Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:57])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+:51]=[N-:52])[CH:46]([O:53][CH2:54][CH:55]=[CH2:56])[CH2:45]2)[CH:7]([CH3:58])[CH:6]([O:59][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1=[O:67])[CH3:2]>C(#N)C.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:57])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+:51]=[N-:52])[CH:46]([O:53][CH2:54][CH:55]=[CH2:56])[CH2:45]2)[CH:7]([CH3:58])[CH:6]([OH:59])[CH2:5][C:4]1=[O:67])[CH3:2]
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O[Si](C)(C)C(C)(C)C)C2C)C(OC)CC3C)CCC1N=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.9 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-azido-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (17.5 mg) in acetonitrile (1 ml) was added a solution of 2% HF in aqueous acetonitrile (100 μl), and the mixture stirred at room temperature. After 4 hours, the solution was diluted with ethyl acetate, extracted with saturated sodium bicarbonate solution and the organic phase dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (10 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH:14]3[CH2:17][N:16]([C:18]([CH:20]4[CH2:22][CH2:21]4)=[O:19])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:23])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[CH:34][C:35]3[O:39][CH:38]=[CH:37][C:36]=3[CH:40]=2)O1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O>[O:39]1[C:35]2[CH:34]=[CH:33][C:32]([C:2]3[CH:7]=[CH:6][C:5]([N:8]4[C:12]([CH2:13][CH:14]5[CH2:17][N:16]([C:18]([CH:20]6[CH2:22][CH2:21]6)=[O:19])[CH2:15]5)=[N:11][NH:10][C:9]4=[O:23])=[CH:4][CH:3]=3)=[CH:40][C:36]=2[CH:37]=[CH:38]1
Reactant: CC1(C)OB(c2ccc3occc3c2)OC1(C)C
Reactant: O=C(C1CC1)N1CC(Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(C1CC1)N1CC(Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2)C1
Temperature: 100 °C
Reaction time: 22 h
Yield: 40.6 %

Procedure:
In a microwave vial purged with nitrogen, a mixture of 4-(4-bromophenyl)-5-{[1-(cyclopropylcarbonyl)-3-azetidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (83 mg, 0.220 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (9 mg, 11 μmol), and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran (59 mg, 0.242 mmol) in 1,4-dioxane (2 mL) and 2M aq potassium carbonate (0.5 mL, 1.00 mmol) was stirred at 100° C. in an oil bath for 22 h. Additional 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran (59 mg, 0.242 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (9 mg, 11 μmol) were added and the reaction mixture was heated at 100° C. in an oil bath for 20 h. The reaction was cooled to room temperature, poured into water (50 mL), and adjusted to pH˜4.5 with 1N aq HCl. The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (ethyl acetate, then 0-10% methanol/ethyl acetate) followed by a second purification by reverse phase HPLC (20-70% acetonitrile/water+0.1% NH4OH) provided the title compound as an ivory solid (37 mg, 38%). MS(ES)+ m/e 415.2 [M+H]+.
Reaction SMILES: C(=O)(O)[O-].[Na+].[Cl:6][CH2:7][C:8](Br)=[O:9].[CH:11]1([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][CH2:12]1>O.C(Cl)Cl>[Cl:6][CH2:7][C:8]([N:18]1[CH2:19][CH2:20][N:15]([CH:11]2[CH2:14][CH2:13][CH2:12]2)[CH2:16][CH2:17]1)=[O:9]
Reactant: C1CC(N2CCNCC2)C1
Reactant: O=C(Br)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(CCl)N1CCN(C2CCC2)CC1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of sodium bicarbonate (15 mmol) in water (5 mL) and DCM (30 mL) at 0° C. is added chloroacetyl bromide (12 mmol), followed by immediate addition of 1-cyclobutylpiperazine (10 mmol). The mixture is stirred at 0° C. for an additional 40 min. To the mixture is added aqueous sodium bicarbonate (15 mL) and DCM (30 mL). The layers are separated and the organic layer is dried (MgSO4) and solvent is removed in vacuo to give 2-chloro-1-(4-cyclobutyl-piperazin-1-yl)-ethanone, which is used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 4.07 (2H, s), 3.64 (2H, t), 3.52 (2H, t), 2.74 (1H, m), 2.36 (2H, t), 2.31 (2H, t), 1.72-2.08 (6H, m); MS (+VE) m/z 217.1 (M++1).
Reaction SMILES: [O:1]=[C:2]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=2[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:4][CH:3]1[NH:25]C(=O)OCC1C=CC=CC=1.[Cl:36]C1C=CC(I)=NC=1>>[NH2:25][CH:3]1[C:2](=[O:1])[N:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:36])=[CH:11][N:10]=2)[C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=2[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:4]1
Reactant: Clc1ccc(I)nc1
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2N(c2ccccn2)C1=O)OCc1ccccc1
Product: NC1N=C(c2ccccc2)c2ccccc2N(c2ccc(Cl)cn2)C1=O

