Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17](NC=O)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].C[CH2:27][N:28](CC)CC>CN1C(=O)CCC1>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:27][NH:28][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1
Reactant: FC(F)(F)c1cc(I)cc(Cl)n1
Reactant: COc1ccc(NC=O)cc1OC
Reactant: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2cc(I)cc(C(F)(F)F)n2)cc1OC
Yield: 36 %

Procedure:
A solution of 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (1.0 equiv.), (3,4-dimethoxyphenyl)methanamide (5.0 equiv.), and Et3N (5.0 equiv.) in NMP (0.7M) was microwaved to 100° C. for 10 min. The solution was directly purified via reverse phase HPLC, the pure fractions were neutralized with solid NaHCO3, extracted with EtOAc, dried with MgSO4, and concentrated to give N-(3,4-dimethoxybenzyl)-4-iodo-6-(trifluoromethyl)pyridin-2-amine in 36% yield. LCMS (m/z): 347.1 (MH+); LC Rt=3.96 min.
Reaction SMILES: [CH3:1][C@H:2]([C:15]([OH:17])=[O:16])[C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][C:11]=2[CH:12]=1.[Cl-:18].O>ClCCl>[CH3:14][O:13][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[CH:12]=[C:3]([C@H:2]([CH3:1])[C:15]([O:17][CH2:1][CH2:2][CH2:3][CH2:12][Cl:18])=[O:16])[CH:4]=[CH:5]2
Reactant: [Cl-]
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Solvent: ClCCl
Solvent: O
Product: COc1ccc2cc([C@H](C)C(=O)OCCCCCl)ccc2c1
Temperature: 0 °C
Reaction time: 10 h

Procedure:
Preparation: 30 g of Naproxen chloride are dissolved in 120 g of dichloromethane. This solution is cooled at 0° C. and a solution of 14.5 g of 1-chloro-3-buthanol in 100 g of dichloromethane is added dropwise in 2 hours. After a completion time of 3 hours at 0° C., 60 g of water are added and is the mixture is stirred for 10 hours. After phase separation, 60 g of water are added to organic phase and the mixture is stirred for 10 hours. After phase separation, the organic phase is concentrated to 120 mL and 4.5 g of potassium carbonate are added. The mixture is refluxed at about 40° C. for 4 hours. After filtration and vacuum concentration, an oil is obtained (HPLC purity 90%).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[CH:10][CH:11]=1)=[O:5].C(N(CC)CC)C.CCOCC.[CH3:25][O:26][C:27]1[CH:37]=[CH:36][C:30]([CH2:31][CH2:32][C:33](Cl)=[O:34])=[CH:29][CH:28]=1>ClCCl>[CH3:25][O:26][C:27]1[CH:37]=[CH:36][C:30]([CH2:31][CH2:32][C:33]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])=[CH:11][CH:10]=2)=[O:34])=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1ccc(CCC(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(NC(=O)CCc2ccc(OC)cc2)cc1
Reaction time: 8 h

Procedure:
A solution of 13.73 g. of benzocaine and 11.56 ml. of triethylamine in 100 ml. of ether is slowly added to a stirred solution of 15 g. of p-methoxyhydrocinnamoyl chloride in 100 ml. of ether. The mixture is stirred overnight, 250 ml. of dichloromethane are added, and the mixture is extracted with 200 ml. of water, then 200 ml. of 10% hydrochloric acid, dried over magnesium sulfate, and evaporated to yield a solid. This solid is crystallized from 200 ml. of toluene, giving 21.4 g. of the desired product as white crystals, m.p. 134°-135.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.[F-:12].[K+]>[Cl-].C([N+](CCCCCCCCCCCCCCCCCC)(C)C)CCCCCCCCCCCCCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:12]
Reactant: [F-]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCCCCCCCC
Agent: [Cl-]
Agent: [K+]
Product: O=[N+]([O-])c1ccc(F)c(Cl)c1
Yield: 68.6 %

