CSc1c(C(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(F)cc12

Procedure:
Following the procedure of Preparation 6, but using ethyl 1-(p-chlorobenzyl)-5-fluoro -α-methyl-3-methylthioindole-2-acetate from Step 1 as starting material and tetrahydrofuran as solvent, the title compound was prepared, mp 136°-140°.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:17][CH:16]=1)C1C=CC=CC=1>[Pd].CO>[CH3:26][N:24]([CH3:25])[CH2:23][CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH2:10])=[CH:16][CH:17]=1
Reactant: CN(C)CCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CN(C)CCOc1ccc(CCCCN)cc1
Yield: 76.2 %

Procedure:
The protected amine 62 (0.552 g, 1.5 mmol) was stirred with 10% palladium on carbon (0.127 g, wet) in methanol (50 mL) at room temperature for 3.5 h under hydrogen (1 atm). After this time, the catalyst was filtered off and the solvent was removed under reduced pressure to give the free amine 63 (0.27 g, 77%) as a white powder. 1H NMR (300 MHz, CD3OD) δ 1.55 (m, 4H), 2.32 (s, 6H), 2.54 (m, 2H), 2.75 (m, 2H), 4.02 (m, 2H), 6.78 (d, 2H), 7.08 (d, 2H).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[O:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:36](=[O:37])[C:35]5[CH:34]=[CH:33][C:32]([N:29]6[CH2:30][CH2:31][O:26][CH2:27][CH2:28]6)=[CH:40][CH:39]=5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)c1ccc(N2CCOCC2)cc1

Procedure:
The title compound, white solid (31.1 mg, 73.2%), MS (ISP) m/z=520.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0818 mmol) and 4-morpholinobenzoic acid.
Reaction SMILES: [OH-:1].[Na+].N[CH2:4][C:5]([OH:7])=O>>[O:1]=[CH:4][C@@H:5]([C@H:4]([C@@H:5]([C@@H:4]([CH2:5][OH:7])[OH:1])[OH:7])[OH:1])[OH:7]
Reactant: NCC(=O)O
Reactant: [OH-]
Agent: [Na+]
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 28 °C
Reaction time: 24 h

Procedure:
The BIBB 10 medium was adjusted to pH 7.0 with 10% sodium hydroxide solution before sterilization. The culture medium was shaken on a rotary shaker at 260 rpm for 24 hours at 28° C., then 3 ml of same were inoculated into 100 ml of fresh BIBB 10 medium supplemented with 0.5% of glycine before inoculation. These cultures were cultivated for 18 hours under the above cultural environment, and after checking the cells were collected by centrifugation (3500 rpm, 10 min.). The mycelium derived from 100 ml of the culture broth was suspended in 4 ml of PH mixture (pH 7.0) containing the following components:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:36]([CH3:37])=[CH:35][C:14]2[N:15]=[C:16]([C:18]3[N:23]=[C:22]4[C:24]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)=[N:25][N:26]([CH3:27])[C:21]4=[CH:20][CH:19]=3)[S:17][C:13]=2[C:12]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:11]1[C:36]([CH3:37])=[CH:35][C:14]2[N:15]=[C:16]([C:18]3[N:23]=[C:22]4[C:24]([N:28]5[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]5)=[N:25][N:26]([CH3:27])[C:21]4=[CH:20][CH:19]=3)[S:17][C:13]=2[C:12]=1[C:38]1[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(n3)c(N3CCN(C)CC3)nn4C)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2nc(-c3ccc4c(n3)c(N3CCN(C)CC3)nn4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 45 °C

