Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][C:3]1[CH:4]=[C:5]([CH3:22])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2.[CH3:23][O-:24].[Na+]>CO>[CH3:23][O:24][CH2:2][C:3]1[CH:4]=[C:5]([CH3:22])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2
Reactant: CCOC(=O)C1=Cc2cc(C)cc(CI)c2OC1C(F)(F)F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C1=Cc2cc(C)cc(COC)c2OC1C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
The ethyl 8-(iodomethyl)-6-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 605e, Step 2 (0.2 g, 0.47 mmole) was dissolved in methanol (5 mL) and then the solution was cooled to 0° C. (ice bath). Sodium methoxide (0.32 mL, 1.41 mmole) was added dropwise to above solution, which was stirred for 2 hours at 0° C. The solution was warmed to room temperature and stirred for an additional 2 hours. The reaction was condensed in vacuo to give a yellow oil (0.15 g, 98%). No further purification was performed: GCMS m/z 330.00 (M+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:22]([O-])=[O:23].[Na+].CO.C(=O)([O-])[O-].[K+].[K+]>C(O)=O.C(OCC)(=O)C>[Cl:1][CH2:2][CH2:3][N:4]([N:22]=[O:23])[C:5]([N:7]([CH2:19][CH2:20][CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: CCCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=N[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=CO
Solvent: CO
Product: CCCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 1 h
Yield: 30.6 %

Procedure:
4.5 g of 1-(2-chloroethyl)-3-n-propyl-3-D-glucopyranosylurea are dissolved in 20 ml of formic acid, and 2.8 g of sodium nitrite are added gradually thereto at 0° to 5° C. for one hour under stirring. The mixture is further stirred at the same temperature for one hour. After the reaction, 20 ml of methanol are added to the reaction mixture. Said mixture is neutralized with potassium carbonate under ice-cooling. Then, 150 ml of ethyl acetate are added to said mixture, and insoluble materials are removed by filtration. The filtrate is washed with an aqueous sodium bicarbonate solution, dried and evaporated to remove solvent. The residue thus obtained is purified by silica gel chromatography(Solvent: methanol-chloroform(1:5)). 1.5 g of 1-(2-chloroethyl)-1-nitroso-3-n-propyl-3-D-glucopyranosylurea are thereby obtained as pale yellow caramel.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[CH:5][CH:4]=1.C1CCN2C(=NCCC2)CC1.[Cl:25][C:26]1[CH:31]=[C:30](Cl)[N:29]=[CH:28][N:27]=1>C(#N)C>[Cl:25][C:26]1[N:27]=[CH:28][N:29]=[C:30]([O:13][C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([NH2:2])=[CH:4][CH:5]=2)[CH:31]=1
Reactant: Nc1ccc(O)c2ccccc12
Reactant: Clc1cc(Cl)ncn1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Nc1ccc(Oc2cc(Cl)ncn2)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-aminonaphthalen-1-ol hydrochloride (6.82 g, 31.4 mmol) in acetonitrile (80 mL) at 0° C. was added drop-wise DBU (11.0 mL, 75.0 mmol). After 10 min 4,6-dichloropyrimidine (5.00 g, 34.0 mmol) was added portion-wise over 5 min and the reaction mixture warmed to RT for 3 hr and then evaporated in vacuo. The residue was diluted with water (250 mL) and sonicated for 15 min and then stirred at RT for 16 hr. The resulting precipitate was isolated by filtration, washed with water (3×100 mL) and dried in vacuo to afford the title compound, Intermediate E3, as a grey solid (8.27 g, 97%); Rt 1.85 min (Method 2, acidic); m/z 272 (M+H)+, (ES+).
Reaction SMILES: [C:1]1(/[C:7](/[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1([CH3:33])[CH:26]=[CH:25][C:24]([S:27]([N:30]=[C:31]=[O:32])(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(Cl)Cl>[C:21]1([CH3:33])[CH:22]=[CH:23][C:24]([S:27]([NH:30][C:31]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]/[CH:8]=[C:7](\[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)/[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:32])(=[O:28])=[O:29])=[CH:25][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: OCCCCC/C=C(\c1ccccc1)c1cccnc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)OCCCCC/C=C(\c2ccccc2)c2cccnc2)cc1
Temperature: 25 °C
Yield: 61.1 %

