Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[OH:11])([O-:3])=[O:2].Br[C:13]([F:20])([F:19])[C:14]([N:16]([CH3:18])[CH3:17])=[O:15].C([O-])([O-])=O.[Na+].[Na+].O>CC(N(C)C)=O>[F:19][C:13]([F:20])([O:11][C:5]1[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[C:14]([N:16]([CH3:18])[CH3:17])=[O:15]
Reactant: CN(C)C(=O)C(F)(F)Br
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(C)C(=O)C(F)(F)Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 33.5 %

Procedure:
A mixture of 2-nitro-5-fluoro-phenol (3.0 g, 19.1 mmol), 2-bromo-2,2-difluoro-N,N-dimethylacetamide (3.9 g, 19.1 mmol) and Na2CO3 (2.1 g, 19.8 mmol) in 30 mL of DMAC was heated to 100° C. overnight. The mixture was then poured on 50 mL of H2O and extracted with TBME (2×50 mL). The combined organic layers were washed with 10% NaOH (50 mL) and dried over Na2SO4. The crude product was obtained after evaporation of all volatiles. Purification by chromatography on silica gave the product (1.8 g, 6.4 mmol, 38% yield) as a yellow oil that solidified upon standing.
Reaction SMILES: B.CSC.[CH2:5]([N:12]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([O:25][CH2:26][CH2:27][NH:28][CH:29]=O)[C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[C:16]([CH3:31])[CH:17]=2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1COCC1>[CH2:5]([N:12]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([O:25][CH2:26][CH2:27][NH:28][CH3:29])[C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[C:16]([CH3:31])[CH:17]=2)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cc1ccc2c(c1)c1c(OCCNC=O)cccc1n2Cc1ccccc1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: CNCCOc1cccc2c1c1cc(C)ccc1n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
Borane-methyl sulfide (0.12 mL, 0.0013 mol) is added to a mixture of 2-[(9-benzyl-6-methyl-9H-carbazol-4-yl)oxy]ethylformamide (0.1565 g, 0.0013 mol) in dry THF (3 mL) and the mixture is stirred overnight at room temperature. The excess borane is cautiously quenched with methanol and the mixture is concentrated under reduced pressure. Methanol and dichloromethane are added to the residue and the solution is again concentrated under reduced pressure (repeated twice). The solids are then dissolved in methanol/dichloromethane and conc. HCl (27 drops) is added. After the mixture had stirred for 1.3 h, the solvent is removed under reduced pressure and the residue is partitioned between dichloromethane and aq. sodium bicarbonate. The combined organic layers are dried over sodium sulfate and concentrated to an oil. The oil is chromatographed on silica gel (40 mL) using acetone/dichloromethane/0.25% NH4OH (10/90, 20/80 and 50/50) to give 0.1300 g (86%) of the title compound; mp 96-96.75° C.; MS (ESI+) for C23H24N2O m/z 345.2 (M+H)+; IR (drift) 1600, 1580, 1467, 1449, 1341, 1307, 1268, 1242, 1151, 1128, 794, 779, 744, 718, 708 cm−1; 1H NMR (CDCl3) δ2.54, 2.61, 3.22, 4.39, 5.48, 6.68, 6.96, 7.11, 7.24, 7.31, 8.09. Anal. Calcd for C23H24N2O: C, 80.20; H, 7.02; N, 8.13. Found: C, 79.88; H, 7.15; N, 8.12.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7]Cl)[CH2:4][O:3]1.[N-:10]=[N+:11]=[N-:12].[Na+]>CN(C=O)C>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][N:10]=[N+:11]=[N-:12])[CH2:4][O:3]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)OCC(CCl)O1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCC(CN=[N+]=[N-])O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
