Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CCN(C2C=CC(NC3C4N(N=CN=4)C(C4C=C(C(N)=O)SC=4)=CN=3)=CC=2)CC1.[Br:32][C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36](Br)=[N:35][CH:34]=1.[C:43]([N:47]1[CH2:52][CH2:51][N:50]([C:53]2[CH:58]=[CH:57][C:56]([NH2:59])=[CH:55][CH:54]=2)[CH2:49][CH2:48]1)([CH3:46])([CH3:45])[CH3:44].C(N(C(C)C)C(C)C)C>CC(O)C>[Br:32][C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36]([NH:59][C:56]2[CH:55]=[CH:54][C:53]([N:50]3[CH2:49][CH2:48][N:47]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:52][CH2:51]3)=[CH:58][CH:57]=2)=[N:35][CH:34]=1
Reactant: Brc1ncc(Br)n2ncnc12
Reactant: CC(C)(C)N1CCN(c2ccc(N)cc2)CC1
Agent: CN1CCN(c2ccc(Nc3ncc(-c4csc(C(N)=O)c4)n4ncnc34)cc2)CC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)N1CCN(c2ccc(Nc3ncc(Br)n4ncnc34)cc2)CC1
Yield: 92.4 %

Procedure:
This compound may be prepared using methods as described for Compound 6, step 1, using 5,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (0.308 g, 1.107 mmol), 4-(4-tert-butyl-piperazin-1-yl)-phenylamine (0.310 g, 1.33 mmol) and N-ethyldiisopropyl-amine (0.289 mL, 1.66 mmol) in 2-propanol (5 mL). The reaction mixture is partitioned between DCM and 1N NaOH, the organic layer is separated and washed with water and brine, dried over MgSO4, filtered and concentrated under vacuum. Trituration of the residue with diethyl ether and petroleum ether affords the title compound (440 mg, 92%) as a cream solid. LCMS: Rt 2.25 min (96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:7][C:6]([C:14]2[CH:22]=[C:21]3[C:17]([CH:18]=[N:19][N:20]3S(C3C=CC=CC=3)(=O)=O)=[C:16]([C:32]3[O:33][C:34]([CH2:37][N:38]4[CH2:44][CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[N:35][N:36]=3)[CH:15]=2)=[CH:5][N:4]=1.[OH-].[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]1[C:8]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:7][C:6]([C:14]2[CH:22]=[C:21]3[C:17]([CH:18]=[N:19][NH:20]3)=[C:16]([C:32]3[O:33][C:34]([CH2:37][N:38]4[CH2:44][CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[N:35][N:36]=3)[CH:15]=2)=[CH:5][N:4]=1
Reactant: COc1ncc(-c2cc(-c3nnc(CN4CCCOCC4)o3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ncc(-c2cc(-c3nnc(CN4CCCOCC4)o3)c3cn[nH]c3c2)cc1NS(C)(=O)=O
Temperature: 20 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
To a solution of N-(2-(methyloxy)-5-{1-(phenylsulfonyl)-4-[5-(tetrahydro-1,4-oxazepin-4(5H)-ylmethyl)-1,3,4-oxadiazol-2-yl]-1H-indazol-6-yl}-3-pyridinyl)methanesulfonamide (50 mg, 0.078 mmol) in 1,4-dioxane (1 ml) was added 2M sodium hydroxide (1 ml, 2.000 mmol) and the mixture stirred at 20° C. for 2 h. The mixture was partitioned between ethyl acetate (5 ml) and saturated ammonium chloride solution (2 ml), separating the layers with a hydrophilic frit. The organic layer was evaporated to dryness under a stream of nitrogen to give the title compound as a pale brown solid (35 mg).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][C:19](F)=[C:20]([F:25])[CH:21]=2)[N:16]([CH2:27][CH2:28][F:29])[C:15]1=[O:30])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][C:19]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:20]([F:25])[CH:21]=2)[N:16]([CH2:27][CH2:28][F:29])[C:15]1=[O:30])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1CCNC1
Reactant: O=c1c2cc(F)c(F)cc2n(CCF)c(=O)n1OCc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=c1c2cc(F)c(N3CCCC3)cc2n(CCF)c(=O)n1OCc1ccccc1
Yield: 83 %

