Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:9]([C:10]([O:12]C)=[O:11])=[CH:8][N:7]=[C:6]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]5[O:24][C:25]([NH:28][CH:29]([CH3:31])[CH3:30])=[N:26][N:27]=5)[CH:21]=4)[N:16]([S:32]([C:35]4[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=4)(=[O:34])=[O:33])[CH:15]=3)[N:5]=2)[CH2:3][CH2:2]1.C1COCC1.O.[OH-].[Li+].Cl>O>[CH:1]1([C:4]2[C:9]([C:10]([OH:12])=[O:11])=[CH:8][N:7]=[C:6]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]5[O:24][C:25]([NH:28][CH:29]([CH3:31])[CH3:30])=[N:26][N:27]=5)[CH:21]=4)[N:16]([S:32]([C:35]4[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=4)(=[O:33])=[O:34])[CH:15]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1cnc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccc(-c4nnc(NC(C)C)o4)cc23)nc1C1CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(C(=O)O)c(C4CC4)n3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methyl 4-cyclopropyl-2-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)pyrimidine-5-carboxylate (110 mg, 0.192 mmol) was treated with THF (2 mL), water (1.0 mL) and lithium hydroxide monohydrate (20 mg, 0.48 mmol) and stirred at RT for 1.5 h. The reaction mixture was treated with a 5 N HCl (0.5 mL) and concentrated on the rotovap. It was then dried further by azeotroping with toluene and drying under high vacuum at 50° C. for 3 h. MS (ESI, pos. ion) m/z: 559.0 (M+H)+. It was then used in the subsequent step with further purification.
Reaction SMILES: Br[CH:2]1[CH2:8][NH:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]2[C:13]([CH3:16])=[N:14][N:15]=[C:3]12.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][C:13]1[N:4]2[C:5]3[CH:12]=[CH:11][C:10]([C:25]4[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=4)=[CH:9][C:6]=3[NH:7][CH2:8][CH2:2][C:3]2=[N:15][N:14]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1nnc2n1-c1ccccc1NCC2Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nnc2n1-c1ccc(-c3ccc(N)nc3)cc1NCC2
Yield: 65.3 %

Procedure:
A solution of bromo-1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (30 mg, 0.11 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (48 mg, 0.22 mmol), Tetrakis(triphenylphosphine)palladium(0) (10 mg) and Cs2CO3 (72 mg, 0.22 mmol) in dioxane (5 mL) and water (1 mL) was heated at 120° C. under microwave for 20 min. The reaction mixture was concentrated to give the crude product, which was purified by prep-TLC (DCM:MeOH=10:1) to afford 5-(1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-8-yl)pyridin-2-amine (21 mg, yield 55%).
Reaction SMILES: [CH2:1]([C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([Br:11])[C:5]=1[OH:12])[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:18].C(=O)([O-])[O-].[K+].[K+]>>[Br:11][C:6]1[C:5]2[O:12][CH:2]([CH2:3][OH:18])[CH2:1][C:4]=2[C:9]([F:10])=[CH:8][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1c(F)ccc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OCC1Cc2c(F)ccc(Br)c2O1
Yield: 69.6 %

