Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([CH3:12])=[CH:10][N:11]=1)=[O:5].[H-].[Na+].Cl[CH2:21][C:22]1[N:23]=[C:24]([CH3:27])[S:25][CH:26]=1>CN(C)C=O.O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4](/[N:6]=[C:7]1\[S:8][C:9]([CH3:12])=[CH:10][N:11]\1[CH2:21][C:22]1[N:23]=[C:24]([CH3:27])[S:25][CH:26]=1)=[O:5]
Reactant: Cc1cnc(NC(=O)c2cc(Cl)ccc2Cl)s1
Reactant: Cc1nc(CCl)cs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cn(Cc2csc(C)n2)/c(=N/C(=O)c2cc(Cl)ccc2Cl)s1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of Example 20A (0.6 g, 2.1 mmol) in N,N-dimethylformamide/tetrahydrofuran (1:4, 20 mL) were added sodium hydride (60% dispersion in mineral oil, 0.1 g, 2.5 mmol), tetrabutylammonium iodide (0.09, 0.23 mmol) and commercially available 4-(chloromethyl)-2-methylthiazole (Maybridge, 0.37 g, 2.5 mmol). The reaction mixture was stirred at 80° C. for 16 hours, cooled, diluted with ethyl acetate (20 mL) and quenched with saturated aqueous NaHCO3 (20 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with water (1×25 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280 ™ (SiO2, 0-50% ethyl acetate in hexanes) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.30 (s, 3 H), 2.63 (s, 3 H), 5.42 (s, 2 H), 7.34-7.39 (m, 2 H), 7.51 (s, 1 H), 7.52 (s, 1 H), 7.88 (t, J=1.5 Hz, 1 H); MS (ESI+) m/z 398 (M+H)+; Anal. Calculated for C16H13Cl2 N30S2 0.75H2O: C, 48.24; H, 3.29; N, 10.55. Found: C, 46.35; H, 3.46; N, 9.97.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C([Li])(CC)C.[CH3:14][Si:15]([CH3:22])([CH3:21])[C:16]#[C:17][C:18](=[O:20])[CH3:19]>CCOCC>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:18]([OH:20])([C:17]#[C:16][Si:15]([CH3:22])([CH3:21])[CH3:14])[CH3:19])=[N:3][CH:4]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CC(=O)C#C[Si](C)(C)C
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CC(O)(C#C[Si](C)(C)C)c1ccc(F)cn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
To a stirred solution of 2-bromo-5-fluoropyridine (1.76 g, 10.00 mmol) in ether (20 mL) maintained under nitrogen at −78° C. was added a solution of s-butyllithium (1.3M in hexane, 10 mL, 13.00 mmol) dropwise. The reaction mixture was then stirred at −78° C. for 1 hr and 4-(trimethylsilyl)but-3-yn-2-one (1.54 g, 10.98 mmol) was added to the reaction mixture dropwise with stirring at −78° C. The resulting solution was stirred at −78° C. for 2 hr and then quenched by the addition of saturated ammonium chloride solution (5 mL) and water (10 mL). The resulting solution was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified on a silica gel column with ethyl acetate/petroleum ether (1:3) to give 1 g (42%) of the title compound as a yellow oil: LC-MS: m/z=+238 (M+H)+.