Procedure:
576 g (3 mol) of 3,4-dichloronitrobenzene, 58 g (0.1 mol) of distearyldimethylammonium chloride and 139 g (2.4 mol) of potassium fluoride were reacted analogously to Example 1. After filtering with suction, the residue was dissolved in water, the organic phase was separated off and the combined organic phases were fractionated. 289 g (69%, relative to potassium fluoride employed) of 3-chloro-4-fluoronitrobenzene were obtained.
Reaction SMILES: CS[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[N:8][CH:9]=[N:10]2)=[C:5]2[NH:13][CH:14]=[N:15][C:4]=12.[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].Cl.BrC1C=C(C=CC=1)N.N>>[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH:20][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[N:8][CH:9]=[N:10]2)=[C:5]2[NH:13][CH:14]=[N:15][C:4]=12
Reactant: Nc1cccc(Br)c1
Reactant: CSc1cc2ncncc2c2[nH]cnc12
Agent: Cl
Agent: N
Product: Brc1cccc(Nc2cc3ncncc3c3[nH]cnc23)c1
Yield: 76.4 %

Procedure:
A solution of 4-methylthioimidazo[4,5-f]quinazoline (0.43 g, 2 mmol), 3-bromoaniline (0.5 g, 3 mmol), and 3-bromoaniline hydrochloride (0.63 g, 3 mmol) is heated under reflux for 16 h. The precipitate of hydrochloride salt is converted directly to the free base with aqueous NH3, and recrystallized from EtOH to give 4-(3-bromoanilino)imidazo[4,5-f]quinazoline (0.52 g, 77%). 1H NMR (DMSO) δ11.53 (1H, brs), 8.79 (1H, s), 8.68 (1H, s), 8.53 (1H, dd, J=1.8, 1.9 Hz), 8.15 (1H, d, J=8.8 Hz), 7.81 (1H, brd, J=8.6 Hz), 7.71 (1H, d, J=8.9 Hz, 1 H), 7.41 (1H, t, J=8.0 Hz), 7.32 (1H, brd, J=7.8 Hz).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:6]([N:7]=[CH:8][N:9]=2)=[C:5]([S:11][CH3:12])[N:4]=[CH:3]1.[I:13][CH2:14][CH2:15][CH2:16]I>>[I-:13].[I:13][CH2:14][CH2:15][CH2:16][N:7]1[C:6]2[C:5]([S:11][CH3:12])=[NH+:4][CH2:3][N:2]([CH3:1])[C:10]=2[N:9]=[CH:8]1
Reactant: ICCCI
Reactant: CSc1ncn(C)c2ncnc1-2
Product: CSC1=[NH+]CN(C)c2ncn(CCCI)c21
Product: [I-]
Temperature: 120 °C
Yield: 28 %

Procedure:
A pressure tube, equipped with a magnetic stirring bar, was charged with Compound 2 (0.54 g, 3 mmole) and 1,3-diiodopropane (2.66 g, 9 mmole). The mixture was heated to ˜120° C. for 3 hours. The residue was extensively washed with ethyl acetate and diethyl ether and dried under vacuum to give 0.4 g of yellow solid Compound 3 (yield ˜28%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:11](=[O:12])[CH:10]=[CH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.[CH2:13]=[CH:14][CH:15]1[CH2:20][CH:19]=[CH:18][CH2:17][CH2:16]1.[H][H]>[Pd].O1CCOCC1>[CH2:16]([CH:17]1[C:10]2[C:11](=[O:12])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7](=[O:8])[C:9]=2[CH2:20][CH2:19][CH2:18]1)[CH2:15][CH2:14][CH3:13]
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: C=CC1CC=CCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: CCCCC1CCCC2=C1C(=O)c1ccccc1C2=O
Reaction time: 3 h
Yield: 59 %

