Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([NH:9][C:10]([C:12]1[S:30][C:15]2[N:16]=[C:17]([NH2:29])[N:18]=[C:19]([C:20]3[CH:25]=[C:24]([OH:26])[C:23]([Cl:27])=[CH:22][C:21]=3[Cl:28])[C:14]=2[CH:13]=1)=[O:11])[CH3:8].ClCCl.Br.Br[CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40]>CN(C=O)C>[CH2:7]([NH:9][C:10]([C:12]1[S:30][C:15]2[N:16]=[C:17]([NH2:29])[N:18]=[C:19]([C:20]3[CH:25]=[C:24]([O:26][CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[C:23]([Cl:27])=[CH:22][C:21]=3[Cl:28])[C:14]=2[CH:13]=1)=[O:11])[CH3:8]
Reactant: CCN(CC)CCBr
Reactant: CCNC(=O)c1cc2c(-c3cc(O)c(Cl)cc3Cl)nc(N)nc2s1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCNC(=O)c1cc2c(-c3cc(OCCN(CC)CC)c(Cl)cc3Cl)nc(N)nc2s1
Temperature: 140 °C

Procedure:
Cesium carbonate was added to a solution of 2-Amino-4-(2,4-dichloro-5-hydroxyphenyl)-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl amide in DMF, 2-Bromo-N,N-diethylethylamine hydrobromide was added and the suspension heated, at ˜140° C., for ˜2 hrs. The resulting suspension was allowed to cool and dichloromethane added. The mixture was washed with water and saturated aqueous sodium chloride solution. The solution was dried over anhydrous sodium sulphate and concentrated to a dark brown gum. The crude product was purified by chromatography on silica eluting with mixtures of dichloromethane and methanol.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[C:11](Cl)(=O)C(Cl)=O>ClCCl.C(OCC)(=O)C.CN(C=O)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)nn1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 6-chloropyridazine-3-carboxylic acid (4.2 g, 26.5 mmol) in a mixture of dichloromethane (100 mL) and ethyl acetate (30 mL) and a few drops of DMF was added oxalyl chloride (3 mL, 34 mmol). The mixture was stirred at room temperature for 4 h until solution was attained, then quenched with 20 mL of methanol. After 15 min, the mixture was concentrated, and the resulting solid was swirled in ether and filtered. The solid was triturated with dichloromethane and the filtrate was evaporated to provide the title compound. 1H NMR (400 MHz, acetone-d6): δ 4.04 (s, 3H), 8.05 (d, 1H), 8.31 (d, 1H).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:11]=[C:12]([N:16]2[C:20]([CH3:21])=[C:19]([C:22]([OH:24])=[O:23])[C:18]([CH3:25])=[N:17]2)[CH:13]=[CH:14][CH:15]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/B(O)O)=[CH:29][CH:28]=1>C(Cl)Cl>[Cl:26][C:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:10]2[CH:11]=[C:12]([N:16]3[C:20]([CH3:21])=[C:19]([C:22]([OH:24])=[O:23])[C:18]([CH3:25])=[N:17]3)[CH:13]=[CH:14][CH:15]=2)=[CH:29][CH:28]=1
Reactant: Cc1nn(-c2cccc(Br)c2)c(C)c1C(=O)O
Reactant: OB(O)/C=C/c1ccc(Cl)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(C)c1C(=O)O
Yield: 63 %