Reaction SMILES: OC[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.Cl.[CH2:14]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1S(O)(=O)=O)[CH2:15][CH2:16]CCCCCCCCC.C(C1C=C2C(=CC=1)CCC2)=O.[OH-].[K+]>O>[CH2:16]1[C:27]2[C:26](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:14][CH2:15]1
Reactant: CCCCCCCCCCCCc1ccccc1S(=O)(=O)O
Agent: Cl
Agent: O=Cc1ccc2c(c1)CCC2
Agent: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Solvent: O
Product: c1ccc2c(c1)CCC2
Reaction time: 0.17 h

Procedure:
A 400 mL reaction vessel fitted with a mechanical stirrer was charged with sorbitol (32 g, 0.18 mol), water (20 g), concentrated HCl (45 g) and dodecylbenzenesulfonic acid (0.4 g). After stirring for 10 min, 5-formylindan (29 g, 0.20 mol) was added. The mixture was stirred for 18 h, then neutralized with aqueous KOH. The solids were collected by filtration and washed with water and methanol to give Indan DBS as a white solid (14 g, 33% yield).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([CH:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:13]2[CH2:16][CH:15]([OH:17])[CH2:14]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCN(CC)CC>C1(C)C=CC=CC=1>[CH:12]([N:13]1[CH2:16][CH:15]([O:17][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:14]1)([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CS(=O)(=O)Cl
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Yield: 41.3 %

Procedure:
Methane sulphonyl chloride (0.5 mL, 6.43 mmol) was added to a solution of 1-(diphenylmethyl)-3-hydroxyazetidine (1.38 g, 5.77 mmol) and Et3N (0.9 mL, 6.46 mmol) in toluene (10 mL) at 0° C. The reaction mixture was stirred and warmed to room temperature overnight. The mixture was quenched with H2O (100 mL) and extracted with EtOAc (100 mL). The organic layer was dried over MgSO4 and concentrated to give pale yellow oil (756 mg, 41%) which was used without further purification.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[Br:12][C:13]1[C:14]([O:31][CH3:32])=[C:15]([CH:21]([NH:23]C(=O)OC(C)(C)C)[CH3:22])[CH:16]=[C:17]([Cl:20])[C:18]=1[CH3:19].C(=O)([O-])[O-].[Na+].[Na+].O>C(Cl)Cl.CCOC(C)=O>[Br:12][C:13]1[C:14]([O:31][CH3:32])=[C:15]([CH:21]([NH:23][C:2](=[O:3])[O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:22])[CH:16]=[C:17]([Cl:20])[C:18]=1[CH3:19]
Reactant: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1Br
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1c(C(C)NC(=O)OCc2ccccc2)cc(Cl)c(C)c1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.7 %

Procedure:
Benzyl chloroformate (0.41 mL, 2.8 mmol) was added to a mixture of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanamine hydrochloride (0.50 g, 1.6 mmol, made from Example 113, step 1, chiral intermediate), and sodium carbonate (670 mg, 6.3 mmol) in methylene chloride (5 mL)/water (1 mL) at 0° C. The reaction was stirred at room temperature for 4 hours. The mixture was diluted with EtOAc, washed with water, brine, dried over Na2SO4, filtered and concentrated. The resultant residue was purified by chromatography eluting with 0 to 20% EtOAc in hexanes to provide the desired product (0.5 g, 76%). LCMS calculated for C18H19BrClNO3Na (M+Na)+: m/z=434.0. found: 434.1.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.[CH3:8][O:9][C:10]1[CH:51]=[CH:50][C:13]([CH2:14][N:15]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([C:23]3[C:24]([NH:31][C:32]4[CH:33]=[N:34][C:35]([O:39][CH3:40])=[C:36]([F:38])[CH:37]=4)=[N:25][CH:26]=[C:27]([CH:30]=3)[CH:28]=O)[N:17]=2)=[CH:12][CH:11]=1.C([BH3-])#N.[Na+]>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[F:38][C:36]1[CH:37]=[C:32]([NH:31][C:24]2[C:23]([C:18]3[N:19]=[C:20]([CH3:22])[N:21]=[C:16]([N:15]([CH2:41][C:42]4[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=4)[CH2:14][C:13]4[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[CH:51][CH:50]=4)[N:17]=3)=[CH:30][C:27]([CH2:28][N:3]3[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]3[CH3:1])=[CH:26][N:25]=2)[CH:33]=[N:34][C:35]=1[O:39][CH3:40]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Reactant: C[C@H]1COCCN1
