Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[Br:10][CH2:11][CH2:12][CH2:13]Br>>[Br:10][CH2:11][CH2:12][CH2:13][O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1]
Reactant: BrCCCBr
Reactant: Oc1cccc(F)c1F
Product: Fc1cccc(OCCCBr)c1F

Procedure:
Analogously to Example 91b, 2.00 g of 2,3-difluorophenol and 30.7 g of 1,3-dibromopropane are reacted. The title compound is obtained as a colourless oil. Rf=0.39 (1:10 EtOAc-heptane); Rt=4.82.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[C:16]([C:20]1[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=1[OH:30])([CH3:19])([CH3:18])[CH3:17]>C1(C)C=CC=CC=1>[C:16]([C:20]1[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=[C:22]([CH:12]([C:11]2[CH:14]=[CH:15][C:8]([F:7])=[CH:9][CH:10]=2)[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:21]=1[OH:30])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: C1CCNCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(C(c2ccc(F)cc2)N2CCCCC2)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
8.29 g (97.33 mmol) of piperidine are added, at room temperature, to a solution of 5.52 g (44.43 mmol) of 4-fluorobenzaldehyde in 50 ml of toluene. The slightly yellow-colored solution is boiled under reflux for 16 hours; approximately 1 ml of water is separated off using a water separator, and a solution of 8.73 g (42.32 mmol) of 2,4-di-tert-butylphenol in 15 ml of toluene is then added dropwise. The reaction mixture is boiled at reflux for further 16 hours and then cooled to room temperature; the solvent is distilled off using a vacuum rotary evaporator. Crystallisation of the residue from iso-propanol/methanol (1:1) yields 15.40 g (91%) of compound (205) (Table 2), m.p. 135-136° C. Molecular weight C26H36FNO (397.58). Analysis, calculated: C 78.55; H 9.13; N 3.52%. Analysis, found: C 78.48; H 9.09; N 3.50%. 1HNMR (300 MHz, CDCl3, ppm): 1.12 (s, 9H); 1.37 (s, 9H); 1.57 (m, 4H); 2.28 (bm, 6H); 4.35 (s, 1H); 6.63 (d, 1H); 6.91 (dt, 2H); 7.08 (d, 1H); 7.32 (bm, 4H).
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[C:9]([C:13]2[N:21]3[C:16]([CH:17]=[N:18][C:19](O)=[N:20]3)=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1.C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C.CN(C)C=O.[NH2:59][C:60]1[CH:68]=[C:67]2[C:63]([C:64]([CH3:71])([CH3:70])[C:65](=[O:69])[NH:66]2)=[CH:62][CH:61]=1>>[O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[C:9]([C:13]2[N:21]3[C:16]([CH:17]=[N:18][C:19]([NH:59][C:60]4[CH:68]=[C:67]5[C:63]([C:64]([CH3:71])([CH3:70])[C:65](=[O:69])[NH:66]5)=[CH:62][CH:61]=4)=[N:20]3)=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CC1(C)C(=O)Nc2cc(N)ccc21
Reactant: O=S1(=O)CCCN1c1cccc(-c2ccc3cnc(O)nn23)c1
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)C(=O)Nc2cc(Nc3ncc4ccc(-c5cccc(N6CCCS6(=O)=O)c5)n4n3)ccc21
Temperature: 65 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
7-[3-(1,1-dioxo-1,2-thiazolidin-2-yl)phenyl]pyrrolo[2,1-f][1,2,4]triazin-2-ol (47 mg, 0.14 mmol) and N-Phenylbis(trifluoromethanesulphonimide) (55.9 mg, 0.156 mmol) were treated with N,N-Diisopropylethylamine (0.100 mL, 0.575 mmol) and N,N-Dimethylformamide (3.00 mL, 38.7 mmol) for 30 min, then 6-Amino-3,3-dimethyl-1,3-dihydro-indol-2-one (31.3 mg, 0.178 mmol) was added and the mixture was stirred at 65° C. overnight. Conc. of the reaction gave a residue, which was chromatographed (silica gel, 20-100% EtOAc:Hex) to afford 6-({7-[3-(1,1-Dioxido-1,2-thiazolidin-2-yl)phenyl]pyrrolo[2,1-f][1,2,4]triazin-2-yl}amino)-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (39 mg; Yield=56%) as a yellow foam. LCMS (HPLC): 1.05 min, m/z=489 (M+H); 1H-NMR (DMSO-d6): 10.28 (s, 1H), 9.50 (s, 1H), 9.01 (s, 1H), 7.96 (d, 1H, J=7.8 Hz), 7.79 (s, 1H), 7.56 (m, 2H), 7.33 (d, 1H, J=8.3 Hz), 7.16 (m, 2H), 7.08 (s, 1H), 6.97 (d, 1H, J=4.7 Hz), 3.80 (t, 2H, J=6.5 Hz), 3.52 (t, 2H, J=7.4 Hz), 2.39 (m, 2H), 1.24 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([CH3:9])([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21]>CN(C)C1C=CN=CC=1.CC(C)=O>[C:19]([O:8][C:3]([CH3:9])([C:4]([F:6])([F:5])[F:7])[C:2]([F:10])([F:11])[F:1])(=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: CC(O)(C(F)(F)F)C(F)(F)F
Reactant: C=C(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: C=C(C)C(=O)OC(C)(C(F)(F)F)C(F)(F)F
Yield: 74.8 %