Procedure:
In analogy to the procedure described in Example 14C], but with 2.8 eq of K3PO4, 1-(3-bromo-phenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid and trans-2-(4-chlorophenyl)vinylboronic acid gave after suspending in CH2Cl2 and filtration the title compound in 63% yield as light yellow solid. MS: 352.2 (M+, 1 Cl).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:17])[CH2:14][NH:15][CH3:16])=[CH:4][CH:3]=1.[CH:25](=O)[CH:26]([CH3:28])[CH3:27].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:17])[CH2:14][N:15]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH3:16])=[CH:6][CH:7]=1
Reactant: CNCC(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)CN(C)CC(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
N-[4,4-Bis-(4-fluoro-phenyl)-butyl]-2-methylamino-acetamide (157 mg, 0.47 mmol) was dissolved in CH2Cl2 (5 mL), treated with isobutyraldehyde (43 mL, 0.47 mmol), stirred for 30 minutes, then cooled to 0° C., treated with NaBH(OAc)3 (150 mg, 0.71 mmol), and stirred overnight at room temperature. The reaction was diluted with EtOAc (100 mL), washed with saturated bicarbonate solution and brine, dried over Na2SO4, and concentrated. The crude material was chromatographed on silica gel eluting with 4% MeOH/CH2Cl2 to give 168 mg (92%) of the desired product as a sticky solid. MS: 389.3 (M+1 for C23H30N2O1F2); sticky solid; TLC (SiO2), Rf 0.44 (6% MeOH/CH2Cl2); HPLC (7:3 CH3CN/H2O with 0.1% TFA, C-18 column) 100%, RT=2.067 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl.[Br:49][C:50]1[CH:51]=[C:52]([CH:56]=[CH:57][CH:58]=1)[CH:53]([OH:55])[CH3:54]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38](=[O:40])[O:55][CH:53]([C:52]2[CH:56]=[CH:57][CH:58]=[C:50]([Br:49])[CH:51]=2)[CH3:54])=[CH:18][CH:17]=1
Reactant: CC(O)c1cccc(Br)c1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OC(C)c4cccc(Br)c4)cc3)c2cc1OC
Temperature: 25 °C
Yield: 46.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (74 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (125 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-bromo-α-methylbenzyl alcohol (75 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (61 mg, yield 44%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([O:12][CH:13]([CH3:15])[CH3:14])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[CH:2].[CH3:16][O:17][C:18](=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1>C(N(CC)CC)C.[Cu]I.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>[CH3:16][O:17][C:18](=[O:27])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([C:9]3([O:12][CH:13]([CH3:15])[CH3:14])[CH2:10][CH2:11]3)=[CH:5][CH:4]=2)=[CH:24][CH:25]=1
Reactant: C#Cc1ccc(C2(OC(C)C)CC2)cc1
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2ccc(C3(OC(C)C)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-isopropoxycyclopropyl)-benzene (Intermediate 66, 95.0 mg, 0.45 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 131.0 mg, 0.45 mmol) in triethylamine (6 mL) was treated with copper(I)iodide (30.0 mg, 0.16 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (111 mg, 0.16 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-8% EtOAc-hexanes) afforded 110.0 mg (70%) of the title compound as an orange oil.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](O)=[CH:4][CH:3]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[C:28](=[O:31])([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:20]([O:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([O:31][CH2:28][CH2:14][CH2:15][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:4][CH:3]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCBr
Reactant: O=C1c2ccccc2C(=O)c2c(O)ccc(O)c21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(OCCCCCCCC)c2c1C(=O)c1ccccc1C2=O
Yield: 37.7 %

Procedure:
1,4-dihydroxyanthracene-9,10-dione (5.0 g, 20.6 mmol), 1-bromooctane (10.0 g, 51.8 mmol), and potassium carbonate (37 g, 0.268 mol) was mixed in N,N-dimethylformamide and heated at 90° C. for 7 h after which the potassium carbonate was filtered off. The reaction mixture was quenched with water and extracted three times with ether. The ether was then washed three times with 1M HCl, one time with water, and evaporated to give a dark yellow solid. This solid was recrystallised in methanol to yield 1,4-bis(octyloxy)anthracene-9,10-dione (1.81 g, 3.88 mmol) as a yellow solid. 1H-NMR (CDCl3, δ): 0.89 (t, 6H), 1.2-1.4 (m, 16H), 1.53 (m, 4H), 1.93 (m, 4H), 4.10 (t, 4H), 7.30 (s, 2H), 7.71 (m, 2H), 8.16 (m, 2H) MS MALDI-TOF (m/z): 464.328
Reaction SMILES: C([Li])(CC)C.[F:6][C:7]1[CH:8]=[C:9]([N:13]2[Si](C)(C)CC[Si]2(C)C)[CH:10]=[CH:11][CH:12]=1.[C:22]1([CH:28]([N:35]2[CH2:38][C:37](=[O:39])[CH2:36]2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C1CCCCC1.C1COCC1>[NH2:13][C:9]1[CH:10]=[CH:11][C:12]([C:37]2([OH:39])[CH2:38][N:35]([CH:28]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:36]2)=[C:7]([F:6])[CH:8]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: C[Si]1(C)CC[Si](C)(C)N1c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: Nc1ccc(C2(O)CN(C(c3ccccc3)c3ccccc3)C2)c(F)c1
Reaction time: 2 h

