Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2](Cl)(Cl)[C:3]([Br:6])(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([C@@H](O)C)[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1.CCCCCC>C1(C)C=CC=CC=1>[Br:6][C@@H:3]([C:32]1[CH:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=[C:30]([C:29]([F:28])([F:44])[F:43])[CH:31]=1)[CH3:2]
Reactant: C[C@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: C[C@@H](Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
Under an argon atmosphere, 1,2-dibromo-1,1,2,2-tetrachloroethane (7.57 g, 23.2 mmol) was dissolved in toluene (12.5 mL), the solution was added with triphenylphosphine (6.1 g, 23.2 mmol) at 0° C., and the mixture was stirred for 30 minutes. This reaction mixture was added dropwise with a solution of (S)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol (1) (5.0 g, 19.4 mmol, >99.5% ee) in toluene (12.5 mL) at 0° C. over 10 minutes or more, and then the mixture was warmed to room temperature, and stirred for 1 hour at the same temperature. The reaction mixture was added with n-hexane (25 mL), and the mixture was filtered through Celite. The filtrate was successively washed with water, saturated aqueous sodium hydrogencarbonate, and saturated brine, dried over sodium sulfate, and then evaporated under reduced pressure. The resulting residue was distilled under reduced pressure (56° C., 0.7 mmHg) to obtain 5.52 g of (R)-1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane (2) as colorless oil (yield: 88.6%).
Reaction SMILES: NC1[CH:3]=[C:4]([CH:12]=CC=1)[C:5](OC(C)(C)C)=O.[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22])([O-:17])=[O:16].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C([O-])([O-])=O.[Na+].[Na+]>CN(C1C=CN=CC=1)C.C1COCC1>[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([O:23][C:4]([CH3:12])([CH3:5])[CH3:3])=[O:22])([O-:17])=[O:16]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)c1cccc(N)c1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 23 °C
Reaction time: 48 h

Procedure:
t-Butyl 3-aminobenzoate ##STR105## A mixture of 3-nitrobenzoic acid (5 g, 30 mmol), di-tert-butyl dicarbonate (20 g, 92 mmol), and DMAP (0.84 g, 6.9 mmol) in THF (60 mL) was stirred at 23° C. for 2 d. The mixture was poured onto ice-water, basified with Na2CO3 and extracted with CH2Cl2 (×3). The combined organic extracts were washed with brine, the solvents evaporated in vacuo and the residue was purified by column chromatography upon silica gel using hexanes-EtOAc (95:5) as eluant to give t-butyl 3-nitrobenzoate (5.4 g, 24 mmol) as a colourless oil.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:13]([CH2:14][O:15]C(=O)C)[O:12][C@H:11]2[C@H:7]([N:8]=[C:9]([NH:19][CH2:20][CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:10]2)[C@H:6]1[O:30]C(=O)C)(=O)C.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C.C(OCC)(=O)C>CO>[CH2:23]([O:22][CH2:21][CH2:20][NH:19][C:9]1[S:10][C@H:11]2[O:12][C@H:13]([CH2:14][OH:15])[C@@H:5]([OH:4])[C@H:6]([OH:30])[C@H:7]2[N:8]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)OC[C@H]1O[C@@H]2SC(NCCOCc3ccccc3)=N[C@@H]2[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: OC[C@H]1O[C@@H]2SC(NCCOCc3ccccc3)=N[C@@H]2[C@@H](O)[C@@H]1O
Yield: 77.4 %