Procedure:
7.3 g of 1,1,1,3,3,3-hexafluoro-2-methyl-2-propanol, 0.2 g of 4-dimethylaminopyridine, 4.9 g of triethylamine and 20 g of acetone were charged into a four-necked flask equipped with a stirrer, a thermometer and a dropping funnel, and were dissolved by stirring. Then, 4.6 g of methacrylic acid chloride was dropwise added to the resulting solution at about 5° C. over 30 minutes, followed by stirring at the same temperature for 3 hours. Thereafter, the reaction solution was washed with water, thereby obtaining 7.5 g of 1,1,1,3,3,3-hexafluoro-2-methyl-2-propyl methacrylate. The 1H-NMR data of the obtained 1,1,1,3,3,3-hexafluoro-2-methyl-2-propyl methacrylate were as follows.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:21])[C:8](Br)=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[O:5])[CH3:2].[C-:22]#[N:23].[K+].O.C(Cl)Cl>CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:21])[C:8]([C:22]#[N:23])=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: [C-]#N
Reactant: CCOC(=O)c1c(-c2ccc(Br)cc2)c(C#N)c(Br)n1C
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)c1c(-c2ccc(Br)cc2)c(C#N)c(C#N)n1C
Temperature: 80 °C
Yield: 90 %

Procedure:
Dissolve 5-bromo-3-(4-bromo-phenyl)-4-cyano-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (205 mg, 0.500 mmol, prepared in example E-265) in DMSO (2.5 mL). Add potassium cyanide (325 mg, 5.0 mmol) to the mixture. Heat the mixture at 80° C. for 16 h. Add H2O (30 mL) and methylene chloride (30 mL) into the reaction mixture. Extract with H2O (5×30 mL). Combine the organic layers, dry over magnesium sulfate, filter, and concentrate under reduced pressure. Purify by flash chromatography (elution with 33% Et2O in hexanes) to provide the title compound (161 mg, 0.450 mmol, 90%). Mass spectrum (m/e): 375.0 (M+18). Rf=0.2 (50% Et2O in hexanes).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[N:16]([CH:17]=2)[C:15]2[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=2[S:13]3)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][Cl:32].O>CN(C=O)C>[Cl:32][CH2:31][CH2:30][O:22][C:20]1[CH:19]=[CH:18][C:15]2[N:16]3[CH:17]=[C:10]([C:7]4[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=4)[N:11]=[C:12]3[S:13][C:14]=2[CH:21]=1
Reactant: ClCCBr
Reactant: O=[N+]([O-])c1ccc(-c2cn3c(n2)sc2cc(O)ccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2cn3c(n2)sc2cc(OCCCl)ccc23)cc1