Procedure:
Intermediate 2A was prepared as described in Intermediate 1A using 5-chloro-2-iodopyridine. The racemate was purified by preparative SFC chromatography (Berger SFC MGII, CHIRALCEL® OJ-H 250×30 mm ID, 5 μm, 80/20 CO2/MeOH, 85 mL/min) to give Intermediate 3A. RT=3.44 min (H2O/CH3OH with TFA, CHROMOLITH® ODS S5 4.6×50 mm, gradient=3 min, wavelength=220 and 254 nm); MS(ES):m/z=497 [M+H+].
Reaction SMILES: [H-].[Na+].[C:3]([CH2:6][C:7](=[O:9])[CH3:8])(=[O:5])[CH3:4].[CH3:10][N:11]([CH3:49])[C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)(O)[CH:19]=[CH:20][CH:21]=[C:22]([C:31]2[CH:36]=[CH:35][C:34]([N:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=2)[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[CH:14][CH:13]=1.Cl([O-])(=O)(=O)=O>CN(C)C=O>[CH3:39][N:37]([CH3:38])[C:34]1[CH:33]=[CH:32][C:31]([C:22]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[CH:21][CH2:20][CH:19]=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([N:11]([CH3:49])[CH3:10])=[CH:13][CH:14]=2)[C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)=[CH:36][CH:35]=1.[C:3]([CH2:6][C:7](=[O:9])[CH3:8])(=[O:5])[CH3:4]
Reactant: COc1ccc(C(=CC=CC(O)(c2ccc(OC)cc2)c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2)cc1
Agent: [H-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(=O)CC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C(=CCC=C(c2ccc(OC)cc2)c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2)cc1
Reaction time: 1 h

Procedure:
1.2 g of a 60% sodium hydride was dispersed in 200 ml of well-dried N,N-dimethylformamide (DMF) in a 300-ml. Erlenmeyer flask. To this dispersion, 3.00 g of acetylacetone was slowly added at room temperature and the mixture was stirred for 1 hour. To this mixture, 12.3 g of 1,5-bis-(p-dimethylaminophenyl)-1,5-bis-(p-methoxyphenyl)-2,4-pentadiene-1-ol-perchlorate prepared in Synthesis Example 2-2 was slowly added. This reaction mixture was stirred at room temperature for 1 hour.
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])OCC.B(F)(F)F.[O:15]=[C:16]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[O:34][C:18]2([CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:20][CH2:19]2)[CH2:17]1.C(N(C(C)C)C(C)C)C>ClCCl>[CH2:9]([O:8][CH:1]([O:5][CH2:6][CH3:7])[CH:17]1[C:18]2([CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])[CH2:20][CH2:19]2)[O:34][C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:16]1=[O:15])[CH3:10]
Reactant: O=C1CC2(CCN(C(=O)OCc3ccccc3)CC2)Oc2ccccc21
Reactant: CCOC(OCC)OCC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(OCC)C1C(=O)c2ccccc2OC12CCN(C(=O)OCc1ccccc1)CC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.7 %

