Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20](OC)[CH:21]=3)[NH:16][CH:15]=2)[CH:5]=[C:4]([Cl:27])[C:3]=1[NH:28][C:29](=[O:31])[CH3:30].[CH3:32]C1NC2C(C=1CC(O)=O)=CC=CC=2.C(NC1C(Cl)=CC(CN)=CC=1Cl)(=O)C>>[Cl:27][C:4]1[CH:5]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]=2[CH3:32])[CH:7]=[C:2]([Cl:1])[C:3]=1[NH:28][C:29](=[O:31])[CH3:30]
Reactant: Cc1[nH]c2ccccc2c1CC(=O)O
Reactant: COc1ccc2[nH]cc(CC(=O)N=C(N)NCc3cc(Cl)c(NC(C)=O)c(Cl)c3)c2c1
Agent: CC(=O)Nc1c(Cl)cc(CN)cc1Cl
Product: CC(=O)Nc1c(Cl)cc(CNC(N)=NC(=O)Cc2c(C)[nH]c3ccccc23)cc1Cl

Procedure:
In a manner similar to that used in the preparation of the compound of example 2, but using 2-(2-methyl-1H-indol-3-yl)acetic acid in step 11 (A) and 4-acetamido-3,5-dichloro-benzylamine (preparation B) in step 11 (B), the title compound was prepared. MS (ESI) (M+H)+=446.08 1H-NMR (500 MHz, CD3OD) δ 7.36-7.50 (m, 3 H), 7.30 (d, J=7.93 Hz, 1 H), 7.00-7.10 (m, 2 H), 4.52 (s, 2 H), 3.92 (s, 2 H), 2.44 (s, 3 H), 2.19 (s, 3 H).
Reaction SMILES: Br[C:2]1[N:3]([C:7]2[N:16]=[CH:15][C:14]3[N:13]([CH3:17])[C:12](=[O:18])[C@@H:11]([CH2:19][CH3:20])[N:10]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[C:9]=3[N:8]=2)[CH:4]=[CH:5][N:6]=1.C(Cl)(Cl)Cl.[C:30]1([C:45]2C=CC=CC=2)[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1P(C(C)(C)C)C(C)(C)C.[Br-].C([Zn+])C1C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:45]([C:2]1[N:3]([C:7]2[N:16]=[CH:15][C:14]3[N:13]([CH3:17])[C:12](=[O:18])[C@@H:11]([CH2:19][CH3:20])[N:10]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[C:9]=3[N:8]=2)[CH:4]=[CH:5][N:6]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3Br)nc2N1C1CCCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Br-]
Solvent: ClC(Cl)Cl
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3Cc3ccccc3)nc2N1C1CCCC1
Temperature: 90 °C
Reaction time: 18 h
Yield: 293.7 %

Procedure:
(R)-2-(2-bromo-1H-imidazol-1-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 65, 0.21 g, 0.518 mmol), Pd2(dba)3, CHCl3 (53 mg, 0.0518 mmol) and biphenyl-2-yldi-tert-butylphosphine (30 mg, 0.103 mmol) were placed in a screw cap vial and a solution of benzyl zinc bromide (1.5 mL, 0.777 mmol in THF) was added. A stream of nitrogen was bubbled through the mixture for 2 minutes and then the vial was sealed and the resulting solution was stirred at 90° C. for 18 h. The reaction mixture was filtered, then purified by flash chromatography with a silica gel column by eluting with a mixture of Hexane:EtOAc and then further purified by preparative HPLC to give the title compound (126 mg). LCMS: 417.2 m/z (M+H)+; ret. Time: 3.80 min (Analytical Method A).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([C:17]1[C:22]([O:23]COCC[Si](C)(C)C)=[CH:21][CH:20]=[CH:19][N:18]=1)=[O:16]>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([C:17]1[C:22]([OH:23])=[CH:21][CH:20]=[CH:19][N:18]=1)=[O:16]
Reactant: C[Si](C)(C)CCOCOc1cccnc1C(=O)c1ccccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccccc1Cl)c1ncccc1O
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
Add trifluoroacetic acid (5 mL) to a solution of (2-chloro-phenyl)-[3-(2-trimethylsilanyl-ethoxymethoxy)-pyridin-2-yl]-methanone (195 mg, 0.54 mmol) in CH2Cl2 (3 mL), stir for 30 minutes. Concentrate; dissolve in 20% i-PrOH/CHCl3, wash with saturated NaHCO3 solution (×2). Dry the combined organic layers over MgSO4 and concentrate. Purify the residue by flash chromatography on silica gel eluting with 0-30% Et2O/hexanes to afford the title compound (102 mg, 82%) as white solid. MS(IS) 233.9 (M+1). TLC: Rf=0.20 (25% Et2O/hexanes).
Reaction SMILES: [CH2:1]([C:5]1([CH2:30][CH2:31][CH2:32][CH3:33])[C:17]2[CH:16]=[C:15]([C:18]#[C:19]C(C)(O)C)[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][C:8]([C:24]#[C:25]C(C)(O)C)=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4].[OH-].[K+]>C1(C)C=CC=CC=1.CC(O)C>[C:24]([C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[C:17](=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=3)[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:30][CH2:31][CH2:32][CH3:33])[C:6]=2[CH:7]=1)#[CH:25]
Reactant: CCCCC1(CCCC)c2cc(C#CC(C)(C)O)ccc2-c2ccc(C#CC(C)(C)O)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: C#Cc1ccc2c(c1)C(CCCC)(CCCC)c1cc(C#C)ccc1-2
Yield: 70.4 %

