Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][N:30]([CH3:37])[CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>C(O)C>[NH3:19].[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([N:34]3[CH2:35][CH2:36][CH:31]([N:30]([CH3:37])[CH3:29])[CH2:32][CH2:33]3)=[O:24])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: CN(C)C1CCNCC1
Solvent: CCO
Product: CN(C)C1CCN(C(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)CC1
Product: N
Yield: 135 %

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (800 mg, 2.03 mmol) in ethanol (10 ml) was treated with N,N-dimethyl-N-(4-piperidinyl)amine (1.23 g, 9.61 mmol) and the resulting mixture was heated under reflux under a nitrogen atmosphere for 3 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed sequentially with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol (90:10) to give a residue which was further purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia (90:10:0.5) to afford the title compound as a yellow oil (653 mg).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:9]=[N:8][C:7]([NH:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)=[N:6][CH:5]=1)[CH3:3].[Br:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](O)=[O:28].C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[Br:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH:1][CH:2]([C:4]1[N:9]=[N:8][C:7]([NH:10][C:11]2[CH:12]=[C:13]([O:21][CH3:22])[C:14]([O:19][CH3:20])=[C:15]([O:17][CH3:18])[CH:16]=2)=[N:6][CH:5]=1)[CH3:3])=[O:28]
Reactant: O=C(O)c1cccc(Br)c1
Reactant: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Reaction time: 18 h
Yield: 74.5 %

Procedure:
To a stirred solution of 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (1.0 g, 3.3 mmol) in N,N-dimethylformamide (10 mL) was added 3-bromobenzoic acid (0.72 g, 3.6 mmol), O-(7-azabenzotriazol-1-yl-N,N,N′N′-tetramethyluronium hexafluorophospahte (1.4 g, 3.6 mmol) and triethylamine (1.0 mL, 7.2 mmol). After stirring for 18 hours the solution was diluted with ethyl acetate (100 mL) and washed with 0.1 N HCl (2×100 mL) and saturated sodium bicarbonate solution (100 mL). The solution was dried with magnesium sulfate and filtered, and silica gel (5 g) was added to the solution, followed by evaporation of the volatiles under reduced pressure. The pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethyl acetate:hexane (20:80) to ethyl acetate:hexanes (100:0) using a RediSep silica gel cartridge (40 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give 3-bromo-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (1.2 g) as a white solid. 1H NMR (CDCl3): δ9.94(s, 1H), 9.05 (d, J=7.2 Hz, 1H), 8.53 (s, 1H), 8.10 (s, 1H), 7.89 (d, J=7.9 Hz, 1H), 7.73 (d, J=7.9 Hz, 1H), 7.43 (dd, J=8.0, 7.8 Hz, 1H), 7.19 (s, 2H), 5.29 (dd, J=7.2, 7.0 Hz, 1H), 3.75 (s, 6H), 3.61 (s, 3H), 1.59 (d, J=7.0 Hz, 3H). MS m/z 488, 500 (M+1, M+3).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.[F:13][C:14]1[CH:15]=[CH:16][C:17]2[C:21]([N:22]3[CH2:28][CH2:27][CH2:26][N:25]([CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH2:24][CH2:23]3)=[CH:20][S:19][C:18]=2[CH:34]=1.C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1.O1CCN(N=C=N)CC1>CN(C=O)C>[F:13][C:14]1[CH:15]=[CH:16][C:17]2[C:21]([N:22]3[CH2:28][CH2:27][CH2:26][N:25]([CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:10]([C:2]4[NH:1][C:9]5[C:4]([CH:3]=4)=[CH:5][CH:6]=[CH:7][CH:8]=5)=[O:12])[CH2:24][CH2:23]3)=[CH:20][S:19][C:18]=2[CH:34]=1
Reactant: NCCCCN1CCCN(c2csc3cc(F)ccc23)CC1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: N=C=NN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCCCN1CCCN(c2csc3cc(F)ccc23)CC1)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
Add indole-2-carboxylic acid (507 mg, 3.15 mmol) to a solution of 4-[4-(6-fluoro-benzo[b]thiophen-3-yl)-[1,4]diazapan-1-yl]butylamine (Example 6) (920 mg, 2.86 mmol), diisopropylethylamine (2.5 mL, 14.3 mmol), 1-hydroxy-1H-benzotriazole (503 mg, 3.72 mmol) and morpholinocarbodiimide (1.39 g, 3.29 mmol) in DMF (10 mL), and stir the solution overnight at room temperature. Remove the solvent under vacuum and dissolve the residue in EtOAc. Wash the organic phase with ether and saturated sodium chloride solution, and dry over MgSO4. Evaporate the solvent under vacuum and purify the crude product by column chromatography (EtOAc/MeOH 7:3) to obtain 716 mg of a colorless solid LC/MS, (LiChrospher 5μ, RP-18, 250 mm CH3CN/Water-gradient 20%→100% (25 min), Flow: 1.5 mL/min) tR=19.89 min, m/z=464.3.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:29][CH:30]1[CH2:32][CH2:31]1.[H-].[Na+].C(OCC)(=O)C>CN(C)C=O.O>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:29][CH:30]2[CH2:32][CH2:31]2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCC1CC1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(CC2CC2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.75 g) and (bromomethyl)cyclopropane (1.36 mL) in N,N-dimethylformamide (10 mL) was added 60% sodium hydride (0.17 g), and the mixture was stirred at room temperature for 15 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.55 g, 63%).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([C:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=5)[CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3].C(N(CC)CC)C.Cl[S:40]([CH2:43][CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47])(=[O:42])=[O:41]>C(Cl)Cl>[CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([C:26]5[CH2:27][CH2:28][N:29]([S:40]([CH2:43][CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47])(=[O:42])=[O:41])[CH2:30][CH:31]=5)[CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: COC(=O)CCCS(=O)(=O)Cl
Reactant: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCNCC5)cc4s3)CC2)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCN(S(=O)(=O)CCCC(=O)OC)CC5)cc4s3)CC2)nc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67.4 %