Procedure:
To a solution of (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-3-(4-methylpiperazin-1-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)benzo[d]thiazol-6-yl)acetate (11 mg, 0.017 mmol) in THF (0.5 mL) and MeOH (0.5 mL) was added 2N NaOH (174 μL). The reaction mixture was heated at 45° C. overnight. The reaction mixture was concentrated, the residue was dissolved in DMF and MeOH, filtered and purified by reverse phase HPLC (10-100% ACN/H2O+0.1% TFA) to give the product. 1H NMR (400 MHz, CD3OD) δ 8.33 (d, J=4.4 Hz, 1H), 7.97 (d, J=4.4 Hz, 1H), 7.85 (s, 1H), 7.70-7.57 (m, 4H), 5.22 (s, 1H), 4.75-4.74 (m, 2H), 3.92 (s, 3H), 3.61-3.59 (m, 2H), 3.36-3.34 (m, 4H), 2.94 (s, 3H), 2.61 (s, 3H), 0.96 (s, 9H). .LCMS-ESI+: calc'd for C32H35ClN6O3S: 619.2 (M+H+); Found: 619.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH:16](O)=[O:17].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:2]([NH:1][CH:16]=[O:17])[CH:7]=1
Reactant: O=CO
Reactant: Nc1cc(Cl)ccc1Oc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=CNc1cc(Cl)ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-amino-5-chloro-2-phenoxybenzene (1.00 g, 4.55 mmol), formic acid (0.34 mL, 9.10 mmol), TBTU (1.46 g, 4.55 mmol), DIEA (2.38 mL, 13.6 mmol) and DCM (20 mL) was stirred at rt for 2 h. The solution was transferred to a separatory funnel, 20 mL of sat. aq. NaHCO3 solution was added and the mixture was extracted DCM. The organics were combined and dried (Na2SO4). Solvent was removed under reduced pressure to give a crude residue which was purified via flash chromatography, eluting with 5% EtOAc in hexanes.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH2:14][C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:24]=1[NH2:25])=[CH:22][CH:21]=[CH:20][CH:19]=2>CN(C)P(N(C)C)(N(C)C)=O.C(#N)C>[NH2:25][C:24]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][C:15]=1[NH:14][C:7]([C:5]1[S:6][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: Nc1cnc2ccccc2c1N
Reactant: Cc1ccc(C(=O)O)s1
Solvent: CC#N
Solvent: O=S(Cl)Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1ccc(C(=O)Nc2cnc3ccccc3c2N)s1
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a solution of 555 mg of 5-methylthiophene-2-carboxylic acid in 9 ml of anhydrous hexamethylphosphoramide and 0.9 ml of anhydrous acetonitrile is added dropwise 455 mg of thionyl chloride at -5°-0° C. under nitrogen. After stirring at the same temperature for 30 minutes, 570 mg of 3,4-diaminoquinoline is added and stirred at 0°-5° C. for 4 hours. The same work-up as described in Example 1 gives 900 mg of 4-amino-3-(5-methylthien-2-ylcarbonylamino)quinoline B4 as a white solid. It is suspended in 15 g of polyphosphate ester and heated at 125° C. with stirring for 3 hours. The mixture is diluted with ice-water and neutralized with 1N sodium hydroxide and extracted with ethyl acetate. The extract is washed with water and saturated sodium chloride, dried over magnesium sulfate, and evaporated. The residue is chromatographed on silica gel with chloroform-methanol (10:1 v/v) as eluent to give 456 mg (48%) of C4 as pale yellow crystals.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1.[Br:14]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:14][C:5]1[O:1][C:2]([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=2)=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc(-c2ccco2)nc1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccc(Br)o2)nc1
Yield: 90.4 %