Procedure:
A solution of 129 (4.5 g, 9.4 mmol) in methanol (40 mL) was treated with potassium carbonate (260 mg, 2 mmol) for 3 hours at room temperature, then neutralized by the addition of acetic acid (0.5 mL). Volatiles were distilled out to give a residue, which was solidified from ethyl acetate. The solids were washed with ethyl acetate (3×20 mL) to give 130 as a light yellow solid (2.58 g, 80%). (ES, m/z) [M+H]+ 355.0; 1H NMR (300 MHz, D2O) δ 7.27-7.37 (m, 5H), 6.17 (d, J=6.3 Hz, 1H), 4.48 (s, 2H), 4.34-4.37 (m, 1H), 4.03-4.07 (m, 1H), 3.88-3.91 (m, 1H), 3.58-3.67 (m, 2H), 3.31-3.55 (m, 5H).
Reaction SMILES: C(OC([NH:8][S:9]([CH:12]1[NH:17][CH2:16][C:15]2[S:18][C:19]([C:21]([N:23]3[CH2:28][CH2:27][N:26]([S:29]([C:32]4[NH:33][C:34]5[C:39]([CH:40]=4)=[CH:38][C:37]([Cl:41])=[CH:36][CH:35]=5)(=[O:31])=[O:30])[CH2:25][CH:24]3[CH2:42][C:43]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[O:44])=[O:22])=[N:20][C:14]=2[CH2:13]1)(=[O:11])=[O:10])=O)(C)(C)C.FC(F)(F)C(O)=O.C(OCC)C>C(Cl)Cl>[NH2:8][S:9]([CH:12]1[NH:17][CH2:16][C:15]2[S:18][C:19]([C:21]([N:23]3[CH2:28][CH2:27][N:26]([S:29]([C:32]4[NH:33][C:34]5[C:39]([CH:40]=4)=[CH:38][C:37]([Cl:41])=[CH:36][CH:35]=5)(=[O:31])=[O:30])[CH2:25][CH:24]3[CH2:42][C:43]([N:45]3[CH2:46][CH2:47][O:48][CH2:49][CH2:50]3)=[O:44])=[O:22])=[N:20][C:14]=2[CH2:13]1)(=[O:10])=[O:11]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)C1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4cc5cc(Cl)ccc5[nH]4)CC3CC(=O)N3CCOCC3)sc2CN1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: NS(=O)(=O)C1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4cc5cc(Cl)ccc5[nH]4)CC3CC(=O)N3CCOCC3)sc2CN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.9 %

Procedure:
In methylene chloride (3 ml) was dissolved 1-[[6-(tert-butoxycarbonylaminosulfonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazine (275 mg), followed by the addition of trifluoroacetic acid (3 ml). The resulting mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure. A saturated solution of hydrochloride. in ethanol (3 ml) was added and the resulting mixture was stirred at room temperature for 1.5 hours. The residue obtained by distilling off the solvent under reduced pressure was added with methylene chloride and water to separate into layers. The water layer was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by preparative thin-layer chromatography (methanol:methylene chloride=1:9) using silica gel. The solid thus obtained was dissolved in a small amount of methylene chloride, followed by solidification by the addition of diethyl ether, whereby the title compound (50 mg) was obtained as a pale yellow solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:10][C:9]([CH:11]=[O:12])=[CH:8][CH:7]=2)=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:10][C:9]([CH2:11][OH:12])=[CH:8][CH:7]=2)=[CH:2]1
Reactant: O=Cc1ccc(-c2ccsc2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccsc2)s1
Yield: 92.1 %

Procedure:
144 mg of the resulting aldehyde compound was reduced with 15.6 mg of lithium aluminium hydride in 4 ml of tetrahydrofuran, and then worked up in a customary manner to give 134 mg (yield 92%) of the captioned compound as a colorless oil.
Reaction SMILES: [NH2:1][CH:2]1[CH:5]([S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:8])=[O:7])[NH:4][C:3]1=[O:15].C(=O)(O)[O-].[Na+].ClCCl.[O:24]([CH2:31][C:32](Cl)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[O:24]([CH2:31][C:32]([NH:1][C@H:2]1[C@H:5]([S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:8])=[O:7])[NH:4][C:3]1=[O:15])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NC1C(=O)NC1S(=O)(=O)c1ccccc1
Reactant: O=C(Cl)COc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N[C@H]1S(=O)(=O)c1ccccc1
Temperature: 0 °C