Procedure:
To a solution of 2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)-6-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazole (60 mg, 0.138 mmol) and triethylamine (0.039 mL, 0.275 mmol) in CH2Cl2 (1.5 mL) at 0° C. was added methyl 4-(chlorosulfonyl)butanoate (41.5 mg, 0.207 mmol). Upon completion of addition, the reaction mixture was stirred at 0° C. for 15 min. At the conclusion of this period, the reaction mixture was allowed to warm to rt, where it stirred for 1 hr. After this time, the reaction mixture was quenched with saturated aq NaHCO3 (3 mL) and then extracted with CH2Cl2 (3×2 mL). The combined organic layers were washed with brine (2 mL), dried (Na2SO4), filtered, and concentrated to yield the crude product. The crude product was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 50% EtOAc) to afford Compound 5B (56 mg, 0.093 mmol, 68% yield). 1H NMR (500 MHz, chloroform-d) ppm 8.21 (2H, br. s.), 7.62-7.66 (2H, m), 7.37-7.42 (1H, m), 6.06-6.10 (1H, m), 5.43-5.51 (1H, m), 4.18-4.29 (2H, m), 4.00-4.06 (2H, m), 3.67-3.82 (4H, m), 3.60 (2H, t, J=5.6 Hz), 3.07-3.14 (2H, m), 2.65-2.72 (2H, m), 2.54 (2H, t, J=7.0 Hz), 2.43 (2H, t, J=7.6 Hz), 2.12-2.26 (4H, m), 1.92-2.05 (2H, m), 1.50-1.65 (3H, m), 0.96 (3H, t, J=7.3 Hz). LC/MS (m/z)=600 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C@@:8]23[O:16][CH2:15][CH2:14][C@@H:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:9]3)[CH:7]=1.[C:26]1(=O)[CH2:30][CH2:29][CH2:28][CH2:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1.O>[CH:26]1([NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C@@:8]34[O:16][CH2:15][CH2:14][C@@H:13]3[CH2:12][S:11][C:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[N:9]4)[CH:7]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(c3cc(N)ccc3F)OCC[C@@H]2CS1
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1=N[C@]2(c3cc(NC4CCCC4)ccc3F)OCC[C@@H]2CS1
Yield: 42.5 %