Agent: [Ti+4]
Agent: CC[O-]
Agent: [BH3-]C#N
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCOC[C@@H]4C)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 105.9 %

Procedure:
(S)-3-methylmorpholine (Aldrich, 0.105 g, 1.041 mmol) and 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinaldehyde (Example 143, Step 2; 0.310 g, 0.520 mmol) were suspended in THF (3 mL) and titanium (IV) ethoxide (0.60 mL, 2.90 mmol) was added. The mixture was sealed and heated at 70° C. overnight. The light brown solution was cooled to 0° C. and excess sodium cyanoborohydride (0.327 g, 5.20 mmol) was added, and the mixture was stirred at 0° C. for 2 h. The resulting solution was quenched with a couple drop of MeOH followed by water. DCM was added to the entire mass and vigorously stirred for 10 min. The mixture was filtered and passed through a short path of Celite® (diatomaceous earth). The filter cake was washed with DCM (3×10 mL). The combined organic phases were concentrated to give a crude residue. Flash column chromatographic purification (short column, SiO2, 100% DCM to 5% MeOH in DCM) provided (S)-4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-((3-methylmorpholino)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (375 mg) as a yellow solid, which was deprotected under similar conditions according to the procedure reported previously (Example 178, Step 4) to afford the title compound (199 mg, 82%) as a yellow solid. m/z (ESI, +ve ion) 441 (M+H)+. 1H NMR (400 MHz, CDCl3) δ (rotatomer mixtures) 12.09 (br. s., 1H) 9.01 (br. s., 1H) 8.15-8.56 (m, 2H) 8.05 (br. s., 1H) 7.26 (br. s., 1H) 4.88-6.53 (m, 1H) 4.32 (br. s., 1H) 4.03 (br. s., 3H) 3.84 (br. s., 4H) 3.57 (br. s., 2H) 2.91 (br. s., 2H) 2.55 (br. s., 3H) 1.21 (d, J=5.28 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]#[CH:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=[O:13].[N+:23]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br)([O-:25])=[O:24].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:20]([C:17]1[CH:16]=[CH:15][C:14]([C:12]([C:3]2[CH:4]=[C:5]([O:8][CH2:9][C:10]#[CH:11])[CH:6]=[CH:7][C:2]=2[NH:1][CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([N+:23]([O-:25])=[O:24])[CH:27]=2)=[O:13])=[CH:19][CH:18]=1)([CH3:22])[CH3:21]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: C#CCOc1ccc(N)c(C(=O)c2ccc(C(C)C)cc2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CCOc1ccc(NCc2cccc([N+](=O)[O-])c2)c(C(=O)c2ccc(C(C)C)cc2)c1
Temperature: 45 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
A mixture of 30 g (102 mmol) (2-amino-5-propargyloxy-phenyl)-(4-isopropyl-phenyl)-methanone, 23.8 g (110 mmol) 3-nitrobenzylbromide and 21 ml (120 mmol) Hünig's base in 160 ml methylene chloride is stirred overnight at 45° C. The resulting dark solution is washed twice with 200 ml water and with brine. Purification of the crude product by chromatography (CH2Cl2/petroleum ether 1:1) affords 34.4 g (79%) of a viscous red oil.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH2:17]1[O:30][C:29]2[CH:28]=[CH:27][C:21]([CH:22]=[CH:23][C:24](O)=O)=[CH:20][C:19]=2[O:18]1>>[CH2:17]1[O:30][C:29]2[CH:28]=[CH:27][C:21](/[CH:22]=[CH:23]/[C:24]3[NH:1][C:2]4[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=4[N:8]=3)=[CH:20][C:19]=2[O:18]1
Reactant: O=C(O)C=Cc1ccc2c(c1)OCO2
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc4c(c3)OCO4)nc2n(CCC)c1=O
Yield: 68.4 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 4.25 g (18.8 mmol) of 5,6-diamino-1,3-dipropyluracil and 4.33 g (22.6 mmol) of 3,4-methylenedioxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane to give 4.92 g (yield 69%) of Compound 18 as a pale yellow powder.