Procedure:
Treatment of 2-allyl-6-bromo-3-fluorophenol (9.01 g, 0.039 mol) with 3-chloroperoxybenzoic acid (77%, 13.46 g, 0.06 mol) followed by potassium carbonate (13.82 g, 0.10 mol) generally according to the reaction procedure described for Intermediate 9 gave 6.71 g (70%) of (±)-(7-bromo-4-fluoro-2,3-dihydro-1-benzofuran-2-yl)methanol as a white solid. Rf=0.20 (silica, ethyl acetate:hexanes 1:4); mp 40-43° C.; Anal. calcd. for C9H8BrFO2.0.2H2O: C, 43.13; H, 3.38. Found: C, 42.94; H, 3.15.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[CH2:20][CH2:19][C:18]([CH2:27][CH2:28][OH:29])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:17][C:16]2=[O:30])[CH:10]=1.CC(C)=[O:33].OS(O)(=O)=O.O=[Cr](=O)=O.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[CH2:20][CH2:19][C:18]([CH2:27][C:28]([OH:33])=[O:29])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:17][C:16]2=[O:30])[CH:10]=1
Reactant: O=C1OC(CCO)(c2ccccc2)CCN1c1cccc(-c2ccc(F)cc2F)c1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Product: O=C(O)CC1(c2ccccc2)CCN(c2cccc(-c3ccc(F)cc3F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 100-mL of flask was charged with 3-(2′,4′-difluorobiphenyl-3-yl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one (1 g, 2.4 mmol) dissolved in acetone (10 mL). Jones reagent (CrO3: 1 g; H2SO4: 1 mL, H2O: 4 mL) was added at 0° C. under N2 protection. The mixture was stirred overnight at rt. Aqueous K2CO3 (5 mL) was added and the mixture was extracted with EtOAc (3×15 mL). The organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The residue (1.03 g) was used directly for the next step.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:44])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:43])[CH2:9][CH2:10][C@@:11]3([C:27]([N:29]4[CH2:34][CH2:33][C:32]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)([C:35]#[N:36])[CH2:31][CH2:30]4)=[O:28])[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]32)[C:3]1([CH3:46])[CH3:45].N1C=CC=CC=1.[CH3:53][C:54]1([CH3:61])[CH2:58][C:57](=[O:59])[O:56][C:55]1=[O:60]>C(OCC)(=O)C>[C:35]([C:32]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:33][CH2:34][N:29]([C:27]([C@:11]23[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]2[C@@H:13]2[C@@:8]([CH3:43])([CH2:9][CH2:10]3)[C@@:7]3([CH3:44])[C@@H:16]([C@:17]4([CH3:20])[C@@H:4]([CH2:5][CH2:6]3)[C:3]([CH3:46])([CH3:45])[C@@H:2]([O:1][C:57](=[O:59])[CH2:58][C:54]([CH3:61])([CH3:53])[C:55]([OH:60])=[O:56])[CH2:19][CH2:18]4)[CH2:15][CH2:14]2)=[O:28])[CH2:30][CH2:31]1)#[N:36]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N3CCC(C#N)(c4ccccc4)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC1(C)CC(=O)OC1=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N3CCC(C#N)(c4ccccc4)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
To a stirred solution of ((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carbonyl)-4-phenylpiperidine-4-carbonitrile (Example 76, 0.5 g, 0.80 mmol) in pyridine (5 ml) dimethyl amino pyridine (0.2 g, 1.6 mmol) was added then 3,3-dimethyldihydrofuran-2,5-dione (0.82 ml) was added and the contents were refluxed for about 16 hours. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with ethyl acetate (30 ml). The organic layer was washed with 5% aqueous HCl, washed with water followed by brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.25 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.95-1.16 (m, 19H); 1.23-1.78 (m, 23H); 2.15-2.59 (m, 11H); 2.77-3.58 (m, 16H); 4.33-4.70 (m, 4H); 5.58-5.60 (s, 1H); 5.78-5.80 (s, 1H); 7.44-7.47 (s, 1H); ES Mass: 753 (100%), [M+1].
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[OH:22][CH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][NH:28][CH2:27]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[OH:22][CH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][N:28]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:27]2
Reactant: OCc1ccc2c(c1)CNC2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1c(F)c(N2Cc3ccc(CO)cc3C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 24.8 %

Procedure:
298 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 179 mg of 5-hydroxymethylisoindoline, 304 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 106 mg of the target compound.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([O:18]C(C)(C)C)=[O:17])=[C:5]2[C@@H:4]2[CH2:23][CH2:24][N:3]12>FC(F)(F)C(O)=O>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([OH:18])=[O:17])=[C:5]2[C@@H:4]2[CH2:23][CH2:24][N:3]12
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Reaction time: 1 h