Procedure:
Sec. butyllithium (22.5 mL) of a 1.3M solution in cyclohexane, 29.5 mmol) was added dropwise to a stirred solution of 1-(3-fluorophenyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane (Example 20, Step 1) (6.0 g, 23.7 mmol) at −78° C. under nitrogen in dry THF (75 mL). After 2 hr a solution of 1-(1,1-diphenylmethyl)azetidine-3one (5.6 g, 23.6 mmol) in dry THF (60 mL) was added dropwise and stirring continued at −78° for 2 hr, when the cooling bath was removed. After reaching room temperature, a solution of saturated ammonium chloride (75 mL) was added followed by water (200 mL). The mixture was extracted with ether (500 mL), washed with brine (100 mL), dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in methanol (150 mL) and anhydrous potassium carbonate (6.0 g, 43.5 mmol) added and then stirred overnight. The suspension was filtered and the filtrate evaporated. The residue was partitioned between ether (500 mL) and water (200 mL). The water was extracted with additional ether (200 mL) and the combined ether extracts washed with brine (100 mL), dried over magnesium sulfate, filtered and evaporated to afford an orange foam. Chromatography over silica gel (150 g, 40-60 μm) eluting with 25-50% ethyl acetate-hexane gave the title compound as a pale yellow foam. 1H NMR δ (CDCl3): 2.62, 3.53, 3.78, 4.41, 6.36, 6.41, 7.03, 7.14-7.30, 7.39-7.47.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:17]=3)[CH:12]=[C:11]2[C:24]([O:26]CC)=O)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.C(N(CC)CC)C.C([O-])([O-])=O.[K+].[K+]>C(O)C>[O:26]=[C:24]1[C:11]2=[CH:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][C:18]=3[N:10]2[CH2:9][C:3]2([CH2:4][CH2:5][O:6][CH2:7][CH2:8]2)[CH2:2][NH:1]1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC3(CN)CCOCC3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1ccc2cc3n(c2c1)CC1(CCOCC1)CNC3=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
To a solution of the crude diethyl 1-{[4-(aminomethyl)tetrahydro-2H-pyran-4-yl]methyl}-1H-indole-2,6-dicarboxylate from the preceding step in ethanol (800 mL) is added triethylamine (16.16 mL, 115.9 mmol) and K2CO3 (16.1 g, 115.9 mmol). The reaction mixture is heated at 80° C. for 2 h and is cooled to room temperature and stirred for an additional 16 h. The solid K2CO3 is removed by filtration and the filtrate is concentrated. The crude compound is purified by flash column chromatography using 3% methanol in CH2Cl2 to afford the title compound (4.2 g, 30% for 3 steps) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:3]=1.CCCCCC.[Li]CCCC.[CH:33]([N:36]=[C:37]=[O:38])([CH3:35])[CH3:34]>C(OCC)C>[CH:33]([NH:36][C:37]([C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:3]=1)=[O:38])([CH3:35])[CH3:34]
Reactant: CN(C)c1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Reactant: CC(C)N=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)NC(=O)c1cc(N(C)C)cc(Oc2cccc(C(F)(F)F)c2)n1
Reaction time: 0.17 h

Procedure:
0.75 g (0.0021 mol) of 2-bromo-4-dimethylamino-6-{3-(trifluoromethyl)phenoxy} pyridine was suspended in about 15 ml of diethyl ether. While cooling the obtained suspension in a dry ice-acetone bath in an argon atmosphere, 1.4 ml of a 1.65M-hexane solution of BuLi (0.0021×1.1 mol) was added thereto, followed by stirring the suspension for about 10 minutes. After 0.35 g (0.0021×2.0 mol) of isopropyl isocyanate dissolved in about 10 ml of diethyl ether was added to the reaction solution, the obtained solution was removed from the bath and stirred at room temperature for about one hour. The reaction solution was mixed with about 5 ml of a 1N-hydrochloric acid aqueous solution, and then distributed in ethyl acetate-saturated sodium bicarbonate water, followed by washing with saturated brine. The organic phase of the obtained solution was dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane) and reversed phase column (Lobor LiCHroprep RP-10; eluting solution: acetonitrile/water), thereby obtaining an aimed product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]([CH3:24])([CH3:23])[C:18]([O:20]CC)=[O:19])[CH:13]=[N:14]2)=[CH:9][CH:8]=1.[Li+].[OH-]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]([CH3:24])([CH3:23])[C:18]([OH:20])=[O:19])[CH:13]=[N:14]2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(C)(C)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C(=O)O)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-(7-((3-chlorobenzyl)oxy)quinolin-3-yl)-2-methylpropanoate (Example 59, 300 mg, 0.78 mmol) in THF (2.6 mL) and MeOH (2.6 mL) was added LiOH (54 mg, 2.25 mmol) in H2O (2.6 mL). The reaction was stirred at ambient temperature overnight. The solvents were removed under reduced pressure, 10% HCl (aq.) (5 mL) was added and the precipitate was collected and dried under vacuum, the crude product was used without further purification in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Si:9]([CH3:12])([CH3:11])[CH3:10])[CH:5]=[C:6]([Br:8])[CH:7]=1.[Li]CCCC.[CH3:18][Si:19](Cl)([CH3:21])[CH3:20].Cl>CCOCC>[CH3:10][Si:9]([CH3:12])([CH3:11])[C:4]1[CH:5]=[C:6]([Br:8])[CH:7]=[C:2]([Si:19]([CH3:21])([CH3:20])[CH3:18])[CH:3]=1
Reactant: C[Si](C)(C)Cl
Reactant: C[Si](C)(C)c1cc(Br)cc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: C[Si](C)(C)c1cc(Br)cc([Si](C)(C)C)c1
Temperature: -68 °C
Reaction time: 0.75 h
Yield: 94 %

