Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[NH:9][N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:12]=2)[CH:3]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[C:27]1[C:28]([C:37]2[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=2)=[N:29][C:30]2[N:31]([N:33]=[C:34]([CH3:36])[N:35]=2)[CH:32]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.C(O)(=O)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[NH:9][N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:41][C:40]4[CH:39]=[CH:38][C:37]([C:28]5[C:27]([C:21]6[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=6[F:19])=[CH:32][N:31]6[N:33]=[C:34]([CH3:36])[N:35]=[C:30]6[N:29]=5)=[CH:44][CH:43]=4)[CH2:15][CH2:14]3)[N:12]=2)[CH:3]=1
Reactant: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccc(F)cc3F)cn2n1
Reactant: Clc1ccnc(-c2nc(C3CCNCC3)n[nH]2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: Cc1nc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6cc(Cl)ccn6)n5)CC4)cc3)c(-c3ccc(F)cc3F)cn2n1
Reaction time: 1 h

Procedure:
192 mg (0.57 mmol) 4-Chloro-2-(5-piperidine-4-yl-2H-[1,2,4]triazole-3-yl)-pyridine×2HCl are dissolved in 4.8 mL NMP. After addition of 0.19 mL triethylamine the reaction mixture is stirred for one hour. 200 mg (0.57 mmol) 4-[6-(2,4-Difluorophenyl)-2-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-benzaldehyde and 0.06 mL acetic acid are added. The reaction mixture is stirred over night at room temperature. 133 mg (0.63 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature for 5 hours. The reaction mixture is treated with saturated NaHCO3. The precipitate is filtered off, washed with water and dried. After chromatography of the precipitate on silica gel (dichloromethane/methanol) 99.1 mg (27.6%) of the desired product are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[CH:6]=O.FC1C=C2C(=CC=1)C=[N:18][CH:17]=[CH:16]2>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8]([CH:16]=[CH:17][N:18]=[CH:6]2)=[CH:9][C:10]=1[F:11]
Reactant: COc1cc(C=O)ccc1F
Reactant: Fc1ccc2cnccc2c1
Product: COc1cc2cnccc2cc1F

Procedure:
Starting from 3-methoxy-4-fluoro-benzaldehyde, the title compound was prepared by the same reaction sequence as 6-fluoro-isoquinoline (5). Rt=0.70 min (Method #4). Detected mass: 178.1 (M+H+).
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[C:13]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)#[N:14]>ClCCl>[Br:2][CH2:3][CH2:4][NH:5][S:21]([C:18]1[CH:17]=[CH:16][C:15]([C:13]#[N:14])=[CH:20][CH:19]=1)(=[O:23])=[O:22]
Reactant: NCCBr
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(S(=O)(=O)NCCBr)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
To an ice cooled solution of 2-bromoethylamine hydrogenbromide (12.2 g, 0.0595 mol) in dry dichloromethane (100 mL) was added triethylamine and the mixture stirred for 15 min. 4-Cyanobenzenesulfonyl chloride (10 g, 0.0486 mol) in dichloromethane was added, dropwise. Stirring was continued at RT for 1 h. The reaction mixture was diluted with dichloromethane, washed with water, followed by brine, then dried over sodium sulfate. Solvents were evaporated and the residue crystallized from petroleum ether to give 12.5 g of the sub-title compound as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:12]=[C:11]([CH2:21][CH2:22][C:23]2[S:24][C:25]([CH2:29][CH3:30])=[C:26]([CH3:28])[N:27]=2)[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:33][C:34]1[CH:35]=[C:36]([CH:41]=[C:42]([CH2:44]Cl)[CH:43]=1)[C:37]([O:39][CH3:40])=[O:38]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([C:9]1[CH:14]=[C:13]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[CH:12]=[C:11]([CH2:21][CH2:22][C:23]2[S:24][C:25]([CH2:29][CH3:30])=[C:26]([CH3:28])[N:27]=2)[N:10]=1)[CH2:44][C:42]1[CH:41]=[C:36]([C:37]([O:39][CH3:40])=[O:38])[CH:35]=[C:34]([Cl:33])[CH:43]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(Cl)cc(CCl)c1
Reactant: CCc1sc(CCc2cc(N3CCOCC3)cc(NC(=O)OC(C)(C)C)n2)nc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1sc(CCc2cc(N3CCOCC3)cc(N(Cc3cc(Cl)cc(C(=O)OC)c3)C(=O)OC(C)(C)C)n2)nc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-tert-butoxycarbonylamino-6-[2-(5-ethyl-4-methyl-1,3-thiazol-2-yl)ethyl]-4-morpholinopyridine (500 mg) obtained in Example 109-(1) was dissolved in dimethylformamide (12 ml), and 60% sodium hydride (58 mg) was added under cooling with ice, followed by stirring at room temperature for one hour. The reaction solution was cooled with ice, and a solution of methyl 3-chloro-5-chloromethylbenzoate (438 mg) in dimethylformamide (5 ml), was added thereto, followed by stirring at room temperature for 13 hours. The reaction solution was diluted with ethyl acetate, washed with water and a saturated sodium chloride aqueous solution and then, dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to obtain the above identified compound (628 mg).
