Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@@H:5]([CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12]2[C:17](=[O:21])[O:18][CH2:19][CH2:20][C:11]3=2)[CH2:4][O:3]1.CS(O)(=O)=O.[CH3:27][OH:28]>>[CH3:27][O:28][C:17]([C:12]1[NH:13][C:14]2[C:10]([C:11]=1[CH2:20][CH2:19][OH:18])=[CH:9][C:8]([CH2:7][C@H:5]1[CH2:4][O:3][C:2](=[O:1])[NH:6]1)=[CH:16][CH:15]=2)=[O:21]
Reactant: O=C1N[C@@H](Cc2ccc3[nH]c4c(c3c2)CCOC4=O)CO1
Reactant: CO
Agent: CS(=O)(=O)O
Product: COC(=O)c1[nH]c2ccc(C[C@H]3COC(=O)N3)cc2c1CCO
Reaction time: 3 h
Yield: 93 %

Procedure:
To a suspension of 500 mg (1.74 mmoles) of the (S)-6-(2-oxo-1,3-oxazolidin-4-ylmethyl)-4,9-dihydro-3H-pyrano-[3,4-b]indol-1-one in 10 ml of methanol were added 0.12 ml (1.9 mmoles) of methanesulphonic acid. The mixture was left under stirring at the reflux temperature for 3 hours. The solvent was evaporated to dryness under reduced pressure, the residue dissolved with 10 ml of a saturated bicarbonate solution and extracted three times with dichloromethane. The combined organic phases were dried and evaporated to dryness and the evaporated solid recrystallised from ethanol to give 517 mg (93%) of the title ester as a yellow crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].P([O-])([O-])(O)=O.[Na+].[Na+].[C:19]([C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].NC1C=CC=CC=1>O.O1CCOCC1>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:1][C:2]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])(=[O:31])=[O:30])=[CH:25][CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: Nc1ccccc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)O)cc1
Reaction time: 0.17 h
Yield: 74.4 %

Procedure:
2-Amino-5-chlorobenzoic acid (200 g, 1.17 mol) was added to a solution of sodium hydrogen phosphate (497 g, 3.50 mol) in water (2.4 L) at 70° C. and was stirred until homogeneous (˜10 min). 4-tert-Butylbenzenesulfonyl chloride (353 g, 1.52 mol), dissolved in 800 mL p-dioxane, was added to the stirring aniline solution in a steady stream over a ½ hour period via a 1 liter addition funnel. The resultant mixture was stirred at 70° C. overnight. The following day, upon LCMS verification of consumption of the aniline, the reaction mixture was divided into two equal portions for ease of handling. Each portion was poured in a slow stream into two liters of rapidly stirring 2 M HCl/H2O in a four liter Erlenmeyer flask. The resultant precipitate was collected by vacuum filtration and washed well with water. The precipitate from each portion were subsequently combined and dried in vacuo to afford 320 g 2-(4-tert-butyl-benzenesulfonylamino)-5-chloro-benzoic acid as an off-white solid (87% yield): HPLC retention time=2.76 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C., using a 1 mL/min flow rate, a 2.5 minute gradient of 20-100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/5% water/94.9% acetonitrile)); MS (ES) M+H expected 368.0, found 368.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][N:7]=1.[Br-:9].[K+].C([O-])(=O)C.[K+].BrBr.S([O-])([O-])=O.[Na+].[Na+]>O>[Br:9][C:4]1[C:5](=[O:8])[NH:6][N:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: O=c1ccc(Cl)n[nH]1
Reactant: [Br-]
Agent: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])[O-]
Solvent: O
Product: O=c1[nH]nc(Cl)cc1Br
Temperature: 25 °C
Yield: 100 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 6-chloropyridazin-3(2H)-one (23, Bulletin of the Korean Chemical Society, 10(6) 614-17; 1989)) (4.00 g, 30.6 mmol), potassium bromide (10.9 g, 91.9 mmol), potassium acetate (4.51 g, 45.9 mmol) and water (36 mL). Bromine (14.6 g, 91.9 mmol) was added, and the reaction mixture was heated at reflux for 2 h. After this time, the reaction was cooled to room temperature and filtered. The filter cake was washed with a solution of sodium sulfite (7.66 g, 60.7 mmol) in water (400 mL) and again with water (300 mL). The collected solids were dried in a vacuum oven at 50° C. overnight to afford a 100% yield (6.40 g) of 24 as an off-white solid: mp 205-206° C.; 1H NMR (500 MHz, DMSO-d6) δ13.52 (br s, 1H), 8.19 (s, 1H); MS (ESI+) m/z 209.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([C:14]1[CH:24]=[CH:23][CH:22]=[C:16]2C(N[C:20](=[O:21])[C:15]=12)=O)(OCC)=[O:10]>CN(C=O)C.CCOC(C)=O>[CH3:8][C:7]1[C:2]([N:1]2[C:9](=[O:10])[C:14]3=[CH:24][CH:23]=[CH:22][CH:16]=[C:15]3[C:20]2=[O:21])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccnc1N
Reactant: CCOC(=O)c1cccc2c1C(=O)NC2=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccnc1N1C(=O)c2ccccc2C1=O
Temperature: 23 °C
Reaction time: 15 h