Reaction SMILES: BrC(Br)C.[CH2:5]([O:12][C:13](=[O:25])[C@H:14]([CH3:24])N(I)C(OC(C)(C)C)=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.I[C:27]1[CH:32]=[CH:31][C:30](C2(C([O-])=O)CC2)=[CH:29][CH:28]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C1COCC1.CC(N(C)C)=O.C(OCC)(=O)C.[Zn].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]>[CH2:5]([O:12][C:13](=[O:25])[CH2:14][CH2:24][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C([O-])C1(c2ccc(I)cc2)CC1
Reactant: C[C@@H](C(=O)OCc1ccccc1)N(I)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC(Br)Br
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: O=C(CCc1ccccc1)OCc1ccccc1
Temperature: 55 °C
Reaction time: 16 h
Yield: 67.1 %

Procedure:
A suspension of zinc (0.874 g) in THF with dibromoethane (0.02 mL) was sonicated at 40° C. for 40 minutes under argon. N-Boc-iodo-L-alanine benzyl ester (4.20 g, 10.4 mmol) and dimethylacetamide (5 mL) were added, and the mixture was heated at 55° C. for 1 hour. tbutyl 1-(4-iodophenyl)cyclopropane-1-carboxylate (3.26 g, 9.48 mmol) in dimethylacetamide (10 mL) was added followed by tris(dibenzylideneacetone)dipalladium(0) (0.33 g) and tri-o-tolylphosphine (0.398 g). Heating was continued under argon for 16 hours. The mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. Chromatography of the residue over silica gel (methylene chloride/hexane 1/3 to methylene chloride/ethyl acetate 95/5) gave 2-(S)-tbutoxycarbonylamino-3-[4′-1″-tbutoxycarbonyl)cyclopropyl]benzenepropanoic acid benzyl ester (3.15 g, 6.36 mmol, 67%).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:34]=[CH:33][C:12]([CH2:13][C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([C:28]([O:30]CC)=[O:29])[CH:20]([C:24]([F:27])([F:26])[F:25])[O:21]3)=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)=O)(C)(C)C.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36].[OH-].[Na+]>Cl.C1COCC1.O.C1COCC1.CO>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[NH2:8][C:9]1[CH:34]=[CH:33][C:12]([CH2:13][C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([C:28]([OH:30])=[O:29])[CH:20]([C:24]([F:27])([F:25])[F:26])[O:21]3)=[CH:16][CH:15]=2)=[CH:11][CH:10]=1
Reactant: CCOC(=O)C1=Cc2ccc(Cc3ccc(NC(=O)OC(C)(C)C)cc3)cc2OC1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(Cc2ccc3c(c2)OC(C(F)(F)F)C(C(=O)O)=C3)cc1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
The ester from Step 1 was dissolved in 0.3 mL HCl in THF/H2O=1/1. The mixture was stirred at r.t for 2 days. Additional 2 mL TFA was added to above solution and the solution was stirred for 2 days. LCMS indicated that there was less than 10% product. The mixture was heated at 50° C. for 4 hrs. After purification, the combined deBoc-ester was redissolved in THF/MeOH=2/1 and NaOH (2.5 N, 2.5 eq). The mixture was stirred at r.t overnight. The mixture was purified by RPHPLC to give the title compound as an amorphous solid: ESHRMS m/z 350.0994 (M+H, C18H15O3F3N, Calc'd 350.0999). 1H NMR (acetone-d6/300 MHz) 7.38 (m, 3H), 7.11 (d, 1H, J=8.4 Hz), 7.00 (d, 1H, J=8.1 Hz), 6.93 (s, 1H), 6.71 (d, 1H, J=8.1 Hz), 5.78 (q, 1H, J=7.2 Hz), 4.04 (s, 2H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[C:9]([O:19][CH:20]2[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]2)=[CH:10][C:11]([F:18])=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.O>[Cl:7][C:8]1[C:9]([O:19][CH:20]2[CH2:25][CH2:24][C:23](=[CH2:1])[CH2:22][CH2:21]2)=[CH:10][C:11]([F:18])=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1cc(Cl)c(OC2CCC(=O)CC2)cc1F
