Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.CCN(CC)CC.[N:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])=[CH:29][CH:28]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([NH:37][CH2:36][CH2:35][CH2:34][CH2:33][C:30]3[CH:29]=[CH:28][N:27]=[CH:32][CH:31]=3)=[O:12])[C:4]=2[CH:3]=1
Reactant: NCCCCc1ccncc1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCCc1ccncc1)N1Cc2ccccc2Oc2ccc(Cl)cc21
Yield: 60.9 %

Procedure:
By the method described in Example 18, the title compound of Example 2 (0.98 g, 3.3 mmol) in 30 mL of CH2Cl2 with molecular sieves #5A (3 g) and Et3N (0.47 mL, 3.36 mmol) was reacted with the title compound of Example 23 (0.5 g, 3.3 mmol) to produce 0.82 g of the title product.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13](Cl)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([N:23]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[NH:24][C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(cc(-c3cccs3)n2Cc2ccccc2)n1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(-c3cccs3)n2Cc2ccccc2)n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 22.8 %

Procedure:
1-Benzyl-5-chloro-2-(2-thienyl)-1H-pyrrolo[3,2-b]pyridine (84 mg, 0.26 mmol, from Step 1), di-tert-butyl hydrazine-1,2-dicarboxylate (90 mg, 0.39 mmol) and Cs2CO3 (130 mg, 0.39 mmol) were combined in toluene (5.0 mL) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (20 mg, 0.026 mmol) was added. The mixture was degassed by a stream of nitrogen through the solution for 10 minutes. The reaction was stirred at 120° C. overnight. The mixture was diluted with DCM, filtered and concentrated, then reconstituted and purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH) to afford 30.8 mg of di-tert-butyl 1-[1-benzyl-2-(2-thienyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]hydrazine-1,2-dicarboxylate. This intermediate was dissolved in AcOH (2.2 mL) and was heated in the microwave to a temperature of 180° C. for 7 minutes. AcOH was removed in vacuo and the product was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (11.3 mg, 13%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)=[O:4].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.C(Cl)CCl.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[O:18]=[C:16]([NH:30][CH2:29][C:28]1[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:33])[F:34])=[CH:32][CH:31]=1)[CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:6]2[CH:19]=[CH:20][CH:21]=[CH:22][C:5]=2[C:3]([O:2][CH3:1])=[O:4])=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccccc1COc1ccc(CC(=O)O)cc1
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccccc1COc1ccc(CC(=O)NCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
(4-{[2-(Methoxycarbonyl)benzyl]oxy}phenyl)acetic acid (50 mg, 0.167 mmol) was dissolved in DCM (2 ml), 4-(Trifluoromethyl)benzylamine (35 mg, 0.2 mmol) was added, then EDC (38 mg, 0.2 mmol) was added and then DMAP (24.4 mg, 0.2 mmol) was added. The mixture was stirred at room temperature overnight. 1% hydrochloric acid (1 ml) and water (1 ml) was added into the mixture. The two phases were separated using a Whatman Filter Tube. The obtained organic solution was evaporated in vacuum and the solid product (72 mg) was left, yield 95%.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:19]=1.[NH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=1[O:30][CH3:31].Cl>>[CH:13]1([N:7]2[CH2:8][CH2:9][C:10](=[O:12])[NH:11][C:5]3[CH:4]=[N:3][C:2]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=4[O:30][CH3:31])=[N:19][C:6]2=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: O=C1CCN(C2CCCCC2)c2nc(Cl)ncc2N1
Agent: Cl
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CCC(=O)N2
Yield: 64.2 %

Procedure:
