Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][CH2:6]O.CN(C1C=CC=CN=1)C.CCN(CC)CC.CS(Cl)(=O)=O.[Li+].[Br-:34]>C(Cl)Cl.CCOCC.CCCCCC>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][CH2:6][Br:34]
Reactant: [Br-]
Reactant: COc1ccccc1CCO
Agent: CN(C)c1ccccn1
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1ccccc1CCBr
Reaction time: 1 h

Procedure:
A solution of 2-methoxyphenethyl alcohol (5.0 g, 32.6 mmol) in 40 ml of CH2Cl2 was added dimethylaminopyridine (DMAP) (10 mg), Et3N (11.4 ml, 81.8 mmol) and MsCl (5.05 ml, 65.2 mmol) at 0° C. After 1 h, the reaction mixture was poured into hexane and it was washed with NaHCO3 (2×), water and dried with MgSO4. Upon removal of solvents, the residue was dissolved in 50 ml of acetone and to the solution was added LiBr (11.34 g, 130.6 mmol). After the solution was heated at reflux for 16 h, it was poured into ether and washed with water, dried with MgSO4, filtered and dried to afford 2-methoxyphenethyl bromide.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH-:8])=[O:7].[C:13]1([CH:19]([O:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=2)[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:8][C:29]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:20])=[CH:23][CH:24]=1)=[O:30])=[O:7]
Reactant: CC(Oc1ccc(N=C=O)cc1)c1ccccc1
Reactant: [NH-]C(=O)c1ccccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(Oc1ccc(NC(=O)NC(=O)c2ccccc2Br)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.0 g of 50% sodium hydride dispersion in mineral oil was added at room temperature to a solution of 4.0 g of 2-bromobenzoyl amide in 25 ml of dry acetonitrile. After stirring for approximately 30 minutes at room temperature, 4.78 g of 4-(1-phenylethoxy)phenylisocyanate were added, the reaction mixture becoming warm and substantially homogeneous. After stirring for another approximately 16 hours at room temperature the reaction mixture was filtered. The filtrate was acidified with dilute hydrochloric acid. The resulting precipitate was sucked off and washed successively with acetonitrile, ethanol and petroleum ether (40-60). The desired product was obtained in a yield of 1.85 g; the melting point was determined on a "Kofler bank" and was 155.5° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[N:10]=[C:6]2[N:5]=[C:4]([CH3:16])[CH:3]=1.[SH-:17].[Na+]>O>[SH:17][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[N:10]=[C:6]2[N:5]=[C:4]([CH3:16])[CH:3]=1
Reactant: [SH-]
Reactant: COC(=O)Cc1nc2nc(C)cc(Cl)n2n1
Agent: [Na+]
Solvent: O
Product: COC(=O)Cc1nc2nc(C)cc(S)n2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.7 %

Procedure:
The product obtained in Step 4 (2 g) and sodium hydrosulfide (1.22 g) were dissolved in 35 ml of water, the solution was stirred at room temperature for 1.5 hours under a nitrogen stream, and the insoluble matters were filtered off. The filtrate was cooled to 0° C., its pH was lowered to 1-2 with 6N hydrochloric acid, the slurry was stirred at that temperature for 30 minutes, and the crystals thus formed were collected by filtration, washed with 30 ml of water and dried, affording 1.44 g of the objective compound.
Reaction SMILES: [S:1](=[O:4])(=[O:3])=[O:2].[OH2:5]>>[S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[OH:2][S:1]([OH:5])(=[O:4])=[O:3].[O:2]=[S:1](=[O:4])=[O:3]
Reactant: O
Agent: O=S(=O)=O
Product: O=S(=O)(O)O

