Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]=[C:3]1[N:7]2[CH2:8][CH2:9][N:10]([C:12]([NH:14][CH2:15][CH2:16][NH:17][CH2:18][CH:19]=[CH2:20])=[O:13])[CH2:11][CH:6]2[C:5]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:4]1.C(=O)([O-])O.[Na+].C(N(CC)CC)C.[C:45](OC(=O)C)(=[O:47])[CH3:46]>C(OCC)(=O)C>[C:45]([N:17]([CH2:18][CH:19]=[CH2:20])[CH2:16][CH2:15][NH:14][C:12]([N:10]1[CH2:9][CH2:8][N:7]2[C:3](=[O:2])[O:4][C:5]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:6]2[CH2:11]1)=[O:13])(=[O:47])[CH3:46]
Reactant: C=CCNCCNC(=O)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CCN(CCNC(=O)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1)C(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
To tetrahydro-3-oxo-1,1-diphenyl-N-[2-[(2-propenyl)amino]ethyl]-3H-oxazolo[3,4-a]pyrazine-7(1H)-carboxamide hydrochloride (0.13 g, 0.29 mmol) was added a 0.5 M aqueous sodium hydrogen carbonate solution (20 mL), and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL). Triethylamine (58 mg, 0.57 mmol) and acetic anhydride (32 mg, 0.31 mmol) were sequentially added thereto, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added ethyl acetate, and the resulting mixture was washed with a 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from diisopropyl ether to obtain the title compound (90 mg, yield 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8]S(C)(=O)=O.[I:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:28]1[CH:29]=[CH:30][C:25]([I:24])=[CH:26][CH:27]=1
Reactant: CS(=O)(=O)OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCOc2ccc(I)cc2)c(Cl)c1

Procedure:
2 g of methanesulfonic acid 3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propyl ester, 1.14 g of 4-iodophenol and 1.96 g of potassium carbonate are stirred for 24 hours at 50° C. in 20 ml of dimethylformamide. The reaction mixture is poured onto water and extracted with ethyl acetate. The organic phase is washed with water and potassium carbonate solution and concentrated. Purification over silica gel yields 1,3-dichloro-5-(3,3-dichloro-allyloxy)-2-[3-(4-iodo-phenoxy)-propoxy]-benzene. 1H-NMR (CDCl3) 300 MHz: 2.28 (m, 2H), 4.13 (t, 2H), 4.22 (t, 2H), 4.58 (d, 2H), 6.10 (t, 1H), 6.71 (d, 2H), 6.81 (s, 2H), 7.55 (d, 2H)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[S:18])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].C(O)C.[OH-].[Na+]>O.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[C:14]1([CH3:17])[CH:13]=[CH:12][C:11]([C:10]2[S:18][C:7]3[CH:8]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[N:9]=2)=[CH:16][CH:15]=1
Reactant: Cc1ccc(C(=S)Nc2ccc(C#N)cc2)cc1
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2nc3ccc(C#N)cc3s2)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
Potassium ferricyanide (5.78 g) was dissolved in distilled water (40 ml) and the whole was heated to 90° C. A suspension containing the compound (1.09 g) obtained in Example 43-2, ethanol (1.0 ml), and a 30% sodium hydroxide aqueous solution (3.2 ml) was dropped to the reaction solution for 5 minutes. The whole was stirred at 90° C. for 3 hours and then cooled to room temperature. The precipitated solid was filtrated out and purified by recrystallization (methanol), thereby obtaining the subject compound (0.53 g) as a white solid.
Reaction SMILES: OCC[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:14]=[C:15]([S:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([CH3:32])[CH:31]=2)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]3[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)=[O:12].NC1C=CC([C:52]#[C:53][CH2:54][CH2:55][CH2:56][OH:57])=CC=1>>[OH:57][CH2:56][CH2:55][CH2:54][C:53]#[C:52][C:6]1[CH:5]=[CH:4][C:9]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([S:19]([C:22]3[CH:23]=[C:24]4[C:29](=[C:30]([CH3:32])[CH:31]=3)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]4[NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=3)(=[O:20])=[O:21])[CH:16]=[CH:17][CH:18]=2)=[O:12])=[CH:8][CH:7]=1
Reactant: Nc1ccc(C#CCCCO)cc1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCO)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(C#CCCCO)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 70, using Intermediate 31 in place of 8-aminooctanol. ES/MS calcd. for C36H33N4O6S+ 649.2. Found m/z=649.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C:5]([N:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[CH2:46]([NH2:54])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53].Cl>C(Cl)Cl.C(Cl)CCl>[CH2:1]([O:3][C:4](=[O:35])[C:5]([N:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([NH:54][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])=[O:33])=[CH:28][CH:27]=2)=[CH:24][CH:25]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][CH:10]=1)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)N(Cc1ccc(-c2ccc(C(=O)O)cc2)cc1)Cc1ccc(C(F)(F)F)cc1
Reactant: CCCCCCCCN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCCCCCCNC(=O)c1ccc(-c2ccc(CN(Cc3ccc(C(F)(F)F)cc3)C(=O)C(=O)OCC)cc2)cc1
Reaction time: 3 h
Yield: 33 %