Procedure:
Continuing with Scheme 1, to a solution of 1 (5.1 g, 30 mmol) in DMF (20 mL) was added portionwise N-bromosuccinimide (5.87 g, 33 mmol) with stirring. The reaction mixture was stirred overnight, then poured onto cold-water. The precipitate that formed was collected, washed with water and dried to give the analytically pure product 2 in 90.4% yield, mp 196° C. 1H nmr (DMSO-d6); δ 6.86 (d, J=3.6 Hz, 1H), 7.38 (d, J=3.6 Hz, 1H), 7.86 (d, J=8.1 Hz, 1H), 8.33 (dd, J=8.1, 2.1 Hz, 1H). 8.98 (d, J=2.1 Hz, 1H). 13C nmr; δ 153.4, 152.7, 149.6, 140.9, 125.4, 117.9, 117.0, 115.0, 114.9, 106.9. MS (m/z, rel.int.); 248 (M+, 100), 220 (10), 169 (25), 141 (80), 114 (30). Calcd for C10H5BrN2O: C, 48.22; H, 2.02; N, 11.25. Found. C, 48.47; H, 2.01; N, 11.34.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:8]([C:19]([F:22])([F:21])[F:20])[CH:7]=1)=O.CO.C([O-])([O-])=O.[K+].[K+]>O>[F:22][C:19]([F:20])([F:21])[C:8]1[CH:7]=[C:6]([NH2:5])[CH:11]=[CH:10][C:9]=1[CH2:12][N:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=C(Nc1ccc(CN2CCCCC2)c(C(F)(F)F)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Nc1ccc(CN2CCCCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,2,2-trifluoro-N-(4-piperidin-1-ylmethyl-3-trifluoromethyl-phenyl)-acetamide (Stage 128.2; 1.427 g, 4.03 mmol) in boiling methanol (42 ml), 20 ml of a 1 N solution of K2CO3 in water are added dropwise. After 2 h stirring, the reaction mixture is cooled to rt, concentrated in vacuo and the residue re-dissolved in AcOEt and water. The aqueous layer is separated off and extracted twice with AcOEt. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated to yield the title compound: MS: [M+1]+=259; 1H-NMR (DMSO-d6): 7.28 (d, 1H), 6.82 (d, 1H), 7.73 (dd, 1H), 5.40 (s, H2N), 3.32 (s, 2H), 2.27 (sb, 4H), 1.46 (m, 4H), 1.39 (m, 2H).
Reaction SMILES: Cl.Cl.[OH:3][CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH:5]1[N:10]1[CH2:15][CH2:14][C:13]2([C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)[CH2:12][CH2:11]1.[I:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br.C(N(CC)CC)C>CCO>[I:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][N:7]1[CH2:8][CH2:9][CH:4]([OH:3])[CH:5]([N:10]2[CH2:15][CH2:14][C:13]3([C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16]3)[CH2:12][CH2:11]2)[CH2:6]1
Reactant: BrCc1cccc(I)c1
Reactant: OC1CCNCC1N1CCC2(CCCc3ccccc32)CC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC1CCN(Cc2cccc(I)c2)CC1N1CCC2(CCCc3ccccc32)CC1

Procedure:
A mixture of 21c and 22c derived from a mixture of 19c and 20c as described above (676 mg, 1.81 mmol), 3-iodobenzylbromide (2.17 mmol, 645 mg), and triethylamine (10 mL) in absolute EtOH (20 mL) was refluxed for 18 h. Volatiles were removed under reduced pressure and the red residue was treated with water. After extraction in dichloromethane (3×30 mL), the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give a dark red semi-solid residue. Chromatographic purification (silica gel, 50% ethyl acetate-hexanes) afforded 276 mg (30%) of the crude product as a yellow oil. The two regioisomers were separated by HPLC (Silica gel, Hexane/Isopropanol/Triethylamine: 98/2/0.02) and 13d was obtained as a white crystalline solid (166 mg, 18%). Only a trace of the other isomer was recovered. The hydrochloride of 13d was prepared in said methanolic saturated HCl and subsequently recrystallized from 50% i-PrOH-hexanes to provide a white powder; mp 245° C. 1H NMR ((CDCl3) δ1.59-2.06 (m, 8, 2 N--C H2 --C H2), 2.41-2.48 (m, 2, Ar--C H2 --CH2), 2.52-2.62 (m, 2, C H2 --CHOH), 2.75-2.78 (m, 4, Ar--CH2 --C H2 --C H2), 2.83-2.92 (m, 2, C H2 --CH2 --CHOH), 3.01-3.06 (d, 2, N--C H2 --CHN, J=10.0 Hz), 3.38-3.56 (m, 3, Ar--CH2 --N+CH--N), 3.85 (s, 1, C H--OH), 7.02-7.31 (m, 5, arom.), 7.44-7.48 (d, 1, arom., J=7.8 Hz), 7.58-7.62 (d, 1, arom., J=7.9 Hz), 7.68 (s, 1, arom.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]2=[N:17][CH:18]=[C:19]([CH2:21]O)[N:20]=[C:15]2[CH:14]=1.O=S(Cl)Cl.[N-:36]=[N+:37]=[N-:38].[Na+].CN(C=O)C>C(Cl)Cl>[N:36]([CH2:21][C:19]1[N:20]=[C:15]2[CH:14]=[C:13]([C:6]3[C:5]4[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=4)[N:8]([CH3:12])[CH:7]=3)[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[C:16]2=[N:17][CH:18]=1)=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(c1)c(-c1cc3nc(CO)cnc3n1COCC[Si](C)(C)C)cn2C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)c(-c1cc3nc(CN=[N+]=[N-])cnc3n1COCC[Si](C)(C)C)cn2C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.4 %