A mixture of 0.25 g (0.00089 mole) of 2-chloro-9-cyclohexyl-5,7,8,9-tetrahydropyrimido[4,5-b][1,4]diazepin-6-one (VI-20), 0.0022 g (0.0013 mole) of 4-amino-3-methoxybenzoic acid and 3 mL of 1 M hydrochloric acid was heated in a sealed vial at 100 degrees for 1.5 hours. After cooling, the solid was collected by filtration to give 0.235 g of 4-(9-cyclohexyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-28a).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.C(=O)([O-])[O-].[K+].[K+].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CN(C=O)C.O>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[CH:7]=[CH:6][N:5]2[CH2:4][CH2:3][CH2:2][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)([O-:16])=[O:15]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cccc2c1ccn2CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccc2c1ccn2CCCN1CCOCC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of 1-(3-bromopropyl)-4-nitro-1H-indole (8.18 g, 28.9 mmol) in anhydrous N,N′-dimethylformamide (200 mL) was added grounded potassium carbonate (12 g, 87 mmol) in portions. Then a solution of morpholine (12.6 g, 144.8 mmol) in N,N′-dimethylformamide was added dropwise. The mixture was stirred at 80° C. for 12 hours, diluted with water and extracted with ethyl acetate. The organic phases were combined, washed by brine, dried over anhydrous sodium sulfate, filtrated and evaporated to afford the product 4-(3-(4-nitro-1H-indol-1-yl)propyl)morpholine, which was used for the next step without purification.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[CH:28]=[C:27]([C:32]([O:34]CC4C=CC=CC=4)=[O:33])[CH:26]=[CH:25]5)[CH:14]=[CH:15][C:16]=3[C:17](=[O:21])[N:18]([CH3:20])[CH3:19])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH-].[Na+]>CO>[C:1]12([C:11]3[CH:12]=[C:13]([C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[CH:28]=[C:27]([C:32]([OH:34])=[O:33])[CH:26]=[CH:25]5)[CH:14]=[CH:15][C:16]=3[C:17](=[O:21])[N:18]([CH3:19])[CH3:20])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CN(C)C(=O)c1ccc(-c2ccc3cc(C(=O)OCc4ccccc4)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)C(=O)c1ccc(-c2ccc3cc(C(=O)O)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
990 mg (2.11 mmol) of this ester, in 25 ml of methanol, are treated with 2 g of sodium hydroxide. The reaction mixture is refluxed for 1 h and it is then treated as in Example 3. After recrystallization from absolute ethanol, 630 mg (66%) of the expected product are isolated, which product melts at 318°-320° C.
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=2)[CH2:5][NH:4][CH2:3]1.[C:17]([CH:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)([CH3:20])([CH3:19])[CH3:18].C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[C:17]([CH:21]1[CH2:26][CH2:25][CH:24]([N:4]2[CH2:5][CH:6]([C:7]3[CH:8]=[CH:9][C:10]([C:13]([CH3:15])([CH3:14])[CH3:16])=[CH:11][CH:12]=3)[CH:2]([CH3:1])[CH2:3]2)[CH2:23][CH2:22]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)C1CCC(=O)CC1
Reactant: CC1CNCC1c1ccc(C(C)(C)C)cc1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC1CN(C2CCC(C(C)(C)C)CC2)CC1c1ccc(C(C)(C)C)cc1

Procedure:
2.17 g (10 millimoles) of 3-methyl-4-(4-tert-butylphenyl)-pyrrolidine (80% of transisomer), 1.54 g (10 millimoles) of 4-tert-butylcyclohexanone, 0.75 g (5.5 millimoles) of zinc(II) chloride and 0.70 g (11 millimoles) of sodium cyanoborohydride in 100 ml of absolute methanol are stirred for 48 hours at 20° C. The solvent is evaporated under reduced pressure, and the residue is dissolved in 5% strength sodium hydroxide solution and methyl tert-butyl ether. The organic phase is washed with sodium chloride solution and water, dried and evaporated under reduced pressure, and the residue is subjected to incipient distillation under 0.4 bar at up to 140° C. Yield: 1.9 g (54%) of a viscous resin.
