Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=1)[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[N+:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([O-:22])=[O:21]>C(Cl)Cl>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH:2]([NH:1][C:27](=[O:28])[C:26]2[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:31][CH:30]=2)[C:3]([O:5][C:6]([CH3:7])([CH3:9])[CH3:8])=[O:4])=[CH:12][C:13]=1[O:18][CH3:19]
Reactant: COc1cc(CC(N)C(=O)OC(C)(C)C)ccc1O
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: COc1cc(CC(NC(=O)c2ccc([N+](=O)[O-])cc2)C(=O)OC(C)(C)C)ccc1O
Reaction time: 1 h
Yield: 44 %

Procedure:
Prepared using General Procedure 5: To a stirred solution of tert-butyl 2-amino-3-(4-hydroxy-3-methoxyphenyl)propanoate INT-1 (1.85 g, 6.93 mmol) and TEA (1.93 mL, 13.9 mmol) in DCM (15 mL) at 0° C. was added 4-nitrobenzoyl chloride (1.29 g, 6.93 mmol) in DCM (10 mL) dropwise. The reaction mixture was stirred for 1 h, diluted with DCM (100 mL) and washed with saturated aqueous NaHCO3 (100 mL). The organic layer was dried over MgSO4, and concentrated. The product was purified by chromatography (EA/hexanes) to afford 1.38 g (44%) of tert-butyl 3-(4-hydroxy-3-methoxyphenyl)-2-(4-nitrobenzamido)propanoate INT-7. LCMS-ESI (m/z) calculated for C21H24N2O7: 416. Found 415 [M−H]−, tR=2.18 min (Method 4).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7]2([CH3:13])[CH2:11][C:10](=[O:12])[NH:9][NH:8]2)=[CH:3][CH:2]=1.[Br:20]Br>C(O)(=O)C>[Br:20][C:17]1[CH:16]=[CH:15][C:14]([C:1]2[CH:6]=[CH:5][C:4]([C:7]3([CH3:13])[CH2:11][C:10](=[O:12])[NH:9][NH:8]3)=[CH:3][CH:2]=2)=[CH:19][CH:18]=1
Reactant: BrBr
Reactant: CC1(c2ccc(-c3ccccc3)cc2)CC(=O)NN1
Solvent: CC(=O)O
Product: CC1(c2ccc(-c3ccc(Br)cc3)cc2)CC(=O)NN1

Procedure:
Analogously to b), 3-(4-biphenylyl)-3-methyl-pyrazolidin-5-one and the calculated theoretically required quantity of bromine in acetic acid give 3-(4'-bromo-4-biphenylyl)-3-methyl-pyrazolidin-5-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:12])[C@H:9](O)[CH3:10])[CH:5]=[CH:6][CH:7]=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[NH2:44][C:45]([CH3:49])([CH3:48])[CH2:46][OH:47]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C@:8]2([OH:12])[O:47][CH2:46][C:45]([CH3:49])([CH3:48])[NH:44][C@H:9]2[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](O)C(=O)c1cccc(Br)c1
Reactant: CC(C)(N)CO
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: C[C@@H]1NC(C)(C)CO[C@@]1(O)c1cccc(Br)c1
Yield: 37.8 %

