Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH:5]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:31])[F:30])=[C:24]([O:32][CH:33]([F:35])[F:34])[CH:23]=1)[N:6]1[CH2:14][C:13]2[C:8](=[C:9]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:21].[OH-].[Na+].Cl>O1CCCC1.O>[F:35][CH:33]([F:34])[O:32][C:24]1[CH:23]=[C:22]([CH:5]([N:6]2[CH2:14][C:13]3[C:8](=[C:9]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:21])[CH2:4][C:3]([OH:36])=[O:2])[CH:27]=[CH:26][C:25]=1[O:28][CH:29]([F:31])[F:30]
Reactant: COC(=O)CC(c1ccc(OC(F)F)c(OC(F)F)c1)N1Cc2cccc(NC(=O)C3CC3)c2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC(c1ccc(OC(F)F)c(OC(F)F)c1)N1Cc2cccc(NC(=O)C3CC3)c2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a solution of 3-(3,4-bis-difluoromethoxy-phenyl)-3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionic acid methyl ester (2.0 g, 4 mmol) in tetrahydrofurane (20 ml) was added NaOH (0.8 ml of 10 N) at room temperature. The solution was stirred overnight at room temperature. The resulted suspension was filtered to get a white solid. The solid was dissolved in water (30 ml) and added conc. HCl dropwise until the pH is about 4. The resulted mixture was extracted with CH2Cl2 (3×40 ml). The organic layer was dried over Na2SO4, filtered and concentrated to give 3-(3,4-bis-difluoromethoxy-phenyl)-3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionic acid as a white solid (1.4 g, 70%): mp, 94–96° C.; 1H NMR (CDCl3) δ 0.86–0.93 (m, 2H, cyclopropyl ring CH2), 1.06–1.12 (m, 2H, cyclopropyl ring CH2), 1.65–1.71(m, 1H, cyclopropyl ring CH), 3.13 (dd, J=6, 16 Hz, 1H, CHHCO), 3.32 (dd, J=9, 16 Hz, 1H, CHHCO), 4.15 (d, J=15 Hz, 1H, CHHN), 4.36 (d, J=15 Hz, 1H, CHHN), 5.78–5.84 (m, 1H, CHN), 6.21 (t, JH-F=75 Hz, 1H, OCF2H), 6.24 (t, JH-F=75 Hz, 1H, OCF2H), 7.01 (d, J=7.5 Hz, 1H, Ar), 7.26–7.28 (m, 3H, Ar), 7.44 (t, J=7.5 Hz, 1H, Ar), 8.43 (d, J=7.5 Hz, 1H, Ar), 10.42 (s, 1H, NHCO); 13C NMR (CDCl3):8.35, 8.38, 16.14,36.55,47.00, 51.29,99.24, 111.36, 111.42, 115.60, 116.84, 117.02, 118.03, 119.74, 119.79, 121.59, 122.76, 125.46, 133.61, 137.09, 138.03, 141.12, 142.21, 142.38, 142.43, 169.63, 173.03, 173.82. Anal. Calcd. for C23H20F4N2O6: C, 55.65; H, 4.06; N, 5.64. Found: C, 55.33; H, 3.96; N, 5.38.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[Cl:9].[CH2:10]([OH:13])[CH:11]=[CH2:12].C(=O)(O)[O-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:9][C:3]1[CH:4]=[C:5]([CH2:12][CH2:11][CH:10]=[O:13])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Clc1ccc(I)cc1Cl
Reactant: C=CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Solvent: CN(C)C=O
Product: O=CCCc1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Yield: 66.8 %

Procedure:
Palladium(II) acetate (0.17 g, 0.73 mmol) was added to a mixture of 1,2-dichloro-4-iodobenzene (2.00 g, 7.33 mmol), prop-2-en-1-ol (0.75 mL, 11 mmol), benzyltriethylammonium chloride (1.67 g, 7.33 mmol) and sodium bicarbonate (1.54 g, 18.3 mmol) in DMF (5 mL) and the mixture was degassed and back filled with Ar three times. The reaction mixture was heated at 60° C. for 2 h. The mixture was diluted with Et2O (15 mL) and H2O (15 mL) and the mixture was filtered through a celite pad. The organic layer was separated and the aqueous layer was extracted with E2O twice. The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by ISCO chromatography (EtOAc/Hexanes 0-10% over 20 min, column 80 g, flow rate 40 mL/min) to give Intermediate 16A (1.0 g, 4.9 mmol, 67% yield) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.78 (2H, t, J=7.3 Hz), 2.91 (2H, t, J=7.3 Hz), 7.03 (1H, dd, J=8.2, 2.1 Hz), 7.29 (1H, d, J=2.3 Hz), 7.35 (1H, d, J=8.0 Hz), 9.81 (1H, s).