Procedure:
(E)-7-Phenyl-7-(3-pyridyl)-6-hepten-1-ol (2.0 g, 7.4 mmoles) was dissolved in methylene chloride (20 ml), and p-toluenesulfonyl isocyanate (1.5 g, 7.6 mmoles) was added to the solution. The mixture was stirred at room temperature for an hour and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using isopropyl ether-ethyl acetate (1:1) as the developing solvent. Recrystallization of the product from ethyl acetate gave 1-(p-toluenesulfonyl)aminocarbonyloxy-(E)-7-phenyl-7-(3-pyridyl)-6-heptene (2.1 g, 60%) (Compound Id-29).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([OH:9])[N:3]=1.C[Si](N[Si](C)(C)C)(C)C.[F:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>S([O-])([O-])(=O)=O.[NH4+].[NH4+].II.C1(C)C=CC=CC=1>[NH2:1][C:2]1[NH:3][C:4](=[O:9])[N:5]([CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[F:19])[C:6](=[O:8])[CH:7]=1
Reactant: Nc1cc(O)nc(O)n1
Reactant: Fc1ccccc1CBr
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: II
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Product: Nc1cc(=O)n(Cc2ccccc2F)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.9 %

Procedure:
A mixture of 4-amino-2,6-dihydroxypyrimidine (10 g, 79.0 mmol), ammonium sulfate (570 mg, 3.95 mmol), and hexamethyldisilizane (60 mL, 292.3 mmol) was heated to reflux for 3.25 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo to afford a white solid. The solid was mixed with toluene (12 mL) under argon and then treated with 2-fluorobenzyl bromide (12.6 mL, 102.7 mmol) and iodine (470 mg, 1.58 mmol). This mixture was heated to reflux for 2 h. A brown suspension was formed. The reaction was stirred at 25° C. overnight. At this time, the reaction mixture was cooled to 0° C. and then treated with a solution of sodium thiosulfate (2.47 g in 40 mL of water). A very thick suspension formed which needed to be stirred by hand. The solids were broken up with a spatula. The mixture was then treated with a saturated aqueous sodium bicarbonate solution (300 mL) and was stirred at 0° C. for 30 min. The resulting solid was collected by filtration and washed well with water, toluene, and then ether. The solid was then dried in vacuo to afford 6-amino-3-(2-fluoro-benzyl)-1H-pyrimidine-2,4-dione (20.80 g, quant.) as a tan solid; LRMS for C11H10FN3O2S(M+H)+ at m/z=236.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].CS(O[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][C:20]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([CH2:31][CH3:32])[N:23]=[CH:22][N:21]=2)=[CH:13][CH:12]=1)(=O)=O>O>[CH2:1]([NH:3][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][C:20]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([CH2:31][CH3:32])[N:23]=[CH:22][N:21]=2)=[CH:13][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)c1c(CC)ncnc1NCCc1ccc(CCOS(C)(=O)=O)cc1
Reactant: CCN
Solvent: O
Product: CCNCCc1ccc(CCNc2ncnc(CC)c2C(=O)OCC)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
A 70% aqueous ethylamine solution (2.14 g, 33.23 mmol) was added to ethyl 4-(2(4-(2-methylsulfonyloxyethyl)phenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate (0.70 g, 1.66 mmol). The mixture was stirred at 100° C. for 2 hours in a sealed tube and cooled to room temperature. Then water (40 ml) was added to the reaction mixture. The mixture was extracted with methylene chloride and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel eluting with ethyl acetate/methanol (=8/2) to give the desired ethyl 4-(2-(4-(2-ethylaminoethyl)phenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate (0.40 g, 65%).
Reaction SMILES: CP(Cl)(=O)OC.[C:7]([O:10][CH:11]([C:27]1[CH:31]([OH:32])[O:30][C:29](=[O:33])[CH:28]=1)[CH2:12][O:13][C:14](=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:9])[CH3:8]>>[C:7]([O:10][CH:11]([C:27]1[CH:31]([OH:32])[O:30][C:29](=[O:33])[CH:28]=1)[CH2:12][O:13][C:14](=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:9])[CH2:8][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCC(=O)OCC(OC(C)=O)C1=CC(=O)OC1O
Agent: COP(C)(=O)Cl
Product: CCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCC)C1=CC(=O)OC1O