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[N:23]([CH3:31])[C:24]5[C:29]([CH:30]=4)=[CH:28][CH:27]=[CH:26][CH:25]=5)=[O:21])=[C:15]([O:32][CH3:33])[CH:14]=3)=[CH:11][S:12][C:8]=2[C:7]([C:34]2[CH:38]=[CH:37][S:36][C:35]=2[CH:39]=[O:40])=[CH:6][N:5]=1>CN(C)C=O.C(Cl)Cl>[NH2:3][C:4]1[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[N:23]([CH3:31])[C:24]5[C:29]([CH:30]=4)=[CH:28][CH:27]=[CH:26][CH:25]=5)=[O:21])=[C:15]([O:32][CH3:33])[CH:14]=3)=[CH:11][S:12][C:8]=2[C:7]([C:34]2[CH:38]=[CH:37][S:36][C:35]=2[CH2:39][OH:40])=[CH:6][N:5]=1
Reactant: COc1cc(-c2csc3c(-c4ccsc4C=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(-c2csc3c(-c4ccsc4CO)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 29.9 %

Procedure:
Sodium borohydride (9.4 mg, 0.223 mmol) was added to a mixture of N-{4-[4-amino-7-(2-formylthien-3-yl)thieno[3,2-c]pyridin-3-yl]-2-methoxyphenyl}-1-methyl-1H-indole-2-carboxamide (40.0 mg, 0.0743 mmol) in N, N-dimethylforamide (5 mL) under an atmosphere of nitrogen gas. The solution was stirred for 20 hours at room temperature after which it was diluted with methylene chloride and was washed with water (10 mL) and brine (10 mL). The organics were dried over magnesium sulfate and the solvent was removed in vacuo. The product was purified via flash chromatography to furnish the title compound as a yellow powder (12.0 mg, 0.0222 mmol). LCMS (Conditions a): (MH+)=541.0, RT=3.70 minutes; 1H NMR (DMSO-d6, 400 MHz) δ 9.51 (s, 1H), 7.99 (d, J=8.2 Hz, 1H), 7.81 (s, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.60 (d, J=5.1 Hz, 1H), 7.57 (d, J=8.6 Hz, 1H), 7.55 (s, 1H), 7.35–7.32 (m, 2H), 7.24 (d, J=5.1 Hz, 1H), 7.21 (d, J=1.56 Hz, 1H), 7.13 (m, 1H), 7.09 (dd, J=8.2, 1.56 Hz, 1H), 5.58 (br, 2H), 4.57 (d, J=5.5 Hz, 2H), 4.02 (s, 3H), 3.90 (s, 3H).
Reaction SMILES: C([O:4][C:5]1[C:6]([CH2:18][CH2:19][CH3:20])=[C:7]([CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[C:12]=1[O:13][CH3:14])[CH:8]=[O:9])(=O)C.Cl>[OH-].[Na+]>[OH:4][C:5]1[C:6]([CH2:18][CH2:19][CH3:20])=[C:7]([CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[C:12]=1[O:13][CH3:14])[CH:8]=[O:9]
Reactant: CCCc1c(C=O)cc([N+](=O)[O-])c(OC)c1OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCc1c(C=O)cc([N+](=O)[O-])c(OC)c1O
Yield: 98.2 %

Procedure:
A suspension of the product from step (b) (39.5 g) in 20% sodium hydroxide solution (140 ml) was heated at 90° for 5 hours. The mixture was cooled and acidified wth dilute hydrochloric acid. The aqueous phase was extracted with ethyl acetate washed with brine, dried, filtered and evaporated to leave a brown oil (33 g) MS; m/e 239.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[O:4][N:3]1[CH2:8][C:9]1[CH:32]=[CH:31][C:12]([O:13][CH2:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][C:22]=3[CH3:30])[CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1.Cl.[CH3:34][O:35][CH2:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].C(N(CC)CC)C>C1COCC1.CO.C(Cl)(Cl)Cl>[CH3:34][O:35][CH2:36][CH:37]1[CH2:42][CH2:41][N:40]([C:27]([C:24]2[CH:25]=[CH:26][C:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][O:13][C:12]4[CH:31]=[CH:32][C:9]([CH2:8][N:3]5[C:2](=[O:1])[NH:6][C:5](=[O:7])[O:4]5)=[CH:10][CH:11]=4)[CH:16]=3)=[C:22]([CH3:30])[CH:23]=2)=[O:28])[CH2:39][CH2:38]1
