Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](C)([CH3:6])[C:3](Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].[Cl:12][C:13]1[CH:48]=[CH:47][C:16]([CH2:17][N:18]2[C:26]3[C:21](=[CH:22][C:23]([O:27][CH2:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)=[CH:24][CH:25]=3)[CH:20]=[C:19]2[CH2:39][C:40]([CH3:46])([CH3:45])[C:41]([O:43][CH3:44])=[O:42])=[CH:15][CH:14]=1.C(C(C(C([O-])=O)O)O)([O-])=O>C(Cl)Cl.CCOC(C)=O>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][N:18]2[C:26]3[C:21](=[CH:22][C:23]([O:27][CH2:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)=[CH:24][CH:25]=3)[C:20]([C:2]([CH3:6])([CH3:3])[CH3:1])=[C:19]2[CH2:39][C:40]([CH3:45])([CH3:46])[C:41]([O:43][CH3:44])=[O:42])=[CH:47][CH:48]=1
Reactant: COC(=O)C(C)(C)Cc1cc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)Cc1c(C(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Trimethylacetyl chloride (4.23 g, 4.32 mL, 35.09 mmol) was added to a cold suspension (0° C.) of AlCl3 (11.7 g, 87.7 mmol) in dry CH2Cl2 (60 mL) under Ar. The yellow mixture was stirred at 0° C. for 15 minutes, and a solution of 9.00 g (17.54 mmol) of methyl 3-[N-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate (prepared in Step A) in CH2Cl2 (40 mL) was added dropwise (over 10 minutes) at 0° C. The reaction mixture was stirred for 10 minutes and slowly poured onto an ice-cold and vigourously stirred mixture of 0.5M aqueous Na, K tartrate (500 mL) and EtOAc (400 mL). After 20 minutes, the aqueous layer was extracted with EtOAc (2×) and the combined organic extracts were washed with H2O (2×), with 1N aqueous NaOH (2×), with H2O (2×) and dried (MgSO4). Filtration and removal of solvents provided a yellow oily residue which was chromatographed on silica gel using EtOAc-hexane (1:4) to give the title compound.
Reaction SMILES: [CH:1]([N:4]1[C:8]([CH3:9])=[C:7]([C:10]([O:12]CC)=[O:11])[CH:6]=[N:5]1)([CH3:3])[CH3:2].[OH-].[Li+]>>[CH:1]([N:4]1[C:8]([CH3:9])=[C:7]([C:10]([OH:12])=[O:11])[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnn(C(C)C)c1C
Agent: [Li+]
Agent: [OH-]
Product: Cc1c(C(=O)O)cnn1C(C)C
Yield: 6.9 %

Procedure:
In a procedure analogous to Example B6, ethyl 1-isopropyl-5-methyl-1H-pyrazole-4-carboxylate (537 mg, 2.74 mmol) and lithium hydroxide (459 mg, 10.95 mmol) were combined to give 1-isopropyl-5-methyl-1H-pyrazole-4-carboxylic acid (32 mg, 70% yield) as an off white solid. MS (ESI) m/z: 169.0 (M+H+).
Reaction SMILES: ClC1C=CC([C@H]([C@H](CC)C=C)C(O)=O)=CC=1.[CH2:17]([OH:22])/[CH:18]=[CH:19]/[CH2:20][CH3:21].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=1>>[CH2:17]([O:22][C:32](=[O:33])[CH2:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=1)[CH:18]=[CH:19][CH2:20][CH3:21]
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: CC/C=C/CO
Agent: C=C[C@@H](CC)[C@H](C(=O)O)c1ccc(Cl)cc1
Product: CCC=CCOC(=O)Cc1ccc(OC)cc1