Procedure:
To a solution of 4,4′-(9,9-dibutyl-9H-fluorene-2,7-diyl)bis(2-methyl-3-butyn-2-ol) (1.04 g, 2.35 mmol) in 20 mL of toluene/i-PrOH (3/1), was added solid KOH (0.39 g). The mixture was heated under reflux for 0.5 h. After cooling, KOH was filtered off and the solvents were evaporated and the residue was purified by column chromatography (heptane/CH2Cl2 70:30 then 20:80) to yield 0.54 g (71%) of 2,7-diethynyl-9,9-dibutyl-9H-fluorene: 1H NMR (200.13 MHz, CDCl3) δ 7.63 (d, J=8.6 Hz, 2H), 7.48 (d, J=8.6 Hz, 2H), 7.46 (s, 2H), 3.15 (s, 2H), 1.94 (m, 4H), 1.07 (m, 4H), 0.67 (t, J=7.2 Hz, 6H), 0.54 (m, 4H); 13C NMR (50.32 MHz, CDCl3) δ 151.0, 140.9, 131.2, 126.5, 120.8, 119.9, 84.5, 77.4, 55.1, 40.0, 25.8, 22.9, 13.7; HRMS (EI) calcd for C25H26 (M+·) m/z 326.2035. found 326.2036. Anal. Calcd for C25H26 (326.48): C, 91.97; H, 8.03. Found: C, 92.17; H, 8.07.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[O:15][C:16]3[C:22]([C:23]4[CH:24]=[C:25]([C:28](O)=[O:29])[S:26][CH:27]=4)=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C[CH2:32][N:33]=C=NCCCN(C)C.Cl.CN.C1COCC1.C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.CCOC(C)=O.ClCCl>[CH3:32][NH:33][C:28]([C:25]1[S:26][CH:27]=[C:23]([C:22]2[C:16]3[O:15][C:14]([NH:13][C:5]4[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)=[N:18][C:17]=3[CH:19]=[CH:20][CH:21]=2)[CH:24]=1)=[O:29]
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc(Nc2nc3cccc(-c4csc(C(=O)O)c4)c3o2)cc(OC)c1OC
Agent: CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1cc(-c2cccc3nc(Nc4cc(OC)c(OC)c(OC)c4)oc23)cs1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 0.04 g (0.083 mmol) 4-[2-(3,4,5-trimethoxy-phenylamino)-benzooxazol-7-yl]-thiophene-2-carboxylic acid, 0.025 g (0.127 mmol) EDC-HCl, 0.016 g (0.128 mmol) DMAP, 0.83 ml (1.7 mmol) methylamine THF solution (2M), 0.012 g (0.088 mmol) HOBt and 4 ml dichloromethane is stirred at room temperature for 72 h. Then EtOAc is added to the reaction mixture and the organic layer is washed with water (2×), dried over MgSO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography (silicagel, hexane:EtOAc=1:2), followed by crystallization from dichloromethane/diethyl ether to afford the title compound as off-white crystals. Rt=2.15 min (Waters Symmetry C8, 2.1×50 mm, detection 210-250 nM, 5% to 100% CH3CN in H2O in 2 min+0.05% TFA, flow rate 1.0 ml/min); MS: 440 (M+1)+; m.p. 260-262° C.
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[N:16]1([CH2:21][CH2:22][CH2:23][C:24]2[N:25]=[N+:26]([O-:37])[C:27]3[CH:36]=[C:35]4[C:31]([CH2:32][CH2:33][CH2:34]4)=[CH:30][C:28]=3[N:29]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[N:16]1([CH2:21][CH2:22][CH2:23][C:24]2[N:25]=[N+:26]([O-:37])[C:27]3[CH:36]=[C:35]4[C:31]([CH2:32][CH2:33][CH2:34]4)=[CH:30][C:28]=3[N+:29]=2[O-:4])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: [O-][n+]1nc(CCCN2CCCC2)nc2cc3c(cc21)CCC3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: [O-][n+]1nc(CCCN2CCCC2)[n+]([O-])c2cc3c(cc21)CCC3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 58.5 %