Procedure:
To an ice-cooled mixture of 7.6 g of 3-amino-4-phenylsulfonyl-2-azetidinone (mixture of cis and trans isomers), 5.1 g of sodium bicarbonate 100 ml of dichloromethane, and 50 ml of water was added dropwise with vigorous stirring 4.0 ml phenoxyacetyl chloride. After 90 minutes the resulting solid was removed by filtration and washed with water and dichloromethane. The solid was dissolved in tetrahydrofuran and precipitated with toluene to give 3.85 g of (3R-trans)-3-phenoxyacetylamino-4-phenylsulfonyl-2-azetidinone, melting point 192°-193° C., dec.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.FC(F)(F)S(O)(=O)=O.[NH2:24][CH2:25][CH2:26][NH:27][C:28]1[C:33]([C:34]([NH2:36])=[O:35])=[CH:32][N:31]=[C:30]2[N:37]([CH3:41])[N:38]=[C:39]([CH3:40])[C:29]=12.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C)C=O>[CH3:41][N:37]1[C:30]2=[N:31][CH:32]=[C:33]([C:34]([NH2:36])=[O:35])[C:28]([NH:27][CH2:26][CH2:25][NH:24][C:5](=[O:6])/[CH:4]=[CH:3]/[C:2]([F:9])([F:8])[F:1])=[C:29]2[C:39]([CH3:40])=[N:38]1
Reactant: O=C(O)/C=C/C(F)(F)F
Reactant: Cc1nn(C)c2ncc(C(N)=O)c(NCCN)c12
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn(C)c2ncc(C(N)=O)c(NCCNC(=O)/C=C/C(F)(F)F)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (21 mg, 0.15 mmol) was dissolved in DCM (2 ml containing one drop of dimethyl formamide), oxalyl chloride was added (19 mg, 0.15 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of 4-(2-aminoethylamino)-1,3-dimethyl-pyrazolo[3,4-b]pyridine-5-carboxamide trifluoromethanesulfonate (40 mg, 0.1 mmol) and diisopropylethylamine (60 μl, 0.35 mmol) dissolved in dimethylformamide (1 ml) and the resulting mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 2.1 mg (0.005 mmol, 5.7%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([N:14]2[CH2:19][CH:18]3[CH:16]([C:17]3([C:21]3[CH:22]=[C:23]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:24]=[CH:25][CH:26]=3)[CH3:20])[CH2:15]2)=O)=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][N:14]2[CH2:15][CH:16]3[CH:18]([C:17]3([C:21]3[CH:22]=[C:23]([NH:27][S:28]([CH3:31])(=[O:29])=[O:30])[CH:24]=[CH:25][CH:26]=3)[CH3:20])[CH2:19]2)=[CH:2]1
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(C(=O)CCc3c[nH]c4ccccc34)CC21
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(CCCc3c[nH]c4ccccc34)CC21
Temperature: 25 °C
Reaction time: 20 h
Yield: 47.9 %

Procedure:
To a solution of N-(3-{3-[3-(1H-indol-3-yl)propanoyl]-6-methyl-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide (Preparation 123, 135 mg, 0.34 mmol) in anhydrous tetrahydrofuran (2.5 ml) under a nitrogen atmosphere at 0° C. was added dropwise lithium aluminium hydride (1.0M solution in tetrahydrofuran, 0.68 ml, 0.68 mmol) and the mixture was stirred at room temperature for 20 h. The rapidly stirred reaction mixture was treated sequentially with water (0.68 ml), sodium hydrogen carbonate (400 mg) and ethyl acetate (15 ml). After 30 min the reaction mixture was filtered and concentrated in vacuo to afford a glassy oil. This was purified by preparative HPLC (condition 8) to give a light brown oil which was partitioned between dichloromethane (15 ml) and aqueous potassium carbonate solution (7% w:v, 5 ml). The layers were separated and the organic layer was washed with water (5 ml), dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a colourless oil (69 mg, 50%).
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16](=[O:28])[C:17]2[CH:22]=[CH:21][C:20]([NH:23][CH2:24][CH2:25][CH3:26])=[CH:19][C:18]=2[Cl:27])[CH2:8][CH2:7][CH2:6]1)(O)=[O:2].[CH:29]([NH2:32])([CH3:31])[CH3:30].P(C#N)(OCC)(OCC)=O.C(OCC)(=O)C>CN(C)C=O>[CH:29]([NH:32][C:1]([CH2:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16](=[O:28])[C:17]2[CH:22]=[CH:21][C:20]([NH:23][CH2:24][CH2:25][CH3:26])=[CH:19][C:18]=2[Cl:27])[CH2:8][CH2:7][CH2:6]1)=[O:2])([CH3:31])[CH3:30]
Reactant: CCCNc1ccc(C(=O)N2CCCC(CC(=O)O)c3ccccc32)c(Cl)c1
Reactant: CC(C)N
Agent: CCOP(=O)(C#N)OCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCNc1ccc(C(=O)N2CCCC(CC(=O)NC(C)C)c3ccccc32)c(Cl)c1
Reaction time: 8 h

