Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[I-].C[N+]1C=CN([C:20](=[O:29])[N:21]([CH3:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)C=1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[C:3]([O:12][C:20](=[O:29])[N:21]([CH3:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: Oc1ncc(C(F)(F)F)cc1Cl
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C(=O)Oc1ncc(C(F)(F)F)cc1Cl)c1ccccc1
Yield: 14.7 %

Procedure:
A solution of 3-chloro-5-(trifluoromethyl)-2-pyridinol (0.59 g, 3.00 mmol), 1-methyl-3-(methyl -phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (15:85)) yielding the title compound (146 mg, 15% yield) as a white solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]1[NH:21][C:22]([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[CH:31]=[C:30]([C:35]2[CH:36]=[C:37]4[C:57](=[CH:58][CH:59]=2)[C:41]2[NH:42][C:43]([C@@H:45]5[CH2:49][CH2:48][CH2:47][N:46]5C(OC(C)(C)C)=O)=[N:44][C:40]=2[CH:39]=[CH:38]4)[CH:29]=[CH:28]3)=[CH:23][N:24]=1)=O)(C)(C)C>C(Cl)Cl>[NH:46]1[CH2:47][CH2:48][CH2:49][C@H:45]1[C:43]1[NH:42][C:41]2[C:57]3[C:37]([CH:38]=[CH:39][C:40]=2[N:44]=1)=[CH:36][C:35]([C:30]1[CH:29]=[CH:28][C:27]2[C:32](=[CH:33][CH:34]=[C:25]([C:22]4[NH:21][C:20]([C@@H:16]5[CH2:17][CH2:18][CH2:19][NH:15]5)=[N:24][CH:23]=4)[CH:26]=2)[CH:31]=1)=[CH:59][CH:58]=3
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc5c(ccc6nc([C@@H]7CCCN7C(=O)OC(C)(C)C)[nH]c65)c4)ccc3c2)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc2cc(-c3cnc([C@@H]4CCCN4)[nH]3)ccc2cc1-c1ccc2c(ccc3nc([C@@H]4CCCN4)[nH]c32)c1
Reaction time: 2 h
Yield: 102 %

Procedure:
TFA (2 mL, 26.0 mmol) was added in one portion to a stirred solution of (5)-tert-butyl 2-(7-(6-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (137 mg) in CH2Cl2 (10 mL) at room temperature. The mixture was stirred for 2 h at room temp. and then the solvents were removed in vacuo. The residue was taken up in 50% methanol/CH2Cl2 and filtered through an MCX cartridge (Strata XC). The cartridge was washed with methanol and the compound was eluted with a solution of NH3 in methanol (2M). The appropriate fractions were concentrated in vacuo to afford 2-((S)-pyrrolidin-2-yl)-7-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-naphtho[1,2-d]imidazole (98 mg, 0.20 mmol) as orange solid. LC-MS retention time 1.245 min; m/z 499.30 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 10% MeOH/90% H2O/0.1% TFA and Solvent B was 10% H2O/90% MeOH/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (TFA salt, 500 MHz, MeOD) δ ppm 8.59 (d, J=8.5 Hz, 1H), 8.43 (d, J=1.5 Hz, 1H), 8.36 (s, 1H), 8.31 (s, 1H), 8.13 (dd, J=8.6, 1.8 Hz, 1H), 8.01-8.10 (m, 3H), 7.90-7.98 (m, 2H), 7.87 (s, 1H), 7.80 (d, J=8.6 Hz, 1H), 5.18 (t, J=7.9 Hz, 1H), 5.05 (t, J=8.1 Hz, 1H), 3.63-3.72 (m, 1H), 3.52-3.63 (m, 3H), 2.61-2.77 (m, 2H), 2.45-2.58 (m, 2H), 2.33-2.43 (m, 2H), 2.20-2.33 (m, 2H).
Reaction SMILES: CN(C)C=O.P(Cl)(Cl)([Cl:8])=O.[I:11][C:12]1[CH:13]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH2:15][NH:16][CH:17]=1>C(Cl)Cl>[Cl:8][C:15]1[C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][C:12]([I:11])=[CH:17][N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)C1=CC(I)=CNC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(I)cnc1Cl
Temperature: 25 °C
Reaction time: 28 h
Yield: 43 %