Procedure:
H2O2 (70%, 2.0 mL, 39 mmol) was added dropwise to a stirred solution of TFAA (5.4 mL, 39 mmol) in DCM (50 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 84 (1.50 g, 4.6 mmol) and TFA (1.5 mL, 19.5 mmol) in DCM (50 mL) at 0° C. The solution was stirred at 20° C. for 6 h, diluted with dilute aqueous NH3 solution (30 mL) and extracted with DCM (3×150 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 85 (846 mg, 35%) as a red gum: 1H NMR δ 8.25 (s, 1H, H-9), 8.20 (s, 1H, H-5), 3.22-3.22 (m, 6H, 3×CH2), 3.11-3.20 (m, 4H, H-6, H-8), 2.80-3.05 (m, 2H, CH2), 2.33-2.43 (m, 2H, CH2), 2.21-2.30 (m, 2H, H-7), 2.13 (br s, 4H, 2×CH2); 13C NMR δ 155.4, 152.4, 151.0, 139.0, 133.9, 115.7, 113.7, 54.2, 53.5 (2), 33.3, 32.8, 27.1, 25.4, 23.8, 23.2 (2); HRMS (FAB+) calcd for C17H23N4O2 (MH+) m/z 315.1821, found 315.1820.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:12][CH2:13][CH2:14][N:15]=[C:16]=[O:17].CO>C1COCC1>[Cl:12][CH2:13][CH2:14][NH:15][C:16]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1)=[O:17]
Reactant: Nc1ccnc2ccccc12
Reactant: O=C=NCCCl
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NCCCl)Nc1ccnc2ccccc12
Reaction time: 18 h

Procedure:
To a solution of 4-aminoquinoline (3.46 g, 24 mmol) in dry THF is added chloroethylisocyanate (3.1 mL, 36 mmol). The reaction mixture is stirred for 18 h. MeOH (10 mL) is added, and stirring is continued for an additional hour. The reaction mixture is evaporated, and partitioned between DCM and aqueous 5% citric acid (150 mL). The aqueous layer is carefully adjusted to pH 9 with solid NaHCO3. The precipitate is filtered, washed with H2O (5×20 mL) and Et2O (2×20 mL), and dried in vacuo at 45° C. to provide the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:31])[CH:16]([N:18]2[CH2:23][CH2:22][C:21]([OH:30])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[CH3:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([O:40][C:41](=[O:57])[C@H:42]([C@@H:44]([C:46]([O:48][C:49](=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47])[OH:45])[OH:43])(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CC(C)=O>[C:49]([O:48][C:46](=[O:47])[C@H:44]([C@@H:42]([C:41]([O:40][C:32](=[O:39])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:57])[OH:43])[OH:45])(=[O:56])[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1.[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:31])[C@@H:16]([N:18]2[CH2:23][CH2:22][C:21]([OH:30])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[CH3:17])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C(=O)c1ccc(OCc2ccccc2)cc1)N1CCC(O)(c2ccccc2)CC1
Agent: O=C(OC(=O)[C@@H](O)[C@H](O)C(=O)OC(=O)c1ccccc1)c1ccccc1
Solvent: CC(C)=O
Product: C[C@@H](C(=O)c1ccc(OCc2ccccc2)cc1)N1CCC(O)(c2ccccc2)CC1
Temperature: 50 °C
Yield: 85.4 %