Procedure:
Compound 4d was synthesized by a procedure similar to that described for (2S,3S)-4a using (R)-1-(3-bromophenyl)-2-hydroxypropan-1-one (10d, 4.0 g, 0.018 mol), Proton sponge (4.5 g, 0.021 mol), triflic anhydride (3.2 mL, 192 mmol), and 2-amino-2-methyl-1-propanol (3.4 g, 0.038 mol) in acetonitrile (50 mL). After purification, 2.04 g (39%) of the free base 4d was isolated and converted to 1.6 g of the hemi-D-tartrate salt, which had >99% ee: mp 129-130° C.; [α]20D +9.6° (c 1.0, CH3OH); 1H NMR (methanol-d4) δ 7.77-7.76 (m, 1H), 7.63-7.53 (m, 2H), 7.38-7.32 (m, 1H), 4.37 (s, 1H), 4.14 (d, 1H, J=12.0 Hz), 3.58-3.39 (m, 2H), 1.57 (s, 3H), 1.32 (s, 3H), 1.07-1.02 (m, 3H); 13C NMR (methanol-d4) δ 178.8, 145.1, 133.3, 131.1, 126.9, 123.6, 96.7, 75.2, 67.7, 55.0, 24.4, 21.5, 14.4; LCMS (ESI) m/z 300.6 [(M-tartrate)+, M=C15H21BrNO5]; Anal. (C15H21BrNO5.0.25H2O) calcd: C, 47.44; H 5.71; N, 3.69. found: C, 47.33; H, 5.84; N, 3.63.
Reaction SMILES: [I:1]I.[N+:3]([C:6]1[CH:17]=[CH:16][C:9]([CH2:10][C@@H:11]([C:13]([OH:15])=[O:14])[NH2:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].S([O-])([O-])(=O)=S.[Na+].[Na+]>S(=O)(=O)(O)O>[I:1][C:8]1[CH:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:17]=[CH:16][C:9]=1[CH2:10][C@@H:11]([C:13]([OH:15])=[O:14])[NH2:12]
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: II
Agent: O=S(=O)(O)O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Product: N[C@@H](Cc1ccc([N+](=O)[O-])cc1I)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 250 mL round bottomed flask equipped with a magnetic stirrer was charged with 60 mL of fuming sulfuric acid (Aldrich) and 12.1 g of iodine (Aldrich). To the resulting dark red solution was added 10.0 g of 4-nitro-L-phenylalanine by slow addition. The flask was fitted with a CaCl2 drying tube and the reaction mixture was stirred at RT for 18 h. The mixture was then poured onto 300 g of crushed ice. A yellow-brown emulsion resulted which was treated with 7.4 g of sodium thiosulfate and stirred. The resulting light brown suspension was basified to pH=9 by addition of solid NaCO3. This was followed by acidification to pH=5.5 by addition of conc. H3SO4. A brown solid precipitated which was collected by filtration and dried in vacuo. This afforded 6.54 g (41%) of 2-iodo-4-nitro-L-phenylalanine as a brown powder, m.p.>200° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH:14][CH2:15][CH2:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[S:12][CH:13]=2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH2:28][CH2:29][CH2:30][CH3:31].C(OCC)(=O)C>CN(C)C=O>[CH2:28]([N:14]([C:11]1[S:12][CH:13]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:10]=1)[CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=1)[CH2:29][CH2:30][CH3:31]
Reactant: COc1ccc(-c2csc(NCCc3ccc(C#N)cc3)n2)cc1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCN(CCc1ccc(C#N)cc1)c1nc(-c2ccc(OC)cc2)cs1
Temperature: 25 °C

Procedure:
600 mg 4-{2-[4-(4-Methoxy-phenyl)-thiazol-2-ylamino]-ethyl}-benzonitrile were dissolved in 30 ml dimethylformamide. 85.9 mg sodium hydride (24% in mineral oil) were added and the reaction mixture stirred at room temperature for thirty minutes. Then 245 μl 1-Iodobutane were added and the reaction mixture stirred at room temperature for two hours. Then 100 ml ethyl acetate were added and the mixture was washed three times with portions of 50 ml water and then dried over MgSO4. The solvents were removed in vacuo and the residue purified by RP-HPLC to obtain 279 mg 4-(2-{Butyl-[4-(4-methoxy-phenyl)-thiazol-2-yl]-amino}-ethyl)-benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1.CO.[BH4-].[Na+]>CC(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][CH:10]1[CH2:11][CH2:12][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:15]1
Reactant: CCOC(=O)N1CCC(=Nc2c(Cl)cccc2Cl)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CO
Product: CCOC(=O)N1CCC(Nc2c(Cl)cccc2Cl)CC1
Reaction time: 1 h