Procedure:
1.77 g (5.4 mmol) of t-butyl (S)-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate are stirred in 14 ml of trifluoroacetic acid at 50° for 3 hours and at 65° for 3.5 hours. Subsequently, the mixture is evaporated to dryness and the residue is heated on a steam-bath for 2.5 hours in a high vacuum. The material is treated with ether, stirred for 1 hour while cooling with ice, the solid material is filtered off under suction while back-washing with ether and then dried. There is obtained (S)-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid of melting point 232°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[N:19]1([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O.C(N(CC)CC)C>[N:19]1([C:25]2[CH:26]=[C:27]([C:28]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([C@@H:8]4[CH2:10][C@H:9]4[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[CH:4][CH:3]=3)=[O:29])[CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(N)cc1
Reactant: O=C(O)c1cccc(N2CCCCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(N3CCCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl]carbamate (105 mg) described in a document (J. Am. Chem. Soc., 2010, 132, 6827.) in acetonitrile (3 mL) were added 3-(piperidin-1-yl)benzoic acid (105 mg) described in a document (J. Med. Chem. 1997, 40, 331.), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (81 mg), 1-hydroxybenzotriazole (57.2 mg) and triethylamine (59 μL). The mixture was stirred at room temperature overnight and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (142 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[S:6](=[O:17])(=[O:16])[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](=S)[NH:10][C:4]=2[CH:3]=1.[NH2:20][CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>C(OCCO)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[S:6](=[O:17])(=[O:16])[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]([NH:20][CH2:21][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: O=S1(=O)c2ccc(Cl)cc2NC(=S)c2ccccc21
Reactant: NCc1cccnc1
Solvent: CCOCCO
Product: O=S1(=O)c2ccc(Cl)cc2N=C(NCc2cccnc2)c2ccccc21

Procedure:
A solution of 0.46 g (1.5 mmol) of 8-chloro-5,5-dioxo-dibenzo[b,f]-1,4-thiazepin-11(10H)-thione in 15 mL of 2-ethoxyethanol was treated with 0.3 mL (3.0 mmol) of 3-(aminomethyl)pyridine and heated at reflux overnight. An additional 0.4 mL of 3-(aminomethyl)pyridine was added and the refluxing continued another night. The solvent was removed under reduced pressure and the residue taken up in EtOAc and washed three times with H2O, then saturated NaHCO3 solution and saturated NaCl solution. Drying over MgSO4 and removal of the solvent under reduced pressure left the crude product. Chromatography on silica gel, eluting with CHCl3 /MeOH (97/3) followed by precipitating the product from acetone with H2O gave an amorphous tan solid. The structure was confirmed by NMR and mass spectroscopy. (m+H)+ =384.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:56])[C@@H:24]([NH:25][C:26](=[O:55])[C@@H:27](C4C=CC(C(OC(C)(C)C)=O)=CC=4N)[NH:28][C:29]([N:31]4[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[C:33](=[O:39])[C:32]4=[O:40])=[O:30])[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:57][S:58][C:59]2[N:63]([CH3:64])[N:62]=[N:61][N:60]=2)=[O:16])C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[C:66]1([CH3:76])[CH:71]=[CH:70][C:69]([S:72]([OH:75])(=[O:74])=[O:73])=[CH:68][CH:67]=1.[C:77](#[N:79])[CH3:78]>>[C:66]1([CH3:76])[CH:67]=[CH:68][C:69]([S:72]([OH:75])(=[O:73])=[O:74])=[CH:70][CH:71]=1.[C:66]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:56])[C@@H:24]([NH:25][C:26](=[O:55])[C@@H:27]([C:1]4[CH:2]=[CH:3][C:77]([NH2:79])=[CH:78][CH:6]=4)[NH:28][C:29]([N:31]4[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[C:33](=[O:39])[C:32]4=[O:40])=[O:30])[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:57][S:58][C:59]2[N:63]([CH3:64])[N:62]=[N:61][N:60]=2)=[O:16])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=1
Reactant: CCN1CCN(C(=O)N[C@@H](C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CSc4nnnn4C)CS[C@H]23)c2ccc(C(=O)OC(C)(C)C)cc2N)C(=O)C1=O
Reactant: CC#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCN1CCN(C(=O)N[C@@H](C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CSc4nnnn4C)CS[C@H]23)c2ccc(N)cc2)C(=O)C1=O