Procedure:
2-Amino-3-picoline (1.00 mL, 8.62 mmol) was dissolved in DMF (30 mL) at 23° C., and treated with solid carboethoxy-phthalimide (1.89 g, 8.64 mmol), followed by TEA (1.44 mL, 10.3 mmol). The resulting solution was stirred at 23° C. for 15 h. After 15 h, the mixture was diluted with EtOAc (50 mL), and washed with saturated NaCl (1×50 mL), H2O (1×50 mL), dried (MgSO4), and concentrated in vacuo to a yellow solid. Purification over silica gel (0 to 50% EtOAc/Hexanes) provided the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:16])[CH2:14][OH:15])[C@H:9]([CH3:17])[CH2:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:23]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][C:26]([Cl:32])=[CH:25][N:24]=1>C1(C)C=CC=CC=1>[Cl:32][C:26]1[CH:27]=[C:28]([N+:29]([O-:31])=[O:30])[C:23]([O:15][CH2:14][C:13]([N:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:19][CH:18]=3)[CH2:8][C@H:9]2[CH3:17])=[O:16])=[N:24][CH:25]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)CO
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ncc(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To a solution of 1-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-hydroxy-ethanone (0.77 g, 2.9 mmol) in dry toluene (30 mL) at 0° C. was added sodium hydride (0.13 g, 3.2 mmol, 60% dispersion in mineral oil). The reaction was stirred for 30 minutes at 0° C. followed by addition of 2,5-dichloro-3-nitro-pyridine (0.60 g, 3.18 mmol) as a solution in toluene (5 mL). The reaction was stirred at ambient temperature overnight. The, reaction was concentrated and chromatographed on silica gel to give the title compound (0.96 g).
Reaction SMILES: [OH:1][C:2]1[C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[CH:16]=[CH:17][C:4]=2[CH:3]=1.[N+](=[CH2:23])=[N-]>CO.CCOCC>[CH3:23][O:19][C:18]([C:15]1[CH:16]=[CH:17][C:4]2[CH:3]=[C:2]([OH:1])[C:8]3[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=3[S:6][C:5]=2[CH:14]=1)=[O:20]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1ccc2c(c1)Sc1ccc(F)cc1C(O)=C2
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1ccc2c(c1)Sc1ccc(F)cc1C(O)=C2
Yield: 78 %

Procedure:
10-Hydroxy-8-fluoro-dibenzo[b,f]thiepin-3-carboxylic acid (4 g; 13.8 mmoles) dissolved in methanol (100 mL) and treated with excess diazomethane in ether. The volatiles removed under vacuum and the residue, taken up in chloroform, is purified by chromatography in Silica Gel. Elution with 20% ethyl acetate in toluene yielded 3.26 g (78%) of the title compound, m.p. 85°-88° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:7](=[O:23])[N:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[S:9](=[O:18])(=[O:17])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[C:19]([N:8]1[C:7](=[O:23])[C:6]([NH:5][CH2:4][CH2:3][CH2:2][O:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:9]1(=[O:18])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)N1C(=O)C(NCCCBr)=C(c2ccccc2)S1(=O)=O
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)N1C(=O)C(NCCCOc2cccnc2)=C(c2ccccc2)S1(=O)=O
Temperature: 140 °C
Yield: 46.5 %