Procedure:
The ester I3a was prepared as described in Step A of example I2, using trans-2-penten-1-ol (49.6 ml; 487.6 mmol) and (4methoxy-phenyl)-acetic acid (81 g; 487.6 mmol) Yield: 57.7 g (52%) of a yellow oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[C:12](Cl)(=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]>CCOCC>[C:12]([CH:4]([C:5]([CH3:7])=[O:6])[C:3]([O:9][CH2:10][CH3:11])=[O:8])(=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCCCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCCCC(=O)C(C(C)=O)C(=O)OCC
Yield: 80.2 %

Procedure:
Sodium hydride (50% in oil, 39.6 g) was added portionwise to a solution of ethyl acetoacetate (107.5 g) in dry ether under nitrogen. Valeryl chloride (100 g) was added dropwise over 21/2 hours to the stirred suspension, and then poured into distilled water (500 ml.), and the ether layer was separated off and dried. The ether was removed to give ethyl 2-valerylacetoacetate (142 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:5][NH:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:16][C:17]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:18]=3[C:19]([O:21]C)=[O:20])[CH:13]=2)[CH2:8]1>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:5][NH:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:16][C:17]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:18]=3[C:19]([OH:21])=[O:20])[CH:13]=2)[CH2:8]1
Reactant: COC(=O)c1cc(OC)ccc1Nc1ccc2c(c1)CC(NCc1ccc(Cl)c(Cl)c1)C2
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Nc2ccc3c(c2)CC(NCc2ccc(Cl)c(Cl)c2)C3)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 23.8 %

Procedure:
The methyl benzoate (0.130 g) was taken up in 20 mL 1:1 THF/MeOH and was treated with 1 M LIOH (3 mL). The mixture was stirred at room temperature for 48 hours. The mixture was then concentrated, and the residual oil was purified by chromatography (MPLC, silica, gradient 95:5 to 75:25 (CH2Cl2/MeOH). Fractions containing the desired product were combined, concentrated, and dried in vacuo overnight to give 2-[2-(3,4-dichlorobenzylamino)-indan-5-ylamino]-5-methoxy-benzoic acid (0.03 g, 24% yield). MS (APCI) m/z 457.0 (M++1). CHN for (C24H22Cl2N2O3·0.6H2O) calc: C, 61.57, H, 4.98, N, 5.98; found: C, 61.23, H, 4.88, N, 5.69.
Reaction SMILES: [C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[N:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:11][CH:10]([NH:26][C:27](=[O:44])[C@@H:28]([NH:36]C(OC(C)(C)C)=O)[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:9]1=[O:45])=[O:6])([CH3:4])([CH3:3])[CH3:2]>Cl.O1CCOCC1>[C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[N:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:11][CH:10]([NH:26][C:27](=[O:44])[C@@H:28]([NH2:36])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:9]1=[O:45])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)C(NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)CN2c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)C(NC(=O)[C@@H](N)Cc1ccccc1)CN2c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
1-tert-Butylcarbonylmethyl-2-oxo-3-[(2S)-(2-tert-butoxycarbonylamino-3-phenylpropionyl)amino]-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (8.06 g) was dissolved in 4N HCl-dioxane (40 ml), the solution was stirred for one hour at room temperature. The reaction mixture was concentrated under reduced pressure, neutralized with saturated aqueous sodium bicarbonate, and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography(ethyl acetate contained water), to thereby obtain 3.01 g of (+)-1-tert-butylcarbonylmethyl-2-oxo-3-[(2S)-(2-amino-3-phenylpropionyl)amino]-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine of first eluent and 3.17 g of (−)-1-tert-butylcarbonylmethyl-2-oxo-3-[(2S)-(2-amino-3-phenylpropionyl)amino]-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine of second eluent.
Reaction SMILES: [OH-].[Na+].Cl.Cl.C([O:7][C:8]([C@@H:10]([NH:21][C@H:22]1[CH2:28][S:27][C@H:26]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)[CH2:25][N:24]([CH2:34][C:35]([OH:37])=[O:36])[C:23]1=[O:38])[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[O:9])C>>[C:8]([C@@H:10]([NH:21][C@H:22]1[CH2:28][S:27][C@H:26]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)[CH2:25][N:24]([CH2:34][C:35]([OH:37])=[O:36])[C:23]1=[O:38])[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([OH:9])=[O:7]
Reactant: CCOC(=O)[C@H](CCCCC1CCNCC1)N[C@H]1CS[C@H](c2cccs2)CN(CC(=O)O)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CN1C[C@@H](c2cccs2)SC[C@H](N[C@@H](CCCCC2CCNCC2)C(=O)O)C1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 76.6 %