Procedure:
To a solution of triethyl orthoformate (71 mL, 0.43 mol)] in dichloromethane (250 mL) at −10° C. under nitrogen was added boron trifluoride diethyletherate (54 mL, 0.43 mol) dropwise over 30 minutes. The mixture was allowed to warm to 0° C. and stirring was continued at 0° C. for 15 minutes. The mixture was then cooled to −78° C. and a solution of benzyl 4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (50 g, 0.14 mol) in dichloromethane (250 mL) was added dropwise over 1 hour, followed by N-ethyl-N-isopropylpropan-2-amine (87 mL, 0.50 mol) over 1 hour at −78° C. The mixture was continued to stir at −78° C. for 30 minutes and then at 25° C. for 15 hours. The reaction mixture was diluted with dichloromethane (750 mL) and then partitioned with saturated sodium bicarbonate solution (500 mL). The organic phase was washed with water (500 mL), saturated sodium chloride solution (500 mL), dried over magnesium sulfate and concentrated under reduced pressure. Purification by silica gel flash chromatography (0-50% ethyl acetate in hexane) afforded benzyl 3-(diethoxymethyl)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (50 g, 78%) as a yellow oil. ESI-MS m/z calc. 453.2. found 408.5 (M+1-OEt)+; Retention time: 2.08 minutes (3 min run).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][C:14]1([CH3:18])[CH2:17][O:16][CH2:15]1>ClCCl.N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:12][CH2:13][C:14]2([CH3:18])[CH2:17][O:16][CH2:15]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(CO)COC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2(C)COC2)cc1
Temperature: 20 °C