Procedure:
To a solution of 4′-({[ethoxy(oxo)acetyl][4-(trifluoromethyl)benzyl]amino}methyl)-1,1′-biphenyl-4-carboxylic acid (100 mg), EDC (47 mg) and HOBt (28 mg) in DCM (4 mL) was added octylamine (0.041 mL). The resulting reaction mixture was stirred for 3 h. DCM (15 mL) and an aqueous solution of HCl (1N, 10 mL) was added. The aqueous layer was extracted with DCM (3×15 mL). The combined organic layers were washed with a saturated solution of NaHCO3 (15 mL) and dried over MgSO4. Evaporation of the solvents gave an oil which was purified by flash chromatography over silica gel (c-Hex/AcOEt 2/1) to give the title compound as a colorless oil (41 mg, 33%). M+(LC/MS(ESI)): 597.8; M−(LC/MS(ESI)): 595.0. HPLC (Condition A), Rt: 6.61 min (HPLC purity: 99.87%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18]2)[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[CH:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27]>>[CH2:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH:17]1[N:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([CH:26]=[O:27])[CH:33]=2)=[CH:3][CH:4]=1)[C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Br)cc1)C1Cc2ccccc2C1
Product: CC(C)(C)OC(=O)N(Cc1ccc(-c2cccc(C=O)c2)cc1)C1Cc2ccccc2C1