Procedure:
To a solution containing 0.12 ml of dry dimethylformamide and 0.14 ml of distilled phosphorus oxychloride in 20 ml of anhydrous methylene chloride are added 0.28 g of methyl 5-iodo-1,2-dihydro-3-pyridinecarboxylate in one portion. The mixture is stirred at room temperature under a nitrogen atmosphere for 28 hours. Workup as described in Procedure 1 yields 0.13 g (43%) of recrystallized methyl 2-chloro-5-iodo-3-pyridinecarboxylate.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:8]=[C:9]([C:17]3[C:18]([CH3:30])([CH3:29])[C:19](=[O:28])[N:20]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[N:21]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH:14]([F:16])[F:15])[CH2:4][CH2:3]1.[CH3:31][C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1>>[CH:2]1([CH2:5][O:6][C:7]2[CH:8]=[C:9]([C:17]3[C:18]([CH3:30])([CH3:29])[C:19](=[O:28])[N:20]([CH:22]4[CH2:27][CH2:26][N:25]([S:38]([C:34]5[CH:35]=[CH:36][CH:37]=[C:32]([CH3:31])[CH:33]=5)(=[O:40])=[O:39])[CH2:24][CH2:23]4)[N:21]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH:14]([F:15])[F:16])[CH2:3][CH2:4]1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CC1(C)C(=O)N(C2CCNCC2)N=C1c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: Cl
Product: Cc1cccc(S(=O)(=O)N2CCC(N3N=C(c4ccc(OC(F)F)c(OCC5CC5)c4)C(C)(C)C3=O)CC2)c1

Procedure:
The title compound is prepared analogously as described for GP1 using 5-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B3*HCl) and 3-methylbenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:16]([OH:20])(=[O:19])[CH:17]=[CH2:18]>C(O)(=O)C>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:18][CH2:17][C:16]([OH:20])=[O:19])=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=CC(=O)O
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Solvent: CC(=O)O
Product: O=C(O)CCNc1ccc(C(=O)c2ccccc2)cc1

Procedure:
1.97 g of 4-aminobenzophenone (0.01 mole) and 1.44 g of acrylic acid (0.02 mole) are dissolved in 10 ml of glacial acetic acid and boiled under reflux for 2 days. The solution is evaporated to dryness in vacuo, and the residue is redissolved in 2 N sodium hydroxide solution, and the solution is extracted several times with diethyl ether. The aqueous solution is adjusted to pH 4-5 with 2 N HCl, and the precipitate is filtered off with suction and washed with water.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8]([CH:9]=[O:10])[C:7]([OH:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].CO[CH2:15][Cl:16].[Cl-].[Al+3].[Cl-].[Cl-]>O>[Cl:16][CH2:15][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=[C:8]([CH:9]=[O:10])[C:7]=1[OH:12]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Reactant: COCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=Cc1cc([N+](=O)[O-])cc(CCl)c1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
While cooling a mixture of 12.0 g of 5-nitrosalicylaldehyde and 100 ml of chloromethyl methyl ether in an ice bath, 43.9 g of anhydrous aluminum chloride was added in small portions to the mixture, followed by stirring at room temperature for 10 minutes and thereafter by refluxing with heating for 22 hours. The reaction mixture was then cooled in an ice bath, and 200 ml of water was added to the mixture with full stirring, whereby white crystals were separated out. The white crystals were collected and dissolved in hot hexane, and the solution was filtered. The mother liquor was thereafter cooled, giving 14.9 g of 3-chloromethyl-5-nitrosalicylaldehyde in the form of white needlelike crystals (yield 72%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].C([N:19]1[CH2:25][CH2:24][C:23]([C:26]#[N:27])=[C:22]([Cl:28])[CH2:21][CH2:20]1)C1C=CC=CC=1>C(Cl)Cl>[Cl:28][C:22]1[CH2:21][CH2:20][N:19]([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[CH2:25][CH2:24][C:23]=1[C:26]#[N:27]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N#CC1=C(Cl)CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Product: N#CC1=C(Cl)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.3 gm=3.9 ml (0.025 mol) of benzyl chloroformate dissolved in 15 ml of methylene chloride, were added dropwise to a solution of 4.9 gm (0.02 mol) of 1-benzyl-4-chloro-5-cyano-2,3,6,7-tetrahydro-1H-azepine in 500 ml of methylene chloride while stirring at room temperature, whereby the temperature rose by 5° C. The mixture was stirred for 5 hours at room temperature and then allowed to stand overnight. The solvent was then removed in a rotary evaporator, and the residue was purified on a silicagel column (toluene/ethyl acetate=8:2). After the corresponding fractions had been concentrated by evaporation, a slightly yellowish oil was obtained with solidified upon standing.
Reaction SMILES: O1C=CC=C1.Cl[C:7]1[N:8]=[C:9]2[CH:19]=[CH:18][O:17][C:10]2=[C:11]2[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]2.[F-:20]>>[F:20][C:7]1[N:8]=[C:9]2[CH2:19][CH2:18][O:17][C:10]2=[C:11]2[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]2
Reactant: Clc1nc2ccoc2c2ccccc12
Reactant: [F-]
Solvent: c1ccoc1
Product: Fc1nc2c(c3ccccc13)OCC2