Procedure:
In one such sulfuric acid recovery facility, the contaminated sulfuric acid is introduced into a furnace along with fuel. The fuel/air mixture is combusted to generate the necessary heat to both vaporize the contaminated sulfuric acid and dissociate the acid and its associated contaminants to form water, carbon dioxide and sulfur dioxide. These gaseous combustion products, together with the nitrogen contained in the air, exit the furnace and are passed firstly through a waste heat boiler to recover waste heat and then through a gas cleaning unit to remove water. Following water removal, the gas stream containing the sulphur dioxide is passed through a catalytic converter where the sulphur dioxide is reacted with oxygen to produce sulphur trioxide. The resulting product is then passed through an absorption tower in which the sulphur trioxide is reacted with water to produce sulfuric acid and/or oleum by the contact process.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](=[NH:5])[NH2:4].[CH:8]1(/[C:12](/O)=[CH:13]/[C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10][CH2:9]1.Cl>C(O)C>[CH:8]1([C:12]2[N:4]=[C:3]([C:2]([F:7])([F:6])[F:1])[N:5]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=2)[CH2:9][CH2:10][CH2:11]1
Reactant: N=C(N)C(F)(F)F
Reactant: CCOC(=O)C(=O)/C=C(\O)C1CCC1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(C2CCC2)nc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.3 %

Procedure:
To a solution of 2,2,2-trifluoroethanimidamide (1.80 g, 13.6 mmol, Matrix) in ethanol (22 mL, 370 mmol) was added a solution of ethyl (3Z)-4-cyclobutyl-4-hydroxy-2-oxobut-3-enoate (2.7 g, 14 mmol, from Step A) in a small volume of ethanol. The solution was cooled in an ice bath and a solution of hydrogen chloride in ethanol (21 mL, 360 mmol, prepared by bubbling HCl gas through the ethanol for 10 minutes) was added. The reaction was allowed to warm to room temperature and stirred overnight. The mixture was added slowly to a saturated solution of sodium bicarbonate. Additional solid potassium carbonate was added. After neutralization was complete, ethanol was removed in vacuo. The product was extracted with three portions of DCM. The combined extracts were dried over sodium sulfate, filtered and evaporated. The product was purified by flash chromatography on silica gel, eluting with a gradient from 0-25% EtOAc/hexanes to afford a yellow oil (1.8 g, 48%). 1H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 4.51 (q, J=7.1 Hz, 2H), 3.81 (p, J=8.6 Hz, 1H), 2.48-2.33 (m, 4H), 2.21-2.08 (m, 1H), 2.03-1.93 (m, 1H), 1.45 (t, J=7.1 Hz, 3H); LCMS (M+H)+: 275.1
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([C:12]([N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@@H:15]2[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:16]2)=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[S:45]1[CH:49]=[CH:48][CH:47]=[C:46]1[CH2:50][NH2:51].C(=O)([O-])O.[Na+]>CN(C=O)C>[C:1]([C:5]1[N:10]=[C:9]([NH:51][CH2:50][C:46]2[S:45][CH:49]=[CH:48][CH:47]=2)[C:8]([C:12]([N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@H:15]2[CH2:20][NH:19][CH2:18][C@@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:16]2)=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2cnc(C(C)(C)C)nc2Cl)CN(C(=O)OC(C)(C)C)C1
Reactant: NCc1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CNC[C@H](N(CC(C)C)C(=O)c2cnc(C(C)(C)C)nc2NCc2cccs2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 6.4 %

Procedure:
To a solution of 1-tert-butyl 3-methyl (3R*,5S*)-5-{[(2-tert-butyl-4-chloropyrimidin-5-yl)carbonyl](isobutyl)amino}piperidine-1,3-dicarboxylate (51.1 mg) and diisopropylethylamine (38 mg) in DMF (0.5 ml) was added a solution of 1-thiophen-2-ylmethanamine (23 mg) in DMF (0.5 ml) and the mixture was stirred at 80° C. overnight. 2% Aqueous sodium hydrogen carbonate was added to the reaction mixture and the mixture was extracted with ethyl acetate, and the extract was concentrated by a nitrogen gas blower. The residue was purified by reversed-phase preparative HPLC, and the object fraction was concentrated by a nitrogen gas blower. The residue was dissolved in trifluoroacetic acid/acetonitrile solution (20% (V/V), 1.0 ml), and the mixture was stirred at room temperature for 6 hr. The reaction mixture was concentrated by a nitrogen gas blower. The residue was neutralized with triethylamine (1 ml), and saturated aqueous sodium hydrogen carbonate was added. The mixture was extracted with ethyl acetate, and the extract was concentrated by a nitrogen gas blower. The residue was purified by reversed-phase preparative HPLC, and the object fraction was concentrated by a nitrogen gas blower to give the object compound (3.1 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[N:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=4)[CH:17]=3)=[C:11]([C:27]([F:30])([F:29])[F:28])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:31][Mg]Br>C1COCC1.Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[N:23]=[CH:22][C:21]([C:24]([OH:26])([CH3:31])[CH3:25])=[CH:20][CH:19]=4)[CH:17]=3)=[C:11]([C:27]([F:28])([F:30])[F:29])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)nc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)nc1
Reaction time: 18 h
Yield: 96.9 %