Procedure:
1.54 ml of a 1N aqueous solution of sodium hydroxide was added to 150 mg of α-{6(R)-[1(S)-ethoxycarbonyl5-(4-piperidyl)pentylamino]-5-oxo-2(S)-(2-thienyl)perhydro-1,4-thiazepin-4-yl}acetic acid dihydrochloride (prepared as described in Example 19), and the mixture was stirred at room temperature for 17 hours. At the end of this time, the reaction mixture was adjusted to a pH value of 4.7 by adding 1N aqueous hydrochlodric acid, and the precipitate was collected by filtration, to give 95 mg of the title compound.
Reaction SMILES: O[C@@:2]1([C:16]2[S:17][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([NH:28][C:29]4[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=4)[N:22]=3)=[CH:19][N:20]=2)[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]1=2.[N-:39]=[N+:40]=[N-:41].[Na+].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:39]([C:2]1([C:16]2[S:17][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([NH:28][C:29]4[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=4)[N:22]=3)=[CH:19][N:20]=2)[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]1=2)=[N+:40]=[N-:41]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccc2c(c1)CCC[C@@]2(O)c1ncc(-c2cc(C)cc(Nc3cc(C(F)(F)F)ccn3)n2)s1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CCCC2(N=[N+]=[N-])c1ncc(-c2cc(C)cc(Nc3cc(C(F)(F)F)ccn3)n2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of (S)-methyl 5-hydroxy-5-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate (100 mg, 0.185 mmol) and sodium azide (36.1 mg, 0.555 mmol) in DCM (2 mL) at rt was added TFA (0.016 mL, 0.203 mmol) dropwise and the mixture was stirred at rt for 16 h, after which time the reaction was heated to 40° C. for 5 days. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude methyl 5-azido-5-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate as a brown oil, which was used as such for the following transformation. MS ESI calcd for C27H22F3N7O2S [M+H]+ 566, found 566.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C(N1C(=O)[C:23]([CH3:26])=[C:22]([CH3:27])[N:21]=[C:20]1[C@H:28]([N:32]([CH2:42][CH2:43][N:44]1C(=O)C2C(=CC=CC=2)C1=O)[C:33](=O)[C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=1)[CH:29]([CH3:31])[CH3:30])C1C=CC=CC=1.O.NN>C(O)C>[CH2:4]([N:5]1[C:1](=[O:11])[C:23]([CH3:26])=[C:22]([CH3:27])[N:21]=[C:20]1[C@H:28]([N:32]1[CH2:42][CH2:43][N:44]=[C:33]1[C:34]1[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=1)[CH:29]([CH3:31])[CH3:30])[C:3]1[CH:2]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1ccc(C(=O)N(CCN2C(=O)c3ccccc3C2=O)[C@@H](c2nc(C)c(C)c(=O)n2Cc2ccccc2)C(C)C)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1ccc(C2=NCCN2[C@@H](c2nc(C)c(C)c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 120 °C