Procedure:
A solution of 78.0 g. (0.495 mole) naphthoquinone and 56.0 g. (0.52 mole) butadiene dimer in 200 ml. dioxane was heated at 90°-95° C. for 1 hour, and then at 80°-90° C. for 3 hours. The solution was then cooled and 2.0 g. 10% palladium-on-charcoal (Pd/C) catalyst added. The mixture was then hydrogenated at 42 psi until the theoretical amount of hydrogen was taken up. After removal of the catalyst by filtration and addition of 2 ml. DBN, a slow stream of air was blown through the solution for 6 hours. The solution was then poured into 2000 ml. water and the mixture extracted three times with 300 ml., 100 ml. portions of cyclohexane. The combined cyclohexane extracts were dried over anhydrous potassium carbonate, treated with Darco activated charcoal (Atlas Chemical Industries), and then filtered. After removal of the solvent by using a steam bath, 73.0 g. of crude product was obtained (59% yield). The product was purified by chromatography on acidic alumina using cyclohexane eluent. An analytical sample, after recrystallization from methanol, had m.p. 64°-65° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](OB(O)O)=[CH:2]1.Br[C:11]1[S:15][C:14]([S:16]([N:19]2[CH:23]=[CH:22][CH:21]=[CH:20]2)(=[O:18])=[O:17])=[CH:13][CH:12]=1>>[S:1]1[CH:5]=[CH:4][C:3]([C:11]2[S:15][C:14]([S:16]([N:19]3[CH:23]=[CH:22][CH:21]=[CH:20]3)(=[O:17])=[O:18])=[CH:13][CH:12]=2)=[CH:2]1
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Reactant: OB(O)Oc1ccsc1
Product: O=S(=O)(c1ccc(-c2ccsc2)s1)n1cccc1

Procedure:
N-[5-(3-thienyl)thiophene-2-sulfonyl]pyrrole was prepared in the same manner as described in Example 32C from 3-thienylboric acid and N-(5-bromothiophene-2-sulfonyl)pyrrole in quantative yield. This was purified by recrystallization using hexane/ethyl acetate as solvent.
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=O)[NH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:19][CH3:20])(=[O:3])[CH3:2].CN(C=O)C.S(Cl)([Cl:34])=O>>[Cl:34][C:12]1[C:11]2[C:16](=[CH:17][C:8]([O:7][CH2:6][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[C:9]([O:19][CH3:20])[CH:10]=2)[N:15]=[CH:14][N:13]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCC(CN1CCCC1)OC(C)=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCC(CN1CCCC1)OC(C)=O

Procedure:
7-(2-Acetoxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (4.7 g) was suspended in thionyl chloride (55 ml), DMF (0.5 ml) was added and the mixture heated at reflex for 1 hour. The thionyl chloride was evaporated under vacuum, toluene was added and the solvent was evaporated. This process was repeated twice. The residue was taken up in ice/water, the pH adjusted to 7.5 with a saturated solution of sodium bicarbonate followed by sodium hydroxide 2N until pH 9 and the aqueous solution extracted twice with dichloromethane. The combined extracts were washed with water and brine, dried over magnesium sulphate and filtered. The filtrate was evaporated under vacuum and the residue triturated with ether to give 4-chloro-7-[2-acetoxy-3-(pyrrolidin-1-yl)propoxy]-6-methoxyquinazoline (4.1 g) as a white foam.
Reaction SMILES: [OH:1][CH:2]([C@@H:5]1[CH2:10][C@H:9]([N:11]([CH:13]([CH3:15])[CH3:14])[CH3:12])[CH2:8][CH2:7][C@@H:6]1[N:16]1[CH2:20][CH2:19][C@H:18]([NH:21]C(=O)OCC2C=CC=CC=2)[C:17]1=[O:32])[CH2:3][CH3:4]>CO.[Pd]>[NH2:21][C@H:18]1[CH2:19][CH2:20][N:16]([C@H:6]2[CH2:7][CH2:8][C@@H:9]([N:11]([CH:13]([CH3:14])[CH3:15])[CH3:12])[CH2:10][C@H:5]2[CH:2]([OH:1])[CH2:3][CH3:4])[C:17]1=[O:32]
Reactant: CCC(O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: CCC(O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reaction time: 4 h
Yield: 101.8 %