Reactant: Cc1cc(C(=O)O)ccc1-c1cccc(COc2ccc(Cn3oc(=O)[nH]c3=O)cc2)c1
Reactant: COCC1CCNCC1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COCC1CCN(C(=O)c2ccc(-c3cccc(COc4ccc(Cn5oc(=O)[nH]c5=O)cc4)c3)c(C)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
3′-({4-[(3,5-Dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy}methyl)-2-methylbiphenyl-4-carboxylic acid (10.8 mg) was dissolved in a THF-methanol [1 ml, 4:1 (v/v)] mixed solution, and the solution was added to 4-(methoxymethyl)piperidine hydrochloride (7.5 mg). DMT-MM (12 mg) and triethylamine (20 μl) were added, followed by overnight stirring at room temperature. Thereafter, chloroform was added to the reaction liquid, and the organic layer was washed with 1 M hydrochloric acid. The organic layer was concentrated, and the residue was purified by a fractional HPLC (Waters, product name: Waters SunFire™ Prep C18OBD™ (19×100 mm, 5 μm)) to obtain 2-{4-[(4′-{[4-(methoxymethyl)piperidin-1-yl]carbonyl}-2′-methylbiphenyl-3-yl)methoxy]benzyl}-1,2,4-oxadiazolidine-3,5-dione (9.0 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:16]=[C:17]([C:36]([CH3:39])([CH3:38])[CH3:37])[C:18]([O:34][CH3:35])=[C:19]([NH:21][C:22](=[O:33])[C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[C:25]([F:32])[CH:24]=3)[CH:20]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-]>[Fe].CO.O>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]([NH:21][C:19]2[CH:20]=[C:15]([C:14]3[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:10][CH:11]=[CH:12][CH:13]=3)[CH:16]=[C:17]([C:36]([CH3:38])([CH3:39])[CH3:37])[C:18]=2[O:34][CH3:35])=[O:33])=[CH:24][C:25]=1[F:32]
Reactant: COc1c(NC(=O)c2ccc([N+](=O)[O-])c(F)c2)cc(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COc1c(NC(=O)c2ccc(N)c(F)c2)cc(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Temperature: 105 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
step 2—To a suspension of 316 (595 mg, 1.12 mmol) in a 1:1 mixture of MeOH/H2O (4 mL each) at RT was added NH4Cl (601 mg, 11.2 mmol) and iron powder (314 mg, 5.62 mmol). The reaction mixture was warmed to 105° C. and stirred overnight. The reaction was cooled to RT and filtered via Büchner funnel and the filtrate was rinsed with DCM. The filtrate was diluted with H2O and extracted with DCM. The extracts were washed with H2O and brine. The combined aqueous phases were back-extracted with DCM. The combined organic extracts were combined, dried (MgSO4), filtered, and concentrated. The crude residue was purified by SiO2 chromatography, eluting with an EtOAc/hexane gradient (0% to 40% EtOAc) to afford 405 mg (72%) of 4-amino-N-[5-(2-benzyloxy-pyridin-3-yl)-3-tert-butyl-2-methoxy-phenyl]-3-fluoro-benzamide (318) as a foamy, yellow solid.