Procedure:
4-Toluenesulfonyl chloride (20 g, 105 mmol) was dissolved in a mixture of dichloromethane (DCM) (50 ml) and pyridine (50 ml) and cooled in an ice bath. 3-(hydroxymethyl)-3-methyloxetane (100 mmol, 9.9 mL) was added dropwise. The temperature was increased to 20° C. overnight. The solution was diluted with DCM (100 mL) and extracted with water. The organic phase was dried over magnesium sulfate and filtered. The volatile solvents were removed by evaporation. The remaining material was concentrated several times with toluene to remove the residual pyridine and then with chloroform to remove the residual toluene. Yield: 22 g of a white crystalline solid (92%). TLC: Rf(petroleum ether/ethyl acetate, 1:1) 0.56.
Reaction SMILES: [CH:1]1([C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:18])(=O)=O.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(OCC)C>[Cl:18][CH:8]([C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CC(=O)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cl)C(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
To a solution of ethyl 3-cyclohexyl-3-oxopropanoate (1.0 g, 5.0 mmol) in diethyl ether (15 mL) was added sulfuryl chloride (750 mg, 5.5 mmol) at 0° C., and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (150 mL) were added to the reaction solution, and the mixture was stirred for 30 min. The organic layer was washed with saturated brine (10 mL) and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give the title compound (870 mg, 60%) as a colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[N:2]1.C(N(C(C)C)CC)(C)C.[CH2:18]([O:20][C:21](=[O:42])[C@H:22]([CH3:41])[CH2:23][C@H:24]([N:38]=[C:39]=[O:40])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)[CH3:19]>CN(C=O)C>[C:29]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:28]=[CH:27][C:26]([CH2:25][C@@H:24]([NH:38][C:39]([N:1]2[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[N:2]2)=[O:40])[CH2:23][C@H:22]([C:21]([O:20][CH2:18][CH3:19])=[O:42])[CH3:41])=[CH:31][CH:30]=1
Reactant: O=C(O)c1cc[nH]n1
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)N=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)n1ccc(C(=O)O)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a vigorously stirred 1:1 mixture of methylene chloride/8% aqueous NaHCO3 (8 mL) at 0° C. is added triphosgene (28.4 mg, 0.096 mmol). After stirring the mixture at 0° C. for 5 minutes, (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride (100 mg, 0.287 mmol) is added and stirring is continued for 15 minutes. The organic phase is separated and dried over sodium sulfate. The solvent is removed under reduced pressure to furnish (2R,4S)-5-biphenyl-4-yl-4-isocyanate-2-methyl-pentanoic acid ethyl ester. Next, to a solution of 1H-pyrazole-3-carboxylic acid (32.2 mg, 0.287 mmol) in DMF (1 mL) is added diisopropylethylamine (0.05 mL, 0.287 mmol). After 15 min a solution of the above (2R,4S)-5-biphenyl-4-yl-4-isocyanato-2-methyl-pentanoic acid ethyl ester in DMF (1 mL) is added dropwise and the mixture is stirred at room temperature for 18 hours. The mixture is purified by preparative HPLC using a gradient of 10% MeCN to 100% MeCN (0.1% TFA). Lyophilization of the appropriate fractions furnishes the title compound. HPLC Retention time 1.5 minutes (condition A); MS 450.3 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08 (d, J=7.07Hz, 3H), 1.10 (t, 3H), 1.86 (t, 2H), 2.52 (m, 1H), 2.85 (m, 1H), 2.98 (m, 1H), 3.98 (q, 2H), 4.11 (m, 1H), 6.85 (d, J=2.65Hz, 1H), 7.28 (d, J=8.08Hz, 2H), 7.33 (t, 1H), 7.44 (t, 2H), 7.57 (d, J=8.21Hz, 2H), 7.63 (d, J=7.33Hz, 2H), 8.29 (d, J=2.65Hz, 1H), 8.58 (d, J=9.22Hz, 1H), 13.33 (s, broad, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>O1CCOCC1.O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[C:4]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:3]=[C:2]2[NH2:1]
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: C1COCCN1
Solvent: O
Solvent: C1COCCO1
Product: COc1cc2nc(N3CCOCC3)nc(N)c2cc1OC
Temperature: 85 °C
Yield: 94.7 %

Procedure:
To solution of 4-amino-2-chloro-6,7-dimethoxyquinazoline (0.240 g, 1 mmol) in 10 ml dioxane was added morpholine (0.350 ml, 4 mmol). The mixture was heated at 85° C. for 4 h. After cooling to room temperature, the reaction mixture was diluted with water and solid was precipitated. The resulting precipitate was collected by filtration and washed with water and little amount of methanol and to give A 6,7-dimethoxy-2-morpholin-4-yl-quinazolin-4-ylamine (0.275 g) in 94% yield.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=1)=[O:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:8][C@H:9]([C:16]([NH:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([I:26])=[CH:24][CH:25]=1)=[O:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccc(I)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CC[C@H](N)C(=O)NCc1ccc(I)cc1
Yield: 99.3 %