Procedure:
To a solution of 1-(6-{4-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-yl]-imidazol-1-yl}-pyridin-3-yl)-ethanone (50 mg, 0.12 mmol) in dry THF (2 mL) was added methylmagnesium bromide (3 M, 44 μL, 0.13 mmol) under nitrogen at room temperature and the resulting mixture stirred for 18 h. The mixture was then diluted with HCl (0.1 N) and then extracted with ethyl acetate. The combined organic extracts were then dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=1:3 to 0:100) afforded the title compound (50.3 mg, 97%) which was obtained as a white solid. MS: m/e=433.3 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15]([CH3:25])=[CH:16][CH:17]=[CH:18][C:19]([CH3:24])=[CH:20][C:21]([O-:23])=[O:22])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][CH2:27]OC(C)=O>>[C:1]([C:5]1[CH:6]=[C:7]([CH:15]([CH3:25])[CH2:16]/[CH:17]=[CH:18]/[C:19](/[CH3:24])=[CH:20]/[C:21]([O:23][CH2:26][CH3:27])=[O:22])[CH:8]=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C=CC=C(C)c1cc(C(C)(C)C)cc(C(C)(C)C)c1)=CC(=O)[O-]
Reactant: CCOC(C)=O
Product: CCOC(=O)/C=C(C)/C=C/CC(C)c1cc(C(C)(C)C)cc(C(C)(C)C)c1

Procedure:
Compound 13 was prepared from 12 in a similar manner as described for compound 7: TLC (5% EtOAc-95% hexanes) Rf 0.88; 1H-NMR (CDCl3) δ1.30 (m, 6H, CH2CH3 +CH3), 1.34 (s, 18H, 6(CH3)), 2.20, (s, 3H, CH3), 2.40 (m, 2H, CH2), 2.85 (m, 1H, CH), 4.14 (m, 2H, CH2CH3), 5.62 (s, 1H, =CH), 6.03 (m, 2H, =CH), 7.00 (d, J=I Hz, 2H, Ar-H), 7.24 (t, J=1 Hz, 1H, Ar-H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:25][C:26](O)=[O:27])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11]3=[O:24])=[CH:9][C:4]=2[O:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl>CN(C=O)C.C1(C)C=CC=CC=1.ClCCl>[CH2:19]([N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2([C:8]3[C:7](=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[C:26](=[O:27])[CH2:25]2)[C:11]1=[O:24])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCN1C(=O)C(CC(=O)O)(c2ccc3c(c2)OCO3)c2ccccc21
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCN1C(=O)C2(CC(=O)c3cc4c(cc32)OCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.9 %