Procedure:
To a solution of the above product, 5-carboxymethyl-1-(4-n-propylamino-2-chlorobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (800 mg) and isopropylamine (1.0 ml) in dimethylformamide (20 ml) is added dropwise diethyl cyanophosphate (391 mg) at room temperature. The mixture is stirred overnight, and thereto is added ethyl acetate. The mixture is washed with water, dried, concentrated, and purified by silica gel column chromatography (solvent; dichloromethane:methanol=50:1), and further crystallized from diethyl ether to give 5-isopropylaminocarbonylmethyl-1-(4-n-propylamino-2-chlorobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (840 mg).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][N:4]=1.[Li]C(CC)C.CNN(NC)[C:20](=[O:22])[CH3:21].O>CCOCC>[F:1][C:2]([F:11])([F:10])[C:3]1[N:4]=[CH:5][C:6]([C:20](=[O:22])[CH3:21])=[CH:7][CH:8]=1
Reactant: CNN(NC)C(C)=O
Reactant: FC(F)(F)c1ccc(Br)cn1
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: O
Product: CC(=O)c1ccc(C(F)(F)F)nc1
Reaction time: 0.17 h
Yield: 54.5 %

Procedure:
To a solution of 2-trifluoromethyl-5-bromopyridine (5.0 g, 22 mmol) in Et2O (50 mL) was added sec-BuLi (0.91 M in cyclohexane, 24 mL, 22 mmol) at −78° C. After 10 minutes of stirring, N,N-dimethylaminoacetamide (2.3 mL, 24 mmol) dissolved in Et2O (10 mL) was added drop wise. Stirring was continued at −78° C. for 1 h and then at rt over night. The reaction mixture was poured into water (100 mL) and the water phase was extracted with Et2O (3×100 mL). Combined organics were washed with water and brine and dried (MgSO4). After careful evaporation of the solvent, the crude was purified by column chromotography (SiO2, pentane/ether 9/1) to give the title compound (2.3 g, 12 mmol, 54%) as a light yellow solid.
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[C:13]([O:16][CH3:17])(=[O:15])[CH3:14].[CH3:18][C:19]([S@@:22]([N:24]=[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26])=[O:23])([CH3:21])[CH3:20]>C1COCC1>[CH3:21][C:19]([CH3:18])([S@@:22]([NH:24][C@:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:26])[CH2:14][C:13]([O:16][CH3:17])=[O:15])=[O:23])[CH3:20]
Reactant: CC(=N[S@@](=O)C(C)(C)C)c1ccccc1
Reactant: COC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C[C@@](C)(N[S@@](=O)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
A solution of i-Pr2NH in THF (25 mL) was cooled to −78° C., n-BuLi (2.5M, 2 mL) was added and the solution was stirred for 1 h. Then methyl acetate (4.48 mmol, 278 mg) was added and the mixture was stirred for 30 min. To this solution Ti(Oi-Pr)3Cl (1 M, 9.4 mL) was added. After 0.5 h, (S)-2-methyl-N-(1-phenylethylidene)propane-2-sulfinamide (500 mg, 2.24 mmol) dissolved in THF (1 mL) was added. The mixture was stirred at −78° C. for 3 h. The reaction was quenched with NH4Cl and warmed to rt. The mixture was diluted with water and filtered. The solid was washed with H2O/EtOAc and filtered. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by preparative TLC to afford (R)-methyl 3-((S)-1,1-dimethylethylsulfinamido)-3-phenylbutanoate (305 mg, 46%). 1H NMR (CDCl3): 1.24 (s, 9H), 1.68 (s, 3H), 3.08 (s, 2H), 3.53 (s, 3H), 5.46 (s, 1H), 7.15-7.18 (m, 1H), 7.23-7.30 (m, 2H), 7.30-7.36 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=[C:6]2[CH:5]=[CH:4][N:3]=1.[CH:19]1([C:22]([NH2:24])=[O:23])[CH2:21][CH2:20]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[N:9]1[CH:8]=[C:7]2[C:2]([NH:24][C:22]([CH:19]3[CH2:21][CH2:20]3)=[O:23])=[N:3][CH:4]=[CH:5][C:6]2=[N:10]1
Reactant: NC(=O)C1CC1
Reactant: Clc1cccc(Cl)c1-n1cc2c(Cl)nccc2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1nccc2nn(-c3c(Cl)cccc3Cl)cc12)C1CC1
Temperature: 25 °C
Yield: 34.3 %