Procedure:
The chloride/fluoride exchange was achieved by the method (reference 3) cited above. Thus 90 mg of 5-chloro-2,3-dihydro-1-oxa-4-aza-cyclopenta[a]naphthalene (Example 217) was suspended in 1.5 mL of Bu4PHF2 and was irradaited under microwave (Smith Reactor) to about 120° C. for 2 hours. After aqueous work up and column purification, 22 mg of fluoride product was obtained (26.9%). LC/MS rt-min (MH+): 1.91 (190) [method B]. The furan derivative (Example 218), 5-chloro-1-oxa-4-aza-cyclopenta[a]naphthalene was sufficiently reactive to be alkylated with the tripeptide directly without fluoride activation.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:12]([NH:14][CH2:15][C:16]([NH:18][C@H:19]([C:25]([NH:27][C@@H:28]([C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:38])[NH:34][N+:35]([O-:37])=[O:36])=[O:26])[CH2:20][CH2:21][C:22](=[O:24])[NH2:23])=[O:17])=[O:13])[CH3:11])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[NH:56]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[C@H:57]([C:63]([NH:65][CH2:66][C:67]([OH:69])=O)=[O:64])[CH2:58][CH2:59][C:60](=[O:62])[NH2:61]>>[NH:56]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[C@H:57]([C:63]([NH:65][CH2:66][C:67]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:12]([NH:14][CH2:15][C:16]([NH:18][C@H:19]([C:25]([NH:27][C@@H:28]([C:39]([O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:38])[NH:34][N+:35]([O-:37])=[O:36])=[O:26])[CH2:20][CH2:21][C:22](=[O:24])[NH2:23])=[O:17])=[O:13])[CH3:11])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4])=[O:69])=[O:64])[CH2:58][CH2:59][C:60](=[O:62])[NH2:61]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)O
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1
Product: CC[C@H](C)[C@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1

Procedure:
Boc-Ile-Ala-Gly-Gln-D-Arg(NO2)-OBzl (3.2 g, 5 m mol) was demasked with respect to the N-masking group, and coupled with Boc-Gln-Gly-OH (1.7 g, 5.5 m mol) in the manner similar to that of Example 1, paragraph 7).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][CH:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[CH3:32][S:33]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][CH:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)[CH:6]=[CH:7][CH:8]=1)(=[O:35])=[O:34]
Reactant: CC(C)S(=O)(=O)NC1Cc2ccc(-c3cccc(CN)c3)cc2C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NC1Cc2ccc(-c3cccc(CNS(C)(=O)=O)c3)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
A solution of N-{5-[3-(aminomethyl)phenyl]-2,3-dihydro-1H-inden-2-yl}-2-propanesulfonamide (69 mg, 0.2 mmol) in dichloromethane (5 ml) was treated with triethylamine (40 mg, 0.4 mmol), followed by methanesulfonyl chloride (25 mg, 0.22 mmol) and the wole mix stirred at room temperature under argon for 1 h. The reaction mix was washed with 0.5M hydrochloric acid, and the organic layer was evaporated under reduced pressure to give a brown oil which was purified by column chromatography on a 1 g SCX column eluting from 0-50% ethyl acetate in 40-60° C. petroleum ether to give the title compound as a yellow oil (46 mg, 55%).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH:12]1([OH:16])[CH2:15][CH2:14][CH2:13]1.[OH-].[K+]>CS(C)=O.O>[Br:1][C:2]1[C:3]([O:16][CH:12]2[CH2:15][CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: OC1CCC1
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cnc(OC2CCC2)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
5-Bromo-6-chloronicotinic acid (CAN 29241-62-1, 2.0 g, 8.46 mmol) was dissolved in DMSO (20.0 mL). Cyclobutanol (793 mg, 857 μL, 11.0 mmol) and potassium hydroxide powder (1.42 g, 25.4 mmol) were added and the mixture was stirred at room temperature overnight. Water (20 mL) was added and the mixture was acidified (under ice-water bath cooling) with 37% HCL in water (pH=2). The suspension was filtered, washed with water and the solid was dried to yield 1.88 g (82%) of the title compound as a white solid; MS (ESI): 270.2 (M−H)−.
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][CH2:8][C:9]([OH:11])=O)=[O:6])[CH:2]=[CH2:3].C(Cl)(=O)C([Cl:15])=O.CN(C)C=O>O1CCCC1>[CH2:1]([O:4][C:5]([O:7][CH2:8][C:9]([Cl:15])=[O:11])=[O:6])[CH:2]=[CH2:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CCOC(=O)OCC(=O)O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=CCOC(=O)OCC(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
A solution of 2-(allyloxycarbonyloxy)acetic acid (3.03 g, 18.9 mmol) obtained from Example 39-(3) in tetrahydrofuran (30 ml) was cooled to 0° C., and to the solution were added oxalyl chloride (2.64 g, 20.8 mmol) and N,N-dimethylformamide (30 μl). The mixture was warmed to room temperature. After the mixture was stirred for 30 minutes, the solvent was distilled off under reduced pressure, and the resulting residue was purified using simple distillation under reduced pressure to give the title compound (3.04 g, yield 90%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(N(CC)CC)C.C(OCC)(=O)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>[C:10]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C#CCCCCCCCCC
Reactant: O=Cc1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCC#Cc1cccc(C=O)c1
Temperature: 55 °C
Reaction time: 6 h
Yield: 109.1 %