Procedure:
To a stirred and refluxing mixture of 250 parts of ethyl 4-[(2,6-dichlorophenyl)imino]-1-piperidinecarboxylate in 160 parts of methanol and 160 parts of 2-propanol are added portionwise 30 parts of sodium borohydride. Upon completion, stirring at reflux temperature is continued for one hour. The warm reaction mixture is poured onto water and the product is extracted with methylbenzene. The extract is dried and evaporated. The residue is crystallized from a mixture of 160 parts of 2,2'-oxybispropane and 160 parts of petroleum ether, yielding 96 parts of ethyl 4-[(2,6-dichlorophenyl)amino]-1-piperidinecarboxylate; mp. 107.2°-116.6° C.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:10]=[C:9]([NH2:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[N:7]=1)([CH3:5])([CH3:4])[CH3:3].N1C=CC=CC=1.[C:27](Cl)([O:29][CH2:30][C:31]([Cl:34])([Cl:33])[Cl:32])=[O:28]>C(Cl)Cl>[C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:27](=[O:28])[O:29][CH2:30][C:31]([Cl:34])([Cl:33])[Cl:32])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[N:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(N)n(-c2cccc([N+](=O)[O-])c2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc([N+](=O)[O-])c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a stirring suspension of 3-t-butyl-1-(3-nitrophenyl)-1H-pyrazol-5-amine hydrochloride (0.500 g, 1.685 mmol, 1.00 eq) and pyridine (0.412 ml, 5.05 mmol, 3.00 eq) in CH2Cl2 (17 ml) at 22° C. was added Troc-Cl (0.244 ml, 1.769 mmol, 1.05 eq). The reaction was stirred overnight at RT. The completed reaction was diluted with CH2Cl2 and washed with 3M HCl (2×). The combined aqueous were extracted with CH2Cl2 (1×). The combined organics were washed with H2O (2×), brine (1×), dried (Na2SO4), filtered ad evaporated. The crude product was purified by flash column chromatography (100% hexanes to 30% EtOAc/hexanes) to afford 2,2,2-trichloroethyl 3-t-butyl-1-(3-nitrophenyl)-1H-pyrazol-5-ylcarbamate (0.67 g, 91% yield) as an oil.
Reaction SMILES: [I:1]I.[NH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=1.CO.C(Cl)(Cl)Cl>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[NH2:3][C:4]1[C:13]([I:1])=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCO
Product: COC(=O)c1cnc(N)c(I)c1
Temperature: 25 °C
Yield: 62.2 %

Procedure:
To a solution of iodine (3.55 g, 14.0 mmol) in 100 mL absolute ethanol at room temperature was added silver sulfate (4.37 g, 14.0 mmol) and methyl 6-aminonicotinate (1.52 g, 10.0 mmol). After 42 hours the reaction was filtered to isolate a tan precipitate. The solid was heated with 20% MeOH/CHCl3 then cooled to room temperature, filtered, and rinsed with MeOH and CHCl3. The filtrate was evaporated, dissolved in hot MeOH, filtered to remove brownish impurities, and then crystallized from MeOH to give the title compound as a light tan solid (1.73 g, 62%).
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[C:23]5[CH:31]=[C:30](F)[N:29]=[CH:28][C:24]=5[N:25]=[CH:26][N:27]=4)=[CH:17][C:16]=3[CH3:33])[CH2:10][CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.CCN(CC)CC>CS(C)=O>[CH:1]1([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[C:23]5[CH:31]=[C:30]([N:34]6[CH2:38][CH2:37][CH2:36][CH2:35]6)[N:29]=[CH:28][C:24]=5[N:25]=[CH:26][N:27]=4)=[CH:17][C:16]=3[CH3:33])[CH2:10][CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1OC1CCN(C(=O)C2CCCC2)CC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cc(Nc2ncnc3cnc(N4CCCC4)cc23)ccc1OC1CCN(C(=O)C2CCCC2)CC1
Yield: 39.9 %