Procedure:
In the manner described in Example 11, 3.40 g of 3-[(1-methyl-1H-tetrazol-5-yl)-thiomethyl]-7β-[(2R)-2-(4-BOC-aminophenyl)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted with 1.38 g of p-toluenesulphonic acid monohydrate in 30 ml of acetonitrile and worked up. 3-[(1-Methyl-1H-tetrazol-5-yl)-thiomethyl]-7β-[(2R)-2-(4-aminophenyl)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester p-toluenesulphonate is obtained. [α]D20 =-32°±1° (0.96% in DMSO).
Reaction SMILES: [CH2:1]=[C:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:13]([N+:20]([O-:22])=[O:21])([N+:17]([O-:19])=[O:18])[N+:14]([O-:16])=[O:15]>O.CO>[N+:14]([C:13]([N+:20]([O-:22])=[O:21])([N+:17]([O-:19])=[O:18])[CH2:1][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9])([O-:16])=[O:15]
Reactant: O=[N+]([O-])C([N+](=O)[O-])[N+](=O)[O-]
Reactant: C=C(C(=O)OCC)C(=O)OCC
Solvent: O
Solvent: CO
Product: CCOC(=O)C(CC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-])C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.4 %

Procedure:
Freshly distilled diethyl methylene-malonate (8.0 g, 0.046 mol) was added dropwise with stirring over a 10 min period to a solution of 16 g (0.1 mol) of nitroform in 25 ml of water and 40 ml of methanol at 0°-5°. The mixture was stirred 16 hrs at room temperature and was then extracted with 100 ml of methylene chloride. The methylene chloride solution was washed with 10% sodium bicarbonate and with water, dried over sodium sulfate and stripped of solvent under vacuum. Column chromatography on 200 g of silica gel (CCl4 --CH2Cl2), filtration through charcoal and removal of solvent gave 13.0 g (87%) of diethyl 2,2,2-trinitroethylmalonate, mp 24°-25°; NMR (CDCl3), 4.23 (q, 4 H, J=7 Hz, CH2CH3), 3.80 (m, 3 H, CH--CH2) and 1.33 (t, 6 H, J=7 Hz, CH3); IR (neat) 1730 (C=O) and 1600 (NO2) cm-1.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH3:21])=[O:18])[CH2:13][CH2:14]SC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI>CC(C)=O.C(#N)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:13][CH2:14][N:19]([C@@H:20]([CH3:21])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]1=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C)C(=O)OC(C)(C)C
Solvent: CI
Solvent: CC(C)=O
Solvent: CC#N
Product: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 27.8 %

Procedure:
A solution of tert-butyl N-[(benzyloxy)carbonyl]-l-methionyl-D-alaninate (11.9 g) in acetone (75 ml) was treated with methyl iodide (18 ml) and stirred at room temperature for 72 h. The reaction mixture was then concentrated under reduced pressure to give an orange solid which was dissolved in acetonitrile (200 ml). Dowex (OH− form) resin (19.42 g) was added and the mixture stirred for 18 h at room temperature. The mixture was filtered and the resin washed with ethyl acetate. The filtrate was evaporated under reduced pressure to afford a yellow oil which was purified by Biotage™ chromatography (eluting with cyclohexane/ethyl acetate 3:2) to give the title compound (2.92 g) as a colourless oil.
Reaction SMILES: FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[CH3:15][O:16][C:17]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH2:28][O:29][CH3:30])=[CH:22]2)=[O:18].[Cl:31][C:32]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:33]=1[CH:34]=O.[OH-].[Na+]>ClCCl.C(Cl)(Cl)Cl>[Cl:31][C:32]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:33]=1[CH2:34][C:22]1[C:21]2[C:25](=[CH:26][CH:27]=[C:19]([C:17]([O:16][CH3:15])=[O:18])[CH:20]=2)[NH:24][C:23]=1[CH2:28][O:29][CH3:30]
Reactant: COCc1cc2cc(C(=O)OC)ccc2[nH]1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COCc1[nH]c2ccc(C(=O)OC)cc2c1Cc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 32.1 %