Procedure:
The title compound was prepared from 1,1-dimethylethyl [(4-bromophenyl)methyl]2,3-dihydro-1H-inden-2-ylcarbamate (Example V-13) and 3-formylphenylboronic acid according to the procedure described in Example VI-16 Step 1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.35 (s, 9 H), 3.00 (d, J=8.56 Hz, 4 H), 4.51 (br. s., 2 H), 7.06-7.19 (m, 4 H), 7.34 (d, J=8.03 Hz, 2 H), 7.69 (t, J=7.67 Hz, 1 H), 7.72-7.77 (m, 2 H), 7.86-7.91 (m, 1 H), 8.01-8.06 (m, 1 H), 8.19-8.24 (m, 1 H), 10.10 (s, 1 H).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH3:16][O:17][C:18](=[O:33])[CH2:19][C:20]1[C:29]([CH3:30])=[C:28](O)[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([F:32])[CH:26]=2)[CH:21]=1.N1C=CC=CC=1.O>ClCCl>[CH3:16][O:17][C:18](=[O:33])[CH2:19][C:20]1[C:29]([CH3:30])=[C:28]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([F:32])[CH:26]=2)[CH:21]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(O)c1C
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Cc1cc2ccc(F)cc2c(OS(=O)(=O)C(F)(F)F)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
Trifluoromethanesulfonic anhydride (0.35 mL, 2.1 mmol) was added drop-wise to a 0° C. solution of (6-fluoro-4-hydroxy-3-methyl-naphthalen-2-yl)-acetic acid methyl ester (400 mg, 1.61 mmol) and pyridine (0.195 mL, 2.42 mmol) in dichloromethane (12.0 mL). The reaction mixture was stirred at 0° C. for 30 minutes. The reaction mixture was warmed to room temperature, and stirred for 4 hours. The reaction mixture was then cooled to 0° C. Water (150 mL) was added, and the mixture was extracted three times with 50 mL portions of dichloromethane. The combined organic layers were dried over Na2SO4, filtered, and evaporated to yield a yellow oil. A solution of this crude product in dichloromethane was evaporated over silica gel, and the resulting silica gel-supported product was subjected to flash chromatography (RediSep® Flash column, 230-400 mesh, 28% ethyl acetate in hexane) to give 514 mg (84%) of (6-fluoro-3-methyl-4-trifluoromethanesulfonyloxy-naphthalen-2-yl)-acetic acid methyl ester as a white, crystalline solid. 1H NMR (300 MHz, CDCl3) δ ppm 7.82 (dd, J=8.9, 5.6 Hz, 1 H), 7.73 (s, 1 H), 7.64 (d, J=10.0 Hz, 1 H), 7.27-7.35 (m, 1 H), 3.84 (s, 2 H), 3.73 (s, 3 H), 2.49 (s, 3 H). HRMS (ES+) cald. for C15H12F4O5S [(M+Na)+] 403.0234, obsd. 403.0233.
Reaction SMILES: [CH2:1]([C:3]([C:16]1[CH:29]=[CH:28][C:19]([O:20][CH2:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[C:18]([CH3:30])[CH:17]=1)([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:9]=2[CH:10]=1)[CH2:4][CH3:5])[CH3:2].[CH3:31][S:32](Cl)(=[O:34])=[O:33].CCN(CC)CC>C(Cl)Cl>[CH3:26][C:23]([CH3:25])([CH3:24])[C:22](=[O:27])[CH2:21][O:20][C:19]1[CH:28]=[CH:29][C:16]([C:3]([C:6]2[O:7][C:8]3[CH:14]=[CH:13][C:12]([O:15][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:11][C:9]=3[CH:10]=2)([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:17][C:18]=1[CH3:30]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(O)ccc2o1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(OS(C)(=O)=O)ccc2o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
A solution of 1-{4-[1-ethyl-1-(5-hydroxy-benzofuran-2-yl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-one (236 mg, 0.579 mmol) in CH2Cl2 (10 mL) was treated with methanesulfonic chloride (99 mg, 0.868 mmol) and Et3N (0.40 mL). The mixture was stirred at 0° C. for 30 min, and the reaction is quenched with MeOH (1.0 mL). The mixture is purified with EtOAc/Hexanes (25%) to obtain the title compound (260 mg, 92%). MS (ES) m/e: 504.2 (M+18).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.CO.[CH3:13][NH2:14]>C(O)C>[CH3:13][NH:14][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2
Reactant: CN
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCO
Solvent: CO
Product: CNc1ncnc2[nH]cnc12
Temperature: 120 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
In 20 mL of a 40% methylamine methanol solution and 20 mL of ethanol, 12.5 g (79 mmol) of 6-chloropurin was dissolved and the solution was sealed in a tube and stirred in the tube at 120° C. for four hours. The reaction solution was concentrated, and then triturated with water and collected on a filter, washed with water, and then vacuum dried to obtain 10.78 g (90%) of methyl-(9H-purin-6-yl)amine as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]4([C:41](=[O:48])[NH:42][CH2:43][C:44]([F:47])([F:46])[F:45])[C:40]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=5[C:34]5[C:29]4=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH2:20][CH2:19]3)=[CH:13][CH:14]=2)[C:9]1=[O:49])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+].[CH2:58](Br)[CH:59]=[CH2:60]>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:60]([N:42]([CH2:43][C:44]([F:45])([F:46])[F:47])[C:41]([C:28]1([CH2:27][CH2:26][CH2:25][CH2:24][N:21]2[CH2:22][CH2:23][N:18]([C:12]3[CH:11]=[C:10]4[C:15]([CH2:16][CH2:17][N:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[C:9]4=[O:49])=[CH:14][CH:13]=3)[CH2:19][CH2:20]2)[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:48])[CH:59]=[CH2:58]
Reactant: C=CCBr
Reactant: O=C1c2cc(N3CCN(CCCCC4(C(=O)NCC(F)(F)F)c5ccccc5-c5ccccc54)CC3)ccc2CCN1Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCN(CC(F)(F)F)C(=O)C1(CCCCN2CCN(c3ccc4c(c3)C(=O)N(Cc3ccccc3)CC4)CC2)c2ccccc2-c2ccccc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
The compound (67 mg) prepared in Example 97 was dissolved in toluene (5 ml), and sodium hydroxide (12 mg), potassium carbonate (28 mg), tetrabutylammonium hydrogensulfate (8 mg), and allyl bromide (0.010 ml) were added to the solution, and the mixture was stirred at 60° C. overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous MgSO4, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by preparative TLC (hexane:ethyl acetate=1:1) to give the title compound (17 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]([OH:16])=O)=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH:58]1[C:66]2[C:61](=[C:62]([CH2:67][NH2:68])[CH:63]=[CH:64][CH:65]=2)[CH:60]=[N:59]1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14](=[O:16])[NH:68][CH2:67][C:62]2[CH:63]=[CH:64][CH:65]=[C:66]3[C:61]=2[CH:60]=[N:59][NH:58]3)=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13])=[O:4]
Reactant: COC(=O)c1sc(C(=O)O)cc1C(F)(F)F
Reactant: NCc1cccc2[nH]ncc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 21.1 %