Procedure:
A solution of benzyl (S)-1-((1S,2R,4R)-2-(1-hydroxypropyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (267 mg) in MeOH (15 mL) was charged with 10% Pd/C, Degussa (100 mg). The reaction flask was evacuated and then back-filled with hydrogen; this was repeated two more times. The reaction was stirred under 60 psi of H2 for 4 h and then filtered and concentrated in vacuo to afford the desired (S)-3-amino-1-((1S,2R,4R)-2-(1-hydroxypropyl)-4-(isopropyl(methyl)amino)cyclohexyl)pyrrolidin-2-one (190 mg) as an oil.
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[O:13].C(O)(=O)C>C(OCC)C.O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]([CH2:11][C:3]([O:7][CH2:8][CH3:9])=[O:10])=[O:13])=[CH:15][CH:16]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)CC(=O)c1ccc(F)cc1
Temperature: 5 °C

Procedure:
21.7 g (0.72 mol) of sodium hydride (80% strength, 20% mineral oil) are weighed into a liter of diethyl ether p.a. and 85.5 g (127 ml, 0.72 mol) of diethyl carbonate (VK 22-010) are subsequently added. A solution of 100 g (0.72 mol) of 4-fluoroacetophenone in 300 ml of diethyl ether are added dropwise to this solution at boiling heat over a period of 4 hours (vigorous, mechanical stirrer necessary; a viscous paste is formed). The mixture is then heated to reflux for a further hour, then cooled to about 5° C. and a solution of 50 ml of acetic acid and 100 ml of Et2O is next added dropwise under N2 at this temperature. About 500 ml of H2O are subsequently added dropwise and the organic phase is separated off. The aqueous phase is extracted once again using Et2O (2×400 ml), and the combined ethereal phases are washed with NaHCO3 solution, dried over MgSO4 and concentrated. The residue is distilled over a short Vigreux column.
Reaction SMILES: I[CH2:2][O:3][C:4](=[S:10])[O:5][CH:6]([CH2:8][CH3:9])[CH3:7].[CH2:11]([O:18][P:19]([O-:29])([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:4](=[S:10])([O:5][CH:6]([CH2:8][CH3:9])[CH3:7])[O:3][CH2:2][O:29][P:19]([O:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: CCC(C)OC(=S)OCI
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CCC(C)OC(=S)OCOP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product of Example 19B (7.3 g, 27 mmoles) and tetrabutylammonium dibenzylphosphate (13.8 g, 26.6 mmol) were mixed in 20 ml of tetrahydrofuran and stirred at room temperature for 24 hours. The mixture was diluted with 100 mL of tetrahydrofuran, filtered through celite and the solvent was evaporated. The residue was resuspended in 200 mL of 20% ethyl acetate in hexane and the precipitate was filtered and washed with an additional 100 mL of 20% ethyl acetate. The organic filtrates were combined and the solvent was evaporated. Final product was obtained by flash chromatography on silica using 20% ethyl acetate in hexane. Fractions containing product were combined and the solvent was removed to give 8.7 g (78%) of a colorless oil. 1H NMR (300 MHz, CDCl3) δ ppm 0.91 (t, J=7.29 Hz, 3 H) 1.31-1.45 (m, 2 H) 1.55-1.65 (m, 2 H) 2.80-2.90 (m, 2 H) 5.07 (d, J=7.80 Hz, 4 H) 5.65 (d, J=13.90 Hz, 2 H) 7.34 (s, 10 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH2:22][CH2:23][C:24]([O:26]C)=[O:25])[N:21]=2)=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.O>[CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[N:21]=2)=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Reaction time: 16 h
Yield: 97.7 %