15.05 g. of 2,2-dimethyl-4-chloromethyl-1,3-dioxolane is dissolved in 100 ml. DMF and 6.5 g. of NaN3 are added. The mixture is stirred at 50° overnight, cooled to room temperature, diluted with 300 ml. C6H6 and washed 5 times with water. The organic phase is dried and evaporated under reduced pressure to give 2,2-dimethyl-4-azidomethyl-1,3-dioxolane.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[N:23]1([C:29]2[CH:34]=[N:33][CH:32]=[CH:31][N:30]=2)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[NH:2]1[CH:3]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([N:26]5[CH2:27][CH2:28][N:23]([C:29]6[CH:34]=[N:33][CH:32]=[CH:31][N:30]=6)[CH2:24][CH2:25]5)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:5]=[N:1]1
Reactant: c1cnc(N2CCNCC2)cn1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCN(c2cnccn2)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 2-(piperazin-1-yl)pyrazine (1.2 equiv) to give 178 (8.7 mg, M+1 460.1)
Reaction SMILES: C([O:3][C:4](=[O:25])[CH:5]([N:10]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([OH:9])([CH3:8])[CH3:7])C.[OH-].[K+].P([O-])(O)(O)=O.[Na+]>CO.O>[CH2:18]([N:10]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:5]([C:6]([OH:9])([CH3:8])[CH3:7])[C:4]([OH:25])=[O:3])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)C(N(Cc1ccccc1)Cc1ccccc1)C(C)(C)O
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(O)C(C(=O)O)N(Cc1ccccc1)Cc1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
To 2.90 g (8.49 mmol) 2-dibenzylamino-3-hydroxy-3-methyl-butyric acid ethyl ester in 300 ml methanol were added 3.21 g (51.0 mmol) potassium hydroxide dissolved in 100 ml water. The mixture was stirred at 60° C. overnight. 500 ml saturated, aqueous sodium dihydrogenphosphate solution were added followed by extraction with ethyl acetate. Chromatography on silicagel with ethylacetate/heptan (50:50 to 100:0) yielded 1.41 g (53%) 2-dibenzylamino-3-hydroxy-3-methyl-butyric acid, MS m/e (%): 312.3 (M−H, 100).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@@H:5]([CH3:7])[C@H:4]([C:8]([OH:10])=O)[O:3]1.[N+]([O-])(O)=O.[N+:15]([O:18][CH2:19][CH2:20][NH2:21])([O-:17])=[O:16].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>>[N+:15]([O:18][CH2:19][CH2:20][NH:21][C:8]([C@@H:4]1[O:3][C:2](=[O:1])[NH:6][C@H:5]1[CH3:7])=[O:10])([O-:17])=[O:16]
Reactant: NCCO[N+](=O)[O-]
Reactant: C[C@@H]1NC(=O)O[C@H]1C(=O)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O=[N+]([O-])O
Product: C[C@@H]1NC(=O)O[C@H]1C(=O)NCCO[N+](=O)[O-]
Yield: 16.6 %

Procedure:
Following a procedure similar to that described in Example 1, but using 312 mg of (4S,5R)-2-oxo-4-methyloxazolidine-5-carboxylic acid, 372 mg of N-(2-nitrooxyethyl)amine nitrate and 0.47 ml of diphenylphosphoryl azide, 83 mg of the title compound were obtained as a colorless oil.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17](=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12]([F:25])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>C(OC(=O)C)(=O)C.C(OCC)(OCC)OCC>[C:1]([N:4]1[CH2:5][CH:6]=[C:7]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17](=[O:24])[C:18](=[CH:22][O:21][CH2:19][CH3:18])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12]([F:25])[CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(C2=CCN(C(C)=O)CC2)cc1F
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(C2=CCN(C(C)=O)CC2)cc1F

Procedure:
A solution of 3.95 g (11.25 mmol) ethyl 4-(1-acetyl-1,2,3,6-tetrahydro-4-pyridyl)-2,5-difluoro-β-oxobenzenepropionate in 25 ml of acetic anhydride and 2.8 ml of triethyl orthoformate was refluxed 1.5 hours. The title compound was isolated as a syrup after evaporation under vacuum in an oil bath at 80° C.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]4[CH2:30][CH2:29][C:27](=[O:28])[NH:26][C:24]=4[CH:25]=3)[CH2:11][CH2:10]2)[C:4]([Cl:8])=[C:5]([Cl:7])[CH:6]=1.C(N(CC)CC)C.[CH2:38]([N:40]=[C:41]=[O:42])[CH3:39]>ClCCl>[Cl:8][C:4]1[C:5]([Cl:7])=[CH:6][CH:1]=[CH:2][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[C:24]3[C:23]([CH2:30][CH2:29][C:27](=[O:28])[N:26]3[C:41]([NH:40][CH2:38][CH3:39])=[O:42])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)N1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of aripiprazole (1.5 g, 3.35 mmol) in dichloromethane (33 mL) was added triethylamine (0.56 mL, 4.01 mmol) and ethyl isocyanate (0.53 mL, 6.69 mmol). The reaction was stirred at room temperature for 5 days. The reaction was quenched with water and extracted with dichloromethane (3×20 mL). The organics were combined, washed with saturated aqueous sodium hydrogen carbonate (20 mL) and brine (20 mL), dried over MgSO4 and concentrated. The product was purified by column chromatography on silica eluting with 0-3% methanol in 1:1 ethyl acetate to dichloromethane. The product was triturated in heptane to remove aliphatic impurities and then filtered and dried. The material was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate (6×15 mL) to afford Compound-72 (0.482 g) as a pink solid.
Reaction SMILES: C(OC([N:8]([C:40](OC(C)(C)C)=O)[C:9](=[O:39])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:22])=[O:21])[CH:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[CH:33][N:32]=2)[CH2:27][CH2:26]1)=[O:24])=O)(C)(C)C.N1C[CH2:50][CH2:49][CH2:48]1>>[CH3:37][C:36]1[C:31]([N:28]2[CH2:27][CH2:26][N:25]([C:23]([C:11]3[CH:12]=[CH:13][C:14]([N:16]4[CH2:20][CH2:19][CH2:18][S:17]4(=[O:21])=[O:22])=[CH:15][C:10]=3[C:9]([N:8]3[CH2:40][CH2:50][CH2:49][CH2:48]3)=[O:39])=[O:24])[CH2:30][CH2:29]2)=[N:32][CH:33]=[C:34]([CH3:38])[CH:35]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Reactant: C1CCNC1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C(=O)N3CCCC3)CC2)c(C)c1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-5-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzamide (100 mg) described in Example 808 and pyrrolidine (15 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (56 mg) was obtained.
Reaction SMILES: [C:1]1([N:7]2[C:15](=[O:16])[C:14]3[C@@H:13]4[C:17]([CH3:19])([CH3:18])[C@@:10]([CH3:20])([CH2:11][CH2:12]4)[C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH3:20][C@@:10]12[C:17]([CH3:19])([CH3:18])[C@@H:13]([C:14]3[C:15](=[O:16])[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[C:9]=31)[CH2:12][CH2:11]2
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3)c(=O)c12
Reactant: CC(C)=CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)=CCn1c2c(c(=O)n1-c1ccccc1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 7.2 %

Procedure:
A mixture of (4S,7R)-7,8,8-trimethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 6; 420 mg, 1.57 mmol), tetrabutylammonium iodide (2.31 g, 6.26 mmol) and 4-bromo-2-methyl-2-butene (720 μL, 6.26 mmol) in dimethylformamide (5 mL) was heated in an oil-bath at 100° C. for 8 h. The solvent was evaporated and the residue was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (2×100 mL) and the combined organic layers were washed with water (5×100 mL) and aqueous sodium thiosulfate (100 mL). The solvent was evaporated and the residue was purified using an ISCO 40 g column, eluting with 90-100% ethyl acetate/hexanes to give (4S,7R)-7,8,8-trimethyl-1-(3-methyl-but-2-enyl)-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (38 mg, 7%) as a viscous yellow oil. APCI(+)-MS (M+H) 337.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)=O>>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:6]1[C:5]([C:3]([OH:2])=[O:4])=[CH:10][C:9]([C:11]2[S:13][CH:24]=[C:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)[N:12]=2)=[CH:8][CH:7]=1)([O-:22])=[O:21]