Procedure:
A mixture of 4-[(3-bromopropyl)amino]-2-tert-butyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.120 g, 0.29 mmol), 3-hydroxypyridine (0.028 g, 0.29 mmol) and K2CO3 (0.207 g, 1.49 mmol) in MeCN (2 mL) was heated in a microwave reactor at 140° C. for 30 mins. The solvent was evaporated and the residue was purified by silica gel column chromatography using a 35-85% EtOAc in hexane mixture as eluant, to give the title compound (0.056 g, 45%) as a solid. 1H NMR (500 MHz, CDCl3): δ 8.28-8.22 (m, 2H), 7.54-7.50 (m, 2H), 7.50-7.42 (m, 3H), 7.24-7.20 (m, 1H), 7.16-7.12 (m, 1H), 5.68 (t, 1H), 3.92 (t, 2H), 3.14-3.08 (m, 2H), 1.90-1.82 (m, 2H), 1.74 (s, 9H); 13C NMR (125 MHz, CDCl3): δ 159.8, 154.7, 142.8, 137.9, 135.2, 131.8, 129.9, 128.8, 125.2, 124.1, 121.3, 107.5, 66.3, 61.8, 42.1, 29.0, 27.8; Mass Spectrum: M+H+ 416.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]=[C:20]([C:22]([NH2:24])=[O:23])[S:21][C:14]=12>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][C:13]1[CH:18]=[CH:17][N:16]=[C:15]3[CH:19]=[C:20]([C:22]([NH2:24])=[O:23])[S:21][C:14]=13)=[CH:6][CH:5]=2
Reactant: NC(=O)c1cc2nccc(Cl)c2s1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(C(N)=O)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-5-ylamine and 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid amide by a procedure analogous to Example 1C. MS: 323 (MH+); HPLC Rf: 3.65 min; HPLC purity: 98%.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[N:22][C:23]#[N:24])OC2C=CC=CC=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:27]([NH2:30])([CH3:29])[CH3:28]>>[C:23]([NH:22][C:14]([NH:13][C:5]1[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=[C:3]([C:2]([F:1])([F:25])[F:26])[CH:4]=1)=[N:30][CH:27]([CH3:29])[CH3:28])#[N:24]
Reactant: CC(C)N
Reactant: N#CN=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Oc1ccccc1
Product: CC(C)N=C(NC#N)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 45 %

Procedure:
N-[3,5-bis(trifluoromethyl)phenyl]-N'-cyano-O-phenylisourea (0.94 mmol, 350 mg) and isopropylamine (1 ml) was stirred in a sealed flask for 19 h at 75° C. After concentration the residue was dissolved in dichloromethane, washed with 1 N aqueous HCl (2×), water, dried (Na2SO4) and concentrated. The residue was crystallized from ethyl acetate and heptane to give the title compound (114 mg, 45%) as white crystals. Mp 176-182° C.; 1H-NMR (CDCl3): δ 1.25 (d, 6H), 4.07 (m, 1H), 5.5 (br d, 1H), 7.71 (br s, 1H), 7.75 (br s, 2H), 8.10 ppm (br, 1H); MA calc for C13H12F6N4 : C, 46.16%; H, 3.58%; N, 16.56%. Found: C, 46.15%; H, 3.64%; N, 16.45%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:44]([C:47]1[CH:55]=[CH:54][C:50]([C:51](O)=[O:52])=[CH:49][CH:48]=1)(=[O:46])[CH3:45].CN1CCOCC1.C(O)(C(F)(F)F)=O>CN1C(=O)CCC1.ClCCl>[C:44]([C:47]1[CH:55]=[CH:54][C:50]([C:51]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:52])=[CH:49][CH:48]=1)(=[O:46])[CH3:45]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1cccc(CN)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1cccc(CNC(=O)c2ccc(C(C)=O)cc2)c1
Yield: 97 %