Procedure:
Methyl 3-(2-(3-(benzyloxy)-5-bromopyridin-2-ylamino)thiazol-4-yl)propanoate (Example 58; 1.500 g, 3.346 mmol) was dissolved in THF (50 mL) and water (25 mL), followed by the addition of sodium hydroxide (0.2676 g, 6.691 mmol), and the mixture was at ambient temperature for 16 hours. The mixture was concentrated, and partitioned between DCM and saturated aqueous NH4Cl. The layers were separated and the aqueous was extracted with DCM/THF and then 100% THF. The combined organics were dried over Na2SO4, filtered and concentrated to give 3-(2-(3-(benzyloxy)-5-bromopyridin-2-ylamino)thiazol-4-yl)propanoic acid (1.42 g, 98% yield) as white solids. 1H NMR (DMSO-d6) δ 2.58 (t, J=7.6 Hz, 2H), 2.82 (t, J=7.6 Hz, 2H), 5.29 (s, 2H), 6.65 (s, 1H), 7.35 (t, J=7.2 Hz, 1H), 7.41 (t, J=7.2 Hz, 2H), 7.58 (s, 1H), 7.60 (s, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.96 (d, J=1.8 Hz, 1H); Mass Spectrum (apci) 434 (M+H).
Reaction SMILES: Cl.Cl.Cl.[F:4][C:5]1[CH:6]=[C:7]([C:12]2[N:13]=[C:14]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:15]([CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:16]=2)[CH:8]=[CH:9][C:10]=1[F:11].Cl[C:31]1[C:32]2[CH2:39][C:38](=[O:40])[NH:37][C:33]=2[N:34]=[CH:35][N:36]=1.CCN(C(C)C)C(C)C>CC(O)C>[F:4][C:5]1[CH:6]=[C:7]([C:12]2[N:13]=[C:14]([CH:24]3[CH2:25][CH2:26][N:27]([C:31]4[C:32]5[CH2:39][C:38](=[O:40])[NH:37][C:33]=5[N:34]=[CH:35][N:36]=4)[CH2:28][CH2:29]3)[N:15]([CH2:17][CH2:18][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:16]=2)[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: O=C1Cc2c(Cl)ncnc2N1
Reactant: Fc1ccc(-c2cn(CCN3CCCC3)c(C3CCNCC3)n2)cc1F
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Cc2c(ncnc2N2CCC(c3nc(-c4ccc(F)c(F)c4)cn3CCN3CCCC3)CC2)N1
Yield: 15.6 %

Procedure:
Combine 4-(4-(3,4-difluoro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl)-piperidine tris hydrochloride (0.3 g; 0.00065 mol), 4-chloro-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.15 g; 0.00083 mol), DIPEA, (1.00 mL, 0.0057 mol) into IPA (9 mL) and heat in a microwave at 80° C. for 1 h; cool and concentrate. Quench with saturated sodium bicarbonate solution and extract with EA. Evaporate the EA and purify by column chromatography using 0-10% MeOH/DCM as eluent to give the title compound (0.05 g; 15.67%). MS (ES+): m/z=494 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].F[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1[C:17]([OH:19])=[O:18].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:15]1[CH:14]=[N:13][CH:12]=[CH:11][C:16]=1[C:17]([OH:19])=[O:18]
Reactant: O=C(O)c1ccncc1F
Reactant: Nc1ccc(Cl)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccncc1Nc1ccc(Cl)cc1Cl
Temperature: -78 °C
Yield: 72 %

Procedure:
2,4-Dichloraniline (162 mg, 1.00 mmol) and 3-fluoropyridine-4-carboxylic acid (141 mg, 1.00 mmol) were dissolved in dry THF (6.0 ml) under argon and the mixture was cooled to −78° C. A solution of LiHMDS (1.0M in THF, 3.5 ml) was added and the reaction mixture was allowed to warm to ambient temperature. After 18 h the reaction was quenched by adding a solution of HCl in dioxane (4.0M, 2.0 ml). The volatiles were removed in vacuo and the crude material was purified by flash chromatography using silica gel and a gradient of 0-10% methanol in DCM as eluent to give 204 mg (721 μmol; 72% yield) of pure desired product.
Reaction SMILES: Br[C:2]1[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:11]([Br:18])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:25][SH:26]>CN(C=O)C.CCOCC>[Br:18][C:11]1[CH:10]=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([S:26][CH3:25])[C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17]
Reactant: CCOC(=O)c1ccc(Br)c(OCCOC)c1Br
Reactant: CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Br)c(OCCOC)c1SC