Reaction SMILES: C([Li])CCC.O1CCCCC1OC1CCCCO1.[CH3:19][CH:20]([OH:23])[C:21]#[CH:22].C[Si](C)(C)[O:26][C:27]1([CH3:35])[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[C:28]1=[O:34].[Cl-].[NH4+]>C1COCC1.CCCCCC>[OH:34][C:28]1([C:22]#[C:21][CH:20]([OH:23])[CH3:19])[C:29]([CH3:33])([CH3:32])[CH2:30][CH2:31][C:27]1([OH:26])[CH3:35]
Reactant: CC1(C)CCC(C)(O[Si](C)(C)C)C1=O
Reactant: C#CC(C)O
Agent: C1CCC(OC2CCCCO2)OC1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(O)C#CC1(O)C(C)(C)CCC1(C)O
Reaction time: 0.17 h
Yield: 75 %

Procedure:
To 7.3 ml of a 1.6M n-hexane solution of n-butyl lithium was added 20 ml of anhydrous THF at -78° C. (bath temperature) in a nitrogen atmosphere, and 1.8 g of a tetrahydropyranyl ether of 3-butyn-2-ol was added dropwise thereto under the same conditions over 10 minutes. After the addition, the mixture was stirred for 30 minutes. Then, 30 ml of an anhydrous THF solution containing 2.1 g of 2-trimethylsiloxy-2,5,5-trimethylcyclopentanone was added dropwise to the mixture under the same conditions over 30 minutes. After the dropwise addition, the mixture was stirred for 5 hours. A saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. After the diethyl ether was removed from the extract by distillation, a 1N hydrochloric acid aqueous solution and methanol were added to the residue, followed by stirring at room temperature for 5 hours. The methanol was removed by distillation under reduced pressure, and the residue was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, and the solvent, etc. were removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2.1 g (yield: 75%) of 4-(1,2-dihydroxy-2,5,5-trimethylcyclopentyl)but-3-yn-2-ol.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH:13]=[O:14])([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CC(=CC)C.Cl([O-])=[O:26].[Na+].P([O-])(O)(O)=O.[Na+].[OH-].[Na+]>O.C(O)(C)(C)C>[CH3:9][C:2]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:13]([OH:26])=[O:14])([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: [O-][Cl+][O-]
Reactant: CCCCCCC(C)(C)c1cc(C=O)ccc1OC
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCCCCCC(C)(C)c1cc(C(=O)O)ccc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.6 %

Procedure:
3-(1,1-Dimethylheptyl)-4-methoxybenzaldehyde (13 g, 49.5 mmol), t-butanol (65 ml) and 2-methyl-2-butene (35.2 ml, 332 mmol) were mixed, and to this solution was added dropwise a solution prepared by mixing sodium chlorite (7.37 g, 64.4 mmol), sodium dihydrogenphosphate (7.73 g, 64.4 mmol) and water (50 ml). The mixture was stirred at room temperature for 12 hours. A 1N sodium hydroxide solution (100 ml) was added, and t-butanol was evaporated under reduced pressure. Conc. hydrochloric acid was added to make the mixture acidic. The aqueous layer was extracted 3 times with ethyl acetate (150 ml). The organic layers were combined, washed with saturated brine (100 ml), and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (n-hexane/ethyl acetate=5/1-2/1) to give 3-(1,1-dimethylheptyl)-4-methoxybenzoic acid (10.7 g, 77%) as colorless crystals.