Procedure:
Pyrrolidine (0.04 mL, 0.52 mmol) was added to a solution of 3-benzyloxy-1-(2-fluoroethyl)-6,7-difluoro-1H-quinazoline-2,4-dione (Example D-4, 0.15 g, 0.42 mmol) and triethylamine (0.36 mL, 2.6 mmol) in 20 mL of acetonitrile. The solution was warmed to reflux for 17 hours, cooled, and concentrated to a solid. The solid was dissolved in chloroform washed with 1N HCl, saturated NaHCO3, brine and dried over magnesium sulfate. The solution was concentrated to give 0.14 g of the title compound as a solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9](Br)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)c1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CN1CCN(c2cccc(C(=O)OC(C)(C)C)c2)CC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 57.3 %

Procedure:
3-Bromo-benzoic acid tert-butyl ester (6.7 g, 26 mmol), N-methyl piperizine (3.4 ml, 31.2 mmol), sodium t-butoxide (3.5 g, 36.4 mmol). 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.12 g, 0.195 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.067 g, 0.065 mmol) were combined in toluene (200 ml), then was heated to 80 degrees C. Argon gas was then bubbled through the solution for 5 minutes. The reaction mixture was heated and stirred for 5 h. The reaction was then cooled to RT, concentrated in vacuo, and chromatographed (silica gel, 4% MeOH: CH2Cl2) to yield the title compound (4.12 g, 58%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([C:13]1[NH:17][C:16](=[O:18])[N:15]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28](Cl)[CH:27]=3)=[C:21]([CH3:33])[N:20]=2)[N:14]=1)([CH3:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][N:35]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[N:36]1.C([O-])([O-])=O.[K+].[K+].[NH4+].[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.CCOC(C)=O.O.O1CCOCC1>[CH2:1]([O:8][CH2:9][C:10]([C:13]1[NH:17][C:16](=[O:18])[N:15]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([C:38]4[CH:37]=[N:36][N:35]([CH3:34])[CH:39]=4)[CH:27]=3)=[C:21]([CH3:33])[N:20]=2)[N:14]=1)([CH3:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(-n2nc(C(C)(C)COCc3ccccc3)[nH]c2=O)ccc1Oc1ccnc(Cl)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(-n2nc(C(C)(C)COCc3ccccc3)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 85 °C
Reaction time: 12 h
Yield: 91.1 %

Procedure:
3-(1-(Benzyloxy)-2-methylpropan-2-yl)-1-(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one (0.41 g, 0.88 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.24 g, 1.14 mmol), and K2CO3 (0.32 g, 2.29 mmol) were suspended in a solution of dioxane (5.0 mL) and water (1.0 mL). The suspension was sonicated and sparged with Ar for 10 min followed by the addition of Pd(PPh3)4 (0.10 g, 0.09 mmol). The reaction mixture was stirred at 85° C. for 12 h, allowed to cool to RT, and suspended between sat. NH4Cl (aq.) (15 mL) and EtOAc (20 mL). The organic phase was collected and the aqueous phase was extracted with EtOAc (3×15 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford an orange oil. The residue was purified by silica gel chromatography (MeOH/DCM) to afford 3-(1-(benzyloxy)-2-methylpropan-2-yl)-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one (0.41 g, 91%) as a viscous, pale yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 11.95 (s, 1H), 8.36 (d, J=5.6 Hz, 1H), 8.26 (s, 1H), 7.96 (s, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.31-7.29 (m, 5H), 7.18 (d, J=2.4 Hz, 1H), 6.66 (dd, J=5.7, 2.4 Hz, 1H), 4.49 (s, 2H), 3.83 (s, 3H), 3.50 (s, 2H), 2.33 (s, 3H), 1.27 (s, 6H); MS (ESI) m/z: 512.3 (M+H+).
Reaction SMILES: [N:1]1([C:6]2([C:10]([O:12]CC)=[O:11])[CH2:9][CH2:8][CH2:7]2)[CH:5]=[CH:4][CH:3]=[N:2]1.O1CCCC1.[OH-].[Na+]>O>[N:1]1([C:6]2([C:10]([OH:12])=[O:11])[CH2:7][CH2:8][CH2:9]2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCOC(=O)C1(n2cccn2)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1(n2cccn2)CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 18.5 %