Reaction SMILES: ICCCC(OC)=O.N1CCCC1.[N:14]1([CH2:19][CH2:20][CH2:21][C:22]([O:24]C)=[O:23])[CH2:18][CH2:17][CH2:16][CH2:15]1.[ClH:26]>C1C=CC=CC=1>[ClH:26].[N:14]1([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)CCCN1CCCC1
Agent: COC(=O)CCCI
Agent: Cl
Solvent: c1ccccc1
Solvent: C1CCNC1
Product: O=C(O)CCCN1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
30.0 g. (0.13 mole) of methyl γ-iodobutyrate [F. F. Blicke, W. B. Wright and M. F. Zienty, J. Amer. Chem. Soc. 63, 2488 (1941)] was combined with 36 g. of pyrrolidine (Aldrich) in 300 ml. of benzene, heated at 60° for 0.5 hours and stirred at room temperature for 16 hours. A dark orange layer formed. The benzene solution was decanted, concentrated and distilled (b.p. 100° at 15 mmHg) to give 10 g. of colorless liquid. The infrared and nmr spectra indicated the product to be methyl γ-pyrrolidinobutyrate. This material was dissolved in 100 ml. of 18% hydrochloric acid and heated at reflux for 28 hours. The solution was concentrated under reduced pressure to give a semisolid which was triturated with acetone and filtered. Recrystallization from acetic acid/acetone gave 8.3 g. (33%) of the desired acid hydrochloride as colorless crystals, m.p. 126° - 127°. The infrared and nmr spectra and consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH3:29])[C:12]1[C:13]2[CH:20]=[CH:19][N:18](COCC[Si](C)(C)C)[C:14]=2[N:15]=[CH:16][CH:17]=1.FC(F)(F)C(O)=O.[OH-].[Li+].C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH3:29])[C:12]1[C:13]2[CH:20]=[CH:19][NH:18][C:14]=2[N:15]=[CH:16][CH:17]=1
Reactant: CN(c1ccc([N+](=O)[O-])cc1F)c1ccnc2c1ccn2COCC[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(c1ccc([N+](=O)[O-])cc1F)c1ccnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 71 mg (0.17 mmol) of N-(2-fluoro-4-nitrophenyl)-N-methyl-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-4-amine in 2 ml of dichloromethane and 1.0 ml (13.0 mmol) of trifluoroacetic acid is stirred at RT for 3 h. The reaction mixture is concentrated under reduced pressure, the residue is taken up in 2 ml of THF, 1.02 ml (1.02 mmol) of aqueous 1 M lithium hydroxide solution are added and the mixture is stirred at RT overnight. To bring the reaction to completion, a further 0.5 ml (0.5 mmol) of lithium hydroxide solution is added, and the mixture is stirred for another night. Saturated sodium bicarbonate solution is added to the mixture, and the mixture is extracted twice with ethyl acetate. The combined organic phases are dried over magnesium sulfate, the solvent is removed under reduced pressure and the residue is purified by preparative HPLC.
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](SC2C=CC(S(O)(=O)=O)=C(N)C=2)=[CH:4][C:3]=1C(O)=O.N1C(Cl)=NC(Cl)=NC=1Cl.[Cl-].[Na+]>>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cc(Sc2cc(C(=O)O)c(N)c3c2C(=O)c2ccccc2C3=O)ccc1S(=O)(=O)O
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: [Cl-]
Agent: [Na+]
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
1-Amino-2-carboxy-4-(3'-amino-4'-sulfophenylthio)anthraquinone (9.4 parts) and cyanuric chloride (3.7 parts) were subjected a to condensation reaction in an aqueous medium in a usual manner, followed by a condensation reaction with 1-aminobenzene-3-β-sulfatoethylsulfone (5.6 parts) at 20° to 40° C. under a weak acid condition. Thereafter, salting out of the reaction mixture with sodium chloride gave an anthraquinone compound of the following formula (free acid form). ##STR270##
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][NH:5][C@H:6]([C:11]([OH:13])=[O:12])[CH2:7][CH2:8][S:9][CH3:10].[Cl-].[Al+3].[Cl-].[Cl-].[Br:22]Br>C(O)(=O)C>[NH2:1][C:2]1[CH:17]=[CH:16][C:15]([Br:22])=[CH:14][C:3]=1[CH2:4][NH:5][C@H:6]([C:11]([OH:13])=[O:12])[CH2:7][CH2:8][S:9][CH3:10]
Reactant: CSCC[C@H](NCc1ccccc1N)C(=O)O
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(=O)O