Reaction SMILES: [CH2-:1][C:2]([CH3:4])=[O:3].[CH2-:5][C:6]([CH3:8])=[O:7].[C:9]([C:12]([C@H:14]([C@@H:16]([C@@H:18]([CH2:20][OH:21])[OH:19])[OH:17])[OH:15])=O)([OH:11])=[O:10].[Si](C=[N+]=[N-])(C)(C)C.C[CH2:30][O:31]CC>CO>[CH2-:1][C:2]([CH3:4])=[O:3].[CH2-:5][C:6]([CH3:8])=[O:7].[C:9]([CH2:12][C:14]([C@H:16]([C@@H:18]([C@@H:20]([CH2:30][OH:31])[OH:21])[OH:19])[OH:17])=[O:15])([OH:11])=[O:10]
Reactant: CCOCC
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [CH2-]C(C)=O
Solvent: CO
Product: O=C(O)CC(=O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The acid (Compound 29) (100 mg, 0.365 mmol) was dissolved in MeOH (3.65 mL, 0.1 M) and cooled to 0° C. After 15 min, 1 M TMSCHN2 in ether (1.82 mL, 5 eq.) was added dropwise via syringe over 15 min. No starting material was detected after 30 min. The reaction was quenched with 5% HOAc/MeOH and the contents evaporated to dryness. Yield: Quant. LRMS (ESI+) m/z 289.1 (M+H)+. 1H-NMR (CDCl3) δ: 1.34 (s, 6H), 1.46 (s, 3H), 1.53 (s, 3H), 3.83 (s, 3H), 4.39 (dd, J=2.4 Hz, 5.2 Hz, 1H), 4.59 (dd, J=2.4 Hz, 7.6 Hz, 1H), 4.67 (dd, J=2.4 Hz, 7.6 Hz, 1H), 5.67 (d, J=5.2 Hz).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=O)[C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[O:14].Cl.[C:32]([O:36][C:37](=[O:44])[C@H:38]([CH2:40][CH:41]([CH3:43])[CH3:42])[NH2:39])([CH3:35])([CH3:34])[CH3:33].C([BH3-])#N.[Na+]>CO.O1CCCC1>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH:12]([C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:19])[CH3:21])=[O:14])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][NH:39][CH:38]([CH2:40][CH:41]([CH3:42])[CH3:43])[C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:44]
Reactant: C[Si](C)(C)CCOC(=O)C(Cc1ccccc1C=O)N1C(=O)c2ccccc2C1=O
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CC(NCc1ccccc1CC(C(=O)OCC[Si](C)(C)C)N1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
Dissolve 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(2-formyl-phenyl)-propionic acid, 2-trimethylsilanyl-ethyl ester (250 mg, 0.590 mmol) in methanol (15 mL) and treat with L-leucine tert-butyl ester hydrochloride (0.66 g, 3.0 mmol). Stir at room temperature for 2 hours with 3A molecular sieves, add sodium cyanoborohydride (0.6 mL of a 1.0M solution in tetrahydrofuran, 0.6 mmol), stir for 0.5 hours, add additional sodium cyanoborohydride (0.3 mL) and stir for 5 hours. Filter through filter aid, evaporate the solvent in vacuo and partition the residue between methylene chloride (100 mL) and saturated sodium hydrogen carbonate (40 mL). Dry (Na2SO4), evaporate the solvent in vacuo and purify by silica gel chromatography (5:1 hexane/ethyl acetate followed by 3:1 hexane/ethyl acetate) to give the title compound (221 mg, 63%).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12](I)[CH:11]=1>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]2[O:16][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:12]=2[CH:11]=1
Reactant: Oc1ccc(Cl)cc1I
Reactant: C#Cc1ccccc1
Product: Clc1ccc2oc(-c3ccccc3)cc2c1

Procedure:
The general procedure was used to convert phenylacetylene and 4-chloro-2-iodophenol to the title product. Purification by flash chromatography (10% CH2Cl2 in hexanes as the eluent) gave the analytically pure product as a white solid (411 mg, 90% yield). 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=6.97, 2H), 7.52 (d, J=2.26, 1H), 7.46-7.35 (m, 4H), 7.21 (dd, J=6.59, 1H), 6.93 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 157.36, 153.22, 130.56, 129.93, 128.98, 128.84, 128.46, 125.03, 124.37, 120.40, 112.10, 100.78. Anal. Calcd. for C14H9ClO: C, 73.53; H, 3.97; Cl, 15.50. Found C, 73.31; H, 3.99; Cl, 15.68. m.p.: 155.5-157° C. (lit., 10156° C.).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.Cl[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[O:20][N:19]=1>>[F:15][C:2]([F:14])([F:1])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=2)[O:20][N:19]=1