Reactant: O=C(CBr)c1cccs1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Product: O=C(O)c1cc(-c2nc(-c3cccs3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 47 %

Procedure:
2′-Nitro-4-(4-thiophen-2-yl-thiazol-2-yl)-biphenyl-2-carboxylic acid (120 mg, 47%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-(2-bromoacetyl)thiophene (available from Maybridge) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 8.51 (d, J=1.7 Hz, 1H), 8.10-8.20 (m, 3H), 7.71 (t, J=8.1 Hz, 1H), 7.57-7.67 (m, 3H), 7.41 (t, J=8.3 Hz, 2H), 7.15 (t, J=4.6 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22](F)=[CH:21][C:20]=1[O:26][CH2:27][CH2:28][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2].CCOC(C)=O.[NH:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1>>[C:1]([O:5][C:6](=[O:39])[CH2:7][C@H:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([N:46]2[CH2:50][CH2:49][CH2:48][CH2:47]2)=[CH:21][C:20]=1[O:26][CH2:27][CH2:28][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNC1
Reactant: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(F)cc1OCCc1cccc2ccccc12
Solvent: CCOC(C)=O
Product: CON(C)C(=O)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(N2CCCC2)cc1OCCc1cccc2ccccc12
Yield: 81 %

Procedure:
A solution of S)-3-[4-fluoro-2-(2-naphthalen-1-yl-ethoxy)-benzenesulfonyl amino]-N-methoxy-N methyl-succinamic acid tert-butyl ester (1.10 g, 2.0 mmol) in pyrollidine (10 mL) was heated at 50° C. for 5 h. The reaction mixture was allowed to cool and then was added EtOAc (150 mL). The resulting solution was washed sequentially with the following solutions: 5% citric acid, saturated NaHCO3, and brine. The organic phase was dried (MgSO4), and then the solvent was removed under vacuum. The resulting crude product was purified using flash silica gel chromatography (25% EtOAc in hexanes). (S)-N-Methoxy-N-methyl-3-[2-(2-naphthalen-1-yl-ethoxy)-4-pyrrolidin-1-yl-benzenesulfonyl amino]-succinamic acid tert-butyl ester was obtained in 81% yield (1.0 g) as a off white foam. MS (APCI) m/z 610.3 (M−1).
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O.O.[Sn](Cl)Cl.[OH-].[Na+]>Cl.O>[NH2:12][C:11]1[C:2]([CH3:1])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1nc2ccccc2cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Cc1nc2ccccc2cc1N
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of 2-methyl-3-nitroquinoline (400 mg, 2.13 mmol) in conc. HCl (8 mL) was heated to 50° C. Tin (II) chloride dihydrate (1.2 g, 5.3 mmol) was added. The mixture was stirred at 50° C. overnight. The mixture was diluted with water (20 mL). The pH was brought to 9 by addition of aqueous 5 N NaOH. The mixture was cooled to 4° C. and extracted with ethyl acetate (2×30 mL). The combined extracts were washed with ice-cold water (40 mL) and dried over anhydrous Na2SO4, filtered, and concentrated to give 3-amino-2-methylquinoine (270 mg, 80%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.84 (d, J=8.4 Hz, 1H), 7.51 (dd, J=1.2, 8.0 Hz, 1H), 7.39-7.30 (m, 2H), 7.16 (s, 1H), 3.77 (s, 2H), 2.56 (s, 3H).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:16])=[O:12])=O)(C)(C)C.[OH:31][C:32]1[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=O.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[NH2:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:20][CH2:21][N:22]([CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[C:39]([CH3:40])[C:32]=2[OH:31])[CH2:23][CH2:24]1)=[O:16])=[O:12]