Procedure:
A suspension of 4-chloro-2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine (25 mg, 0.084 mmol), cyclopropanecarboxamide (16 mg, 0.19 mmol), Xantphos (14 mg, 0.024 mmol), Pd2(dba)3 (14 mg, 0.016 mmol) and Cs2CO3 (152 mg, 0.470 mmol) in dry dioxane (4.0 mL) was sealed in a microwave vial after degassing with nitrogen. The mixture was irradiated at 160° C. for 60 minutes in the microwave and then cooled to room temperature. The solid material was removed via filtration and the filtrate was purified via prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to afford N-(2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridin-4-yl)cyclopropanecarboxamide (10 mg, 35% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.19 (br, 1H), 8.90 (s, 1H), 7.99 (d, J=6.5 Hz, 1H), 7.79-7.67 (m, 3H), 7.39 (d, J=6.0 Hz, 1H), 2.13 (m, 1H), 0.92-0.86 (m, 4H). LCMS (Method A): RT=5.50 min, m/z: 347.0 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH:4]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:7]=1[CH2:20][O:21]C(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.ClCCl>[CH3:1][O:2][C:3](=[O:33])[CH:4]([NH:25][C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:7]=1[CH2:20][OH:21]
Reactant: COC(=O)C(Cc1ccc(OCc2ccccc2)cc1COC(C)=O)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(Cc1ccc(OCc2ccccc2)cc1CO)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of 3-(2-acetoxymethyl-4-benzyloxy-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester (1.85 g, 4.0 mmol) in methanol (40 mL) was added potassium carbonate (560 mg, 4.0 mmol) at room temperature and stirred for 1 h. The reaction mixture was diluted with dichloromethane (150 mL), washed with 1.0 M aqueous hydrogen chloride and dried (Na2SO4) to give the pure 3-(4-benzyloxy-2-hydroxymethyl-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester in almost quantitative yield. To the alcohol (800 mg, 1.93 mmol) in dichloromethane (50 mL) was added methanesulfonyl chloride (0.18 mL, 2.3 mmol) followed by triethylamine (0.38 mL, 2.70 mmol) at 0° C. and then brought to room temperature. After 1 h, the reaction mixture was washed with aqueous sodium hydrogencarbonate, dried (Na2SO4). The solvent was removed, dissolved the crude product in anhydrous THF (20 mL) followed by addition of 2.0 M solution of methylamine in THF (10 mL) in a sealed tube. The sealed tube was heated at 80° C. for a period of 12 h and then removed the solvent. The crude product was purified by flash chromatography using 30% ethyl acetate in hexane to give (8-benzyloxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-carbamic acid tert-butyl ester in 39% overall yield. 1H NMR (500 MHz, CDCl3): in δ 7.40-7.31 (m, 5 H), 7.01-7.00 (m, 1 H), 6.83-6.82 (m, 1 H), 6.66 (s, 1 H), 5.91-5.90 (m, 1 H), 5.13-5.01 (m, 4 H), 3.50-3.46 (m, 1 H), 3.03 (s, 3 H), 2.85-2.78 (m, 1 H), 1.45 (s, 9 H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[C:4]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=[O:8])=[O:5].[C:22](Cl)(=O)[C:23](Cl)=[O:24].NC(N)=O.Cl>ClCCCl>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[C:4]([N:6]1[C:23](=[O:24])[CH2:22][N:9]([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[C:7]1=[O:8])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(Cl)cc1
Agent: Cl
Agent: NC(N)=O
Solvent: ClCCCl
Product: O=C1CN(c2ccc(Cl)cc2)C(=O)N1C(=O)c1c(Cl)cccc1Cl