Procedure:
A solution of (S)-methyl 4-(tert-butoxycarbonylamino)-5-(4-iodobenzylamino)-5-oxopentanoate (2.129 g, 4.47 mmol) in DCM (15 mL) and TFA (10 mL) was stirred at room temperature for 4 h. After the solvent was evaporated, the reaction mixture was diluted with DCM, washed with sat. K2CO3 aqueous solution and concentrated in vacuo to afford (S)-methyl 4-amino-5-(4-iodobenzylamino)-5-oxopentanoate (1.67 g). A solution of (S)-methyl 4-amino-5-(4-iodobenzylamino)-5-oxopentanoate (1.67 g), Boc-Glu(OMe)—OH.DCHA (1.97 g, 4.44 mmol), EDCI (1.02 g, 5.33 mmol), HOBt (0.599 g, 4.44 mmol) in DCM (100 mL) containing DIPEA (2.26 mL) was stirred at room temperature under nitrogen for 20 h. The reaction mixture was diluted with DCM, washed with 1N HCl aqueous solution, sat. NaHCO3 aqueous solution and brine. The organic phase was separated and evaporated under reduced pressure to give a crude product, which was purified by flash chromatography with hexane/ethyl acetate as eluent to give (S)-methyl 4-(tert-butoxycarbonylamino)-5-((S)-1-(4-iodobenzylamino)-5-methoxy-1,5-dioxopentan-2-ylamino)-5-oxopentanoate (2.137 g, 77% over 2 steps) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J=8.4 Hz, 2H), 7.20 (s, 1H), 7.00 (d, J=8.4 Hz, 2H), 5.44 (brs, 1H), 4.48-4.30 (m, 3H), 4.06-4.02 (m, 1H), 3.69 (s, 6H), 2.54-2.37 (m, 4H), 2.20-1.93 (m, 3H), 1.37 (s, 9H); MS (ESI), 620 (M+H)+.
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH2:14][CH2:13][C:12]=2[CH:16]=1>C(Cl)(Cl)(Cl)Cl>[Br:2][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH2:14][CH2:13][C:12]=2[CH:16]=1
Reactant: OCCc1ccc2c(c1)CCO2
Reactant: BrP(Br)Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCCc1ccc2c(c1)CCO2
Temperature: 25 °C

Procedure:
Phosphorus tribromide (0.37 g) was added to a solution of 5-(2-hydroxyethyl)-2,3-dihydrobenzofuran (0.612 g--see Preparation 8) in carbon tetrachloride (3 ml) and the mixture was heated under reflux for 3 hours. On cooling to room temperature, the mixture was partitioned between 10% aqueous sodium carbonate (20 ml) and dichloromethane (20 ml). The layers were separated and the aqueous layer Was extracted with dichloromethane (2×10 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give the title compound as an oil which crystallised on standing, yield 0.584 g, m.p. 60°-62° C.
Reaction SMILES: [F:1][CH:2]([F:17])[CH2:3][O:4][C:5]1[N:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:6]=1[C:7](O)=[O:8].S(Cl)([Cl:20])=O>CN(C=O)C.C(Cl)Cl>[F:1][CH:2]([F:17])[CH2:3][O:4][C:5]1[N:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:6]=1[C:7]([Cl:20])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])cnc1OCC(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc([N+](=O)[O-])cnc1OCC(F)F

Procedure:
A mixture of 2-(2,2-difluoroethyl)oxy-5-nitro-nicotinic acid (310 mg, 1.25 mmol), 2.0 mL thionyl chloride, 5.0 mL DCM and one drop of DMF was refluxed for 4 h and concentrated i.vac. The corresponding acid chloride was directly used for the next step without further purification.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[C:11]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[C:18]([Cl:24])[CH:17]=2)[N:13]([CH3:25])[N:12]=1.Cl[C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=1.O>COCCOC>[Cl:24][C:18]1[CH:17]=[C:16]([C:14]2[N:13]([CH3:25])[N:12]=[C:11]([C:5]3[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:4]=3[Cl:3])[N:15]=2)[CH:21]=[CH:20][C:19]=1[CH2:22][O:23][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(CO)c(Cl)c1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(COc2ccc(C(F)(F)F)cn2)c(Cl)c1
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 56.7 %