Procedure:
Using methyl methylphosphonochloridate in place of dodecanoyl chloride in the above-described procedure for making 4-(1-acetoxy-2-dodecanoyloxyethyl)-5-hydroxy-2(5H)-furanone, the product obtained is 4-[1-acetoxy-2-OP(O)(OCH3)(CH3) ethyl)-5-hydroxy-2(5H)-furanone.
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][N:5]([CH3:8])[C:6]=1I.C([Mg]Br)C.[CH2:13]([Sn:17](Cl)([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[NH4+].[Cl-]>C1COCC1.O>[CH2:22]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[C:6]1[N:5]([CH3:8])[CH:4]=[N:3][C:2]=1[I:1])[CH2:23][CH2:24][CH3:25]
Reactant: Cn1cnc(I)c1I
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1c(I)ncn1C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
4,5-Diiodo-1-methyl-1H-imidazole (40.0 g) was stirred in anhydrous THF (560 mL) at ambient temperature and ethylmagnesium bromide (3M in ether, 42.0 mL) was added over 20 minutes under an inert atmosphere. The resulting white precipitate was stirred for 30 minutes then tributyltin chloride (34.2 mL) added dropwise. The resulting clear solution was stirred for 1 hr, then saturated aqueous NH4Cl (50 mL) and water (300 mL) were added. The reaction mixture was extracted with DCM (500 mL), washed with water (3×300 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica eluting with hexane:EtOAc (1:1) to afford the title compound as a colourless oil (45.1 g, 76%);
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C[O:12][C:13]1C=CC=C[C:14]=1N1CCN(CCO)CC1>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:14][CH2:13][OH:12]
Reactant: COc1ccccc1N1CCN(CCO)CC1
Reactant: c1ccc2c(c1)CCNC2
Product: OCCN1CCc2ccccc2C1
Yield: 60 %

Procedure:
2-(3,4-Dihydro-1H-isoquinolin-2-yl)-ethanol (31A) is prepared from 1,2,3,4-tetrahydro-isoquinoline as described for 28A.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[CH3:29][N:30]([CH3:42])[C:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)=[O:32].C(=O)(O)[O-].[Na+].ClCCl>C(#N)C.CCOC(C)=O.Cl[Pd-2](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.CO>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:37]3[CH:38]=[C:33]([CH:34]=[CH:35][CH:36]=3)[C:31]([N:30]([CH3:42])[CH3:29])=[O:32])[N:3]=2)[NH:8][CH:9]=1
Reactant: CN(C)C(=O)c1cccc(B(O)O)c1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(Br)nc12
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC#N
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(C(=O)N(C)C)c3)nc12
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 53.7 %