Procedure:
The Sasrin resin was prepared as described in Step 2 of Example 3. The resin (500 mg) was heated with a solution of 3-methoxybenzylamine (600 μl) in NMP (6 ml) at 70° C. for 4 hours. The resin was then washed with DMF and dichloromethane and then shaken with a solution of PyBop® (1.04 g, 2 mmol), 4-acetylbenzoic acid (0.33 g, 2 mmol), 4-methylmorpholine (4 mmol) in NMP (6 ml) at room temperature overnight. A small aliquot of the resin was treated with 20% TFA in dichloromethane to give the intermediate, (4-acetylphenyl)-N-[(3-methoxyphenyl)methyl]carboxamide (HPLC: 23.94 min (97%); MS; MH+=284 (as required)). The resin was then heated at 95° C. for 7 hours in DMFDMA (5 ml).
Reaction SMILES: [CH2:1]([C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[C:18]([O:25]C)[CH:19]=[CH:20][CH:21]=2)[N:16]=1)[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([O:13]C)[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[OH-].[Na+].N.[Na+].[Cl-]>Br.CO>[CH2:2]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([OH:13])[CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH2:1][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[C:18]([OH:25])[CH:19]=[CH:20][CH:21]=2)[N:16]=1
Reactant: COc1cccc2ccc(CCc3ccc4cccc(OC)c4n3)nc12
Agent: Br
Agent: N
Agent: [Cl-]
Solvent: CO
Product: Oc1cccc2ccc(CCc3ccc4cccc(O)c4n3)nc12
Temperature: 25 °C
Yield: 97 %

Procedure:
The product has already been described in: C. Kitamura et al., J. Chem. Soc., Perkin Trans. 1 2000, 781-785, from which this stage of synthesis was very slightly altered. It has also been described but obtained by another method of synthesis in: M. Albrecht et al., Synthesis 1999, 10, 1819-1829. A solution of 2,2′-(1,2-ethanediyl)-bis[8-(methyloxy)quinoline] (2.83 g; 8.23 mmol) in 48% hydrobromic acid (150 ml) is heated under reflux for 24 hours. After cooling to ambient temperature, the mixture is neutralised with a 3M aqueous solution of sodium hydroxide, leading to the formation of a green precipitate. The product is extracted with dichloromethane then washed in water and brine. The organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum to yield 7 in the form of a pale green powder (2.53 g; 8.00 mmol, yield=97%). NMR-1H (250 MHz, CDCl3) δ, ppm: 9.35 (s large, 2H); 8.20 (d, 3J (H, H)=8.5 Hz, 2H); 7.53 (d, 3J (H, H)=8.5 Hz, 2H); 7.37 (m, 2H); 7.32 (dd, 3J (H, H)=6.5 Hz, 4J (H, H)=2.0 Hz, 2H); 7.05 (dd, 3J (H, H)=6.5 Hz, 4J (H, H)=2.0 Hz, 2H); 3.57 (s, 4H). MS (CID, NH3) m/z: 317 (MH+). Analysis (%) for C20H16N2O2.0.1NaBr: calculated C, 73.53. H, 4.93. N, 8.58. found C, 73.81. H, 4.73. N, 8.50. UV/vis [CH3OH/20 mM Tris-HCl pH=7.4 containing 150 mM NaCl (1/1, v/v)]: λ nm (ε M−1 cm−1)=204 (71,800), 248 (74,200), 305 (5,200).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH:18]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][C@@H:31]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:30]1>CCCCO>[Br:1][C:2]1[C:3]([N:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:30]2)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH:18]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: COc1ccc(Cn2cc(C(=O)Nc3c[nH]c4ncc(Br)c(F)c34)cn2)cc1
Solvent: CCCCO
Product: COc1ccc(Cn2cc(C(=O)Nc3c[nH]c4ncc(Br)c(N5CCC[C@@H](NC(=O)OC(C)(C)C)C5)c34)cn2)cc1
Temperature: 155 °C
Yield: 18.5 %