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C1CCC(Oc2cc(F)c(C(=O)OC)cc2Cl)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a suspension of methyltriphenylphosphonium bromide (1.61 g, 4.51 mmol) in anhydrous tetrahydrofuran (20 mL) was added a solution of potassium tert-butoxide (0.541 g, 4.82 mmol) in anhydrous tetrahydrofuran (15 mL) dropwise over 3 minutes at 0° C. The mixture was stirred under a nitrogen atmosphere at 0° C. for 1 h. To this solution was added a solution of methyl 5-chloro-2-fluoro-4-((4-oxocyclohexyl)oxy)benzoate (1.05 g, 3.48 mmol) in anhydrous tetrahydrofuran (15 mL) dropwise over 3 minutes. The mixture was stirred at ambient temperature for 21 h, then diluted with water (200 mL). The mixture was extracted with ethyl acetate (200 mL) and the organic phase was washed with water (50 mL) and brine (150 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with a gradient of 0-10% ethyl acetate in hexanes to afford the title compound as a colorless syrup (0.866 g, 83% yield): 1H NMR (300 MHz, CDCl3) δ 7.94 (d, J=7.7 Hz, 1H), 6.67 (d, J=12.2 Hz, 1H), 4.68 (s, 2H), 4.56-4.50 (m, 1H), 3.87 (s, 3H), 2.48-2.40 (m, 2H), 2.17-2.09 (m, 2H), 1.92-1.86 (m, 4H); MS (ES+) m/z 299.00 (M+1).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5].N1C=CN=C1.Cl[Si:16]([CH3:19])([CH3:18])[CH3:17]>CN(C)C=O>[CH3:17][Si:16]([CH3:19])([CH3:18])[O:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5]
Reactant: C[Si](C)(C)Cl
Reactant: C#CCC(O)CCCC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C#CCC(CCCC)O[Si](C)(C)C
Reaction time: 60 h

Procedure:
To a cold solution of 166 g of 4-hydroxy-1-octyne [Prostaglandins, 10, 289 (1975)], and 240 g of imidazole in one liter of dimethylformamide is added dropwise 202 g of chlorotrimethylsilane. The mixture is allowed to stand at room temperature for 2 to 3 days. The mixture is partitioned with water and hexane. The hexane layer is washed with brine dried over magnesium sulfate, and concentrated. Distillation of the residue gives a colorless liquid, bp 38° C. (0.2 mm).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17](=[O:23])[N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:12][CH2:11]2)=[O:9])[N:6]=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:33](O)=[O:34])[CH:31]=2)[CH:26]=[CH:25]1>>[O:9]=[C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17](=[O:23])[N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:12][CH2:11]1)[CH2:7][C:5]1[N:6]=[C:2]([NH:1][C:33]([C:30]2[CH:31]=[C:32]3[C:27]([CH:26]=[CH:25][NH:24]3)=[CH:28][CH:29]=2)=[O:34])[S:3][CH:4]=1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: Nc1nc(CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cs1
Product: O=C(Nc1nc(CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cs1)c1ccc2cc[nH]c2c1

Procedure:
In analogy to example 37.5, 2-(2-amino-thiazol-4-yl)-1-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethanone (example 37.4) was coupled with indole-6-carboxylic acid, using general method D, to give 1H-indole-6-carboxylic acid (4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide. Off-white solid. MS 481.5 ([M+H]+)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH2:9][C:10]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[N:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:4][CH2:3]1.C([N-]C(C)C)(C)C.[Li+].[CH:34](=[O:37])[CH2:35][CH3:36].O>O1CCCC1.C(Cl)(Cl)Cl>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]([CH:34]([OH:37])[CH2:35][CH3:36])[C:10]([N:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)=[N:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:7]1
Reactant: CCC=O
Reactant: CN1CCN(C2=Nc3ccccc3N=C(N3CCN(C)CC3)C2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCC(O)C1C(N2CCN(C)CC2)=Nc2ccccc2N=C1N1CCN(C)CC1
Temperature: -30 °C
Yield: 92 %

Procedure:
A suspension of 2,4-bis(4-methyl-1-piperazinyl)-3H-[1,5]benzodiazepine (17.024 g, 50 mmol) in tetrahydrofuran (200 ml) under constant flow of argon was cooled to −30° C. A solution of lithium diisopropylamide (LDA) (2 M, 37.5 ml, 75 mmol) was added dropwise. Thus obtained dark brown suspension was allowed to warm to −5° C., and then again cooled to −30° C. Propionaldehyde (5.50 ml, 75 mmol) was added during 5 min. The resulting pale brown suspension was allowed to warm to 10° C., while strongly agitated water (250 ml) was added. The solution was transferred to a separating funnel, chloroform (150 ml) was added and the phases were separated. The water phase was extracted with chloroform (2×50 ml). The combined organic phases were dried over anhydrous Na2SO4 and the solvent was evaporated at reduced pressure. The crude product was suspended in hexane (750 ml), filtered off and washed with hexane (75 ml) to give 18.34 g (92%) of the title compound as an off-white powder. For analytical purposes the product was recrystallised from ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].C(N(CC)CC)C.