Reactant: Cc1cccc(C=O)c1O
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cccc(CN2CCC(CNC(=O)CNC(=O)c3cc(F)c(F)cc3N)CC2)c1O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (0.050 mmol), 2-hydroxy-3-methylbenzaldehyde (0.25 mmol), methanol (1.0 mL), and acetic acid (0.040 mL) was added NaBH3CN (0.40 mmol) in methanol (0.50 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×2). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated. The resulting material was dissolved into ethyl acetate/methanol=5:1 (1 mL), loaded onto Varian™ Si column, eluted off using ethyl acetate/methanol=5:1 (5 mL), and concentrated. The residue was dissolved in methanol (2 mL) and 4 N HCl in dioxane (0.50 mL) was added. The solution was stirred at room temperature overnight and concentrated. The residue was dissolved in methanol, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×2). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated. Preparative TLC afforded 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(2-hydroxy-3-methylbenzyl)piperidine (Compound No. 2106): The purity was determined by RPLC/MS (97%); ESI/MS m/e 447.0 (M++H, C23H28F2N4O3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[S:11]([N:14]([CH:28]([CH3:30])[CH3:29])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)(=[O:13])=[O:12].O.O.Cl[Sn]Cl>CCO>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([S:11]([N:14]([CH:28]([CH3:29])[CH3:30])[C:15]2[CH:16]=[CH:17][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:23])[F:24])=[CH:19][CH:20]=2)(=[O:13])=[O:12])[CH:4]=1
Reactant: CC(C)N(c1ccc(C(C)(O)C(F)(F)F)cc1)S(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CC(C)N(c1ccc(C(C)(O)C(F)(F)F)cc1)S(=O)(=O)c1cc(N)ccc1Cl
Temperature: 75 °C
Reaction time: 2 h

Procedure:
A solution of 2-chloro-N-isopropyl-5-nitro-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl]benzenesulfonamide (11) (704 mg, 1.50 mmol, 1.0 equiv) in EtOH (40 mL) was treated with SnCl2.2H2O (1.70 g, 7.50 mmol, 5.0 equiv). After stirring at 75° C. for 2 h, the reaction mixture was concentrated under reduced pressure, diluted (EtOAc) and washed (3×1 M aqueous NaOH and 1×brine). The organics were dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography of the residue (SiO2, 30-40% EtOAc/Hexane, gradient elution) gave the product as a white foam. 1H NMR (DMSO-d6, 500 MHz) δ 7.59 (d, J=8.6 Hz, 2H), 7.28 (d, J=8.6 Hz, 1H), 7.12 (d, J=8.6 Hz, 2H), 7.08 (d, J=2.8 Hz, 1H), 6.73 (dd, J=2.8, 8.6 Hz, 1H), 6.65 (s, 1H), 5.67 (s, 1H), 4.50-4.42 (m, 1H), 1.67 (s, 3H), 1.04 (d, J=6.6 Hz, 3H), 1.03 (d, J=6.6 Hz, 3H). MS (ESI) 437 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([CH3:18])=[CH:4][CH:3]=1.O.[NH2:20][NH2:21]>N1C=CC=CC=1>[CH3:18][C:5]1[CH:4]=[CH:3][C:2]2[NH:20][N:21]=[C:14]3[C:15]=2[C:6]=1[C:7](=[O:17])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]3=1
Reactant: NN
Reactant: Cc1ccc(Cl)c2c1C(=O)c1ccccc1C2=O
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc2[nH]nc3c2c1C(=O)c1ccccc1-3