Procedure:
To a solution of [3-(1,3-benzodioxo1-5-yl)-2-oxo-1-pentyl-2,3-dihydro-1H-indol-3-yl]acetic acid (0.28 g, 0.73 mmol) was added one drop of DMF and oxalyl chloride (0.32 mL, 3.7 mmol) in toluene (10 mL). The mixture was stirred at ambient temperature overnight and concentrated under vacuum to dryness to afford a brown oil. This substance was dissovled in dichloromethane (15.0 mL) followed by the addition of tin (IV) chloride (0.07 mL, 0.57 mmol) at 0° C. The mixture was stirred at ambient temperature overnight and quenched with ice water. The mixture was poured into water (100 mL), and the mixture was extracted with dichloromethane (150 mL). The organic layer was washed with water, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to flash column chromatography to afford the title compound (0.09 g, 67%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.31 (td, 1H), 7.14 (s, 1H), 7.02 (td, 1H), 6.97-6.92 (m, 2H), 6.22 (s, 1H), 6.03-5.98 (m, 2H), 3.87-3.63 (m, 2H), 3.17 (d, 1H), 2.85 (d, 1H), 1.79-1.66 (m, 2H), 1.41-1.30 (m, 4H), 0.88 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 201.4, 177.5, 154.8, 151.8, 149.6, 143.1, 132.5, 131.6, 128.9, 123.4, 123.2, 108.9, 103.5, 102.6, 102.5, 53.8, 47.7, 40.5, 29.0, 27.1, 22.3, 14.0; MS (ES+), m/z 386.1 (M+23), 364.1 (M+1).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][NH:16][C:10]3=[N:9][C:8]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30]CC)=[O:29]>>[C:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][N:16]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:10]3=[N:9][C:8]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCCCBr
Reactant: c1ccc(-c2nc3c(nc2-c2ccccc2)NCCC3)cc1
Product: O=C(O)CCCCN1CCCc2nc(-c3ccccc3)c(-c3ccccc3)nc21

Procedure:
This compound was prepared from 2,3-diphenyl-5,6,7,8-tetrahydropyrido[3,2-b]pyrazine (Example 4.1 step 1) and ethyl 5-bromovalerate analogously to 7-(6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1(2H)-yl)heptanoic acid (Example 1 step 1 and step 2. Step 1 was carried out using microwave radiation).
Reaction SMILES: C(O[C:6]1[C:7](=[O:16])[C:8](=[O:15])[C:9]=1[NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])CCC.[CH3:17][C:18]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21]>O1CCCC1>[C:11]([NH:10][C:9]1[C:8](=[O:15])[C:7](=[O:16])[C:6]=1[NH:21][CH2:20][C:19]1[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:18]=1[CH3:17])([CH3:12])([CH3:13])[CH3:14]
Reactant: CCCCOc1c(NC(C)(C)C)c(=O)c1=O
Reactant: Cc1ccc(CN)c(C)c1
Solvent: C1CCOC1
Product: Cc1ccc(CNc2c(NC(C)(C)C)c(=O)c2=O)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
A solution of 3-butoxy-4-tert-butylamino-cyclobut-3-ene-1,2-dione (1.13 g, 5.0 mmol, Example 1) and 2,4-dimethylbenzylamine (0.68 g, 5.0 mmol, a mixture of 2,4- and 2,6-dimethylbenzylamine isomers) in tetrahydrofuran (10 mL) was stirred at room temperature for approximately 16 hours. Removal of solvent, thorough trituration of the residue with diethyl ether and drying provided 1.07 g of crude product. Three recrystallizations of this material from acetonitrile gave 0.67 g (47%) of the title compound as a white solid: mp 228°-229° C.; 1H NMR (DMSO-d6) δ7.57 (m, 1H), 7.48 (s, br, 1H), 7.17 (d, 1H), 7.03 (s, br, 1H), 7.00 (d, br, 1H), 4.69 (d, 2H), 2.27 (s, 3H), 2.24 (s, 3H), 1.35 (s, 9H) ppm. IR (KBr): 3310, 1785, 1670 cm-1 ; MS (m/z) 286 (M+). HPLC indicates a major component (98.7%).
Reaction SMILES: Cl.C([O:9][P:10]([CH2:19][C@H:20]([OH:23])[CH2:21][NH2:22])([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])C1C=CC=CC=1.C([NH:34][C@H:35]([C:40](O)=[O:41])[CH2:36][CH:37]([CH3:39])[CH3:38])(OCC1C=CC=CC=1)=O>>[NH2:34][C@@H:35]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:40]([NH:22][CH2:21][C@@H:20]([OH:23])[CH2:19][P:10]([CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)(=[O:11])[OH:9])=[O:41]
Reactant: NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Product: CC(C)C[C@H](N)C(=O)NC[C@@H](O)CP(=O)(O)CC1CCCCC1