Procedure:
(6-(5-Methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanol (0.63 g, 1.4 mmol) in DCM (10 mL) was treated with SOCl2 (0.115 mL, 1.58 mmol) and stirred for about 15 min at ambient temperature. The solvents were evaporated then sodium azide (0.280 g, 4.31 mmol) and DMF (5 mL) were added. The mixture was then stirred at ambient temperature overnight. The solvent was evaporated and the residue was partitioned between water (30 mL) and EtOAc (25 mL). The aqueous layer was washed with EtOAc (15 mL) then the combined organic solutions were dried over anhydrous MgSO4, filtered, and concentrated to give 2-(azidomethyl)-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (0.58 g, 87%): LC/MS (Table 2, Method a) Rt=3.42 min; MS m/z: 464 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:16]1[NH:17][C:18]2[CH:24]=[C:23]([C:25]([OH:27])=O)[CH:22]=[CH:21][C:19]=2[N:20]=1.[CH3:28][NH:29][CH3:30].C1COCC1.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>[CH3:28][N:29]([CH3:30])[C:25]([C:23]1[CH:22]=[CH:21][C:19]2[N:20]=[C:16]([C:3]3[CH:4]=[C:5]([C:8]4[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=4)[CH:6]=[CH:7][C:2]=3[OH:1])[NH:17][C:18]=2[CH:24]=1)=[O:27]
Reactant: COc1ncccc1-c1ccc(O)c(-c2nc3ccc(C(=O)O)cc3[nH]2)c1
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ncccc1-c1ccc(O)c(-c2nc3ccc(C(=O)N(C)C)cc3[nH]2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 2-[2-hydroxy-5-(2-methoxy-pyridin-3-yl)-phenyl]-3H-benzoimidazole-5-carboxylic acid (containing 1 equivalent of DMA, 44 mg, 0.1 mmol), dimethylamine in THF (0.5 mL, 2 M, 1 mmol) and HATU (38 mg, 0.1 mmol) in DMF (1.5 mL) was added DIEA (26 mg, 0.2 mmol). The reaction mixture was stirred at room temperature for 1 h and heated at 65° C. for 15 h, and then evaporated under reduced pressure. The residue was purified by chromatography (500:10:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (31 mg, 80%). 1H NMR (MeOH-d4) δ 3.05 (s, 3H), 3.12 (s, 3H), 3.95 (s, 3H), 7.00-7.06 (2H), 7.31 (d, J=9 Hz, 1H), 7.52-7.75 (4H), 8.08-8.14 (2H). ESI-MS m/z 389.5 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1.[I:16]N1C(=O)CCC1=O>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][C:7]=1[I:16]
Reactant: O=C1CCC(=O)N1I
Reactant: O=C1OC(CO)CN1c1cccc(F)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C1OC(CO)CN1c1ccc(I)c(F)c1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A solution of alcohol 103 (10.74 g, 50.9 mmol) in trifluoroacetic acid (TFA, 50 mL) was treated with N-iodosuccinimide (12.03 g, 53.45 mmol, 1.05 equiv) at 25° C. and stirred for 2 h. When TLC and HPLC/MS showed the reaction was complete, the reaction mixture was concentrated in vacuo. The residue was then treated with H2O (100 mL) and 20% EtOAc/hexane (100 mL) at 25° C., and the resulting mixture was stirred at 25° C. for 30 min before being cooled to 0-5° C. for 2 h. The white solids were collected by filtration, washed with H2O (2×25 mL) and 20% EtOAc/hexane (2×25 mL), and dried in vacuo to afford the desired (SR)-3-(3-fluoro-4-iodo-phenyl)-5-hydroxymethyl-oxazolidin-2-one 104 (15.1 g, 88% yield) as an off-white powder. This product was directly used in subsequent reactions without further purification. 