Procedure:
17.18 g of 3,5-Dibromo-trimethylsilyl-benzene, 55.8 mmol, was dissolved in 380 ml Et2O. The solution was chilled to −68° C., and 22.3 mL of n-BuLi (2.5 M in hexanes), 55.8 mmol, were added within 18 minutes. The solution changed its color from clear to yellow, and was stirred for 45 minutes at −68° C. 7.5 mL TMSCl, 59 mmol, were added within six minutes. The temperature of solution rose within one hour to −33° C., and after another 30 minutes to −18° C. The solution was stirred overnight at room temperature. 60 mL of 2M HCl were added to the white suspension. Stirring for 30 minutes resulted in two clear phases. Et2O-phase was dried with MgSO4, filtered, and solvent evaporated. Raw product was distilled at a temperature of 70-76° C. and 0.1-0.2 mbar. All pure fractions were combined and gave 15.8 g of product (52.4 mmol, 94%). 1H-NMR (CHCl3=7.24ppm): δ 7.56 (s, 2H), 7.50 (t, 1H), 0.25 (s, 6×3H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[F:11]F.C(=O)([O-])[O-].[Ca+2]>O>[F:11][C:5]1[N:4]=[C:3]([C:8]([NH2:10])=[O:9])[C:2]([OH:1])=[N:7][CH:6]=1
Reactant: FF
Reactant: NC(=O)c1nccnc1O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: NC(=O)c1nc(F)cnc1O

Procedure:
In 200 mL of water was suspended 1.0 g of 3-hydroxy-2-pyrazinecarboxamide. At room temperature, 10% fluorine gas (a fluorine gas diluted with nitrogen gas) was introduced at a rate of 45 mL per minute for a period of 25 minutes. Then, nitrogen gas was introduced for 45 minutes, and the liquid reaction mixture was neutralized with calcium carbonate, the deposited precipitate was filtered off, the filtrate was concentrated under reduced pressure, and the solid product thus obtained was purified by silica gel column chromatography [eluent: n-hexane:ethyl acetate=5:1] to obtain 0.008 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide as a white-colored solid product.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:20][CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:12]([N+:17]([O-])=O)[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:28][CH3:29])=[C:5]([CH3:30])[O:4][N:3]=1>C(OCC)(=O)C.CO.[Pd].O.CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:20][CH2:21][CH:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:28][CH3:29])=[C:5]([CH3:30])[O:4][N:3]=1
Reactant: COc1cc2c(NCC3CCOCC3)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Agent: [Pd]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COc1cc2c(NCC3CCOCC3)c(N)cnc2cc1-c1c(C)noc1C
Yield: 40.4 %

Procedure:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-3-nitro-N-((tetrahydro-2H-pyran-4-yl)methyl)quinolin-4-amine (for a preparation see Intermediate 16) (1.2 g, 2.91 mmol) was dissolved in a mixture of ethyl acetate (60 ml) and methanol (10 ml) and hydrogenated over Pd/C (0.310 g, 2.91 mmol, 5% w/w, 50% water, Type E101 NO/W) for 24 h at atmospheric pressure under a hydrogen burette. The mixture was filtered and evaporated and the residue was dissolved in DCM (3 ml) and loaded onto a 50 g silica column, then eluted with 0-15% 2M methanolic ammonia/DCM and product containing fractions evaporated in vacuo to give 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-((tetrahydro-2H-pyran-4-yl)methyl)quinoline-3,4-diamine (0.45 g, 1.177 mmol, 40.4% yield) as a pale yellow solid. LCMS (formate) Rt 0.68 min, MH+ 384
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)([O-:16])=[O:15]>ClCCl>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([S:23]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:25])=[O:24])=[CH:21][CH:22]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.3 %