Procedure:
A mixture of 2-Bromo-7-(2-methoxy-phenyl)-5-(toluene-4-sulfonyl)-5H-pyrrolo[2,3-b]pyrazine (30 mg, 0.065 mmol), 3-dimethylaminocarbonylphenyl boronic acid (25.3 mg, 0.130 mmol) and dichlorobis(triphenylphosphino)palladium(II) (2.5 mg, 0.003 mmol) in acetonitrile (1 mL) and aqueous solution of sodium bicarbonate (2M, 1 mL) was irradiated in a Personal Chemistry Optimizer at 90° C. for 15 minutes. The crude reaction mixture was distributed between dichloromethane and a saturated aqueous solution of sodium bicarbonate. The aqueous phase was then extracted with dichloromethane and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude brown residue was then dissolved in MeOH (5 mL), 5N KOH (50 μL) and the mixture was stirred at room temperature for 75 minutes. Removal of the solvents resulted in a yellow residue, which was then purified by flash silica gel chromatography using a gradient of ethyl acetate in hexanes, then 10% MeOH in EtOAc to afford 3-[7-(2-Methoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-N,N-dimethyl-benzamide (13.0 mg, 54% yield) as a pale yellow solid. 1H-NMR (500 MHz, CD3OD) δ 8.89 (m, 1H), 8.80 (m, 1H), 8.40 (m, 1H), 8.25 (m, 2H), 7.62 (m, 1H), 7.50 (m, 1H), 7.25 (m, 1H), 7.10 (m, 2H), 3.97 (m, 3H), 3.17 (m, 3H), 3.10 (m, 3H). MS: m/z 373.1 [MH+].
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].F[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>CN(C)C=O>[CH3:1][O:2][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CO
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1N1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
A solution of methanol (0.178 ml, 10.0 mmol) in N,N-dimethylformamide (1 ml) was added dropwise to a suspension of 60% sodium hydride (0.176 g, 4.40 mmol) in N,N-dimethylformamide (5 ml) under ice cooling, and the mixture was stirred at room temperature for 1 hour. 1-(2-Fluoro-4-nitrophenyl)piperidine (compound of Reference Example 3; 0.448 g, 2.00 mmol) was added to the reaction mixture under ice cooling, and the mixture was refluxed for 20 hours. Ice water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=5:1) to give the title compound (0.395 g, 84%) as a yellow solid.
Reaction SMILES: Cl.C(N=[C:5]1[N:14]([CH2:15][C:16]#[N:17])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:19])[C:11]=2[Cl:18])[NH:6]1)#N.C(=O)([O-])[O-:21].[K+].[K+]>C(O)CO>[Cl:18][C:11]1[C:10]([Cl:19])=[CH:9][CH:8]=[C:7]2[C:12]=1[CH2:13][N:14]1[CH2:15][C:16](=[O:21])[NH:17][C:5]1=[N:6]2
Reactant: O=C([O-])[O-]
Reactant: N#CCN1Cc2c(ccc(Cl)c2Cl)NC1=NC#N
Agent: Cl
Agent: [K+]
Solvent: OCCO
Product: O=C1CN2Cc3c(ccc(Cl)c3Cl)N=C2N1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97.1 %

Procedure:
To a mixture of 15 ml of ethylene glycol and 2 ml (0.02 moles) of cc. hydrochloric acid, warmed to 120° C., 2.50 g (0.01 mole) of (2-cyanoimino-5,6-dichloro-1,2,3,4-tetrahydroquinazolin-3-yl) acetonitrile are added, and the solution is stirred at the same temperature for 20 minutes. Then it is cooled to room temperature and made neutral with 10% potassium carbonate solution. The separated crystals are filtered off. Thus 2.72 g (97.1%) of crude 6,7-dichloro-1,5dihydroimidazo[2,1-b]quinazolin-2[3H]-one base are obtained (m.p.>300° C., HPLC content: 97.2%), which is dissolved in a hot mixture of 15 ml of methanol and 16 ml of cc. ethanolic hydrogen chloride (hydrogen chloride content: 0.76 moles/1000 ml) and allowed to crystallize. Then it is cooled, the separated product is filtered off and washed with a slight amount of ethanol.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][C:14]([OH:16])=O.C([Li])CCC.Cl>C1COCC1.CCCCCC>[F:11][C:8]([F:9])([F:10])[C:6]1[CH:7]=[C:2]2[C:3]([CH2:12][CH2:13][C:14]2=[O:16])=[CH:4][CH:5]=1
Reactant: O=C(O)CCc1ccc(C(F)(F)F)cc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1CCc2ccc(C(F)(F)F)cc21
Reaction time: 0.25 h
Yield: 51.1 %