Procedure:
120 g (0.289 mol) racemic 1-(4-benzyloxy-phenyl)-2-(4-hydroxy-4-phenyl-piperidin-1-yl)-1-propanone and 1360 ml acetone were charged to a 3 liter flask equipped with a mechanical stirrer, a thermometer and a reflux condenser. The resulting solution was warmed to 50° C., then 105 g (0.293 mol) di-O-benzoyl-D-tartaric acid was added followed by a 200 ml acetone rinse. The solution was stirred at 50° C. and a suspended solid formed after about 25 minutes. The suspension was stirred as an additional 5 hours at 50° C., and then the mixture was cooled to room temperature over 1 hour. The suspension was filtered and the solid cake was washed with 500 ml acetone. The solid was dried at about 45° C. under vacuum (10 mmHg) overnight, giving 191 g (86% yield) (2S)-1-(4-benzyloxy-phenyl)-2-(4-hydroxy-4-phenyl-piperidin-1-yl)-1-propanone di-O-benzoyl-D-tartaric acid salt.
Reaction SMILES: C1COCC1.[F:6][C:7]([F:37])([F:36])[O:8][C:9]1[CH:35]=[CH:34][C:12]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[C:25]4[CH:26]=[CH:27][C:28]([C:30]([O:32]C)=[O:31])=[CH:29][C:24]=4[N:23]=[CH:22]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.[OH-].[Na+]>CO>[F:37][C:7]([F:6])([F:36])[O:8][C:9]1[CH:35]=[CH:34][C:12]([CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]3[C:25]4[CH:26]=[CH:27][C:28]([C:30]([OH:32])=[O:31])=[CH:29][C:24]=4[N:23]=[CH:22]3)=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc2c(c1)ncn2-c1ccc(OCc2ccc(OC(F)(F)F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)ncn2-c1ccc(OCc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 70 °C

Procedure:
A 0.5M THF solution of methyl 1-(4-{[4-(trifluoromethoxy)benzyl]oxy}phenyl)-1H-benzimidazole-5-carboxylate (3.7 g, 8.4 mmol) was treated with 10M NaOH (8.4 mL, 84 mmol) and enough methanol to make the mixture homogeneous. The reaction mixture was then heated at 70° C. for 24 h, after which it was concentrated in vacuo, taken up in water and acidified to pH 4 with 2M HCl(aq). The resulting precipitate was filtered and washed with water to afford 1-(4-{[4-(trifluoromethoxy) benzyl]oxy}phenyl)-1H-benzimidazole-5-carboxylic acid. 1H NMR (DMSO-d6, 400 MHz) δ 5.26 (s, 2H), 7.26-7.29 (m, 2H), 7.43 (d, 2H, J=8.0 Hz), 7.58 (d, 1H, J=8.0 Hz), 7.63-7.66 (m, 4H), 7.94 (dd, 1H, J=8.8 Hz, 1.6 Hz), 8.33 (d, 1H, J=0.8 Hz), 8.62 (s, 1H); MS (ES+): m/z 429 (MH+).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][OH:15])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>C1COCC1>[S:23]([O:15][CH2:14][CH2:13][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:11][CH:10]=1)(=[O:25])(=[O:24])[CH3:26]
Reactant: CCCCCc1ccc(CCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCc1ccc(CCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 3-(4-pentylphenyl)propanol (30.8 g, 149 mmol) and triethylamine (22 ml, 155 mmol) in THF (300 ml) was added mesyl chloride (11.6 ml, 150 mmol) at 0° C., and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into ice and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate anhydride, and the organic layer was concentrated to give the object compound as an oily substance. 42.4 g, (yield 100%)
Reaction SMILES: [N:1]1[N:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]2=[N:3][C:2]=1[C:15]([OH:17])=O.C[N:19](C)C=O.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.ClC1C=CC2N=NN(O)C=2C=1.[Cl-].[NH4+].C(N(CC)C(C)C)(C)C>C(#N)C.O>[N:1]1[N:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]2=[N:3][C:2]=1[C:15]([NH2:19])=[O:17]
Reactant: O=C(O)c1nc2n(n1)-c1ccccc1OCC2
Reactant: CN(C)C=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccc(Cl)cc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: NC(=O)c1nc2n(n1)-c1ccccc1OCC2
Reaction time: 3 h
Yield: 27.5 %