Procedure:
A solution of Cyclopentyl-{4-[4-(6-fluoro-pyrido[3,4-d]pyrimidin-4-ylamino)-2-methyl-phenoxy]-piperidin-1-yl}-methanone (50 mg, 0.11 mmol), pyrrolodine (15.8 mg, 0.222 mmol), and NEt3 (33.7 mg, 0.333 mmol) in DMSO (1 mL) was heated to 120° C. for 12 h. The reaction was concentrated and purified by preparative HPLC to give the title compound as a yellow solid (22 mg, 40%). MS: 501.4 (MH+); 1H NMR (DMSO-d6, 400 MHz): δ 8.84 (s, 1H), δ 8.30 (s, 1H), δ 7.50-7.54 (m, 2H), δ 7.24 (s, 1H), δ 6.08 (d, J=8.72 Hz, 1H), δ 6.55 (s, 1H), δ 4.52 (m, 1H), δ 3.70 (m, 3H), δ 3.48-3.65 (m, 4H) δ 2.86-2.94 (m, 1H), δ 2.22 (s, 3H), 1.53-2.00 (m, 17H)
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[CH2:26][CH2:27]Br>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:27][CH2:26][C:25]4[CH:29]=[CH:30][CH:31]=[C:23]([O:22][CH3:21])[CH:24]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: COc1cccc(CCBr)c1
Product: COc1cccc(CCN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)c1
Yield: 34 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 3-methoxyphenethyl bromide. Yield: 34%. MS M+H calculated 410.18. Found 410.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.16 μM.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:12][CH2:13][C@@:14]([CH3:22])([S:18]([CH3:21])(=[O:20])=[O:19])[C:15]([OH:17])=O)[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.O.ON1C2C=CC=CC=2N=N1.[O:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH:44]1[O:49][NH2:50].Cl.CN(CCCN=C=NCC)C>ClCCl>[CH:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:12][CH2:13][C@@:14]([CH3:22])([S:18]([CH3:21])(=[O:20])=[O:19])[C:15]([NH:50][O:49][CH:44]3[CH2:45][CH2:46][CH2:47][CH2:48][O:43]3)=[O:17])[CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@@](CCn1cc(C2CCCCC2)cn1)(C(=O)O)S(C)(=O)=O
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@](CCn1cc(C2CCCCC2)cn1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 22.6 %

Procedure:
To a solution of ((2R)-4-(4-cyclohexyl-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)butanoic acid (30 mg, 0.091 mmol, 1 eq) in dichloromethane (5 mL) under nitrogen, was added DIPEA (24.9 mg, 0.193 mmol, 0.0340 mL, 2.12 eq) followed by 1-hydroxybenzotriazole monohydrate (27.0 mg, 0.176 mmol, 1.93 eq). The solution was allowed to stir for 30 minutes before being treated with O-tetrahydro-2H-pyran-2-yl-hydroxylamine (14.3 mg, 0.122 mmol, 1.34 eq) and then dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (24.9 mg, 0.130 mmol, 1.43 eq). The mixture was then allowed to stir for 3 hours at RT. The reaction mixture was then adsorbed onto silica gel and purified by flash chromatography eluting with 5-100% EtOAc/Hpt to give (2R)-4-(4-cyclohexyl-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (8.8 mg, 23% yield). LC-MS M+H+428.1.
Reaction SMILES: C([NH:4][C@@H:5]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][CH:6]1[OH:7])(=O)C.[ClH:16]>O>[ClH:16].[OH:7][CH:6]1[O:8][C@H:9]([CH2:14][OH:15])[C@@H:10]([OH:13])[C@H:11]([OH:12])[C@H:5]1[NH2:4]
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: Cl
Solvent: O
Product: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 70 °C
Yield: 161.2 %