Procedure:
The phthalimide protected amine, N-[(R)-1-(1-benzyl-4,5-dimethyl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-2-methyl-propyl]-N-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-4-methyl-benzamide, (0.075 g, 0.13 mMol) was treated with hydrazine monohydrate (0.013 ml, 0.26 mMol) in ethanol (1 mL at 70° C. for 12 h. The reaction was filtered, concentrated under vacuum and dissolved in toluene (1 mL) and heated to 120° C. for 20 h. The reaction was concentrated under vacuum, taken up in CH3CN and purified by reverse phase HPLC (YMC, ODS-A, 20 min, 5–90% gradient, CH3CN : H2O, 0.1% TFA) The fractions were collected and evaporated to give the title compound as a clear oil. (0.016 g): MS (ES) m/e 429.4 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:17][C:16]=2[CH2:27][N:28]2[CH2:32][CH2:31][O:30][C:29]2=[O:33])[CH:7]=1)C.CO.[OH-].[Li+]>O>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:34])=[O:3])=[CH:7][C:8]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[CH:17][C:16]=1[CH2:27][N:28]1[CH2:32][CH2:31][O:30][C:29]1=[O:33]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N3CCOCC3)cc2CN2CCOC2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(CC(=O)O)cc1Oc1ccc(N2CCOCC2)cc1CN1CCOC1=O
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
{4-Methoxy-3-[4-morpholin-4-yl-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-phenyl}-acetic acid ethyl ester (0.43 mmol) ini MeOH and H2O was treated with lithium hydroxide, and the reaction was stirred at 60° C. for 20 minutes. The mixture was acidified and concentrated, and the reside was purified by preparative HPLC to give the title compound.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:12]1[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]1[OH:14].[C:21]1([CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][NH2:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(O)C>[C:30]1([CH:27]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:28][NH:29][C:2]2[C:3]3[N:4]=[CH:5][N:6]([C:7]=3[N:8]=[C:9]([NH2:11])[N:10]=2)[C@@H:12]2[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]2[OH:14])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Nc1nc(Cl)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reactant: NCC(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1

Procedure:
A mixture of 1.25 g of 6-chloro-2-amino-9-(β-D-ribofuranosyl)purine, 0.899 g of 2,2-diphenylethylamine and 0.503 g of triethylamine is heated under reflux in 30 ml of absolute ethanol under a nitrogen atmosphere for 18 hours. The solvent is evaporated to dryness and residue is treated with 50 ml of cold water. The insoluble organic material is filtered, dried, and purified by medium pressure liquid chromatography on silica gel. The product is eluted with 10% methanol-chloroform. Evaporation of the solvent from the pure fractions affords a colorless solid material. Crystallization from a mixture of CHCl3 -2-propanol (10:1) and hexane affords N6 -(2,2-diphenylethyl)-2-aminoadenosine, mp 134°-137° C.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@H:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([OH:28])=[O:27])[N:3]=1.[CH3:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:21][O:20][C:13]1[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=1[CH2:11][N:9]1[CH2:10][C:6]2[C:5]([F:23])=[C:4]([NH:24][C@H:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([OH:28])=[O:27])[N:3]=[C:2]([C:37]3[CH:36]=[N:35][N:34]([CH3:33])[CH:38]=3)[C:7]=2[C:8]1=[O:22]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@H](CC(C)C)C(=O)O)nc(Cl)c3C2=O)c(OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(CN2Cc3c(F)c(N[C@H](CC(C)C)C(=O)O)nc(-c4cnn(C)c4)c3C2=O)c(OC)c1

Procedure:
A solution of (R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)-4-methylpentanoic acid (1.1 g, 2.361 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.456 g, 11.81 mmol) and bis(triphenylphosphine)palladium chloride (1.657 g, 2.361 mmol) in dioxane (10 mL) and saturated aq Na2CO3 (10.00 mL) was heated to 120° C. for 30 min. After filtering out the solids, the solvent was removed from the filtrate. The resulting residue was dissolved in MeOH and DCM and was purified via preparative HPLC eluting with water (0.05% TFA) and ACN (40-70% gradient, 0.035% TFA). The collected fractions were combined and the solvent stripped to dryness via rotary evaporation to yield the title compound. [M+H] calc'd for C26H30FN5O5, 512. found, 512.
Reaction SMILES: C(O[C:4]1[CH2:10][C:9](=[O:11])[N:8]([CH2:12][C:13]([N:15]([CH:22]([CH3:24])[CH3:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[C:7]2[CH:25]=[CH:26][CH:27]=[CH:28][C:6]=2[N:5]=1)C.[OH:29][C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=1)[C:33]([NH:35][NH2:36])=O>C(O)(=O)C>[OH:29][C:30]1[CH:31]=[C:32]([C:33]2[N:5]3[C:4]([CH2:10][C:9](=[O:11])[N:8]([CH2:12][C:13]([N:15]([CH:22]([CH3:23])[CH3:24])[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[O:14])[C:7]4[CH:25]=[CH:26][CH:27]=[CH:28][C:6]=43)=[N:36][N:35]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: CCOC1=Nc2ccccc2N(CC(=O)N(c2ccccc2)C(C)C)C(=O)C1
Reactant: NNC(=O)c1cccc(O)c1
Solvent: CC(=O)O
Product: CC(C)N(C(=O)CN1C(=O)Cc2nnc(-c3cccc(O)c3)n2-c2ccccc21)c1ccccc1
Temperature: 120 °C