Procedure:
10.3 g of N-(2,6-dichlorobenzoyl)-N'-(p-chlorophenyl)-urea are boiled in 100 ml of dry 1,2-dichloroethane containing 3 ml of oxalylchloride for 24 hours. The urea dissolves with the evolution of hydrochloric acid. After concentration by evaporation and after the addition of 25 ml of ligroin the residue becomes crystalline. The substance mauy be recrystallized from 30 mls of benzene. Melting point 157° C. Yield 8 g.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[F:12][C:13]([F:20])([F:19])[C:14]1([CH2:17][OH:18])[CH2:16][CH2:15]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:12][C:13]([F:20])([F:19])[C:14]1([CH2:17][O:18][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:16][CH2:15]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1(C(F)(F)F)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2(C(F)(F)F)CC2)cc1
Reaction time: 8 h
Yield: 49.4 %

Procedure:
p-Toluenesulfonyl chloride (9.6 g, 50.35 mmol) was added at 0° C. to a mixture of (1-trifluoromethyl-cyclopropyl)-methanol (7 g, 49.96 mmol), triethylamine (7.7 mL, 55.24 mmol) and DMAP (0.61 g, 4.996 mmol) in 100 mL of DCM. The resulting mixture was stirred at 0° C. to RT overnight before being washed with aqueous 1M HCl. The aqueous layer was back extracted twice with DCM. The combined organic layers were dried (Na2SO4), filtered, and evaporated. The residue was purified by SiO2 flash chromatography (120 g SiO2, hexanes/[hexanes/Et2O 8/2] 100 to 0% hexanes) to give 7.26 g of toluene-4-sulfonic acid 1-trifluoromethyl-cyclopropylmethyl ester (49% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[H-].[Na+].[OH:11][C:12]1[CH:17]=[CH:16][O:15][CH2:14][CH:13]=1>CN(C)C=O.[Cl-].[Na+].O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OC1=CCOC=C1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(OC2CCOCC2)nc1
Temperature: 0 °C
Yield: 87.2 %

Procedure:
A solution of 2,5-dibromopyridine (9.5 g, 40 mmol) in N,N-dimethylformamide (100 mL) was treated with sodium hydride (60% dispersion in mineral oil, 2.4 g, 60 mmol). The mixture was cooled to 0° C. and 4-hydroxypyran (3.8 mL, 40 mmol) was added slowly. The resultant mixture was stirred at room temperature for 24 hours, then was added to dilute brine solution and was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, was filtered, and the solvent was removed in vacuo. The residue was purified by silica gel chromatography (40:1 hexanes-ethyl acetate) to afford 9.0 g (87% yield) of the title compound. 13C NMR (100 MHz, CDCl3) d 162.0, 147.6, 141.5, 113.5, 111.7, 70.3, 65.7, 32.1; MS (AP/Cl) 258.2, 260.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[C:5]2[C:10]([CH:11]=[C:12]3[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2)([O-])=O.[ClH:18]>C(O)(=O)C>[ClH:18].[NH2:1][C:4]1[C:5]2[C:10]([CH:11]=[C:12]3[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=[N+]([O-])c1c2ccccc2cc2ccccc12
Agent: Cl
Solvent: CC(=O)O
Product: Nc1c2ccccc2cc2ccccc12

Procedure:
In a preferred specific form of the invention 9-nitroanthracene is reacted with hydrated tin chloride and acetic acid in the presence of concentrated HCl to produce an aqueous solution of 9-aminoanthracene hydrochloride salt, and the solution is stirred in air at room temperature while 5% aqueous ammonia solution is added slowly until the pH rises to 1.8 to 2.0, the solution is stirred at this pH for at least 5 minutes and then further 5% aqueous ammonia is added slowly to bring the pH up to the range 5.8 to 6.0 and the stirring is continued at that pH for 3 to 6 hours and then further 5% aqueous ammonia is added to bring the pH into the range 8.5 to 9.0 with continued stirring, and the yellow solid which precipitates out is recovered.