Reaction SMILES: NC1SC2C=CC=CC=2C=1C(OCC)=O.BrC1C=CC(Br)=CC=1[N+]([O-])=O.[Br:27][C:28]1[CH:48]=[CH:47][C:31]([NH:32][C:33]2[S:37][C:36]3[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=3[C:34]=2[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:30]([N+:49]([O-])=O)[CH:29]=1.Cl.[Sn](Cl)Cl>C(O)C.CS(C)=O>[NH2:49][C:30]1[CH:29]=[C:28]([Br:27])[CH:48]=[CH:47][C:31]=1[NH:32][C:33]1[S:37][C:36]2[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=2[C:34]=1[C:42]([O:44][CH2:45][CH3:46])=[O:43]
Reactant: CCOC(=O)c1c(Nc2ccc(Br)cc2[N+](=O)[O-])sc2ccccc12
Agent: CCOC(=O)c1c(N)sc2ccccc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CS(C)=O
Solvent: CCO
Product: CCOC(=O)c1c(Nc2ccc(Br)cc2N)sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-aminobenzo[b]thiophene-3-carboxylate (6.0 g), 2,5-dibromonitrobenzene (8.5 g) and dimethyl sulfoxide (70 ml), crude crystals (7.3 g) of ethyl 2-(4-bromo-2-nitroanilino)benzo[b]thiophene-3-carboxylate were obtained. Without purification, in the same manner as in Starting Material Synthesis Example 21 and using ethanol (70 ml), 18% hydrochloric acid (70 ml) and tin(II) chloride.dihydrate (15.7 g), ethyl 2-(2-amino-4-bromoanilino)benzo[b]thiophene-3-carboxylate (3.3 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C@H:5]2[O:7][C@H:8]([CH:10]([OH:13])[CH2:11][CH3:12])[CH2:9][C@H:4]2[O:3]1.N1C=CN=C1.[C:20]([Si:24](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:23])([CH3:22])[CH3:21].CCOC(C)=O>CN(C=O)C>[CH3:14][C:2]1([CH3:1])[O:6][C@H:5]2[O:7][C@H:8]([CH:10]([O:13][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:11][CH3:12])[CH2:9][C@H:4]2[O:3]1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCC(O)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Yield: 81.7 %

Procedure:
To a solution of 1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propan-1-ol (compound 1e, 2.02 g, 10 mmol) in DMF (30 mL) was added imidazole (6.5 g, 100 mmol) and tert-butylchlorodiphenylsilane (8.22 g, 30 mmol) with stirring. After being stirred at room temperature for 2 hours, the resulting solution was diluted by EtOAc (200 mL), washed with water, brine and dried over Na2SO4. The organic layer was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:10 EtOAc in petroleum ether) to afford 3.6 g of 1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propoxy-tert-butyl-diphenyl-silane (compound 3a).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=O)[CH2:3][CH2:2]1.[CH:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([OH:15])[CH:9]=1>CN(C)C=O.O>[OH:15][C:10]1[CH:11]=[CH:12][C:13]([N:14]2[C:1](=[O:7])[CH2:2][CH2:3][C:4]2=[O:6])=[CH:8][CH:9]=1
Reactant: O=C1CCC(=O)O1
Reactant: Nc1ccc(O)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCC(=O)N1c1ccc(O)cc1
Temperature: 170 °C
Yield: 94 %

Procedure:
A solution of succinic anhydride (100 g, 1 mol) in dimethylformamide (50 g) was added slowly to a stirred solution of p-aminophenol (109 g, 1 mol) in dimethylformamide (150 g) at a temperature between 25° and 30° C. After 1.5 h the reaction mixture was transferred to a film evaporator in which dimethylformamide (160 g) was separated off at a pressure of 0.05 bar and a temperature of 130° C. A solution of p-toluenesulphonic acid (2 g) in methanol (18 g) was added to the residue obtained, the temperature was increased to 170° C. and dimethylformamide and water were evaporated at a pressure of 13 mbar. The brown solid material thus obtained was dissolved in dimethylformamide having a temperature of 90° C., water was added to the solution until it became turbid, the turbid solution was allowed to adopt ambient temperature and the crystals obtained were filtered off. The N-(4-hydroxyphenyl)succinimide was obtained in a yield of 94 % and with a purity of more than 99%.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48]([OH:50])=O)[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]([NH2:65])[CH2:59][C:60]2[S:61][CH:62]=[CH:63][N:64]=2)=[CH:54][CH:53]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O.CCOCC>[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]([NH:65][C:48]([C:33]2([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:38][CH2:37][N:36]([C:39]3[C:40]4[CH:47]=[CH:46][NH:45][C:41]=4[N:42]=[CH:43][N:44]=3)[CH2:35][CH2:34]2)=[O:50])[CH2:59][C:60]2[S:61][CH:62]=[CH:63][N:64]=2)=[CH:54][CH:53]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: NC(Cc1nccs1)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(Cc2nccs2)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Reaction time: 8 h
Yield: 94.5 %

Procedure:
HATU (0.418 g, 1.10 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (0.361 g, 1.0 mmol), 1-(4-chlorophenyl)-2-(thiazol-2-yl)ethanamine (Intermediate 95) (0.318 g, 1.00 mmol) and N,N-diisopropylethylamine (0.348 mL, 2.00 mmol) in N-methyl-2-pyrrolidinone (5.0 mL) at room temperature under argon. The resulting solution was stirred overnight. Et2O was added to precipitate the rude product, which was filtered, washed plentifully with Et2O and dried in vacuo to give tert-butyl 4-(1-(4-chlorophenyl)-2-(thiazol-2-yl)ethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (0.550 g, 94%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:37])[N:7]3[CH2:14][C:13]4([CH2:19][CH2:18][N:17](C(OCC5C6C=CC=CC=6C6C5=CC=CC=6)=O)[CH2:16][CH2:15]4)[CH2:12][C:8]3=[N:9][C:10]=2[CH:11]=1.N1CCCCC1>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:37])[N:7]3[CH2:14][C:13]4([CH2:15][CH2:16][NH:17][CH2:18][CH2:19]4)[CH2:12][C:8]3=[N:9][C:10]=2[CH:11]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC2(CC1)Cc1nc3cc(Br)ccc3c(=O)n1C2
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: O
Product: O=c1c2ccc(Br)cc2nc2n1CC1(CCNCC1)C2

Procedure:
A solution of (9H-fluoren-9-yl)methyl 6′-bromo-9′-oxo-3′,9′-dihydro-1′H-spiro[piperidine-4,2′-pyrrolo[2,1-b]quinazoline]-1-carboxylate (0.6 g, 1.1 mmol, 1 equiv) and piperidine (4 mL) in DCM (50 mL) was stirred at room temperature overnight. The reaction mixture was then diluted with water and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[N:36]1([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.[C:45]1([C:51]2([C:57]([OH:59])=[O:58])[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[N:36]1([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:54]3[CH2:53][CH2:52][C:51]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)([C:57]([OH:59])=[O:58])[CH2:56][CH2:55]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: Cl
Agent: NC(=O)N1CCCCC1