[Cl-].[Cl:18][C:19]1[S:20][S+:21]=[C:22](Cl)[C:23]=1[Cl:24]>C(Cl)Cl>[Cl:24][C:23]1[C:22](=[N:5][C:4]2[CH:3]=[C:2]([Cl:1])[CH:8]=[C:7]([Cl:9])[CH:6]=2)[S:21][S:20][C:19]=1[Cl:18]
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: Clc1s[s+]c(Cl)c1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Clc1cc(Cl)cc(N=c2ssc(Cl)c2Cl)c1

Procedure:
18.5 g of 3,5-dichloro-aniline were dissolved in 300 ml of methylene chloride and 50 ml of triethylamine and 31.0 g of 3,4,5-trichloro-1,2-dithiolium chloride were introduced at 10°-15° C. The mixture was stirred for about 12 hours, until a test for aromatic amine, by diazotizing and coupling, proved negative. The resulting dark solution was then washed three times with 200 ml of water, dried over potassium carbonate and filtered over a column of aluminum oxide, to remove impurities that imparted a color. The filtrate was reduced to dryness in vacuo and the residue was recrystallized from petroleum ether.
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][NH:19][C:16]3=[N:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[I:22]Cl.ClCCl.CCOC(C)=O>N1C=CC=CC=1>[I:22][C:21]1[C:15]2[C:16](=[N:17][CH:18]=[C:13]([C:10]3[CH:9]=[CH:8][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[CH:12][CH:11]=3)[N:14]=2)[NH:19][CH:20]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc3[nH]ccc3n2)cc1
Reactant: ClI
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc3[nH]cc(I)c3n2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.79 %

Procedure:
To 2-(4-isopropylsulfonylphenyl)-5H-pyrrolo[2,3-b]pyrazine (9 g, 29.86 mmol) in pyridine (90.00 mL) at RT was added a 1M solution of iodine monochloride in dichloromethane (32.85 mL of 1 M, 32.85 mmol). The resulting dark brown solution was stirred at RT for 4 hours then taken into EtOAc and washed with aqueous sodium thiosulphate/NaHCO3×2 then with brine, then dried over MgSO4 and concentrated under reduced pressure. The solid residue was triturated with acetonitrile, filtered and washed with acetonitrile, dried in vacuo to give the subtitle compound (5.97 g, 13.97 mmol, 46.79%). 1H NMR (400.0 MHz, DMSO) δ 12.72 (s, 1H), 9.03 (s, 1H), 8.46 (d, J=8.5 Hz, 2H), 8.23 (s, 1H), 8.01 (d, J=8.5 Hz, 2H), 3.49 (t, J=6.8 Hz, 1H) and 1.20 (d, J=6.8 Hz, 6H) ppm; MS (ES+) 428.0.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH:10]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])[CH2:9]2)=[CH:6][C:5]([C:26]#[N:27])=[CH:4][C:3]=1[NH:28]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:28][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH:10]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])[CH2:9]2)[C:2]=1[Cl:1])[C:26]#[N:27]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCN(C3COC3)C(C(=O)N3CCOCC3)C2)c1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(N)c(Cl)c(N2CCN(C3COC3)C(C(=O)N3CCOCC3)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
(+/−) Tert-butyl (2-chloro-5-cyano-3-(3-(morpholine-4-carbonyl)-4-(oxetan-3-yl)piperazin-1-yl)phenyl)carbamate (112 mg, 0.221 mmol) was taken up in DCM (3 mL) and TFA (0.341 mL, 4.43 mmol) was added. The reaction was stirred at rt for 1 h. The solvent was removed in vacuo and the material was azeotroped 2× with DCM and 2× with MeOH, then dried under vacuum. The solid was dissolved in EtOAc, then washed with 2M K3PO4 solution. The organic layer was dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography (0-5% MeOH/DCM). (+/−) 3-amino-4-chloro-5-(3-(morpholine-4-carbonyl)-4-(oxetan-3-yl)piperazin-1-yl)benzonitrile (36 mg) was obtained as a colorless foam.