Procedure:
To a stirred solution of 2-(4-nitrophenyl)imidazo[2,2-b]benzothiazol-7-ol (2) (1 equivalent) in anhydrous DMF at rt are added potassium carbonate (2-3 equivalents) and 1-bromo-2-chloroethane (2-3 equivalents), and the mixture is stirred at a temperature between rt and 60° C. until the reaction is substantially complete as monitored by LCMS or TLC. The mixture is added to water and the resulting aqueous mixture is extracted with EtOAc. The organic layer is separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel flash chromatography to afford 7-(2-chloro-ethoxy)-2-(4-nitro-phenyl)-benzo[d]imidazo[2,1-b]thiazole.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][N:10]1[C:19]1[C:28]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=2[N:22]=[C:21]([Cl:29])[N:20]=1>CN(C)C=O>[ClH:29].[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:21]1[N:20]=[C:19]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9]2)[C:28]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=2[N:22]=1
Reactant: Cc1ccccc1N
Reactant: Clc1nc2c(c(N3CCc4ccccc4C3)n1)CCCC2
Solvent: CN(C)C=O
Product: Cc1ccccc1Nc1nc2c(c(N3CCc4ccccc4C3)n1)CCCC2
Product: Cl
Yield: 49.1 %

Procedure:
After 2-methylaniline(0.30 ml, 2.7 mmol) was added to a mixture solution of 4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloro-5,6,7,8-tetrahydroquinazoline(0.75 g, 2.5 mmol) and dimethylformamide(5 ml), 0.50 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:16][C:17]([C:19]2[CH:20]=[C:21]3[C:26](=[C:27]([C:29]#[CH:30])[CH:28]=2)[O:25][C:24]([CH3:32])([CH3:31])[CH2:23][C:22]3([CH3:34])[CH3:33])=[O:18])[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]([O:11]C(C)(C)C)=[O:10].O1CCOCC1>C(O)=O>[C:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:16][C:17]([C:19]2[CH:20]=[C:21]3[C:26](=[C:27]([C:29]#[CH:30])[CH:28]=2)[O:25][C:24]([CH3:31])([CH3:32])[CH2:23][C:22]3([CH3:34])[CH3:33])=[O:18])=[CH:3][C:2]=1[F:1])([OH:11])=[O:10]
Reactant: C#Cc1cc(C(=O)Oc2ccc(CC(=O)OC(C)(C)C)c(F)c2)cc2c1OC(C)(C)CC2(C)C
Solvent: O=CO
Solvent: C1COCCO1
Product: C#Cc1cc(C(=O)Oc2ccc(CC(=O)O)c(F)c2)cc2c1OC(C)(C)CC2(C)C

Procedure:
Following General Procedure E and using 8-ethynyl-2,2,4,4-tetramethyl chroman-6-carboxylic acid-3-fluoro-4-tert-butoxycarbonylmethyl-phenyl ester (Compound 28, 0.085 g, 0.21 mmol), 1,4-dioxane (2 mL) and formic acid (8 mL) followed by recrystallization from 10-20% ethyl acetate in hexane, the title compound was obtained (0.055 g, 75%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N+:18]([O-:20])=[O:19])[C:9]1=[O:21])[C:4]([O:6][CH3:7])=[O:5].C(Cl)Cl.N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>>[Si:30]([O:1][CH2:2][C@@H:3]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N+:18]([O-:20])=[O:19])[C:9]1=[O:21])[C:4]([O:6][CH3:7])=[O:5])([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H](CO)n1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)n1ccc2c([N+](=O)[O-])cccc2c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A round bottom flask was charged with (R)-methyl 3-hydroxy-2-(5-nitro-1-oxoisoquinolin-2(1H)-yl)propanoate (4 g, 0.01 mol), methylene chloride (40 mL, 0.5 mol) and 1H-imidazole (1.6 g, 0.023 mol) and tert-butyldimethylsilyl chloride (2.3 g, 0.015 mol) were added at 0° C. and the reaction allowed to warm to room temperature and stirred for 16 h. The reaction mixture was quenched with water and extracted with methylene chloride. Solvent was removed under reduced pressure to recover the pure product as an orange solid. MS m/z=407.5 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].Cl.[CH3:16][NH:17][CH3:18].C(N(CC)CC)C>C(Cl)Cl.O>[CH3:16][N:17]([CH3:18])[S:11]([C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:13])=[O:12]
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Yield: 73.8 %