1H NMR (300 MHz, DMSO-d6) δ 3.58 (dd, 1H, J=4.2, 12.6 Hz), 3.67 (dd, 1H, J=3.0, 12.6 Hz), 3.67 (dd, 1H, J=6.3, 9.0 Hz), 4.07 (t, 1H, J=9.0 Hz), 4.72 (m, 1H), 5.21 (br. s, 1H, OH), 7.22 (dd, 1H, J=2.4, 8.4 Hz), 7.58 (dd, 1H, J=2.4, 11.1 Hz), 7.81 (dd, 1H, J=7.8, 8.7 Hz). C10H9FINO3, LCMS (EI) m/e 338 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:38][C:11]3[C:12](=[O:37])[N:13]([CH2:16][C:17]4[N:22]=[C:21]([O:23][CH2:24][C@H:25]5[CH2:29][CH2:28][CH2:27][N:26]5C(OC(C)(C)C)=O)[CH:20]=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:38][C:11]3[C:12](=[O:37])[N:13]([CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([O:23][CH2:24][C@H:25]5[CH2:29][CH2:28][CH2:27][NH:26]5)[N:22]=4)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccc(Cn2ncc3cc(-c4ccc(Cl)cc4)sc3c2=O)n1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1c2sc(-c3ccc(Cl)cc3)cc2cnn1Cc1cccc(OC[C@H]2CCCN2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl (2R)-2-{[(6-{[2-(4-chlorophenyl)-7-oxothieno[2,3-d]pyridazin-6(7H)-yl]methyl}pyridin-2-yl)oxy]methyl}pyrrolidine-1-carboxylate (380 mg, 0.69 mmol) was dissolved in 4M HCl in dioxane (1 mL) and stirred at ambient temperature for 3 h. The solvent was evaporated and the title compound was used directly in the next step. Yield: 310 mg (99%). 1H NMR (399.961 MHz, CDCl3) δ 8.39 (s, 1H), 7.89 (t, J=8.0 Hz, 1H), 7.59 (d, J=8.5 Hz, 2H), 7.50 (s, 1H), 7.41 (d, J=8.7 Hz, 2H), 7.15 (d, J=7.5 Hz, 1H), 7.07 (d, J=8.5 Hz, 1H), 5.59 (d, J=14.9 Hz, 1H), 5.42 (d, J=14.9 Hz, 1H), 4.83-4.71 (m, 1H), 4.58-4.51 (m, 1H), 4.17-4.06 (m, 1H), 3.47-3.28 (m, 2H), 2.27-2.02 (m, 3H), 1.98-1.84 (m, 1H). MS (ESI+) 453.2 (M+1H+)
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]2)=[C:4]([CH3:23])[C:3]=1[CH3:24].[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[N:7]=[N:6][C:5]([N:8]3[CH2:13][CH2:12][CH:11]([N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]3)=[C:4]([CH3:23])[C:3]=2[CH3:24])=[CH:28][CH:27]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1c(Cl)nnc(N2CCC(N(C)C(=O)OC(C)(C)C)CC2)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(-c2ccc(F)cc2)nnc(N2CCC(N(C)C(=O)OC(C)(C)C)CC2)c1C
Yield: 59.9 %

Procedure:
Heat a mixture of tert-butyl 1-(6-chloro-4,5-dimethylpyridazin-3-yl)piperidin-4-yl(methyl)carbamate (1.5 g, 4.23 mmol), 4-fluorophenylboronic acid (887 mg, 6.34 mmol), Cs2CO3 (5.51 g, 16.9 mmol) and (SP-4-1)-bis[bis(1,1-dimethylethyl)(4-methoxyphenyl)phosphine-κP]dichloro-palladium (J. Org. Chem. 2007, 72, 5104-5112) (29 mg, 0.042 mmol) in a mixture of 1,4-dioxane (30 mL) and H2O (10 mL) under N2 at 90° C. overnight. Partition the reaction mixture between H2O and CH2Cl2. Separate the layers, and extract the aqueous layer with CH2Cl2. Combine the organic layers, dry over Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by flash silica gel chromatography (gradient of 0 to 2% 2 M NH3/MeOH in CH2Cl2) to provide the title compound as a white foam (1.05 g, 60%). ES/MS m/z 415.2 (M+1).