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxamide (230 mg, 0.518 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (311 mg, 1.55 mmol) in n-BuOH (2.5 mL) was heated to 155° C. for 48 hours in a sealed tube. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Gilson) to provide (R)-tert-butyl 1-(5-bromo-3-(1-(4-methoxybenzyl)-1H-pyrazole-4-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (60 mg, 18% yield).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:12]1[N:20]=[C:19]2[C:15]([N:16]=[C:17]([CH2:22][N:23]3[CH2:28][CH2:27][N:26]4[CH2:29][CH2:30][CH2:31][CH:25]4[CH2:24]3)[N:18]2[CH3:21])=[C:14]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[N:13]=1>>[CH2:24]1[N:23]([CH2:22][C:17]2[N:18]([CH3:21])[C:19]3[C:15]([N:16]=2)=[C:14]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[N:13]=[C:12]([N:3]2[C:4]4[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=4[N:6]=[C:2]2[CH3:1])[N:20]=3)[CH2:28][CH2:27][N:26]2[CH2:29][CH2:30][CH2:31][C@@H:25]12
Reactant: Cn1c(CN2CCN3CCCC3C2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: Cc1nc2ccccc2[nH]1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN4CCC[C@H]4C3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-methylbenzimidazole and racemic 4-(2-chloro-8-((hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)-9-methyl-9H-purin-6-yl)morpholine were reacted. The enantiomers were separated by SFC to give 415. LCMS m/z: 488.2 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@H:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7][C@@H:8]2O)=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O.O>O1CCCC1>[Cl:20][C@@H:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C@H:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7]1
Reactant: O=S(Cl)Cl
Reactant: O[C@H]1C[C@@H](c2ccccc2)c2ccc(Cl)cc21
Solvent: C1CCOC1
Solvent: O
Product: Clc1ccc2c(c1)[C@@H](Cl)C[C@H]2c1ccccc1
Temperature: 25 °C

Procedure:
A solution of (1S,3S)-6-chloro-3-phenylindan-1-ol (Va) (17 g) (synthesized as in example 8) in tetrahydrofuran (130 ml) is cooled with an ice bath. Thionyl chloride (9.9 g) in tetrahydrofuran (50 ml) is added drop wise at 4-5° C., and then the mixture is stirred over night at ambient temperature. A mixture of water and ice (approximately 25 ml) is added, and stirring is continued until all the ice has melted. The phases are separated, and the organic phase is washed twice with sodium bicarbonate (5% in water, 25 ml). The water phases are then combined, extracted with the organic phase, and then extracted with ethyl acetate (50 ml). The organic phases are then combined, dried with magnesium sulfate, filtered, and evaporated to dryness using a rotary evaporator. Yield 18.7 g (102%) of the title compound as an oil, which partly solidifies. The content of (1S,3R)-3,5-dichloro-1-phenylindan is 18% according to NMR.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][O:17][C:18]1[N:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:21]2[CH:22]=[N:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[C:11]=1[CH3:12]
Reactant: COc1ccc(B(O)O)cn1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)cn1

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 6-methoxypyridin-3-ylboronic acid (0.308 g, 2.0 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 19.5 h to give 4-chloro-5,7-difluoro-2-(6-methoxypyridin-3-yl)-3-methylquinoline as a white solid. Mass Spectrum (ESI) m/e=321.0 (M+1).
Reaction SMILES: C1(S(N2CCNC(=O)[C@H]2CC#C)(=O)=O)C=CC=CC=1.[F:20][C:21]([F:42])([F:41])[C:22]1[CH:23]=[C:24]([S:28]([N:31]2[CH:36]=[CH:35][NH:34][C:33](=[O:37])[C@H:32]2[CH2:38][C:39]#[CH:40])(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1>>[CH2:38]([C@H:32]1[N:31]([S:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:41])([F:42])[F:20])[CH:23]=2)(=[O:30])=[O:29])[CH2:36][CH2:35][NH:34][C:33]1=[O:37])[C:39]#[CH:40]
Reactant: C#CC[C@@H]1C(=O)NC=CN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: C#CC[C@@H]1C(=O)NCCN1S(=O)(=O)c1ccccc1
Product: C#CC[C@@H]1C(=O)NCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1