Procedure:
To crude 4,5-dihydrobenzo[b][1,2,4]triazolo[1,5-d][1,4]oxazepine-2-carboxylic acid (0.177 g) in N,N-dimethylformamide (1.55 mL, 20.0 mmol) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.761 g, 2.00 mmol) and 6-chloro-1-hydroxybenzotriazole (0.339 g, 2.00 mmol) (FIG. 18). The reaction was stirred vigorously, and to the reaction was added ammonium chloride (0.285 g, 5.34 mmol). Then, N,N-diisopropylethylamine (0.465 mL, 2.67 mmol) was added after 10 minutes. After 3 hours the reaction was taken to dryness. Preparative HPLC (acetonitrile/water) gave amide 87 (0.0485 grams, 31% over two steps). 1H NMR (500 MHz, CDCl3) δ 8.22 (d, J=8.2 Hz, 1H), 7.30 (t, J=7.7 Hz, 1H), 7.22 (t, J=7.7 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 6.97 (s, 1H), 5.75 (s, 1H), 4.49 (t, J=5.7 Hz, 2H), 3.48 (t, J=4.0 Hz, 2H). LRMS m/z Calcd. for C12H10N4O2: 230.08038, found: 231.08 [M+1].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=O)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:15]=2[C:30]#[N:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CSC>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:15]=2[CH2:30][NH2:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(NC(=O)c3ccccc3F)c2C#N)CC1
Solvent: CSC
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(NCc3ccccc3F)c2CN)CC1
Temperature: 70 °C
Yield: 68.5 %

Procedure:
To a solution of 4-[2-cyano-3-(2-fluorobenzoylamino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (1.282 g, 3.02 mmol) was added BH3.DMS (10M in THF). Aftering heating at 70° C. in an open flask for 20 minutes to remove the dimethyl sulfide, the reaction was then heated under reflux for 4 hours. To the cooled solution was added MeOH slowly and the resulting mixture was stirred at room temperature for an hour. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting brown residue was purified by flash chromatography to give 4-[2-aminomethyl-3-(2-fluoro-benzylamino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (858 mg, 67%). MS (M+H)+:415.3
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:40])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@H:12]3[C@H:16]([C:17]([F:20])([CH3:19])[CH3:18])[CH2:15][C@@H:14]([CH2:21][O:22][Si](C(C)(C)C)(C4C=CC=CC=4)C4C=CC=CC=4)[O:13]3)[C:6]=2[N:7]=1.[NH4+].[F-]>CO>[NH2:1][C:2]1[NH:3][C:4](=[O:40])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@H:12]3[C@H:16]([C:17]([F:20])([CH3:19])[CH3:18])[CH2:15][C@@H:14]([CH2:21][OH:22])[O:13]3)[C:6]=2[N:7]=1
Reactant: CC(C)(F)[C@@H]1C[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O[C@H]1n1c(=O)sc2c(=O)[nH]c(N)nc21
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(F)[C@@H]1C[C@@H](CO)O[C@H]1n1c(=O)sc2c(=O)[nH]c(N)nc21
Yield: 24.2 %

Procedure:
A mixture of 5-amino-3-[(2R,3R,5S)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]-3-(1-fluoro-1-methyl-ethyl)tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione (compound 40h, 66 mg, 0.12 mmol) and NH4F (133 mg, 3.6 mmol) in methanol was heated under reflux for 1.5 hrs. The resulting mixture was concentrated in vacuo and the residue was purified by preparative HPLC to afford 10 mg of 5-amino-3-[(2R,3R,5S)-3-(1-fluoro-1-methyl-ethyl)-5-(hydroxymethyl)tetrahydrofuran-2-yl]-6H-thiazolo[4,5-d]pyrimidine-2,7-dione (Example 40) as a white solid.
Reaction SMILES: [Cl-:1].[Li+].[F:3][C:4]([F:24])([C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[CH2:5]OS(C1C=CC(C)=CC=1)(=O)=O>CN1CCCC1=O>[Cl:1][CH2:5][C:4]([F:24])([F:3])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19]
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)C(F)(F)C(F)(F)F)cc1
Reactant: [Cl-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: FC(F)(F)C(F)(F)C(F)(F)CCl

Procedure:
For example, to prepare 1,1-dichloro-2,2,3,3,4,4,4-heptafluorobutane, 2,2,3,3,4,4,4-heptafluorobutanol and p-toluenesulfonyl chloride are reacted to form 2,2,3,3,4,4,4-heptafluorobutyl-p-toluenesulfonate. Then, N-methylpyrrolidone, lithium chloride, and the 2,2,3,3,4,4,4-heptafluorobutyl-p-toluenesulfonate are reacted to form 1-chloro-2,2,3,3,4,4,4-heptafluorobutane. Finally, chlorine and the 1-chloro-2,2,3,3,4,4,4-heptafluorobutane are reacted to form the 1,1-dichloro-2,2,3,3,4,4,4-heptafluorobutane.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[NH2:16][C:17]1[CH:18]=[C:19]([C:23]2[NH:27][N:26]=[N:25][N:24]=2)[CH:20]=[CH:21][CH:22]=1>>[O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([S:12]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[NH:27][N:26]=[N:25][N:24]=4)[CH:18]=3)(=[O:14])=[O:13])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(-c2cnco2)cc1
Yield: 23 %