Procedure:
To a stirred solution of morpholine (5.2 mL, 59.7 mmol) and triethylamine (11.2 mL, 79.6 mmol) in dichloromethane (300 mL) was added the solution of 4-nitro-benzenesulfonyl chloride (8.8 g, 39.8 mmol) in dichloromethane (50 mL) at 0° C. The mixture solution was stirred at room temperature for 4 h and then washed with brine (50 mL×2) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford 4-(4-nitro-benzenesulfonyl)-morpholine (10.0 g, 92.5%) as a white powder: MS (ESI) M+1=273.0.
Reaction SMILES: [H-].[Na+].[CH:3]([OH:6])([CH3:5])[CH3:4].Cl[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][N:9]=1>C1COCC1>[Cl:14][C:13]1[C:8]([O:6][CH:3]([CH3:5])[CH3:4])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Clc1cccnc1Cl
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Oc1ncccc1Cl
Temperature: 5 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To a 3-necked flask equipped with a dropping funnel, thermometer and a condenser was added sodium hydride (64.10 g, 60% w/w dispersion in oil, 1.07 mol) followed by THF (1.65 L). The suspension was cooled to 5° C. and iso-propanol (128 mL, 1.07 mol) was added dropwise over 50 minutes. Upon complete addition the ice bath was removed and the mixture was brought to room temperature and left to stir for 1 hour. Then 2,3-dichloropyridine (154.6 g, 1.11 mol) was added and the reaction mixture brought to a gentle reflux and left to stir for 18 hours. The reaction mixture was cooled to 5-10° C. and was carefully quenched with brine:water mixture (50:50; 100 mL) followed by water (300 mL). The aqueous layer was extracted with ethyl acetate (3×600 mL), the organic layers combined and washed with brine, dried over magnesium sulphate, filtered and evaporated in vacuo to give the title compound as a dark red oil (164 g, 89%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]=[C:6]1[CH:15]([CH3:16])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:17][CH3:18])[C:7]1=[O:19])[CH3:2].C1C(=O)N([Br:28])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:20])[CH:5]=[C:6]1[CH:15]([CH3:16])[CH:14]([Br:28])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:17][CH3:18])[C:7]1=[O:19])[CH3:2]
Reactant: CCOC(=O)C=C1C(=O)c2cccc(OC)c2CC1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C=C1C(=O)c2cccc(OC)c2C(Br)C1C
Temperature: 25 °C
Yield: 68 %

Procedure:
A mixture of (5-methoxy-3-methyl-1-oxo-3,4-dihydro-1H-naphthalen-2-ylidene)-acetic acid ethyl ester (480 mg), NBS (420 mg), and AIBN (30 mg) in CCl4 (18 mL) was refluxed for 3 hours. The reaction mixture was then cooled to room temperature, quenched with saturated sodium bicarbonate solution and extracted with dichloromethane (2×). The combined organics were washed with water, dried (Na2SO4), concentrated, and purified by flash column chromatography to give a light brown solid (420 mg) LCMS-ESI+ (m/z): [M+H]+ calcd for C16H18BrO4: 353.03. Found: 352.91.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].S(Cl)([Cl:12])=O.[CH2:14](O)[CH3:15]>>[ClH:12].[CH2:14]([O:8][C:7]([C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][NH:1]1)=[O:9])[CH3:15]
Reactant: O=S(Cl)Cl
Reactant: CCO
Reactant: O=C(O)[C@@H]1CCCCN1
Product: CCOC(=O)[C@@H]1CCCCN1
Product: Cl
Temperature: 25 °C
Yield: 35 %

Procedure:
Crude (S)-(-)-2-piperidinecarboxylic acid (19.5 g, prepared as described in example 26) was suspended in ethanol (250 ml), and thionyl chloride (40 ml, 0.46 mol) was added dropwise. After addition was complete, the suspension was heated at reflux temperature for 2 h. The mixture was filtered hot, and the filtrate was cooled to room temperature. Filtration and evaporation in vacuo afforded an oil, which was crystallised by rubbing. Ethanol (10 ml) was added, followed by slow addition of diethyl ether (150 ml). The precipitated solid was filtered off, washed with diethyl ether and dried by suction to give 13.8 g (35% calculated from 2-piperidinecarboxylic acid) (S)-(-)-2-piperidinecarboxylic acid ethyl ester hydrochloride.