Procedure:
The apparatus for this test consisted of a 1 liter round bottom vessel heated with a heating mantel. The ingredients, 150 grams of water, 21 g of 98% N-acetylglucosamine and 238 grams of 36.7% hydrochloric acid, were mixed together and added to the reaction vessel. The stirred reaction mix was heated up to 70° C. and mixed for 3 hours at which time the mixture was transferred to a beaker and cooled to 20° C. Few crystals were present. The mixture was transferred back into the reaction vessel and 10 grams of N-acetylglucosamine added. The reactor was reheated to 70° C. and reacted for 3 hours, cooled to 4° C. overnight. The crystals present were filtered and washed with ethanol, vacuum dried and assayed (20 g of glucosamine hydrochloride at 99.9%). The filtrate was transferred back into the reaction vessel and 10 g of N-acetylglucosamine were added. The reactor was again heated to 70° C., reacted for 3 hours, cooled overnight to 4° C., filtered, ethanol washed, vacuum dried and assayed (16.1 g of glucosamine hydrochloride at 99.6%). The filtrate was again returned to the reactor, 41.5 grams added and the reaction cycle repeated. Thirty-three grams of glucosamine hydrochloride resulted from the 4th cycle with an assay of 99.5%. The total yield was 86% with all the glucosamine hydrochloride produced 99+in assay and white in color. This material did not need recrystallization.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[C:5]([NH:7][N+:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[S:18]([O:23]C)([O:21][CH3:22])(=[O:20])=[O:19]>>[CH3:22][O:21][S:18]([O-:23])(=[O:20])=[O:19].[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[C:5]([N:7]([N+:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:22])=[O:6]
Reactant: O=C(N[n+]1ccccc1)c1ccc(Cl)c(Cl)c1
Reactant: COS(=O)(=O)OC
Product: CN(C(=O)c1ccc(Cl)c(Cl)c1)[n+]1ccccc1
Product: COS(=O)(=O)[O-]

Procedure:
1-(3,4-dichlorobenzamido)pyridinium internal salt (20 parts) and dimethyl sulphate (100 parts) were heated together at 100° C for four hours. On cooling, crystals separated which were filtered off, washed and dried to give 1-(3,4-dichloro-N-methylbenzamido) pyridinium methyl sulphate (15 parts), melting point 135° C.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[C:17]([Cl:18])=[C:16]([Cl:19])[C:10]2[S:11][C:12]([CH2:14][OH:15])=[CH:13][C:9]=2[CH:8]=1)C>C(O)C.Cl.O>[Cl:18][C:17]1[C:7]([O:6][CH2:5][C:4]([OH:20])=[O:3])=[CH:8][C:9]2[CH:13]=[C:12]([CH2:14][OH:15])[S:11][C:10]=2[C:16]=1[Cl:19]
Reactant: CCOC(=O)COc1cc2cc(CO)sc2c(Cl)c1Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(O)COc1cc2cc(CO)sc2c(Cl)c1Cl
Yield: 9 %