Procedure:
Sodium hydride (60%, 0.12 g) is added to 1,2-dimethoxyethane (50 ml) and a solution of 3-(2-chloro-6-fluorophenyl)-5-(3-chloro-4-hydroxymethylphenyl)-1-methyl-1H-1,2,4-triazole (1.00 g) in 1,2-dimethoxyethane (20 ml) is added dropwise thereto at -5° C., which is stirred for 15 minutes. To the reaction solution is added dropwise a solution of 2-chloro-5-trifluoromethyl pyridine (0.60 g) in 1,2-dimethoxyethane (20 ml) at -5° C., which is stirred for 15 minutes. The reaction mixture is warmed to room temperature, poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography to give 0.80 g of desired compound (refractive index: 1.5879).
Reaction SMILES: [CH3:1][S:2][CH:3]([S:6][CH3:7])[S:4][CH3:5].[Li]CCCC.Br[CH:14]1[C:24]2=[C:25]3[C:20](=[CH:21][CH:22]=[CH:23]2)[CH:19]=[CH:18][CH:17]=[C:16]3[CH2:15]1>C1COCC1.CCCCCC>[CH3:1][S:2][C:3]([S:6][CH3:7])([S:4][CH3:5])[CH:15]1[C:16]2=[C:25]3[C:20](=[CH:19][CH:18]=[CH:17]2)[CH:21]=[CH:22][CH:23]=[C:24]3[CH2:14]1
Reactant: BrC1Cc2cccc3cccc1c23
Reactant: CSC(SC)SC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSC(SC)(SC)C1Cc2cccc3cccc1c23
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tris(methylthio)methane (22 g) was dissolved in THF (100 ml) under N2 at -78° C. 1.6 M BuLi in hexane solution (95 ml) was added slowly to yield a dense white precipitate. 1-Bromoacenaphthene (31.4 g) was dissolved in 20 ml of dry THF and added slowly to the above suspension to yield, after 10 minutes, a colorless solution. This was allowed to warm to room temperature, with the development of a brown color, and stirred overnight.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([C:8]2[C:9]3[CH:16]=[CH:15][N:14]([S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:19])=[O:18])[C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[I:36]I>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15]([I:36])[N:14]([S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:19])=[O:18])[C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ncnc2c1ccn2S(=O)(=O)c1ccccc1
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)cc1-c1ncnc2c1cc(I)n2S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of Example 3B (2.5 g, 6.52 mmol) in 50 mL tetrahydrofuran at −78° C. was added 2M lithium diisopropylamide (4.89 mL, 9.78 mmol) over 5 minutes. The solution was stirred at −78° C. for 30 minutes and a solution of iodine (3.31 g, 13.04 mmol) in tetrahydrofuran (50 mL) was added over 5 minutes. The mixture was stirred at −78° C. for 2 hours and quenched with 50 mL 1M sodium thiosulfate. The aqueous layer was extracted with ethyl acetate (3×50 mL) and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound, which was used without further purification. MS (ESI+) m/z 509.51 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.[K].[S:15]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:21][CH:20]=1)(=[O:18])(=[O:17])[NH2:16]>CN1CCCC1=O>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=[C:2]([NH:16][S:15]([C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:23][CH:24]=2)(=[O:17])=[O:18])[CH:7]=1
Reactant: Clc1cc(Cl)nc(N2CCCC2)n1
Reactant: CC(=O)Nc1ccc(S(N)(=O)=O)cc1
Agent: [K]
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(N3CCCC3)n2)cc1
Yield: 58.9 %

Procedure:
0.58 g (0.00266 mol) of 4,6-dichloro-2-pyrrolidin-1-yl-pyrimidine and 1.36 g (0.00539 mol) of N-(4-sulfamoyl-phenyl) -acetamide potassium salt were stirred in 10 ml of 1-methyl-2-pyrrolidone at 140° C. for 8 hours. Then, the solvent was distilled off in a high vacuum, the residue was partitioned in ethyl acetate/water and extracted. The aqueous phase was made acid with 4N HCl and extracted with ethyl acetate. Both organic phases were combined and concentrated. The residue was recrystallized from a small amount of ethanol and the mother liquor was chromatographed over silica gel with cyclohexane/ethyl acetate 2:1 as the eluent. There was obtained a total of 0.62 g (66%) of N-[4-(6-chloro-2-pyrrolidin-1-yl-pyrimidin-4-ylsulfamoyl)-phenyl]-acetamide as whitish crystals; m.p. 229-233° C.