Procedure:
To ethyl 1-(1H-pyrazol-1-yl)cyclobutanecarboxylate (688 mg, 3.54 mmol) were added tetrahydrofuran (8 mL) and water (0.9 mL). Aqueous sodium hydroxide (1N, 4 mL, 4 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and to the residue was added aqueous hydrochloric acid (1N, 1 mL). The mixture was extracted with dichloromethane (3×). The combined organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound (108.9 mg). The material was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:9][C@@H:8]2[C@@H:4]([C@@H:5]([CH2:11][OH:12])[O:6][CH:7]2[OH:10])[O:3]1.[C:14](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:13])[O:9][C@@H:8]2[C@@H:4]([C@@H:5]([CH2:11][O:12][C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:6][CH:7]2[OH:10])[O:3]1
Reactant: CC1(C)O[C@@H]2[C@@H](CO)OC(O)[C@@H]2O1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CC1(C)O[C@@H]2[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)OC(O)[C@@H]2O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2,3-O-Isopropylidene-D-ribofuranose (15.7 g, 83.1 mmol) was dissolved in pyridine (100 mL) and trityl chloride (27.8 g, 0.1 mol) was added. The mixture was stirred at room temperature for 24 h. The solvent was evaporated and the residue purified by column chromatography on silicagel using hexanes/ethyl acetate (v.v=4:1) as eluant.
Reaction SMILES: COC1C=CC(C[N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=CC=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Br[C:72]1[CH:79]=[CH:78][C:77]([C:80]([F:83])([F:82])[F:81])=[CH:76][C:73]=1[C:74]#[N:75].CC(C)([O-])C.[Na+].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:74]([C:73]1[CH:76]=[C:77]([C:80]([F:81])([F:82])[F:83])[CH:78]=[CH:79][C:72]=1[N:20]1[CH2:19][CH2:18][O:17][C:16]2[CH:21]=[C:12]([S:9]([NH:8][C:22]3[S:23][CH:24]=[CH:25][N:26]=3)(=[O:10])=[O:11])[CH:13]=[CH:14][C:15]1=2)#[N:75]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Reactant: N#Cc1cc(C(F)(F)F)ccc1Br
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: 130 °C
Reaction time: 1 h
Yield: 26.7 %

Procedure:
A microwave vial was charged with N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (INTERMEDIATE M, 0.150 g, 0.359 mmol), xantphos (0.042 g, 0.072 mmol), 2-bromo-5-(trifluoromethyl)benzonitrile (Apollo Scientific) (0.135 g, 0.539 mmol), Pd2(dba)3 (0.033 g, 0.036 mmol) and sodium tert-butoxide (0.069 g, 0.719 mmol). The mixture was diluted with toluene (3.59 mL), purged with nitrogen, and heated at 130° C. in the microwave for 1.5 h. After cooling to rt, trifluoroacetic acid (0.554 mL, 7.19 mmol) was carefully added and the reaction was stirred for 1 h. The reaction mixture was diluted with water, and washed with DCM (×2). organics were dried via phase separator, and concentrated under a vacuum. The material was then purified via reverse-phase preparative HPLC, 0.1% TFA in CH3CN/H2O, gradient 25% to 90% over 25 min to provide 4-(2-cyano-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.045 g, 0.096 mmol) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.82-3.91 (m, 2 H) 4.28-4.39 (m, 2 H) 6.76-6.85 (m, 2 H) 7.18 (dd, J=8.56, 2.10 Hz, 1 H) 7.21-7.28 (m, 2 H) 7.71 (d, J=8.70 Hz, 1 H) 8.06 (dd, J=8.71, 2.15 Hz, 1 H) 8.40 (d, J=1.27 Hz, 1 H) 12.66 (br. s., 1 H). m/z (ESI) 467.0 (M+H)+.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:24])[C@@H:14]([NH:16][C:17](=[O:23])[C@@H:18]([OH:22])[CH:19]([CH3:21])[CH3:20])[CH3:15])[NH:8]1)=[O:6].O.O.[OH-].[Li+].Cl>O1CCCC1>[OH:22][C@@H:18]([CH:19]([CH3:21])[CH3:20])[C:17]([NH:16][C@@H:14]([CH3:15])[C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:7]([C:5]([OH:6])=[O:4])[NH:8]1)=[O:24])=[O:23]
Reactant: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)O)N1
Reaction time: 0.75 h