Procedure:
Ethyl 2,4-dibromo-3-(2-methoxyethoxy)benzoate (32.2 g) was stirred in DMF (80 ml) with potassium carbonate (36 g). To the resultant suspension was added a solution of methane thiol (13 ml) in DMF (20 ml). The resultant mixture was stirred overnight at room temperature. It was then diluted with ether, and the mixture washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness. The residue was purified by column chromatography on silica eluting with ethyl acetate and cyclohexane (1:20) which yielded ethyl 4-bromo-3-(2-methoxyethoxy)-2-methylsulphenylbenzoate (3.5 g) as an oil which was not further characterized.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[CH:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:25][C:26]([C:28]1[N:29]([NH:33][CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][CH:32]=1)=[O:27])[CH:23]=[CH2:24].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:22]([O:25][C:26]([C:28]1[N:29]([N:33]([C:17](=[O:19])[CH2:16][C:11]2[NH:10][C:9]3[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=3[S:13](=[O:14])(=[O:15])[CH:12]=2)[CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][CH:32]=1)=[O:27])[CH:23]=[CH2:24]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)C=C(CC(=O)O)N2
Reactant: C=CCOC(=O)c1cccn1NCCC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C=CCOC(=O)c1cccn1N(CCC(C)C)C(=O)CC1=CS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetic acid (Example 8i, 0.1 g, 0.3 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL). 1-(3-Methyl-butylamino)-1H-pyrrole-2-carboxylic acid allyl ester (Example 1c, 0.07 g, 0.3 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.06 g, 0.315 mmol). Then N-methylmorpholine (0.07 mL, 0.63 mmol) was added into the above reaction mixture. The mixture was stirred at 25° C. for 4 h. The solution was poured into 1.0 M aqueous hydrochloric acid solution (50 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude desired product, 1-[[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetyl]-(3-methyl-butyl)-amino]-1H-pyrrole-2-carboxylic acid allyl ester (0.3 mmol) as a yellow oil, which was used in the next step without further purification. LC-MS (ESI) calcd for C24H30N4O7S2 550.16, found 551.6 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([NH2:13])=[O:12])[C:6](=[O:14])[CH2:5]2.[C:15](OC(=O)C)(=[O:17])[CH3:16].O.Cl>CN(C1C=CN=CC=1)C.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([NH2:13])=[O:12])[C:6](=[O:14])[CH:5]2[C:15](=[O:17])[CH3:16]
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)C1C(=O)N(C(N)=O)c2ccc(Cl)cc21
Reaction time: 0.5 h

Procedure:
A stirred slurry of 842 mg (4.0 mmole) of 5-chloro-2-oxindole-1-carboxamide and 1.08 g (8.8 mmole) of 4-(N,N-dimethylamino)pyridine in 15 ml of N,N-dimethylformamide was cooled to ice-bath temperature, and then a solution of 449 mg (4.4 mmole) of acetic anhydride in 5 ml of N,N-dimethylformamide was added dropwise. Stirring was continued for ca. 30 minutes, and then the reaction mixture was poured into a mixture of 75 ml of water and 3 ml of 3N hydrochloric acid. The resulting mixture was cooled in an ice-bath and the solid was recovered by filtration. The solid was recrystallized from acetic acid to give 600 mg of fluffy, pale pink crystals, m.p. 237.5° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH2:21][N:22]([CH3:24])[CH3:23])=[N:19][N:18]=[C:17]2[CH2:25]O)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].CS(Cl)(=O)=O.[CH2:32]([NH2:35])[C:33]#[CH:34]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH2:21][N:22]([CH3:24])[CH3:23])=[N:19][N:18]=[C:17]2[CH2:25][NH:35][CH2:32][C:33]#[CH:34])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: CN(C)Cc1nnc(CO)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: C#CCN
Agent: CS(=O)(=O)Cl
Product: C#CCNCc1nnc(CN(C)C)n1-c1ccc(Cl)cc1C(=O)c1ccccc1

Procedure:
In the manner given in Example 47, 5-chloro-2-[3-(hydroxymethyl)-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-4-yl]benzophenone is treated first with methanesulfonyl chloride followed by propargylamine to give 5-chloro-2-[3-[[(2-propynyl)amino]methyl]-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-4-yl]benzophenone.