Procedure:
To a solution of 3-Trifluoromethyl-thiophene-2,5-dicarboxylic acid 2-methyl ester (630 mg, 2.47 mmol) in anhydrous DMF (12 mL) was added triethylamine (1.03 mL, 7.41 mmol), HBTU (1.41 g, 3.71 mmol), HOBT (0.40 mg, 2.96 mmol), and C-(1H-Indazol-4-yl)-methylamine (400 mg, 2.72 mmol). The mixture was stirred at room temperature 5 h, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-80% EtOAc in hexane to afford the desired product (0.20 g, 21% yield).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:25][N:26]1[C:30]2[CH:31]=[C:32]([C:35]([OH:37])=O)[CH:33]=[CH:34][C:29]=2[N:28]=[N:27]1.CN(C=O)C.CCN(C(C)C)C(C)C.[CH2:52]([O:54][C:55](=[O:75])[C@H:56]([OH:74])[CH2:57][C@H:58]([NH2:73])[CH2:59][C:60]1[CH:65]=[CH:64][C:63]([C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([Cl:72])[CH:67]=2)=[CH:62][CH:61]=1)[CH3:53]>>[CH2:52]([O:54][C:55](=[O:75])[C@H:56]([OH:74])[CH2:57][C@H:58]([NH:73][C:35]([C:32]1[CH:33]=[CH:34][C:29]2[N:28]=[N:27][N:26]([OH:25])[C:30]=2[CH:31]=1)=[O:37])[CH2:59][C:60]1[CH:65]=[CH:64][C:63]([C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([Cl:72])[CH:67]=2)=[CH:62][CH:61]=1)[CH3:53]
Reactant: O=C(O)c1ccc2nnn(O)c2c1
Reactant: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1ccc2nnn(O)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.3 %

Procedure:
HATU (328 mg, 862 μmol) was added to a solution of 1-hydroxy-1H-1,2,3-benzotriazole-6-carboxylic acid (154 mg, 862 μmol) in DMF (1.5 mL, 19.5 mmol) and the resulting mixture was stirred at room temperature for 10 minutes. DIPEA (0.3 mL, 1.7 mmol) was added to the mixture, followed by (2R,4R)-4-amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid ethyl ester (200 mg, 575 μmol) and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and the resulting residue was purified by reverse phase chromatography (35-80% MeCN in water with 0.05% TFA) to yield the title compound (197 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:22])[CH2:10][C:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1.[CH2:23](O)[CH2:24][OH:25].CC1C=CC(S(O)(=O)=O)=CC=1>CC1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:10][C:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH:12]=3)[O:25][CH2:24][CH2:23][O:22]2)[CH:6]=[CH:7][CH:8]=1
Reactant: OCCO
Reactant: CCOC(=O)N1CC=C(CC(=O)c2cccc(OC)c2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC=C(CC2(c3cccc(OC)c3)OCCO2)CC1

Procedure:
A mixture of 30 parts of ethyl 2,3-dihydro-4-[2-(3-methoxyphenyl)-2-oxoethyl]-1(6H)-pyridinecarboxylate, 15 parts of 1,2-ethanediol, 0.1 parts of 4-methylbenzenesulfonic acid and 135 parts of methylbenzene is stirred and refluxed overnight. The reaction mixture is cooled and evaporated, yielding 30 parts of ethyl 2,3-dihydro-4-[2-(3-methoxyphenyl)-1,3-dioxolan-2-ylmethyl]-1(6H)-pyridinecarboxylate as a residue.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([OH:8])=[N:6][CH:7]=1.IC.[C:12]([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5](=[O:8])[N:6]([CH3:12])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ncc(Br)cc1F
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(Br)cc(F)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.3 %

Procedure:
A mixture of 5-bromo-3-fluoropyridin-2-ol (1 g, 5.2 mmol), iodomethane (356 mg, 5.7 mmol) and K2CO3 (1.4 g, 10.4 mmol) in DMF (10 mL) was stirred at rt for 12 h. The mixture was treated with water (70 ml) and extracted with EtOAc (3×50 ml). The combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (1 g, 93%) as a white solid which was carried forward without purification. LCMS (M+H)+=207.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([N:15]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+].O>O1CCCC1>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][N:15]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Nc1ccc(CC(=O)N2CCCCCC2)cc1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)Nc1ccc(CCN2CCCCCC2)cc1