Procedure:
A solution of tert-butyl ((4aS,7aS)-7a-(5-amino-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (Step D, Preparation 3, 32 mg, 0.087 mmol), cyclopentanone (23.38 μL, 0.261 mmol), sodium triacetoxyborohydride (55.4 mg, 0.261 mmol) and acetic acid (14.96 μL, 0.261 mmol) in THF (435 μL) was stirred at rt for 12 h, and LC/MS showed a very clean reaction. The crude reaction mixture was purified by reverse phase preparative HPLC on a Luna C18 column (10 μM, 30×100 mm) eluting with 0-100% B (A: 95% eater/5% MeCN/10 nM NH4OAc, B: 5% water/95% MeCN/10 mM NH4OAc) over 12 min to give tert-butyl ((4aS,7aS)-7a-(5-(cyclopentylamino)-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (16 mg, 0.037 mmol, 42.2% yield) as a white solid. 1H NMR (500 MHz, CHLOROFORM-d) δ 6.90 (dd, J=11.1, 8.7 Hz, 1H), 6.74 (dd, J=6.4, 2.9 Hz, 1H), 6.51 (dt, J=8.7, 3.3 Hz, 1H), 4.22-4.14 (m, 1H), 4.04 (q, J=7.9 Hz, 1H), 3.74 (quin, J=6.1 Hz, 1H), 3.31 (dd, J=13.3, 3.1 Hz, 1H), 3.03 (br. s., 1H), 2.84 (dd, J=13.4, 4.3 Hz, 1H), 2.47-2.31 (m, 1H), 2.25-2.15 (m, 1H), 2.09-1.97 (m, 2H), 1.80-1.57 (m, 4H), 1.53-1.43 (m, 2H), and 1.50 (9H, s). MS (M+H)+: 436.3.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([O:17]CC=C)=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:11](=[O:32])[N:10]2[S:33]([CH3:36])(=[O:35])=[O:34])=[C:5]([S:37]([CH3:40])(=[O:39])=[O:38])[CH:4]=1)#[N:2].N1CCOCC1>C1COCC1.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>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=3)[C:11](=[O:32])[N:10]2[S:33]([CH3:36])(=[O:34])=[O:35])=[C:5]([S:37]([CH3:40])(=[O:38])=[O:39])[CH:4]=1)#[N:2]
Reactant: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(S(C)(=O)=O)[C@@H]1c1ccc(C#N)cc1S(C)(=O)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CC1=C(C(=O)O)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(S(C)(=O)=O)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.6 %

Procedure:
The reaction was carried out under argon. Allyl (4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-3-(methylsulfonyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (288 mg, 0.482 mmol) and morpholine (1.5 eq., 63 mg, 0.723 mmol) were initially charged in dry THF (5 ml) at RT. The reaction mixture was degassed repeatedly (evacuation followed by venting with argon). Under protective gas, tetrakis(triphenylphosphine)palladium(0) (0.05 eq., 28 mg, 0.024 mmol) was added, and the reaction mixture was stirred at RT for 1.5 h (HPLC control). The mixture was then concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Gromsil C-18; mobile phase: acetonitrile/water+0.1% TFA 10:90→75:25). This gave the title compound as a solid (187 mg, 70% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:23])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.Cl[C:25]1[O:26][C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[O:26]1[C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=[C:25]1[NH:23][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[C:8]([C:3]2[N:4]([CH3:7])[N:5]=[CH:6][C:2]=2[Br:1])[CH:9]=1
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCCN1CCCCC1
Reactant: Clc1nc2ccccc2o1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Br)c1-c1cc(Nc2nc3ccccc3o2)ccc1OCCN1CCCCC1
Temperature: 60 °C
Yield: 18.4 %