Procedure:
To a solution of 80 g of 2-chloro-5nitrobenzenesulfonyl chloride (Example A-1 above) in 200 ml of methylene chloride heated to reflux, was slowly added a solution of 30 g of dimethylamine hydrochloride in 30 ml of water followed by a dropwise addition of triethylamine. After completion of the addition, the reaction mixture was refluxed for 20 minutes, cooled to room temperature and concentrated by rotatory evaporation. The residue was treated with water and the resulting solid was filtered and recrystallized from ethanol, affording 61 g of the title compound, mp 138°-140° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:28])[C:10]([C:12]1[S:24][C:23]2[C:22]3[CH:21]=[C:20]([C:25](O)=O)[CH:19]=[CH:18][C:17]=3[O:16][CH2:15][C:14]=2[CH:13]=1)=[O:11].[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:28])[C:10]([C:12]1[S:24][C:23]2[C:22]3[CH:21]=[C:20]([CH2:25][N:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)[CH:19]=[CH:18][C:17]=3[O:16][CH2:15][C:14]=2[CH:13]=1)=[O:11]
Reactant: CN1CCNCC1
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)O)ccc1OC2)c1ccc(F)cc1F
Product: CN1CCN(Cc2ccc3c(c2)-c2sc(C(=O)N(C)c4ccc(F)cc4F)cc2CO3)CC1

Procedure:
Following the procedure of Examples 25 and 70 and General Procedure E, 2-((2,4-difluorophenyl)(methyl)carbamoyl)-4H-thieno[3,2-c]chromene-8-carboxylic acid and 1-methylpiperazine were coupled to give 136bp.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](F)(=[O:10])=[O:9].C[Si]([C:16]([F:19])([F:18])[F:17])(C)C>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:16]([F:19])([F:18])[F:17])(=[O:10])=[O:9]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=S(=O)(F)c1ccccc1F
Product: O=S(=O)(c1ccccc1F)C(F)(F)F

Procedure:
reacting the 2-fluorobenzenesulfonyl fluoride, Ruppert's reagent (CH3SiCF3), and tris(dimethylamino)sulfonium difluorotrimethylsilicate to provide 1-fluoro-2-((trifluoromethyl)sulfonyl)benzene and isolating or not isolating the 1-fluoro-2-((trifluoromethyl)sulfonyl)benzene;
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([OH:14])=O)[C:6]=2[CH:5]=[CH:4][NH:3]1.[C:15]12([CH2:25][NH2:26])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.CN(C)C=O>>[C:15]12([CH2:25][NH:26][C:12]([C:7]3[C:6]4[CH:5]=[CH:4][NH:3][C:2](=[O:1])[C:11]=4[CH:10]=[CH:9][CH:8]=3)=[O:14])[CH2:22][CH:21]3[CH2:20][CH:19]([CH2:18][CH:17]([CH2:23]3)[CH2:16]1)[CH2:24]2
Reactant: O=C(O)c1cccc2c(=O)[nH]ccc12
Reactant: NCC12CC3CC(CC(C3)C1)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cccc2c(=O)[nH]ccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1,2-dihydro-1-oxoisoquinoline-5-carboxylic acid (0.107 g, 0.000566 mol), 1-adamantanemethylamine (0.120 mL, 0.000679 mol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.141 g, 0.000735 mol), 1-hydroxybenzotriazole (0.099 g, 0.00074 mol) and triethylamine (0.12 mL, 0.00085 mol) in N,N-dimethylformamide (2 mL, 0.02 mol) was stirred at room temperature for 18 hours. The mixture was poured onto water (100 ml) and extracted with ethyl acetate (3×100 ml). The combined extracts were dried over sodium sulfate and reduced in vacuo to afford the title compound.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1.CCN(CC)CC>C(Cl)(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1)=[O:4]
Reactant: Nc1ccncn1
Reactant: O=C(Cl)CCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccncn1
Reaction time: 0.25 h
Yield: 64.1 %