Procedure:
Step 4, Method B of Example 1 was substantially repeated in this Example 5 except for employing ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride and N-Cbz-L-leucine as the starting materials. Subsequent hydrogenation of the resulting benzyl ester in accordance with the procedures of Step 5, Method A of Example 1 yielded the title compound. 1H NMR (CD3OD, 300 MHz): δ 4.18-3.98 (m, 1H), 3.83 (t, 1H), 3.52-3.38 (m, 1H), 3.35-3.20 (m, 1H), 1.95 (br d, 2H), 1.83-1.58 (m, 9H), 1.52 (dd, 2H), 1.42-1.15 (m, 3H), 1.10-0.95 (m, 8H). 31P NMR (CD3OD, 300 MHz): δ 41. LCMS m/z: [M+H]+=349.2.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:8])[O:4][C:5](=[O:7])[CH:6]=1.[Al](Br)(Br)[Br:10].BrBr>C(OCC)(=O)C>[Br:10][C:6]1[C:5](=[O:7])[O:4][C:3](=[O:8])[C:2]=1[CH3:1]
Reactant: CC1=CC(=O)OC1=O
Reactant: Br[Al](Br)Br
Agent: BrBr
Solvent: CCOC(C)=O
Product: CC1=C(Br)C(=O)OC1=O
Temperature: 120 °C
Yield: 9023.2 %

Procedure:
A mixture of 3-methyl-2,5-furandione (citraconic anhydride, 1 g), AlBr3 (26 mg) and Br2 (0.46 mL) was heated at 120° C. overnight. Ethyl acetate was then added and the organic phase was washed with HCl 0.1% and then with brine. The organic phase was dried and concentrated in vacuo to give the crude product (1.680 g) that was used without further purification.
Reaction SMILES: I[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]([O:10][CH3:11])[CH:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])[C:7]([CH:8]=[O:9])=[CH:6][N:5]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1cc(I)c(C=O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(C#C[Si](C)(C)C)c(C=O)cn1
Yield: 67 %

Procedure:
4-Iodo-6-methoxynicotinaldehyde (0.41 g, 1.6 mmoles), trimethylsilylacetylene (0.35 mL, 2.8 mmol), PdCl2(PPh3)2 (catalytic amount), CuI (catalytic amount), triethylamine (2 mL) and THF (10 mL) were stirred at 60° C. for 2 h. The volatiles were evaporated and the residue was taken up in water and extracted with ether. The organic phase was dried, filtered and concentrated. Purification by column chromatography with EtOAc-heptanes (1:3) as eluent gave 0.25 g (68% yield) of 6-methoxy-4-[(trimethylsilyl)ethynyl]nicotinaldehyde.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:59][Si:60]([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61])[CH2:21][NH:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([C@@H:43]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[CH2:44][CH2:45][N:46]([CH:50]([CH3:52])[CH3:51])[CH:47]([CH3:49])[CH3:48])[CH:37]=3)=[CH:27][CH:26]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[Si:60]([O:59][C@H:20]([C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:19])[NH:17]2)[CH2:21][NH:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([C@@H:43]([C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:44][CH2:45][N:46]([CH:47]([CH3:49])[CH3:48])[CH:50]([CH3:52])[CH3:51])[CH:37]=2)=[CH:27][CH:26]=1)([C:63]([CH3:66])([CH3:64])[CH3:65])([CH3:62])[CH3:61]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCOc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(OCc4ccccc4)c4[nH]c(=O)ccc34)cc2)ccc1O)C(C)C
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCOc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c4[nH]c(=O)ccc34)cc2)ccc1O)C(C)C
Temperature: 70 °C
Reaction time: 1 h