Procedure:
To a mixture of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenylamine (0.034 g, 0.09 mmol) and 2-chlorobenzoxazole (0.016 g, 0.11 mmol) in isopropanol (1 mL), DIEA (0.031 mL, 0.18 mmol)) was added. The reaction mixture was heated at 60° C. for 4 days, concentrated then subjected to a purification by prep HPLC. The corresponding fractions were collected and lyophilized to afford Compound 199 (TFA salt) as an off-white solid in 18.4% yield. LCMS m/z (%)=496 (M+H 79Br, 90), 498 (M+H 81Br, 100). 1H NMR (400 MHz, Acetone-d6) δ: 11.80 (bs, 1H), 8.04 (dd, J=2.8, 9.0 Hz, 1H), 7.91 (d, J=2.8 Hz, 1H), 7.61 (s, 1H), 7.48-7.42 (m, 2H), 7.36 (d, J=9.0 Hz, 1H), 7.27 (dt, J=1.0, 7.6 Hz, 1H), 7.18 (dt, J=1.2, 7.8 Hz, 1H), 4.72-4.63 (m, 1H), 4.60-4.5 (m, 1H), 3.80 (s, 3H), 3.81-3.42 (m, 4H and water), 2.95-2.82 (m, 2H), 1.95-1.80 (m, 4H), 1.55-1.30 9 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH:14]([CH2:23][CH2:24][OH:25])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]>ClCCl>[CH3:8][S:9]([O:13][CH:14]([CH2:23][CH2:24][O:25][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:11])=[O:10]
Reactant: COC(=O)CCCCC(O)CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCCC(CCOS(C)(=O)=O)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
Under an argon atmosphere, triethylamine (0.7 ml, 5.05 mmol) and methanesulfonyl chloride (0.3 ml, 3.71 mmol) were added to a solution of (±)-methyl 6,8-dihydroxyoctanoate (320 mg, 1.68 mmol) in dichloromethane (8.4 ml) at 0° C. The mixture was stirred at 0° C. for 30 min, then quenched with ice water (20 ml) and extracted with dichloromethane (20 ml). The organic extract was washed with 2 M hydrochloric acid (20 ml), saturated sodium bicarbonate solution (20 ml) and brine (20 ml). The organic phase was dried over magnesium sulphate and the solvent was evaporated under reduced pressure to give the crude product which was purified using flash column chromatography with hexane-ethyl acetate (2:3) to give (±)-methyl 6,8-bis(methylsulfonyloxy)octanoate (581 mg, 99% yield) as a clear yellow oil. Rf 0.30 (hexane-ethyl acetate, 3:2).
Reaction SMILES: [N:1]1([C:10]2[C:11](=[O:26])O[C:13](=[O:25])[C:14]=2[C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH3:24])[CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C[Si](C)(C)[NH:29][Si](C)(C)C.CO>C1(C)C=CC=CC=1>[N:1]1([C:10]2[C:11](=[O:26])[NH:29][C:13](=[O:25])[C:14]=2[C:15]2[C:19]3[C:18](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:17]([CH3:24])[CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Cn1cc(C2=C(n3ccc4ccccc43)C(=O)OC2=O)c2ccccc21
Reactant: C[Si](C)(C)N[Si](C)(C)C
Solvent: CO
Solvent: Cc1ccccc1
Product: Cn1cc(C2=C(n3ccc4ccccc43)C(=O)NC2=O)c2ccccc21
Reaction time: 1 h
Yield: 46.1 %

Procedure:
A mixture, 163 mg of 3-(1-indolyl)-4-(1-methyl-3-indolyl)furan-2,5-dione, 2.6 g of hexamethyldisilazane, 0.6 g of methanol and 50 ml of toluene was stirred at 40° C. for 1 hour and then at 110° C. for 1 hour. The mixture was evaporated and the residue was chromatographed on silica gel with 10% methanol in dichloromethane to give 75 mg of 3-(1-indolyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 235°-236° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:22])[CH2:10][S:11][C:12]2[NH:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][N:13]=2)=[CH:5][C:4]=1[F:23])#[N:2].[BH4-].[Na+]>CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:22])[CH2:10][S:11][C:12]2[NH:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][N:13]=2)=[CH:5][C:4]=1[F:23])#[N:2]
Reactant: CCOC(=O)c1cnc(SCC(=O)c2ccc(C#N)c(F)c2)[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1cnc(SCC(O)c2ccc(C#N)c(F)c2)[nH]1