Product: CSCC[C@H](NCc1cc(Br)ccc1N)C(=O)O
Reaction time: 24 h
Yield: 45 %

Procedure:
2.54 gm (0.01 mol) of N-(2-amino-benzyl)-methionine and 100 gm of aluminum chloride were dissolved in 50 cc of anhydrous acetic acid while gently heating. Then, the mixture was brought to room temperature and, while stirring, 0.52 cc (0.01 mol) of bromine diluted in 20 cc of acetic acid was added slowly. A light-colored precipitate was formed. After the addition of bromine was finished, the precipitate was centrifuged off, washed with ample acetic acid and then with anhydrous ether, and dried in a dryer. Then, the product was dissolved in 40 cc of water, and the pH of the solution was adjusted to 6 by addition of dilute ammonia while cooling it on an ice water bath. The mixture was allowed to stand for 24 hours, whereupon the new precipitate was centrifuged off, washed with water and dried in drying chamber. (Solvent of the crystallizate: alcohol at 50° C.). The melting point of the product was 207° C., and the yield was 45% of theory.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:26]([O:28][C:29](=[O:34])[CH2:30]C(O)=O)[CH3:27]>O1CCCC1>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[O:6])[CH2:30][C:29]([O:28][CH2:26][CH3:27])=[O:34]
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cccc([N+](=O)[O-])c1C
Yield: 76.4 %

Procedure:
A solution of 2-methyl-3-nitrobenzoic acid (10.0 g, 55.2 mmol) and carbonyldiimidazole (13.4 g, 82.8 mmol) in tetrahydrofuran (200 mL) is stirred at room temperature for 2 hours under an argon atmosphere. The magnesium salt of malonic acid monoethyl ester (47.4 g, 165 mmol) is added and the reaction mixture is heated at reflux for 18 hours. The reaction mixture is quenched with water (200 mL) and acidified to pH=1 with concentrated HCl. The product is extracted into ethyl acetate and washed with 1.0 N HCl, saturated aqueous sodium bicarbonate, and brine. The organic layer is dried over magnesium sulfate and evaporated. Recrystallization of the residue gives ethyl 2-methyl-3-nitro-β-oxobenzenepropanoate (10.6 g, 76%), mp=50-51° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[F:11][C:12]([F:19])([F:18])[C:13]1[CH:14]=[N:15][NH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:8]([C:5]1[CH:4]=[N:3][C:2]([N:15]2[CH:14]=[C:13]([C:12]([F:19])([F:18])[F:11])[CH:17]=[N:16]2)=[N:7][CH:6]=1)([O-:10])=[O:9]
Reactant: FC(F)(F)c1cn[nH]c1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cnc(-n2cc(C(F)(F)F)cn2)nc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 61.6 %

Procedure:
To a solution of 2-chloro-5-nitropyrimidine (1.5 g, 9.4 mmol) and 4-(trifluoromethyl)-1H-pyrazole (1.41 g, 10.3 mmol) in acetonitrile (40 mL) was added potassium carbonate (2.60 g, 18.8 mmol). The reaction was heated to 80° C. and stirred overnight. The reaction was concentrated and the residue was diluted with water and extracted with ethyl acetate (2×40 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave 5-nitro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidine (1.5 g, 62%) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ): 9.48 (s, 2H), 8.92 (s, 1H), 8.05 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11](=O)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: COc1ccc(-c2cc3ccccc3c(=O)[nH]2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2cc3ccccc3c(Cl)n2)cc1
Temperature: 110 °C
Yield: 96 %

Procedure:
3-(4-Methoxyphenyl)isoquinolin-1-one (1.70 g) was added to phosphorus oxychloride (10 ml), and the resulting mixture was heated at 110° C. for 3 hr. The reaction mixture was evaporated, and to the resulting residue were added ethyl acetate and water. The resulting organic layer was washed with water, an aqueous solution of sodium bicarbonate and brine, and then dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a white powder (1.76 g, yield; 96%).