Procedure:
Trifluoroacetic acid (1.14 g) and triethylsilane (2.33 g) are dissolved in dichloromethane (10 ml), and the resulting solution is cooled at 0° C., to which is dropwise added a solution of 5-methoxycarbonyl-2-(methoxymethyl)indole (1.10 g) and 2,4-dichlorobenzaldehyde (0.96 g) dissolved in dichloromethane (20 ml). The reaction mixture is stirred at 0° C. for 3 hours, and thereafter an aqueous solution of 10% sodium hydroxide (5 ml), chloroform (40 ml) and a saturated saline solution (40 ml) are added thereto in that order for liquid-liquid separation. The organic layer is dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified through silica gel column chromatography (ethyl acetate/hexane=3/7) to obtain 3-(2,4-dichlorobenzyl)-5-methoxycarbonyl-2-(methoxymethyl)indole (161) (0.61 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([NH2:9])[C:3]=1[OH:10].[CH3:11][C:12]1([N:18]2[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C([BH3-])#N.C(O)(=O)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([NH:9][CH:21]2[CH2:22][CH2:23][N:18]([C:12]3([CH3:11])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH2:19][CH2:20]2)[C:3]=1[OH:10]
Reactant: CC1(N2CCC(=O)CC2)CCOCC1
Reactant: Cc1cc(N)c(O)c(F)c1
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(F)c(O)c(NC2CCN(C3(C)CCOCC3)CC2)c1
Temperature: 25 °C
Yield: 46.5 %

Procedure:
2-Amino-6-fluoro-4-methylphenol (D16, 49 mg, 0.34 mmol) was dissolved in DCM (3 mL) and 1-(4-methyltetrahydro-2H-pyran-4-yl)-4-piperidinone (D12, 68 mg, 0.34 mmol), polymer supported cyanoborohydride (160 mg, 0.69 mmol, 4.3 mmol/g) and acetic acid (0.10 mL, 1.72 mmol) were all added at room temperature. The mixture was reacted at 100° C. in the microwave for 10 min. The mixture was then cooled to room temperature, filtered and the solvent was removed under vacuum to give the crude product, an orange oil, which was purified via flash column chromatography (silica, DCM to 0.5% NH3/9.5% MeOH/90% DCM) to give 2-fluoro-4-methyl-6-{[1-(4-methyltetrahydro-2H-pyran-4-yl)-4-piperidinyl]amino}phenol (D17, 51 mg, 42%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[N:10]([CH3:21])[N:9]=2)=[C:4]([F:22])[CH:3]=1.[N+:23]([O-])([OH:25])=[O:24]>>[Cl:1][C:2]1[C:7]([N+:23]([O-:25])=[O:24])=[CH:6][C:5]([C:8]2[C:12]([C:13]([F:16])([F:14])[F:15])=[C:11]([C:17]([F:18])([F:19])[F:20])[N:10]([CH3:21])[N:9]=2)=[C:4]([F:22])[CH:3]=1
Reactant: Cn1nc(-c2ccc(Cl)cc2F)c(C(F)(F)F)c1C(F)(F)F
Reactant: O=[N+]([O-])O
Product: Cn1nc(-c2cc([N+](=O)[O-])c(Cl)cc2F)c(C(F)(F)F)c1C(F)(F)F
Temperature: 0 °C
Yield: 59 %