Procedure:
Using the procedure described for compound 51, (R)-4-(3-trifluoromethylbenzenesulfonyl)-3-(prop-2-ynyl)-3,4-dihydropyrazin-2(1H)-one afforded the title compound as a tan solid.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:16]3[CH:21]=[CH:20][C:19]([CH:22](O)[CH3:23])=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:26]>ClCCl>[Br:26][CH:22]([C:19]1[CH:20]=[CH:21][C:16]([C:8]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:12][N:11]3[CH:13]=[CH:14][N:15]=[C:10]3[N:9]=2)=[CH:17][CH:18]=1)[CH3:23]
Reactant: BrP(Br)Br
Reactant: CC(O)c1ccc(-c2nc3nccn3cc2-c2ccccc2)cc1
Solvent: ClCCl
Product: CC(Br)c1ccc(-c2nc3nccn3cc2-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
100 mg of the product of step 1 were dissolved in dichloromethane, cooled to 0° C. and 86 mg PBr3 were added. The mixture was stirred at room temperature for 24 h. Ice was added, the mixture extracted with dichloromethane and water, the organic layer were dried over Na2SO4 and the solvent was evaporated. The crude product may be used without further purification.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1.[O:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.[Cl-].[NH4+]>O1CCCC1>[Br:13][C:9]1[CH:8]=[C:7]([C:17]2[CH2:18][CH2:19][O:14][CH2:15][CH:16]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Brc1cccc(Br)c1
Reactant: O=C1CCOCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Brc1cccc(C2=CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
n-Butyllithium (2.64 M, 37.9 mL) was added dropwise to a solution of 1,3-dibromobenzene (23.5 g) in tetrahydrofuran (469 mL) at −78° C. The mixture was stirred at the same temperature for 30 minutes, and then tetrahydro-4H-pyran-4-one (10.0 g) was added dropwise. The mixture was stirred at the same temperature for 30 minutes and then warmed to room temperature. After stirring at room temperature for four hours, an ammonium chloride solution was added to the reaction mixture to terminate the reaction. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in toluene (400 mL). p-Toluenesulfonic acid monohydrate (2 g) was added and the mixture was stirred with heating under reflux for two hours. The reaction mixture was cooled to room temperature and purified by NH-silica gel column chromatography to obtain the title compound (21.4 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([C@H:10]1[CH2:15][C@H:14]([NH:16][CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12][N:11]1[C:28](=[O:37])[C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([Cl:36])[CH:30]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:38]I>COCCOC>[CH2:3]([C@@H:10]1[CH2:15][C@@H:14]([N:16]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)[CH3:38])[CH2:13][CH2:12][N:11]1[C:28](=[O:37])[C:29]1[CH:30]=[C:31]([Cl:36])[CH:32]=[C:33]([Cl:35])[CH:34]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CI
Reactant: O=C(c1cc(Cl)cc(Cl)c1)N1CC[C@@H](NCc2ccnc3ccccc23)C[C@@H]1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CN(Cc1ccnc2ccccc12)[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
13.4 mg (0.446 mmol) of an 80% strength suspension of sodium hydride in mineral oil (suspended in hexane and decanted) are added in one portion to a solution of 150 mg (0.297 mmol) of (2S*,4R*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine in 2 ml of 1,2-dimethoxyethane at 0° C. After 10 minutes at 0° C., the mixture is left to stir at RT for 30 minutes, again cooled to 0° C., and 22 μl (0.357 mmol) of methyl iodide are added. The mixture is then stirred at RT for 96 hours. The solvent is stripped off in a rotary evaporator, and the residue is chromatographed on silica gel with toluene/ethyl acetate (1:1). The title compound ##STR78## is obtained (20 mg, 13%) as white roam. TLC: toluene/ethyl acetate (1:1) Rf =0.45; FD-MS: M+ =517, 519.