Procedure:
8-(benzyloxy)-5-[(1R)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-({2-[4-(4-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}butoxy)phenyl]ethyl}amino)ethyl]quinolin-2(1H)-one (Preparation 31, 406 mg, 0.45 mmol), ammonium formate (560 mg, 9.0 mmol) and 20% palladium hydroxide on carbon (60 mg) were mixed in methanol (8 ml) and stirred at 70° C. for 1 hour under nitrogen. Further ammonium formate (300 mg, 4.8 mmol) and 20% palladium hydroxide on carbon (30 mg) were then added and heating continued at 70° C. for further 1 hour. Reaction mixture was then cooled and filtered, the filtrate was collected and the solvent removed in vacuo. The residue was dissolved in methanol (8 ml) and ammonium formate (560 mg, 8.9 mmol) and 20% palladium hydroxide on carbon (60 mg) were added and stirred at 70° C. for 1 hour under nitrogen. Reaction mixture was then cooled and filtered, the filtrate was collected and the solvent removed in vacuo. Residue was dissolved in ethyl acetate (25 ml) and saturated aqueous sodium hydrogen carbonate (25 ml). Organics were separated and washed with brine (15 ml), dried (magnesium sulphate) and solvent was removed in vacuo to furnish the title compound as a yellow solid, 305 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](C(C)(C)C)[N:5]=[CH:4][C:3]=1[C:12]1[NH:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1.N[C:22]1C=CN=CC=1C1NC2C=CC=CC=2N=1.N>O1CCOCC1>[CH:4]1[C:3]2[C:12]3[N:16]([CH:22]=[N:1][C:2]=2[CH:7]=[CH:6][N:5]=1)[C:15]1[C:14](=[CH:20][CH:19]=[CH:18][CH:17]=1)[N:13]=3
Reactant: Nc1ccncc1-c1nc2ccccc2[nH]1
Reactant: CC(C)(C)c1cc(N)c(-c2nc3ccccc3[nH]2)cn1
Agent: N
Solvent: C1COCCO1
Product: c1ccc2c(c1)nc1c3cnccc3ncn21
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 26.6 g (100 mmol) of 2-(4-amino-6-tert-butylpyridin-3-yl)benzimidazole (employed as equimolar mixture with 2-tert-butylbenzimidazole as obtained from synthesis 18)) and 1 mol of the corresponding carboxylic acid chloride is heated for 8 to 40 h under reflux in the case of carboxylic acid chlorides which boil below 150° C. or at 150° C. to 180° C. in the case of carboxylic acid chlorides which boil above 150° C., until the 2-(4-aminopyridin-3-yl)benzimidazole derivative has reacted. The reaction mixture is allowed to cool to 80° C., optionally diluted with 100 ml of dioxane, then stirred into a mixture of 500 ml of conc. ammonia solution and 500 g of ice and stirred for a further 3 h. The solid is subsequently filtered off with suction, washed twice with 100 ml of water each time and dried in vacuo. The solid is taken up in 1000 ml of ethyl acetate, filtered through a short silica-gel column, rinsed with 500 ml of ethyl acetate, the ethyl acetate is removed in vacuo, and the brown residue is recrystallised from methanol. The solids obtained in this way are freed from low-boiling components and non-volatile secondary components by sublimation (p about 1×10−5 mbar, T about 180-220° C.). Purity according to 1H-NMR typically >99.5%.
Reaction SMILES: [O:1]=[C:2]([CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH2:6][CH3:7])=O.[C:11]1([NH:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[C:11]1([NH:17][N:18]=[C:3]([O:5][CH2:6][CH3:7])[C:2](=[O:1])[CH:8]([CH3:10])[CH3:9])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(=O)C(C)C
Reactant: NNc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=NNc1ccccc1)C(=O)C(C)C

Procedure:
A mixture of ethyl 2-oxo-3-methylbutanoate (23.76 g) and phenylhydrazine (25 ml) was heated at 60° C. in toluene for about one hour, during which time a slight vacuum was used in order to remove the water. After removing the solvent, the residue was chromatographed on silica gel, using a 4/1 petroleum ether/ethyl acetate mixture as eluent, in order to give the desired product in the form of a yellow oil.