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cccc(C(F)(F)F)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 23 using 4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole: MS (ES) m/z 437 (M+1).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([Cl:10])[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:12][C:13]([F:17])([F:16])[CH2:14][OH:15].[H-].[Na+].O>CN(C)C=O>[Cl:10][C:8]1[C:7]([F:11])=[CH:6][C:3]([C:4]#[N:5])=[C:2]([O:15][CH2:14][C:13]([F:17])([F:16])[F:12])[N:9]=1
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(F)c(Cl)nc1OCC(F)(F)F
Temperature: 120 °C
Yield: 75.8 %

Procedure:
A mixture of 2,6-dichloro-5-fluoro-nicotinonitrile (900 mg, 5.7 mmol), 2,2,2-trifluoro-ethanol (570 mg, 5.7 mmol), and NaH (60%) (273 mg, 6.8 mmol) in N,N-dimethylformamide (15 mL) was heated at 120° C. overnight. The reaction mixture was poured into water, and extracted with ethyl acetate (2×). The solvent was removed to give the title compound (1100 mg, 76%). MS (DCI/NH3) m/z 255 (M)+, 257 (M+2)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([O:12][CH3:13])[CH:7]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:6]2.[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH:30]=O.C(OC)(OC)OC.[BH4-].[Na+]>CO.O>[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH2:30][NH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([O:12][CH3:13])[CH:7]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:6]2
Reactant: CCCN(CCC)CCCCC1Cc2cc(CN)ccc2C1OC
Reactant: O=Cc1ncc[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Solvent: O
Product: CCCN(CCC)CCCCC1Cc2cc(CNCc3ncc[nH]3)ccc2C1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
The compound (45.0 mg) obtained in Example 127-13 was dissolved in methanol (2.25 ml) and added with 2-imidazole carboxaldehyde (19.5 mg) and trimethyl orthoformate (43.1 mg), followed by stirring at room temperature for 1 hour. Under ice-cooling, sodium borohydride (15.4 mg) was added to the solution, and the whole was stirred at room temperature for 30 minutes. The reaction solution was added with water and then subjected to separation/extraction with chloroform. The extract was washed with saturated saline solution, dried with anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (54.8 mg) as a yellow oily substance.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[I:11])=O.[C:12]([NH:19][C:20]([NH2:22])=[NH:21])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[I-].[Na+]>CN(C=O)C>[C:15]([O:14][C:12]([N:19]1[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[I:11])=[CH:2][N:21]=[C:20]1[NH2:22])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: O=C(CBr)c1ccccc1I
Reactant: CC(C)(C)OC(=O)NC(=N)N
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1c(-c2ccccc2I)cnc1N
Temperature: 25 °C
Reaction time: 72 h
Yield: 57.5 %

Procedure:
To a solution of 2-bromo-1-(2-iodophenyl)ethanone (2.70 g, 8.31 mmol) in anhydrous DMF (27 mL) was added Boc-guanidine (4.00 g, 24.9 mmol) and sodium iodide (2.47 g, 16.6 mmol). The reaction was stirred at ambient temperature for 72 hours upon which the mixture was partitioned between EtOAc (150 mL) and water (75 mL). The organic layer was successively washed with water (3×50 mL) and brine (2×50 mL) before being dried (Na2SO4) and evaporated to dryness. The resulting crude oil was purified via flash column chromatography (10-30% EtOAc/CH2Cl2) to obtain the target 2-amino-5-(2-iodophenyl)imidazole-1-carboxylic acid tert-butyl ester (1.84 g, 58%) as a tan foam: mp=121° C. (dec.); 1H NMR (400 MHz, DMSO-d6) δ 7.92 (m, 1H), 7.27 (dd, 1H, J=1.6, 8.0 Hz), 7.49 (s, 1H), 7.41 (m, 1H), 7.00 (m, 1H), 6.59 (br s, 2H), 1.57 (s, 9H); 13C NMR (100 MHz, DMSO-d6) δ 149.6, 148.8, 140.3, 137.4, 130.1, 128.8, 128.1, 108.6, 95.7, 85.0, 27.5; HRMS (ESI) calcd for C14H17IN3O2 (MH+) 386.0360. found 386.0359.