Procedure:
The amide, Hexahydro-1-[4-(methylsulfonylamino)phenylacetyl]-1H-azepine from Preparation 21 (2.8 g, 9.03 mmol) is reduced with 1.1 g of lithium aluminum hydride in 100 ml of tetrahydrofuran for 2 days at room temperature. The suspension is cooled; a saturated solution of sodium potassium tartrate is carefully added and then water. The solids are filtered and washed with tetrahydrofuran. The combined filtrates are evaporated. The residue is suspended in sodium bicarbonate and extracted with methylene chloride. The organic layer is washed with water, dried and evaporated. The residue is chromatographed on silica gel eluting 10% methanol-0.5% ammonium hydroxide-methylene chloride to yield the title compound, an oil. The MS had M/Z 296 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH2:11].[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O.C1(=O)C=CC(=O)C=C1>CC(O)C.O>[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[NH:11][C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: O=Cc1ccco1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Agent: O=C1C=CC(=O)C=C1
Solvent: O
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc2nc(-c3ccco3)[nH]c2c1

Procedure:
A mixture of 1,2-diamino-4-nitrobenzene (31 g, 0.2 mol) and 2-furancarboxaldehyde (25 g, 0.26 mol) in 2-propanol is treated with p-benzoquinone (24 g, 0.22 mol). The reaction mixture is heated under reflux for 2 h. The reaction solution is diluted with water to precipitate the product. After drying, the crude product weighs 46 g (100%). Recrystllization from nitromethane provides an analytical sample which melts at 228°-229° C. Anal. Calcd for C11H7N3O3 ; C, 57.64; H, 3.08; N, 18.34. Found: C, 57.55; H, 3.04; N, 18.53.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[OH:10].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.[C:36](OC)(OC)(OC)[CH3:37]>CCO>[Br:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]2[N:1]=[C:36]([CH3:37])[O:10][C:3]=2[CH:4]=1
Reactant: Nc1c(O)cc(Br)cc1F
Reactant: COC(C)(OC)OC
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCO
Product: Cc1nc2c(F)cc(Br)cc2o1
Temperature: 90 °C
Yield: 73 %

Procedure:
A mixture of 2-amino-5-bromo-3-fluorophenol (1 equiv), ytterbium(iii) trifluoromethanesulfonate (0.01 equiv), and trimethyl orthoacetate (1.2 equiv) in EtOH (1.3 M) was heated to 90° C. for 2 h. The reaction mixture was filtered through celite and washed with EtOH. The residual filtrate was concentrated in vacuo, then saturated aqueous sodium bicarbonate added and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified using silica gel chromatography (0 to 60% ethyl acetate in hexane) to afford the title compound (73% yield). MS (ESI) m/z 232.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([C:30]2C=CC=CC=2)=O)=[CH:23][CH:22]=1.[BH4-].[Na+].[OH-].[Na+]>C1COCC1.[Ti].CCOC(C)=O.O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH:28]([CH3:30])[CH2:27][C:24]4[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=4)[CH2:15][CH2:14]3)[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CC(=O)c2ccccc2)cc1
Reactant: Clc1ccc(-c2nsc(N3CCNCC3)n2)cc1
Agent: [Ti]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COc1ccc(CC(C)N2CCN(c3nc(-c4ccc(Cl)cc4)ns3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-(4-chlorophenyl)-5-(piperazin-1-yl)-1,2,4-thiadiazole (100 mg, 356 μmol), 4-methoxyphenylacetophenone (64.3 mg, 392 μmol) and titanium IV propoxide (152 mg, 158 μl, 534 μmol) in 2 mL THF was stirred for 3 h at RT. NaBH4 (40.4 mg, 1.07 mmol) was added in three portions. MeOH (0.2 mL) was added and stirred over the weekend at RT. Water (5 mL), EtOAc (10 mL) and aq. 2N NaOH (3 mL) was added, stirred for 10 min and filtered over a dicalit-plug. The aqueous layer was separated and extracted once with EtOAc (20 mL). The organic layers were washed with brine (1×20 mL), dried over Na2SO4, filtered off and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with a gradient formed from heptane and EtOAc and again with preparative HPLC to yield, after evaporation of the product containing fraction, 39 mg (25%) of the title compound as off-white solid. MS (m/e): 429.2 (MH+).