Procedure:
To a solution of 3-bromobenzaldehyde (30.3 g) and 1-undecyne (29.5 g) in triethylamine (120 ml) was added bis(triphenylphosphine)palladium(II) chloride (1.9 g) followed by copper(I) iodide (0.25 g). The mixture was stirred in the dark at 55° C. for 6 hrs, under nitrogen. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to yield 45.8 g of 3-(1-undecynyl)benzaldehyde, as an oil.
Reaction SMILES: [SH:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]#[CH:21].CC(C)=O>O>[C:7]1([C:4]2[N:3]=[C:2]([S:1][CH2:21][C:20]#[CH:19])[O:6][N:5]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Sc1nc(-c2ccccc2)no1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C#CCSc1nc(-c2ccccc2)no1
Yield: 74 %

Procedure:
A mixture of 5-mercapto-3-phenyl-1,2,4-oxadiazole (100 parts), potassium carbonate (39 parts), propargyl bromide (66 parts) and dry acetone (500 parts) was heated at reflux for one hour. The solution was cooled, poured into water and extracted with chloroform. The extract was washed and dried and the solvent evaporated off to give 3-phenyl-5-propargylthio-1,2,4-oxadiazole (90 parts, 74% yield), melting point 39.40° C.
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8]([Cl:11])[N:9]=[CH:10][C:5]=2[S:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH2:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.CC(C1C=C(C(C)C)C(C2C(P(C(C)(C)C)C(C)(C)C)=CC=CC=2)=C(C(C)C)C=1)C>O1CCOCC1>[Cl:11][C:8]1[N:9]=[CH:10][C:5]2[S:4][CH:3]=[C:2]([C:23]3[CH:24]=[C:19]([NH2:18])[CH:20]=[CH:21][CH:22]=3)[C:6]=2[N:7]=1
Reactant: Clc1ncc2scc(Br)c2n1
Reactant: Nc1cccc(B(O)O)c1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1cccc(-c2csc3cnc(Cl)nc23)c1
Temperature: 90 °C
Reaction time: 6 h
Yield: 73.2 %