Procedure:
The product from Step G (3.00 g, 9.00 mmol) was suspended in methanol (20 mL). Sodium borohydride (340 mg, 9.00 mmol) was added in portions at 0° C., and the suspension was stirred until it became homogeneous (1 hour). The reaction was quenched by the addition of saturated aqueous ammonium chloride until hydrogen evolution ceased. The resulting suspension was concentrated in vacuo and then partitioned between ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide the title product as an off-white solid which was sufficiently pure for use in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:15][CH3:16])[S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:17])=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:24][N:25]([CH:27]=O)C.Br[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:40][CH2:41][CH2:42]C2C3C(=CC=CC=3)NC=2)(=[O:39])=[O:38])=[CH:33][CH:32]=1>O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:15][CH3:16])[S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:17][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([S:37]([NH:40][CH2:41][CH2:42][C:24]4[NH:25][C:27]5[C:8]([CH:7]=4)=[CH:9][CH:4]=[CH:5][CH:6]=5)(=[O:39])=[O:38])=[CH:33][CH:32]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: CCc1nc2c(N)nc3cc(O)ccc3c2s1
Reactant: CN(C)C=O
Reactant: O=S(=O)(NCCc1c[nH]c2ccccc12)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: CCc1nc2c(N)nc3cc(OCc4ccc(S(=O)(=O)NCCc5cc6ccccc6[nH]5)cc4)ccc3c2s1
Temperature: 75 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-amino-2-ethylthiazolo[4,5-c]quinolin-7-ol (245 mg, 1.0 mmol), cesium carbonate (1.3 g, 4.0 mmol), and DMF (20 mL) was stirred at 75° C. for 10 minutes. {[4-(Bromomethyl)phenyl]sulfonyl}[2-(indol-3-yl)ethyl]amine (432 mg, 1.1 mmol) was added in portions over a period of 30 minutes. Several small additions of {[4-(bromomethyl)phenyl]sulfonyl}[2-(indol-3-yl)ethyl]amine were made over several hours. The reaction mixture was diluted with water (250 mL) and then extracted with chloroform (3×100 mL). The extracts were combined and concentrated under reduced pressure. The residue was purified by HPFC eluting with a gradient of 0-20% CMA in chloroform over 700 mL and then with 20% CMA in chloroform over 400 mL. The resulting solid was recrystallized from 100:1 acetonitrile:water to provide 6 mg of 4-{[(4-amino-2-ethylthiazolo[4,5-c]quinolin-7-yl)oxy]methyl}-N-[2-(1H-indol-2-yl)ethyl]benzenesulfonamide as an off-white solid, mp 100.0-101.0° C. MS (APCI) m/z 558 (M+H)+; Anal. calcd for C29H27N5O3S2: C, 62.46; H, 4.88; N, 12.56. Found C, 62.27; H, 4.63; N, 12.73.
Reaction SMILES: C12N([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)CC1CCNC2.[CH:19]12[CH2:25][NH:24][CH:23]1[CH2:22][N:21]([C:26]([C:28]1[N:29]=[C:30]([CH3:40])[S:31][C:32]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[F:39])=[O:27])[CH2:20]2.ClC1C=NC2C(=CC=CC=2)N=1>>[F:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:32]1[S:31][C:30]([CH3:40])=[N:29][C:28]=1[C:26]([N:21]1[CH2:22][CH:23]2[CH:19]([CH2:25][N:24]2[C:9]2[CH:18]=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:20]1)=[O:27]
Reactant: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Reactant: Cc1nc(C(=O)N2CC3CNC3C2)c(-c2ccccc2F)s1
Agent: Clc1cnc2ccccc2n1
Product: Cc1nc(C(=O)N2CC3CN(c4cnc5ccccc5n4)C3C2)c(-c2ccccc2F)s1

Procedure:
The compound was prepared in a manner analogous to Intermediate 2, Step A, using Intermediate 21 and 2-chloro-quinoxaline as staring materials. (ESI) mass calcd. for C24H20FN5OS, 445.52; m/z found, 446.3 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Li+].[Li+].[Br:18][CH2:19][C:20](Br)=[O:21]>O1CCOCC1>[Br:18][CH2:19][C:20]([N:2]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[CH3:1])=[O:21]
Reactant: CNc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CN(C(=O)CBr)c1ccc([N+](=O)[O-])cc1
Reaction time: 18 h

Procedure:
23.5 g (0.15 mol) of N-methyl-4-nitroaniline are dissolved in 400 ml of dioxane and combined with 22.2 g (0.3 mol) of lithium carbonate. Then 32.2 g (0.18 mol) of bromoacetylbromide are added dropwise in such a way that the internal temperature does not exceed 33° C. After 18 hours' stirring the reaction solution is evaporated down to 100 ml, combined with 500 ml of water and stirred for 1 hour. The precipitate formed is suction filtered, washed with water and dried. The crude product is stirred in 400 ml of ethyl acetate at 40° C. Then the insoluble matter is filtered off, the solution is evaporated down and the solid residue is triturated with ether.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]#[N:8])=[CH:4][CH:3]=1.[Br:9]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:9][CH2:1][C:2]1[S:6][C:5]([C:7]#[N:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C#N)s1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)s1
Temperature: 25 °C
Yield: 22.7 %

Procedure:
5-Methylthiophene-2-carbonitrile (500 mg, 4.06 mmol) in carbon tetrachloride (10 mL) was stirred with N-bromosuccinimide (867 mg, 4.87 mmol) and 2,2′-azobis(isobutyronitrile) (133 mg, 0.810 mmol) at 60° C. for 4.5 hours and allowed to cool to room temperature. After addition of saturated aqueous sodium thiosulfate, the reaction mixture was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1␣1/1 (v/v)) to give the title compound as a yellow oil (186 mg, yield 23%).