Procedure:
To a solution of 2-(4-ethoxy-2-oxo-2,3-dihydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl-acetamide (Preparation 5(B) (177 mg, 0.466 mmol) in glacial acetic acid (4 mL) was added 3-hydroxy benzhydrazide (90 mg, 0.591 mmol). The reaction was heated to 120° C. for 3 hours, was cooled to room temperature, and was concentrated in vacuo. The residue was triturated with 50% Et2O in hexanes and the solids were filtered. The solids were dissolved in CH2Cl2 and the organic solution was washed with aqueous NaHCO3, dried (MgSO4) and concentrated to provide 244 mg of 2-[1-(3-hydroxy-phenyl)-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-phenyl-acetamide. 1H NMR (CD3OD) δ7.74 (s, 2H), 7.56-7.18 (m, 10H), 6.91 (m, 1H), 4.86 (m, 1H), 4.30-4.10 (m, 2H), 3.98 (d, 1H), 3.71 (d, 1H), 1.06 (m, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C(N(CC)CC)C.[F:18][C:19]([F:36])([F:35])[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:27]([C:32](Cl)=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][CH:21]=1>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:32]([C:27]2[C:26]([C:23]3[CH:24]=[CH:25][C:20]([C:19]([F:18])([F:35])[F:36])=[CH:21][CH:22]=3)=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:33])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: Nc1cccc([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc([N+](=O)[O-])c1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.9 %

Procedure:
To a solution of 3-nitroaniline (28.8 g, 209 mmol, 1 equiv) in THF (1000 mL, 35 volumes), was added triethylamine (70 mL, 500 mmol, 2.4 equiv). 3-Nitroaniline can be obtained from Aldrich, Milwaukee, Wis. A solution of 4′-trifluoromethyl-biphenyl-2-carbonyl chloride (71.3 g, 250 mmol, 1.2 equiv) in THF (250 mL, 3.5 volumes) was added dropwise over 30 minutes. The reaction was stirred at room temperature for 48 hours. The slurry was then filtered through diatomaceous earth and the filtrate was concentrated. Water (700 mL, 24 volumes) was added and the slurry was stirred at room temperature for 12 hours. The solids were collected by filtration and dried under vacuum at 40° C. to provide 4′-trifluoromethyl-biphenyl-2-carboxylic acid (3-nitro-phenyl)-amide (80.7 g, 100%) as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH2:13][CH2:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.CN(C)CCCN=C=NCC.O.O[N:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=N1.C1(N)C=CC=CC=1N>CN(C=O)C.CN(C)C1C=CN=CC=1>[NH2:36][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[NH:38][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH2:13][CH2:12]2)[CH:9]=[CH:10][C:2]=1[Cl:1]
Reactant: On1nnc2ccccc21
Reactant: CN(C)CCN1CCN(c2ccc(Cl)c(C(=O)O)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCN1CCN(c2ccc(Cl)c(C(=O)Nc3ccccc3N)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.2 %