Procedure:
The product was prepared according to General Procedure 6, described in Example 65, with 4-(1,3-oxazol-5-yl)benzenesulfonyl chloride (17.2 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8.0 mg, 0.050 mmol). The title compound was obtained in 23% yield (4.2 mg). MS (ESI+) calcd mass for C16H12N6O3S 368.069159, found 368.069509.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[O:14][C:13](=[O:15])[N:12]([CH2:16][C@@H:17]2[C@H:20]([NH:21][C:22](=[O:49])/[C:23](=[N:37]\[O:38][C:39]([CH3:48])([CH3:47])[C:40]([O:42]C(C)(C)C)=[O:41])/[C:24]3[N:25]=[C:26]([NH:29]C(OC(C)(C)C)=O)[S:27][CH:28]=3)[C:19](=[O:50])[N:18]2[S:51]([OH:54])(=[O:53])=[O:52])[CH2:11]1)C1C=CC=CC=1.C(OC[C@@H]1OC(=O)N(C[C@@H]2[C@H](NC(=O)/C(=N\OC(C)(C)C(OC(C)(C)C)=O)/C3N=C(NC(OC(C)(C)C)=O)SC=3)C(=O)N2)C1)C1C=CC=CC=1.B(Cl)(Cl)Cl>C(Cl)Cl>[NH2:29][C:26]1[S:27][CH:28]=[C:24](/[C:23](=[N:37]/[O:38][C:39]([CH3:48])([CH3:47])[C:40]([OH:42])=[O:41])/[C:22]([NH:21][C@@H:20]2[C:19](=[O:50])[N:18]([S:51]([OH:54])(=[O:53])=[O:52])[C@@H:17]2[CH2:16][N:12]2[CH2:11][C@H:10]([CH2:9][OH:8])[O:14][C:13]2=[O:15])=[O:49])[N:25]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2CN2C[C@H](COCc3ccccc3)OC2=O)cs1
Agent: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CN2C[C@H](COCc3ccccc3)OC2=O)cs1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1CN1C[C@H](CO)OC1=O)c1csc(N)n1)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 2 %

Procedure:
To a solution of tert-butyl 2-(((Z)-(2-(((2R,3S)-2-(((R)-5-((benzyloxy)methyl)-2-oxooxazolidin-3-yl)methyl)-4-oxoazetidin-3-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoate (2R,3S)-2-(((R)-5-((benzyloxy)methyl)-2-oxooxazolidin-3-yl)methyl)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-4-oxoazetidine-1-sulfonate (80 mg, 0.1 mmol) in DCM (10 mL) was added BCl3 (1 M in DCM, 0.6 mL). After stirring at rt for 15 min, the reaction mixture was quenched with EtOH and concentrated in vacuo. The crude residue was purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (1.1 mg, 2%). LCMS: m/z=549.0 (M−1); 1H NMR (400 MHz, D2O): δ 6.96 (s, 1H), 5.29 (d, J=5.2 Hz, 1H), 4.48 (m, 2H), 3.73-3.35 (m, 6H), 1.36 (s, 3H), 1.35 (s, 3H).
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C(OC1N=NC(C(C2C=CC=CC=2)=C)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.C([O:54][C:55]1[N:56]=[N:57][C:58]([C:69]([C:71]2[CH:76]=[CH:75][C:74]([F:77])=[CH:73][CH:72]=2)=[CH2:70])=[CH:59][C:60]=1[O:61]CC1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>O1CCCC1>[F:77][C:74]1[CH:75]=[CH:76][C:71]([CH:69]([C:58]2[CH:59]=[C:60]([OH:61])[C:55](=[O:54])[NH:56][N:57]=2)[CH3:70])=[CH:72][CH:73]=1
Reactant: C=C(c1ccc(F)cc1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: C=C(c1ccccc1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(c1ccc(F)cc1)c1cc(O)c(=O)[nH]n1

Procedure:
Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-(1-phenylethenyl)pyridazine (Intermediate 41) except that the solvent mixture used for the hydrogenation consisted of ethyl acetate and tetrahydrofuran and the product was recrystallised from a mixture of heptane and MTBE.