Procedure:
7-Bromo-2-chlorothieno[3,2-d]pyrimidine (3.645 g, 14.61 mmol) was dissolved in dioxane (44 mL) and 2.0 N sodium carbonate (22 mL, 43.83 mmol) and 3-aminophenylboronic acid (2 g, 14.61 mmol) were added. After flowing nitrogen to the mixture solution for 10 minutes, Pd2(PPh3)Cl2 (615 mg, 0.88 mmol) and t-ButylXphos (558 mg, mmol) were added. The reaction mixture solution was stirred at 90° C. for 6 hours and filtered with celite. The filtrate was diluted with ethyl acetate and washed with brine. The organic layer was concentrated by drying with magnesium sulfate. Purification by chromatography (20% ethyl acetate/hexane) yielded the target compound (2.8 g, 73% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C@H:10]2[CH:23]=[O:24])[CH:5]=[CH:6][C:7]=1[Cl:8].C[Si](C)(C)[C:27]([F:30])([F:29])[F:28].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:11][C@H:10]2[CH:23]([OH:24])[C:27]([F:30])([F:29])[F:28])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](C=O)C1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](C(O)C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a solution (2.6 mL) of tert-butyl (6R,7R)-7-(3,4-dichlorophenyl)-6-formyl-1,4-oxazepane-4-carboxylate (100 mg) in THF were added a solution (1.0 M, 0.534 mL) of trimethyl(trifluoromethyl)silane (190 mg) and tetrabutylammonium fluoride in THF under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1 M hydrochloric acid (0.5 ml), and the mixture was further stirred for 3 hr. Distilled water was added, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (91.7 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[C:12]([CH3:24])[C:11]([CH2:25][O:26][C:27]([CH3:32])([CH3:31])[C:28](O)=[O:29])=[N:10]1.Cl.CN(C)CCCN=C=NCC.FC1C(O)=C(F)C(F)=C(F)C=1F.[NH2:57][CH2:58][C:59]1[CH:67]=[CH:66][C:62]([C:63]([OH:65])=[O:64])=[CH:61][CH:60]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)=[C:12]([CH3:24])[C:11]([CH2:25][O:26][C:27]([CH3:32])([CH3:31])[C:28]([NH:57][CH2:58][C:59]2[CH:60]=[CH:61][C:62]([C:63]([OH:65])=[O:64])=[CH:66][CH:67]=2)=[O:29])=[N:10]1
Reactant: Cc1c(COC(C)(C)C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(C(F)(F)F)cc1
Reactant: NCc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(COC(C)(C)C(=O)NCc2ccc(C(=O)O)cc2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 600 mg of 2-[1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-2-methyl-propionic acid in 9 ml of DMF, 283 mg of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC), 271 mg of pentafluorophenol and 300 mg of NEM was added and the reaction mixture was stirred for 3 h at room temperature. Then, 278 mg of 4-Aminomethyl-benzoic acid and 424 mg of NEM in 10 ml of DMF were added. After 16 h the reaction mixture was diluted with water and filtered through a chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. Yield: 204 mg.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)O1.Cl[C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:34]=[N:35][NH:36][CH:37]=3)=[CH:29][CH:28]=2)[CH2:24][NH:25][CH3:26])=[CH:19][CH:18]=1>>[CH3:26][NH:25][CH2:24][CH:23]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:34]=[N:35][NH:36][CH:37]=2)=[CH:29][CH:28]=1)[C:20]1[CH:19]=[CH:18][C:17]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:22][CH:21]=1
Reactant: CNCC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Product: CNCC(c1ccc(-c2cccnc2)cc1)c1ccc(-c2cn[nH]c2)cc1

Procedure:
By following the procedure described in Example 1 but substituting 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine and coupling to {2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine*, the title compound was obtained. LC/MS: (PS-B3) Rt 2.42 [M+H]+ 355. 1H NMR (Me-d3-OD) δ 1.94 (AcOH, s), 2.72 (3H, s), 3.73 (2H, d), 4.46 (1H, t), 7.41 (2H, d), 7.51-7.56 (3H, m), 7.63 (2H, d), 7.70 (2H, d), 7.96 (2H, s), 8.10 (1H, dt), 8.53 (1H, dd), 8.80 (1H, d). *This starting material can be made by the method described in Example 21.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:8]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11]>CN(C)C(=O)C>[C:10]([C:9]1[CH:8]=[CH:15][C:14]([F:16])=[CH:13][C:12]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)#[N:11]
Reactant: N#Cc1ccc(F)cc1F
Reactant: C1CNCCN1
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(F)cc1N1CCNCC1
Temperature: 122 °C
Reaction time: 1.5 h

Procedure:
A mixture of piperazine (Aldrich; 3.99 g), 2,4-difluorobenzonitrile, and N,N-dimethylacetamide (20 mL) is stirred for 1.5 h at 122° C. After cooling, the mixture is partitioned between dichloromethane and satd. aq. sodium bicarbonate. The organic layers are dried over magnesium sulfate and concentrated. The residue is chromatographed on silica gel and the appropriate fractions are combined and concentrated to give 1.44 g of 1(2-cyano-5-fluorophenyl)piperazine; 1H NMR (CDCl3) δ 3.01, 3.30, 6.56, 6.63, 7.40.