Procedure:
To a solution of 2-chloro-5-[4-(2-dimethylaminoethyl)-piperazin-1-yl]-benzoic acid (0.40 g, 1.29 mmol) in dry DMF (5 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (0.25 g, 1.29 mmol), followed by 1-hydroxybenzotriazole hydrate (1-HOBt) (0.11 g, 0.77 mmol) and dimethyl-pyridin-4-yl-amine (DMAP) (0.08 g, 0.64 mmol). After 3 h stirring at room temperature, 1,2-phenylenediamine (0.21 g, 1.93 mmol) was added, and the resulting mixture was stirred at room temperature overnight. The solution was evaporated under reduced pressure, then diluted with dichlomethane (20 mL) and washed with saturated Na2CO3 solution (2×5 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The resulting solid was purified by flash chromatography (eluent:dichloromethane:MeOH:NH3 in MeOH (2M)/9:0.5:0.5) to obtain 0.18 g (35%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[C:4]([C:15]2[O:16][C:17]([CH2:20][OH:21])=[CH:18][CH:19]=2)[C:3]=1[N:22]=O.[H][H]>C(O)C.[Pd]>[NH2:22][C:3]1[C:4]([C:15]2[O:16][C:17]([CH2:20][OH:21])=[CH:18][CH:19]=2)=[N:5][N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[C:2]=1[NH2:1]
Reactant: Nc1c(N=O)c(-c2ccc(CO)o2)nn1Cc1ccccc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1c(-c2ccc(CO)o2)nn(Cc2ccccc2F)c1N

Procedure:
The compound from Example 5A (8 g) is dissolved in ethanol, treated with 0.5 g of 5% strength palladium on carbon and hydrogenated for 15 minutes in a Parr apparatus at a hydrogen pressure of 2 bar. The solution is filtered off with suction through kieselguhr and used for the next batch (Rf=0.21, T1E1, SiO2).
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH3:27][S:28][CH2:29][CH2:30][O:31][C:32]([NH:34][C:35]1[N:43]=[CH:42][N:41]=[C:40]2[C:36]=1[N:37]=[CH:38][N:39]2[CH2:44][C:45](O)=[O:46])=[O:33]>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:45](=[O:46])[CH2:44][N:39]2[CH:38]=[N:37][C:36]3[C:40]2=[N:41][CH:42]=[N:43][C:35]=3[NH:34][C:32]([O:31][CH2:30][CH2:29][S:28][CH3:27])=[O:33])[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: CSCCOC(=O)Nc1ncnc2c1ncn2CC(=O)O
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Solvent: O=C(O)C(F)(F)F
Product: CSCCOC(=O)Nc1ncnc2c1ncn2CC(=O)N1CCN(S(=O)(=O)c2nc3ccccc3s2)C(=O)C1

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [6-N-(2-methylthioethoxycarbonyl)-adenine-9-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 10.80 (brs, 1H), 8.61 (d, 1H), 8.42 (s, 0.6H), 8.39 (s, 0.4H), 8.35 (m, 1H), 8.27 (m, 1H), 7.73 (m, 2H), 5.42 (s, 1.2H), 5.30 (s, 0.8H), 4.57 (s, 0.8H), 4.34-4.25 (m, 4.4H), 4.09 (m, 2.0H), 3.88 (t, 0.8H), 2.79 (t, 2H), 2.13 (s, 3H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Na].C(O)(=O)C.O>CO>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C=O)cc1
Agent: [Na]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)Oc1ccc(CO)cc1
Yield: 41 %

Procedure:
To the solution of 4-formylphenol acetate (6.0 g, 36.4 mmol) in 60 ml of methanol was added sodium boronhydride (1.50 g, 39.6 mmol) at 0° C. The resultant mixture was stirred for 1 hour, neutralized with acetic acid and then poured into water. The mixture was extracted three times with ether and the combined organic layer was dried over magnesium sulfate. After removal of solvent, the compound was purified by flash chromatography using heptane/ethyl acetate (80/20-70/30) as eluent in a yield of 41%.