Procedure:
To (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester 1e (502 mg, 1.16 mmol) suspended in tetrahydrofuran (15 mL) and water (3 mL) was added lithium hydroxide monohydrate (69 mg, 1.65 mmol). The reaction mixture was stirred for 45 minutes and then hydrochloric acid (2 M, 0.75 mL) was added. The reaction mixture was stirred for 5 minutes and then evaporated. The crude residue was used directly in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][CH2:12]CC(O)=O)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C1C[O:30]CC1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][CH2:12][OH:30])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: O=C(O)CCCn1ccc2ccc(Br)cc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: OCCn1ccc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a 250 mL round bottom flask equipped with a stir bar was added compound (i), above, (3.0 g; 10.6 mmol) and THF (50 mL). The mixture was cooled to 0° C. and diisobutylaluminium hydride (1M in toluene)(42.5 mL; 42.5 mmol) added. The reaction mixture was stirred at room temperature for 2 h, cooled to 0° C. and the quenched with sodium sulfate decahydrate. The resulting thick gel was refluxed for 1 h, after which it was filtered through a pad of celite. Upon removing the solvent in vacuo a yellow oil was isolated, which was subjected to column chromatography on silica gel using hexanes:ethyl acetate (90:10) to yield the title compound as a bright greenish-yellow oil (1.8 g; 71%). 13C NMR (CDCl3): δ 136.9, 129.1, 127.5, 122.8,122.3, 115.3, 122.5, 101.8, 61.7, and 48.7.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[Cl:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:37]=1[N:36]=[C:35]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[CH:34]=[CH:33]2>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:41]2[CH2:42][CH2:43][N:38]([C:35]3[CH:34]=[CH:33][C:32]4[C:37](=[C:28]([Cl:27])[CH:29]=[CH:30][CH:31]=4)[N:36]=3)[CH2:39][CH2:40]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: Clc1cccc2ccc(N3CCNCC3)nc12
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc4cccc(Cl)c4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 8-chloro-2-piperazin-1-yl-quinoline.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.S(=O)(=O)(O)O.[CH3:20]O>>[CH3:20][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][C:4]=1[C:11]([F:12])([F:13])[F:14]
Reactant: CO
Reactant: O=C(O)c1ccc(O)cc1C(F)(F)F
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)cc1C(F)(F)F

Procedure:
4-hydroxy-2-trifluoromethyl-benzoic acid (5.0 g, 24.0 mmol) was dissolved in MeOH (50 mL) and a catalytic quantity of sulfuric acid was added. The mixture was refluxed overnight, after which the solvent was evaporated under reduced pressure; the crude was dissolved in DCM and washed with saturated NaHCO3. The organic phase was dried and evaporated under reduced pressure, and the product was used without further purification.
Reaction SMILES: [CH:1]1([C:6]2[CH:33]=[CH:32][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[C:16]5=[CH:15][C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:34]([F:37])([F:36])[F:35])[CH2:5][CH2:4][CH2:3][CH2:2]1.NC(CS)C(O)=O>C(O)(C(F)(F)F)=O>[CH:1]1([C:6]2[CH:33]=[CH:32][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([OH:27])=[O:26])[C:16]5=[CH:15][C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:34]([F:37])([F:35])[F:36])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Agent: NC(CS)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC1CCn2c1cc1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
tert-Butyl 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.800 g, 1.558 mmol) was added to a solution of 2-amino-3-mercaptopropanoic acid (0.189 g, 1.558 mmol) in TFA (10 mL). The reaction mixture was stirred at 23° C. for 15 min in a 20 mL sealed scintillation vial. After 15 min the reaction mixture was poured into ice water and a precipitate formed. The precipitate was collected by filtration, washed with hexanes (3×20 mL) and dried (vacuum oven) to provide the title compound as a white solid (0.595 g). LCMS m/z=458.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53-1.74 (m, 4H), 1.79-1.89 (m, 2H), 1.94-2.04 (m, 2H), 2.15-2.26 (m, 1H), 2.51-2.69 (m, 2H), 2.72-2.83 (m, 1H), 3.23-3.27 (m, 1H), 3.58 (quintet, J=7.20 Hz, 1H), 3.91-4.00 (m, 1H), 4.05-4.14 (m, 1H), 5.13 (s, 2H), 6.01 (s, 1H), 6.77 (dd, J=8.72, 2.40 Hz, 1H), 7.07 (d, J=2.27 Hz, 1H), 7.19 (d, J=8.84 Hz, 1H), 7.62 (d, J=8.08 Hz, 1H), 7.68-7.71 (m, 2H), 12.27 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)[CH3:2].[C:25](Cl)(=[O:27])[CH3:26].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[C:25]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][C:9]=1[O:12][CH3:13])[N:3]([CH2:1][CH3:2])[C:4]([C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=1)=[C:5]2[C:14]#[N:15])(=[O:27])[CH3:26]
Reactant: CCn1c(-c2ccc([N+](=O)[O-])cc2)c(C#N)c2ccc(OC)cc21
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCn1c(-c2ccc([N+](=O)[O-])cc2)c(C#N)c2cc(C(C)=O)c(OC)cc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 30.3 %