Procedure:
A suspension of 6.05 g of ethyl[(6,7-dichloro-2-hydroxymethylbenzo[b]thien-5-yl)oxy]acetate in 40 ml of 95% ethanol and 56 ml of 3N hydrochloric acid is stirred under reflux for 1 hr. The cooled mixture is diluted with 200 ml of water and made acidic with concentrated hydrochloric acid until pH=2. The precipitate is extracted into ethyl acetate (3×200 ml) and the combined organic extracts are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. Recrystallization of the residue from acetone-hexane gives 0.5 g of [(6,7-dichloro-2-hydroxymethylbenzo[b]thien-5-yl)oxy]acetic acid, mp 187.5°-118.5°.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([F:31])[CH:37]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(F)c2)CC1
Yield: 35 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 3-fluorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a yellow oil (35%).
Reaction SMILES: [Li].C(=N[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)C.[C:11](O)(=O)[C:12](O)=[O:13].CC[O:19]CC>O>[O:13]1[CH2:12][CH2:11][CH2:5][CH2:10][CH:9]1[CH:8]=[CH:7][CH:6]=[O:19]
Reactant: CCOCC
Reactant: CC=NC1CCCCC1
Reactant: O=C(O)C(=O)O
Agent: [Li]
Solvent: O
Product: O=CC=CC1CCCCO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (tetrahydro-2H-pyran-2-yl)carboxaldehyde (1 molar equivalent) in ether is added to a cold (-70° C.), rapidly-stirred solution of the freshly-generated lithium salt of ethylidenecyclohexylamine (1 molar equivalent) in ether. The resulting reaction mixture is allowed to warm to room temperature, then is maintained at room temperature for 24 hours. After cooling to 0° to 5° C., the reaction mixture is diluted with water, stirred at 0° to 5° C. for 1/2 hour and evaporated in vacuo at 40° to 50° C. leaving a residual oil which is treated with oxalic acid (2 molar equivalents) and water. Steam distillation of this mixture is continued until a clear distillate is obtained. The steam distillate is extracted with ether and the organic extract, dried over sodium sulfate, and filtered. Evaporation of the filtrate in vacuo at 40° C. provides the title compound as a mobile oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:20][N:19]=3)[O:15][N:14]=2)[CH:10]=[C:9]([CH3:29])[C:4]=1[O:5][CH2:6][CH2:7][NH2:8])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:61](O)(=[O:64])[CH2:62][OH:63]>C1COCC1.CN(C=O)C>[CH2:1]([C:3]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:20][N:19]=3)[O:15][N:14]=2)[CH:10]=[C:9]([CH3:29])[C:4]=1[O:5][CH2:6][CH2:7][NH:8][C:62](=[O:63])[CH2:61][OH:64])[CH3:2]
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OCCN
Reactant: O=C(O)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OCCNC(=O)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
To a solution of the compound of Example 48 (50 mg, 127 μmol) in THF (2 mL) and DMF (2 mL), EDC hydrochloride (27 mg, 139 μmol), HOBt (19 mg, 139 μmol), DIPEA (25 mg, 190 μmol) and glycolic acid (11 mg, 139 μmol) is added. The mixture is stirred at rt for 1 h before it is concentrated and separated by prep. HPLC to give the title compound (32 mg) as a colourless oil; LC-MS: tR=1.05 min, [M+H]+=453.08; 1H NMR (CDCl): δ1.00 (d, J=6.5 Hz, 6H), 1.31 (t, J=7.3 Hz, 3H), 1.89-2.00 (m, 1H), 2.37 (s, 3H), 2.47 (s, 3H), 2.63 (d, J=7.0 Hz, 2H), 2.73 (q, J=7.5 Hz, 2H), 3.75-3.83 (m, 2H), 3.93-3.99 (m, 2H), 4.23 (s, 2H), 7.03-7.15 (m, 1H), 7.94 (s, 2H), 8.09 (s, 1H), 8.55 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[CH2:12](B1OC(C)(C)C(C)(C)O1)[CH:13]=[CH2:14]>[Pd]>[CH2:14]([C:2]1[CH:3]=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1)[CH:13]=[CH2:12]
Reactant: COc1cc(Br)cc(OC)c1
Reactant: C=CCB1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Product: C=CCc1cc(OC)cc(OC)c1

Procedure:
The Pd-catalyzed cross-coupling reaction of 5-Bromo-1,3-dimethoxybenzene with allyl boronic acid pinacol ester produced 5-allyl-1,3-dimethoxybenzene 1 in excellent yield. AlI3 will be used for demethylating 5-Allyl-1,3-dimethoxybenzene with CS2 as solvent to produce 5-allylresorcinol 2. The bis(phosphinite) PCP ligands 3 will be obtained by diphosphorylation of 5-allylresorcinol 2 with the respective chlorophosphine and sodium hydride as a base. Iridium complexes 4 will be obtained from reaction of the respective PCP ligands 3 with [Ir(COD)Cl]2 or [Ir(COE)2Cl]2. Hydrosilylation of complexes 4 will produce the hydrosilylated complexes 5. Reaction of complexes 5 with silica gel will afford the Si2O-supported Ir complexes 6. To date, 5-allyl-1,3-dimethoxybenzene 1 has been prepared in 92% yield.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[H-].[Na+].[CH2:26](Br)[C:27]#[CH:28].O>CN(C=O)C>[Cl:1][C:2]1[C:11]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)=[CH:10][C:5]2[N:6]([CH2:28][C:27]#[CH:26])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: C#CCBr
Reactant: Cn1c(C(F)(F)F)ccc(-c2cc3[nH]c(=O)oc3cc2Cl)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCn1c(=O)oc2cc(Cl)c(-c3ccc(C(F)(F)F)n(C)c3=O)cc21
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
0.20 g (0.58 mmol) of 3-(6-chlorobenzoxazolin-2-on-5-yl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone was dissolved in 10 ml of DMF, and 0.026 g (0.65 mmol) of 60% sodium hydride was added thereto at room temperature, followed by stirring for 0.5 hour. Further, 0.09 g (0.76 mmol) of propargyl bromide was added thereto, followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The organic layer was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 0.17 g (yield: 78%) of the desired product. Melting point: 187-189° C.