Procedure:
To a solution of 3-[2-bromo-4-(trifluoromethyl)phenyl]propanoic acid (6.40 g, 21.5 mmol) in THF (300 mL) and hexane (80 mL) at −78° C. was added a 2.5 M solution of n-butyllithium in hexane (19 mL). After being stirred for 15 min, the mixture was poured into a 2 N HCl solution (150 mL). The two layers were separated and the water layer was extracted by ether. The combined organic layers were washed with NaHCO3 solution, water, brine, dried over MgSO4 and concentrated. Column chromatography on silica (10-20% EtOAC in hexane) provided the title compound (2.2 g, 51%) as an oil. MS calculated for C10H7F3O: (M+H)+ 201. found 201.0.
Reaction SMILES: O[C:2]1([CH2:8][CH:9]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CN(S(F)(F)[F:35])C.O>C(Cl)Cl>[F:35][C:2]1([CH2:8][CH:9]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CN(C)S(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)NC(CN(C)C(=O)OC(C)(C)C)CC2(O)CCCCC2)cc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)NC(CN(C)C(=O)OC(C)(C)C)CC2(F)CCCCC2)cc1
Yield: 19.9 %

Procedure:
To a solution of tert-butyl 3-(1-hydroxycyclohexyl)-2-(4-methylphenylsulfonamido)-propyl(methyl)carbamate (9.23 g, 21 mmol) in dry CH2Cl2 (100 mL) at −78° C. was added (dimethylamino)sulfur trifluoride (4.2 g, 32 mmol). The reaction mixture was poured into water (80 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica eluted with 10:90 hexanes/EtOAc to afford a light yellow solid. The crude product was purified further by preparative HPLC to give tert-butyl 3-(1-fluorocyclohexyl)-2-(4-methylphenylsulfonamido)propyl(methyl)carbamate (1.85 g). 1H NMR (400 MHz, CDCl3): 1.24-1.52 (m, 19H), 1.74-1.79 (m, 3H), 2.42 (s, 3H), 2.50 (s, 3H), 3.15 (m, 1H), 3.40 (m, 2H), 7.30 (d, 2H), 7.72 (d, J=8.4, 2H). MS (E/Z): 443 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:4][CH:3]=1.[Li+].[OH-].O.Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(-c2ccc(Br)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cn(-c2ccc(Br)cc2)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 50 °C
Reaction time: 16 h
Yield: 85.9 %

Procedure:
Part A: To a stirred solution of ethyl 1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate (6.10 gram, 0.0139 mol) in THF (70 mL) is added LiOH (0.67 gram, 0.0278 mol) and water (70 mL). The resulting mixture is stirred for 16 hours at 50° C. to give a clear solution. After cooling to room temperature, HCl (1N solution, 28 mL) is added to give an oily precipitate which completely solidifies on continued stirring and addition of water (70 mL). The precipitate is collected by filtration, washed with water and dried in vacuo to give 1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylic acid (4.92 gram, 86% yield). Melting point: 138–142° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:22])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18].[CH3:23]I>CN(C=O)C>[CH3:3][O:4][C:5](=[O:22])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[N:15]([CH3:23])[C:16](=[O:21])[C:17]([F:19])([F:18])[F:20]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NC(=O)C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1N(C)C(=O)C(F)(F)F
Reaction time: 1 h