Procedure:
A solution of chloroacetyl chloride (1.22 mmol) in anhydrous CHCl3 (2.4 mL) was added slowly to a mixture of 4-aminopyrimidine (1.11 mmol) and Et3N (1.66 mmol) in anhydrous CHCl3 (22 mL) at room temperature. The bright yellow mixture gradually turned orange and after 4 hr the reaction was quenched with H2O (1 mL). After stirring for 15 min the mixture was concentrated to dryness under reduced pressure and the residue purified by flash silica gel chromatography (1-2% MeOH/dichloromethane) to give a yellow solid (122 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH:7]([N:12]=[C:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:8][CH2:9][CH:10]=[CH2:11])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[C:1]([O:5][C:6](=[O:26])[C:7]([N:12]=[C:13]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:8][CH2:9][CH:10]=[CH2:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CCCC(N=C(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCC(N=C(c1ccccc1)c1ccccc1)(C(=O)OC(C)(C)C)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A solution of 2-(benzhydrylidene-amino)-hex-5-enoic acid tert-butyl ester (350 mg, 1 mmol) in THF (5 mL, 0.2 M) was cooled to −78° C. and treated with sodium bis(trimethylsilyl)amide (2.2 mL, 1.0 M, 2.2 equiv) drop wise over 5 min and stirred for 30 min. After adding benzoyl chloride (140 μl, 1.2 mmol, 1.2 eq), the reaction mixture was warmed up to room temperature and stirred for an additional 1.5 h. The solution was cooled to 0° C. and quenched with water (5 mL). The resulting solution was diluted with ethyl acetate and washed successively with water and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by MPLC (1-40% ethyl acetate in heptane gave 2-(benzhydrylidene-amino)-2-benzoyl-hex-5-enoic acid tert-butyl ester (477 mg, 1 mmol, 100%).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C[Mg+].[Br-].[C:29]([C:31]1[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][C:32]=1[F:39])#[N:30]>C(Cl)Cl.CCOCC.C1COCC1>[C:29]([C:31]1[CH:38]=[CH:37][C:34]([CH:35]([C:2]2[N:3]=[CH:4][N:5]([C:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:6]=2)[OH:36])=[CH:33][C:32]=1[F:39])#[N:30]
Reactant: N#Cc1ccc(C=O)cc1F
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#Cc1ccc(C(O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-iodo-1-(triphenylmethyl)imidazole (2.93 g, 6.71 mmol) in dry CH2Cl2 (30 mL), under argon, was added MeMgBr (2.35 mL of a 3.0M solution in Et2O, 7.05 mmol), dropwise. The resulting solution was stirred at ambient temperature for 1 hour, then transferred dropwise into a stirred solution of 4-cyano-3-fluorobenzaldehyde, as described in Example 11, Step B, (1.00 g, 6.71 mmol) in dry THF (30 mL), under argon, at −78° C. After 30 min, the reaction mixture was quenched with saturated aqueous NH4Cl (50 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was triturated with EtOAc to yield the desired alcohol as a white solid.
Reaction SMILES: [F:1][C:2]([F:17])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:15][NH2:16])=[O:14].C(N(CC)CC)C.[C:25](Cl)(=[O:27])[CH3:26]>C(OCC)C>[C:25]([NH:16][NH:15][C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[C:2]([F:17])[F:1])(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: NNC(=O)CCCCCCCCCC=C(F)F
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)NNC(=O)CCCCCCCCCC=C(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
A solution of 0.5 gram (0.002 mole) of 12,12-difluoro-11-dodecenoic acid hydrazide and 0.3 gram (0.003 mole) of triethylamine in 20 ml of diethyl ether was stirred, and 0.2 gram (0.003 mole) of acetyl chloride was added. The reaction mixture was stirred at ambient temperature for 30 minutes and was filtered. The filtrate was in turn washed with aqueous 10% hydrochloric acid, aqueous 10% sodium hydroxide, and an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure yielding 0.4 gram of 12,12-difluoro-11-dodecenoic acid 2-acetylhydrazide. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[C:7]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:12])[CH2:8][CH2:9][C:10]#[CH:11].C(N(CC)CC)C>CN(C)C=O.O.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>[NH:3]1[C:2]([C:11]#[C:10][CH2:9][CH2:8][C:7]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[CH:6][N:5]=[CH:4]1
Reactant: C#CCCC(=O)OCc1ccccc1
Reactant: Ic1c[nH]cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCC#Cc1cnc[nH]1)OCc1ccccc1
Temperature: 75 °C
Yield: 68.8 %