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 32.3 g of 1-chloro-4-methyl-9,10-dihydro-9,10-anthracenedione prepared in Example 25-a in 150 ml pyridine was added 15 ml of hydrazine monohydrate [CAS No. 7803-57-8], followed by stirring at 90° C. overnight. After removing the solvent, to the resulting residue was added 65 ml of ethanol to give crystals. The crystals were collected by filtration, sequentially washed with moisture ethanol and ethanol, and dried in vacuo, to give 26.6 g of the title compound as ocher yellow needles.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH2:11][C:12]([OH:14])=[O:13]>C(O)(=O)C.CC1CCCCC1>[Br:1][C:7]1[C:6]([CH3:10])=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[C:4]([CH3:3])=[CH:9][CH:8]=1
Reactant: Cc1cccc(C)c1CC(=O)O
Reactant: BrBr
Solvent: CC1CCCCC1
Solvent: CC(=O)O
Product: Cc1ccc(Br)c(C)c1CC(=O)O
Temperature: 45 °C
Reaction time: 16 h

Procedure:
At 45° C., a solution of 62.5 g [391 mmol] of bromine in 120 ml of glacial acetic acid is added dropwise over a period of 1 hour to a solution of 47.6 g [290 mmol] of 2,6-dimethylphenylacetic acid in 300 ml of glacial acetic acid. The reaction mixture is then stirred at 45° C. for another 16 hours and concentrated on a rotary evaporator. The solid obtained is stirred in 180 ml of methylcyclohexane at room temperature for 4 hours. After filtration, the residue is washed twice with in each case 60 ml of methylcyclohexane and then dried. This gives 64.9 g of a solid. GC(sil.) analysis: 97.7% pure (89.9% of theory).
Reaction SMILES: C([O:5][C:6](=[O:21])[CH:7]=[CH:8][C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[N:13]=1)(C)(C)C>FC(F)(F)C(O)=O>[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:12]2[N:13]=[C:9]([CH:8]=[CH:7][C:6]([OH:21])=[O:5])[S:10][CH:11]=2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)C=Cc1nc(-c2ccc(F)cc2)cs1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C=Cc1nc(-c2ccc(F)cc2)cs1

Procedure:
The crude product obtained in step (b) was stirred with 10 ml of 90% trifluoroacetic acid at room temperature for 1 h. After concentration, the residue was dissolved in a dilute sodium hydroxide solution and extracted with ethyl acetate. The aqueous phase was acidified with hydrochloric acid, and the precipitated product was filtered off with suction and dried. Yield: 1.52 g.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14]([NH2:16])=[N:13][CH:12]=[N:11][C:10]=3[N:9]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:38]([CH2:40][NH2:41])[OH:39]>CN(C=O)C>[OH:39][CH2:38][CH2:40][NH:41][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][CH:25]=[C:17]([N:9]2[C:10]3[N:11]=[CH:12][N:13]=[C:14]([NH2:16])[C:15]=3[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8]2)[CH:18]=1
Reactant: Nc1ncnc2c1c(-c1ccccc1)cn2-c1cccc(C(=O)O)c1
Reactant: NCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccccc1)cn2-c1cccc(C(=O)NCCO)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.0 g of 3-(5-phenyl-4-aminopyrrolo[2,3-d]pyrimidin-7-yl)benzoic acid (Example 15) is dissolved in 25 ml of warm DMF and the solution is cooled to 0° C. The mixture is treated with 0.54 g of carbonyldiimidazole and stirred at RT for 2 h. 0.19 g of ethanolamine is then added dropwise and the mixture is allowed to warm to RT and is stirred for 3 h. The mixture is then concentrated in an RE. The residue is dissolved in methylene chloride and the solution is crystallized overnight at 0° C. After filtration, the residue is dissolved in methylene chloride and chromatographed on silica gel (methylene chloride/methanol 15:1). The product-containing fractions are concentrated and the residue is taken up in a little methylene chloride and crystallized overnight at 0° C. The crystals formed are filtered off and dried under HV. N-(2-Hydroxyethyl)-3-(5-phenyl-4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-benzamide having a melting point of 194°-198° C. is obtained.