Procedure:
1-Ethyl-6-methoxy-2-(4-nitrophenyl)-1H-indole-3-carbonitrile (100 mg, 0.3 mmol), prepared by the method of example 1Gc is suspended in 1,2-dichloroethane (500 μL) at 0° C. Acetyl chloride (50 μL, 0.69 mmol) is added, followed by AlCl3 (55 mg, 0.4 mmol) in one portion. This is stirred at 0° C. for 1 hour, at room temperature for 4 hours, and at 45° C. overnight. The reaction mixture is then partitioned between CH2Cl2 and H2O. The organic layer is dried and concentrated. Purification by silica gel chromatography (195:5 CH2Cl2/EtOAc) yields 5-acetyl-1-ethyl-6-methoxy-2-(4-nitro-phenyl)-1H-indole-3-carbonitrile (33 mg, 29%) as an orange solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:19][CH2:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH2:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCC/C=C\CCCI
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCC/C=C\CCCOc1ccc(C(=O)OC)cc1
Yield: 100.1 %

Procedure:
90 mg of 32 (590 μmol) and 81 mg of K2CO3 (590 μmol) are added to 150 mg of 13 (535 μmol) in anhydrous DMF (2 mL). After reaction for 7 hours at 90° C., the reaction medium is concentrated, taken up in DCM and then washed with water. 163 mg of a yellow oil are obtained, and are chromatographed on silica gel in pentane/ethyl acetate (80/1). 129 mg of the expected coupling product are isolated in the form of a yellow oil, i.e. a yield of 79%.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([OH:19])[C:5]2[N:6]=[CH:7][N:8]([C:17]=2[N:18]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]1.[NH2:20][CH2:21][CH2:22][C:23]1[N:27]=[CH:26][NH:25][CH:24]=1>COCCO>[NH:25]1[CH:24]=[C:23]([CH2:22][CH2:21][NH:20][C:2]2[NH:3][C:4](=[O:19])[C:5]3[N:6]=[CH:7][N:8]([C:17]=3[N:18]=2)[C@@H:9]2[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]2)[N:27]=[CH:26]1
Reactant: NCCc1c[nH]cn1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)nc(Cl)nc32)C[C@@H]1O
Solvent: COCCO
Product: O=c1[nH]c(NCCc2c[nH]cn2)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 0 °C

Procedure:
A mixture of 2-chloro-2′-deoxyinosine (6.0 g, 20.97 mmol) and histamine (4.4 g, 40 mmol) in 2-methoxyethanol (60 ml) was heated in a steel bomb at 110° C. for 12 hrs. The bomb was cooled to 0° C., opened carefully and the precipitated solid was filtered. The solid was washed with methanol and acetone and crystallized from DMF/water to give 6 g (79%) of pure 125. mp 220-222° C.
Reaction SMILES: P(=O)(O)(O)[OH:2].CS([C:9]1[N:18]2[C:12]([CH2:13][C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[CH:16]=[CH:17]2)=[N:11][N:10]=1)=O>O>[N:11]1[NH:10][C:9](=[O:2])[N:18]2[CH:17]=[CH:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[CH2:13][C:12]=12
Reactant: O=P(O)(O)O
Reactant: CS(=O)c1nnc2n1C=Cc1ccccc1C2
Solvent: O
Product: O=c1[nH]nc2n1C=Cc1ccccc1C2

Procedure:
To 3 ml of 80% phosphoric acid was added 0.245 g of 3-methylsulfinyl-11H-s-triazolo[3,4-b][3]benzazepine and the mixture was heated on an oil bath at 130°-140° C. for 1 hour. Following addition of water, the crystals were collected by filtration and dried. By the above procedure was obtained 2,11-dihydro-3H-s-triazolo[3,4-b][3]benzazepin-3-one. Recrystallization from chloroform-methanol yielded colorless needles, m.p. 210°-211° C.