Procedure:
To a stirred suspension of NaH (112 mg, 2.80 mmol, 60% dispersion in mineral oil) in DMF (5 mL) at 0° C. was added 3-nitro-2-(2,2,2-trifluoro-acetylamino)-benzoic acid methyl ester (750 mg, 2.55 mmol) portion wise. The resulting mixture was stirred for 1 h, then MeI (175 mL, 2.80 mmol) was added and the progress of the reaction was followed by LCMS. Upon consumption of 3-nitro-2-(2,2,2-trifluoro-acetylamino)-benzoic acid methyl ester, the reaction mixture was quenched with aqueous NH4Cl, and extracted with EtOAc. The combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using ethyl acetate-hexane to provide 2-[methyl-(2,2,2-trifluoro-acetyl)-amino]-3-nitro-benzoic acid methyl ester. MS m/z: 275.0 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:8])[N:5]([CH3:7])[CH:6]=1.[N:9]1([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[N:27]=[CH:26][C:25]4=[CH:28][CH:29]=[C:30](B5OC(C)(C)C(C)(C)O5)[N:24]4[N:23]=3)=[CH:17][CH:16]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>>[CH3:7][N:5]1[CH:6]=[C:2]([C:30]2[N:24]3[C:25]([CH:26]=[N:27][C:22]([NH:21][C:18]4[CH:19]=[CH:20][C:15]([N:9]5[CH2:14][CH2:13][O:12][CH2:11][CH2:10]5)=[CH:16][CH:17]=4)=[N:23]3)=[CH:28][CH:29]=2)[N:3]=[C:4]1[CH3:8]
Reactant: CC1(C)OB(c2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)OC1(C)C
Reactant: Cc1nc(Br)cn1C
Product: Cc1nc(-c2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)cn1C

Procedure:
[7-(1,2-Dimethyl-1H-imidazol-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-morpholin-4-yl-phenyl)-amine was prepared from 4-bromo-1,2-dimethyl-1H-imidazole and (4-morpholin-4-yl-phenyl)-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine in an analogous manner to Example 1042b. Product isolated as a yellow solid (11 mg, 10%). m.p.=decomposed at 250° C.; LCMS (m/e) 390 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.62 (s, 1H), 7.85 (s, 1H), 7.55 (d, 2H, J=8.9 Hz), 7.27-7.23 (m, 1H), 6.97 (d, 2H, J=8.9 Hz), 6.81 (d, 1H, J=4.8 Hz), 6.56 (bs, 1H), 3.93-3.87 (m, 4H), 3.64 (s, 3H), 3.18-3.12 (m, 4H), 2.46 (s, 3H).
Reaction SMILES: [Mg].C1C[O:5][CH2:4]C1.Br[C:8]1[S:9][CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].Cl>CN(C=O)C>[CH2:13]([C:12]1[CH:11]=[CH:10][S:9][C:8]=1[CH:4]=[O:5])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: C1CCOC1
Reactant: CCCCCCCCCCCCCCc1ccsc1Br
Agent: Cl
Agent: [Mg]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCc1ccsc1C=O
Yield: 50 %

Procedure:
Magnesium turnings (0.528 g, 22 mmol) dissolved and 60 mL of dry THF was placed in a 100 mL round bottom flask. 2-Bromo-3-tetradecylthiophene (7.2 g, 20 mmol) was added dropwise to above solution. The mixture was refluxed until almost all the magnesium turnings disappeared. After the mixture was transferred to a clean flask, dry DMF (4 mL) was added dropwise. The mixture was refluxed overnight and cooled in an ice bath. A 5% HCl solution (20 mL) was added to the reaction mixture. The organic portion was extracted by dichloromethane, washed by a 10% KOH solution (50 mL×3), and dried by MgSO4. After removal of the solvent, the crude product was purified by column chromatography on silica gel (using 5% ethyl acetate in hexane as an eluant) to give 3-teradecylthiophene-2-carboxaldehyde as a colorless oil (yield=50%).