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 4-phenylpiperidine-4-carboxylic acid piperidine-amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[CH:16]=[C:17]([O:27][CH3:28])[C:18]=1OS(C(F)(F)F)(=O)=O>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH3:11][O:12][C:13]1[CH:14]=[C:15](/[CH:29]=[CH:30]/[C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[CH:16]=[C:17]([O:27][CH3:28])[CH:18]=1
Reactant: COc1ccc(/C=C/c2cc(OC)c(OS(=O)(=O)C(F)(F)F)c(OC)c2)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=CO
Product: COc1ccc(/C=C/c2cc(OC)cc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a round-bottomed flask (100 mL) equipped with magnetic stir bar was charged anhydrous DMF (6 mL) and triethylamine (960 mg, 9.5 mmol, 5 equiv). In dropwise fashion, 98% formic acid (437 mg, 9.5 mmol, 5 equiv) was added over 10 min. After allowing the mixture to cool to room temperature, a previously prepared solution of 7 (790 mg, 2 mmol) in anhydrous DMF (3 mL) was added in one portion followed by Pd(OAc)2 (21 mg, 0.09 mmol) and DPPF (105 mg, 0.18 mmol). A reflux condenser was equipped and the reaction mixture was heated under N2 to an internal temperature of 80° C. After 20 min the mixture had become dark and the reaction was complete by TLC analysis. The mixture was cooled to room temperature and partitioned between H2O (50 mL) and Et2O (50 mL). A rag layer formed and the mixture was filtered through medium filter paper. The organic layer was separated and washed with H2O (50 mL) and then brine (50 mL). After drying over anhydrous MgSO4, evaporation of the organic phase under reduced pressure left a pale brown oil that slowly crystallized (470 mg, 91%), mp. 55-57° C., lit 56-57° C. 1H NMR (CDCl3): δ 7.45 (d, J=8.9 Hz, 2H), 7.05 (d, J=16 Hz, 1H), 6.90 (d, J=16 Hz, 1H), 6.89 (d, J=8.6 Hz, 2H), 6.65 (d, J=2.2 Hz, 2H), 6.38 (t, J=2.5 Hz, 1H), 3.83 (s, 9H); 13C NMR (CDCl3): 161.20, 139.93, 130.16, 128.96, 128.02, 126.81, 114.37, 104.57, 99.86, 55.57, 55.53. Anal. Calcd for C17H18O3: C, 75.53; H, 6.71. Found: C, 75.53; H, 6.62. (E. Späth and K. Kromp, Ber., 74, 189 (1941)).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([S:17]([N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32]([F:35])[CH:33]=4)[N:28]([S:36]([CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])(=[O:38])=[O:37])[CH:27]=3)[CH2:22][CH2:21]2)(=[O:19])=[O:18])[CH:13]([C:45](O)=[O:46])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[NH:56][O:57][Si](C)(C)C.CO>C(Cl)Cl.CN(C=O)C>[OH:57][NH:56][C:45]([CH:13]1[CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:16][CH2:15][N:14]1[S:17]([N:20]1[CH2:21][CH2:22][CH:23]([C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([F:35])[CH:33]=3)[N:28]([S:36]([CH2:39][CH2:40][Si:41]([CH3:43])([CH3:44])[CH3:42])(=[O:37])=[O:38])[CH:27]=2)[CH2:24][CH2:25]1)(=[O:18])=[O:19])=[O:46]
Reactant: C[Si](C)(C)CCS(=O)(=O)n1cc(C2CCN(S(=O)(=O)N3CCN(C(=O)OCc4ccccc4)CC3C(=O)O)CC2)c2cc(F)ccc21
Reactant: C[Si](C)(C)NO[Si](C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: C[Si](C)(C)CCS(=O)(=O)n1cc(C2CCN(S(=O)(=O)N3CCN(C(=O)OCc4ccccc4)CC3C(=O)NO)CC2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 86.3 %

Procedure:
To a solution of 4-benzyloxycarbonyl-1-{4-[5-fluoro-1-(2-trimethylsilylethane-sulfonyl)indol-3-yl]piperidine-1-sulfonyl}piperazine-2-(RS)-carboxylic acid(288 mg, 0.40 mmol), [prepared as described in Step 6 above] in methylene chloride (5 ml) at 0° C. were added a few drops of DMF and oxalyl chloride (89 ml, 1.0 mmol). The reaction mixture was warmed to RT over 1 h, and stirring was continued for an additional 14 h. The reaction mixture was concentrated in vacuo, redissolved in methylene chloride (5 ml) and cooled to 0° C. N,O-bis-trimethylsilyl hydroxylamine (0.304 ml, 1.42 mmol) added, the reaction was warmed to RT, stirred for 3 h, and then recooled to 0° C. After adding methanol (3 ml), the mixture was stirred for an additional 30 min., and then concentrated in vacuo. The residue was partitioned between methylene chloride (50 ml) and aqueous 2.4 M HCl (10 ml), the organic layer was separated and washed with saturated aqueous sodium bicarbonate, dried over MgSO4, and concentrated in vacuo to afford N-hydroxy-4-benzyloxycarbonyl-1-{4-[5-fluoro-1-(2-trimethylsilylethanesulfonyl)-indol-3-yl]-piperidine-1-sulfonyl}piperazine-2-(RS)-carboxamide as a yellow foam (250 mg, 86%). The residue was used without further purification.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]Cl)=[CH:9][CH:8]=1)[CH:4]=[CH2:5].[N:15]1([CH2:20][CH2:21][OH:22])[CH:19]=[CH:18][N:17]=[N:16]1.O>CN(C=O)C>[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:22][CH2:21][CH2:20][N:15]2[CH:19]=[CH:18][N:17]=[N:16]2)=[CH:9][CH:8]=1)[CH:4]=[CH2:5]
Reactant: OCCn1ccnn1
Reactant: C=CCOc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(COCCn2ccnn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
197 mg (8.21 mmol) 95% sodium hydride were given at −50° C. to a solution of 1.00 g (5.47 mmol) 1-allyloxy-4-chloromethyl-benzene and 619 mg (5.47 mmol) 2-(1H-[1,2,3]-triazol-1-yl)-ethanol in 9.0 ml DMF. The mixture was allowed to warm slowly to r.t., stirred overnight and 10 ml water was added. The formed oil was collected with 10 ml dichloromethane, the aqueous phase extracted with 10 ml dichloromethane and the combined organic phases dried over Na2SO4.
Reaction SMILES: O=[C:2]1[C:10]2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH2:13][C:14]([NH2:16])=[O:15].O.NN.CO.[N:22]1[C:31]2[C:26](=[CH:27][C:28]([CH2:32][C:33]3[N:37]4[N:38]=[C:39](C(=O)C)[CH:40]=[CH:41][C:36]4=[N:35][N:34]=3)=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1>C(O)(=O)C>[N:22]1[C:31]2[C:26](=[CH:27][C:28]([CH2:32][C:33]3[N:37]4[N:38]=[C:39](/[C:2](=[N:3]/[O:12][CH2:13][C:14]([NH2:16])=[O:15])/[CH3:10])[CH:40]=[CH:41][C:36]4=[N:35][N:34]=3)=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: NC(=O)CON1C(=O)c2ccccc2C1=O
Reactant: CC(=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Agent: NN
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: C/C(=N\OCC(N)=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A microwave tube was charged with 2-(1,3-dioxoisoindolin-2-yloxy)acetamide (intermediate V) (166 mg, 0.76 mmol), hydrazine monohydrate (34.4 mg, 0.69 mmol) and 2 mL of methanol. It was heated at 95° C. for 12 h under microwave irradiation. After cooling, solid was removed by filtration and the solution was concentrated under reduced pressure. The residue was diluted with methanol, then 1-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (41.2) (32 mg, 0.105 mmol) and 0.3 mL of acetic acid were added and the mixture was stirred at 40° C. overnight. After concentration, the residue was purified by prep-HPLC to afford the title compound. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.86 (dd, 1H), 8.33-8.27 (m, 2H), 7.98-7.95 (m, 2H), 7.78 (dd, 1H), 7.69 (d, 1H), 7.50 (dd, 1H), 7.31 (d, 2H), 4.77 (s, 2H), 4.63 (s, 2H), 2.32 (s, 3H). LCMS (method A): [MH]+=376, tR=4.02 min.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:25][C@H:24]([CH2:26][O:27][C:28](=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@@H:14]([O:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:12]2[OH:13])=[C:4]([NH2:36])[N:3]=1.N1C=CC=CC=1.[O:43](S(C(F)(F)F)(=O)=O)[S:44]([C:47]([F:50])([F:49])[F:48])(=O)=[O:45]>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:25][C@H:24]([CH2:26][O:27][C:28](=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@@H:14]([O:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:12]2[O:13][S:44]([C:47]([F:50])([F:49])[F:48])(=[O:45])=[O:43])=[C:4]([NH2:36])[N:3]=1
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OS(=O)(=O)C(F)(F)F
Temperature: 10 °C
Yield: 95 %

Procedure:
To a heterogeneous mixture of crystallized 2-chloro-9-(3′,5′-di-O-benzoyl-β-D-ribofuranosyl)-adenine (F) (65 g, purity: 94.7% by A % HPLC, 120.7 mmol) in DCM (650 mL) and pyridine (65 mL) at about 0 to 20° C. under an atmosphere of N2(g) was added Tf2O (85.1 g, 301.6 mmol) dropwise whilst maintaining the temperature within the range of 0 to 20° C. The mixture turned clear and the reaction was deemed complete when the HPLC purity of F was not more than 1%. The mixture was washed with saturated NaHCO3 (325 mL) and the organic phase was washed with 2 N H2SO4 (325 mL) at room temperature The organic phase was dried using 3 Å molecule sieves until the Karl Fischer titration value was <=1000 ppm. The organic phase was evaporated in vacuo at 40° C. until about 290 g of residue (including about 130 mL of DCM) remained. The residue was directly used in the next step. The typical purity of 2-chloro-9-(3′,5′-di-O-benzoyl-2′-O-trifluoromethylsulfonyl-β-D-ribofuranosyl)-adenine (G) was >=95% and the yield was >=95%. 1H NMR (300 MHz, CDCl3) δ 8.11 (dd, J=8.3, 1.2 Hz, 2H), 7.98 (dd, J=8.3, 1.2 Hz, 2H), 7.87 (s, 1H), 7.70-7.60 (m, 1H), 7.59-7.46 (m, 3H), 7.41 (t, J=7.7 Hz, 2H), 6.34-6.23 (m, 2H), 6.16 (dd, J=5.3, 3.2 Hz, 1H), 6.07 (bs, 2H), 4.86 (dd, J=12.2, 3.3 Hz, 1H), 4.81-4.74 (m, 1H), 4.65 (dd, J=12.2, 4.2 Hz, 1H).
Reaction SMILES: I[C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([CH2:33][NH2:34])[C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([CH2:33][NH2:34])[C:28]([C:31]#[C:32][C:2]3[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][N:9]4[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11][CH2:10]4)=[CH:4][CH:3]=3)=[N:29][CH:30]=2)=[CH:21][CH:20]=1
Reactant: CC1CCN(CCOc2ccc(I)cc2)CC1
Reactant: C#Cc1ncc(-c2ccc(Cl)cc2)cc1CN
Product: CC1CCN(CCOc2ccc(C#Cc3ncc(-c4ccc(Cl)cc4)cc3CN)cc2)CC1

Procedure:
The product was prepared analogously to Example 7.1e starting from 1-[2-(4-iodophenoxy)ethyl]-4-methylpiperidine and [5-(4-chlorophenyl)-2-ethynylpyridin-3-yl]methylamine. Yield: 70 mg (21% of theoretical); C28H30ClN3O (M=460.010); calc.: molpeak (M+H)+:460/462 (Cl); found: molpeak (M+H)+:460/462 (Cl); HPLC-MS: 5.30 minutes (method D).