Reaction SMILES: [CH3:1][CH:2]1[O:6][CH2:5][C:4]2[S:7][C:8]([NH:13][C:14]([C:16]34[CH2:25][CH:20]5[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]5)[O:17]3)[CH2:23]4)=[O:15])=[C:9]([C:10](O)=[O:11])[C:3]1=2.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.[F:60][C:61]1([F:65])[CH2:64][NH:63][CH2:62]1>CN(C)C=O.C(OCC)(=O)C>[F:60][C:61]1([F:65])[CH2:64][N:63]([C:10]([C:9]2[C:3]3[CH:2]([CH3:1])[O:6][CH2:5][C:4]=3[S:7][C:8]=2[NH:13][C:14]([C:16]23[CH2:25][CH:20]4[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]4)[O:17]2)[CH2:23]3)=[O:15])=[O:11])[CH2:62]1
Reactant: FC1(F)CNC1
Reactant: CC1OCc2sc(NC(=O)C34CC5CC(CC(C5)O3)C4)c(C(=O)O)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1OCc2sc(NC(=O)C34CC5CC(CC(C5)O3)C4)c(C(=O)N3CC(F)(F)C3)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the product from example 43A (90 mg, 0.25 mmol) in N,N-dimethylformamide (0.5 mL) was added O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (380 mg, 1 mmol), N,N diisopropylethylamine (0.3 mL, 1.7 mmol), and 3,3-difluoroazetidine hydrochloride (130 mg, 1 mmol). The mixture was stirred at room temperature for 18 hours, diluted with ethyl acetate (10 mL) and washed with water and brine. The organic extract was dried over MgSO4 and concentrated. Purification by chromatography (0 to 75% ethyl acetate in hexane gradient) afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.28 (d, J=6.4 Hz, 3H) 1.63-2.06 (m, 11H) 2.18 (s, 2H) 4.35-4.71 (m, 4H) 4.81-5.00 (m, 2H) 5.29-5.42 (m, 1H) 11.12 (s, 1H). MS (DCI/NH3) m/z 439.1 (M+H)+.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[C:14]1[C:15](OC(=O)C)=[C:16]([I:20])[CH:17]=[CH:18][CH:19]=1)(=O)C.[F:25][B-:26]([F:29])([F:28])[F:27].[Na+]>C(Cl)Cl>[F:25][B-:26]([F:29])([F:28])[F:27].[C:1]1([I+:20][C:16]2[CH:17]=[CH:18][CH:19]=[CH:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(=O)Oc1cccc(I)c1OC(C)=O
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc([I+]c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 93.4 %

Procedure:
Phenylboronic acid (0.79 g, 6.5 mmol), methylene chloride (62 ml), and boron trifluoride ethyl ether complex (0.97 g, 6.8 mmol) were charged and cooled to 0° C. A solution of diacetoxy iodobenzene (2.0 g, 6.2 mmol) in methylene chloride (62 ml) was added dropwise. The reaction was carried out at 0° C. for 1.5 hours. A saturated aqueous solution of sodium fluoroborate (13.6 g, 124.2 mmol) was added dropwise, and the mixture was extracted with addition of water and methylene chloride. The organic layer was dried with anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by recrystallization to give the title compound (2.13 g, 93.5%).