Procedure:
Add bis(triphenylphosphine)palladium(II) chloride (0.14 g; 0.1 equiv; 0.20 mmoles) and copper(I) iodide (0.039 mg; 0.1 equiv; 0.20 mmoles) to a deoxygenated solution of 4-iodo-1H-imidazole (0.388 g; 1.0 equiv; 2.00 mmoles), benzyl pent-4-ynoate (0.376 g; 1.0 equiv; 2.00 mmoles), and triethylamine (0.84 mL; 3 equiv; 6.0 mmoles) in dimethylformamide (8 mL). Heat the mixture to 75° C. for 16 hours, then dilute the mixture with water (30 mL) and extract 3× with ethyl acetate. Wash the combined organic extracts with brine, dry over magnesium sulfate, filter, and concentrate to provide the crude product. Purify the crude product by column chromatography (0 to 10% methanol in dichloromethane) to afford benzyl 5-(1H-imidazol-5-yl)pent-4-ynoate (0.35 g; 69%) as a colorless oil: MS (m/z): 255(M+1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:20])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[C:7]([NH2:19])[CH:6]=1.N1C=CC=CC=1.[Cl:27][CH2:28][CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:2][O:3][C:4](=[O:20])[C:5]1[CH:6]=[C:7]([NH:19][S:31]([CH2:30][CH2:29][CH2:28][Cl:27])(=[O:33])=[O:32])[CH:8]=[C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:10]=1
Reactant: COC(=O)c1cc(N)cc(OCc2ccccc2)c1
Reactant: O=S(=O)(Cl)CCCCl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(NS(=O)(=O)CCCCl)cc(OCc2ccccc2)c1
Reaction time: 16 h
Yield: 88.7 %

Procedure:
A suspension of 3-amino-5-benzyloxy-benzoic acid methyl ester hydrochloride (D50) (5.0 g, 17 mmol, 1 equiv) in CH2Cl2 (100 ml) was treated with DMAP (400 mg, 3.2 mmol) and pyridine (3.5 g, 44 mmol, 2.6 equiv) followed by 3-chloropropanesulfonyl chloride (3.54 g, 20 mmol, 1.2 equiv) dropwise at room temperature. The resulting mixture was stirred for 16 h then concentrated in vacuo. The residue was dissolved in AcOEt (200 ml) and the resulting solution was washed with 2N aqueous HCl solution (100 ml) followed by saturated aqueous NaHCO3 solution (100 ml), dried over MgSO4 and concentrated in vacuo to give 3-benzyloxy-5-(3-chloro-propane-1-sulfonylamino)-benzoic acid methyl ester (D52) (6.0 g, 97%) as a pale pink solid. [M+H]+=366.1, RT=2.34 min