Procedure:
10.5 g (30 mmol) of 3-(4-chloro-2-fluorophenyl)-l-methyl-4,5-di(trifluoromethyl)-1H-pyrazole were added, at (-40)° C. to 90 ml of concentrated nitric acid, whereupon the mixture was stirred for 1 hour. Then, the mixture was stirred in 0.8 1 of ice-water. The product of value was subsequently extracted with dichloromethane. The organic phase was dried over magnesium sulfate and finally concentrated. Yield: 59%.
Reaction SMILES: C([O-])(=[O:3])C.[Na+].[Cl:6][C:7]1[CH:8]=[C:9]([NH:25][C:26](=[O:30])[C:27]([OH:29])=[O:28])[CH:10]=[C:11]([Cl:24])[C:12]=1[O:13][C:14]1[N:15]=[N:16][C:17](Cl)=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=1>C(O)(=O)C>[Cl:6][C:7]1[CH:8]=[C:9]([NH:25][C:26](=[O:30])[C:27]([OH:29])=[O:28])[CH:10]=[C:11]([Cl:24])[C:12]=1[O:13][C:14]1[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[C:17](=[O:3])[NH:16][N:15]=1
Reactant: CC(=O)[O-]
Reactant: CC(C)c1cc(Oc2c(Cl)cc(NC(=O)C(=O)O)cc2Cl)nnc1Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)c1cc(Oc2c(Cl)cc(NC(=O)C(=O)O)cc2Cl)n[nH]c1=O
Temperature: 100 °C
Yield: 56.1 %

Procedure:
A mixture of glacial acetic acid (55 mL), sodium acetate (1.2 g, 14.7 mmol) and N-[3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-oxalamic acid (28) (1.7 g, 4.2 mmol) was heated to 100° C. for 24 h. The reaction mixture was cooled to room temperature and was concentrated under vacuum. The resulting solid was diluted with water (50 mL). The mixture was made acidic to pH=3 by the addition of glacial acetic acid. The solids were filtered and rinsed well with water and dried on the funnel. The solid was slurried in 1:1:2 isopropyl acetate: methyl tert-butyl ether:hexanes (3 mL) and then was heated to reflux. The mixture was cooled and filtered. A slight amount of impurity was detected by TLC. The solid was slurried in isopropyl acetate (10 mL) and filtered. The resulting pure solid was dried under high vacuum for 24 h and then dried in a vacuum oven at 80° C. for 24 h to afford N-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-oxalamic acid (29) (0.91 g, 56%) as a white solid; EI(+)-HRMS m/z calcd for C15H13Cl2N3O5 (M+H) 386.0305, found 386.0308. Molecular Weight=386.1940; Exact Mass=385.0232
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:11]([CH3:41])[CH:12]=[C:13]([CH:15]([OH:40])[C:16]3[N:17]=[CH:18][N:19]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:20]=3)[CH:14]=2)=[O:9])=[CH:4][CH:3]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:11]([CH3:41])[CH:12]=[C:13]([C:15]([C:16]3[N:17]=[CH:18][N:19]([C:21]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:20]=3)=[O:40])[CH:14]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1C(=O)c1ccc(Cl)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cn1cc(C(=O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1C(=O)c1ccc(Cl)cc1
Yield: 91.2 %

Procedure:
A solution 2.2 g of (4-chloro-phenyl)-{4-[hydroxy-(1-trityl-1H-imidazol-4-yl)-methyl]-1-methyl-1H-pyrrol-2-yl}methanone in 50 mL of CH2Cl2 was stirred with 2.5 g of activated manganese dioxide overnight. The reaction was filtered and the filtrate was evaporated in vacuo to give 2.0 g of (4-chlorophenyl)-[1-methyl-4-(1-trityl-1H-imidazole-4-carbonyl)-1H-pyrrol-2yl]methanone. CI-MS m/z=556 (M++H).