Reaction SMILES: CS(C)=O.[OH-].[Na+].[Br-].[C:8]([CH2:11][CH2:12][CH2:13][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:10])=[O:9].[CH3:33][C:34]1[CH2:35][C:36]([CH:46]([CH3:50])[CH2:47][CH:48]=O)([O:44][CH3:45])[C:37]([CH3:43])=[C:38]([CH3:42])[C:39]=1[O:40][CH3:41]>O.C1COCC1>[CH3:45][O:44][C:36]1([CH:46]([CH3:50])[CH2:47][CH:48]=[CH:13][CH2:12][CH2:11][C:8]([OH:10])=[O:9])[C:37]([CH3:43])=[C:38]([CH3:42])[C:39]([O:40][CH3:41])=[C:34]([CH3:33])[CH2:35]1
Reactant: COC1=C(C)CC(OC)(C(C)CC=O)C(C)=C1C
Reactant: O=C(O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: O
Product: COC1=C(C)CC(OC)(C(C)CC=CCCC(=O)O)C(C)=C1C
Temperature: 80 °C
Yield: 62 %

Procedure:
DMSO (30 ml) was added to sodium hydroxide (1 g, 24 mmole, 60% oil suspension was washed with hexane and dried under reduced pressure) under an atmosphere of argon, followed heating at 80° C. for 1 hour with stirring. After cooling, 3-carboxypropyltriphenyl phosphonium bromide (4.6 g, 11 mmole) was added to the solution, followed by stirring at room temperature. After stirring for 10 minutes, a THF solution (5 ml) of 3-(3,5,6-trimethyl-1,4-dimethoxyphenyl)butanal (2.7 g, 11 mmole) was added dropwise to the mixed solution. The reaction solution was stirred at room temperature for 2 hours, and water (50 ml) was added to it. The organic layer was washed with toluene (100 ml), and the water layer was adjusted to pH 4 with 2N hydrochloric acid, followed by extraction with IPE. The organic layer was washed with water, dried and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluting solution: IPE) to give 7-(1,4-dimethoxy-3,5,6-trimethylphenyl)-4-octenoic acid (2.2 g, 68%). δ8.80 (1H,COOH), 5.38(2h,m), 3.63(3H,s), 3.60(3H,s), 3.25 (1H,s), 2.40(6H,m), 2.25(3H,s), 2.15(6H,s), 1.30(3H,d,7Hz)
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>N1C=CC=CC=1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][N:8]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: CC(C)c1ccc(N)nc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Product: CC(C)c1ccc(NS(=O)(=O)c2ccc(F)cc2)nc1
Reaction time: 8 h
Yield: 66.4 %

Procedure:
5-isopropylpyridin-2-amine (300 mg, 2.20 mmol) and 4-fluorobenzene-1-sulfonyl chloride (557 mg, 2.86 mmol) were dissolved in pyridine (3 mL) and left to stand overnight. The reaction mixture was concentrated in vacuo and the crude product extracted to the organic phase of an acidic workup between ethyl acetate and 5% citric acid. The organic phase was passed through a hydrophobic frit and concentrated in vacuo to give the title compound (430 mg). LCMS (2 min, formic) Rt 0.90 min, m/z (ES+) 295 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:17])[CH:14]=3)[CH2:9][NH:8]2)=[CH:4][CH:3]=1.C([CH:27]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][NH:28]1)C1C=CC=CC=1>>[C:5]([C:33]1[CH:32]=[CH:31][C:30]([CH2:29][NH:28][CH2:27][CH2:36][N:8]2[CH:7]([CH2:6][C:5]3[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:17])[CH:14]=3)[CH2:9]2)=[CH:35][CH:34]=1)([CH3:18])([CH3:6])[CH3:4]
Reactant: Fc1ccc2c(c1)CC(Cc1ccc(Cl)cc1)NC2
Reactant: c1ccc(CC2Cc3ccccc3CN2)cc1
Product: CC(C)(C)c1ccc(CNCCN2Cc3ccc(F)cc3CC2Cc2ccc(Cl)cc2)cc1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 78 using 3-(4-chlorobenzyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline obtained in Example 55-a) instead of 3-benzyl-1,2,3,4-tetrahydroisoquinoline to obtain a title compound as a light yellow oily substance.