Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[N:7]=[C:6](N[C@H](C2N(C3C=CC=CC=3)C(=O)C3C(C=2)=CC=CC=3C2C=CN=C(OC)C=2)C)[C:5]([C:36]([OH:38])=O)=[CH:4][N:3]=1.[CH2:39]([N:41]=[C:42]=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.CNC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:39][N:41]([CH3:42])[C:36]([C:5]1[CH:6]=[N:7][CH:2]=[N:3][CH:4]=1)=[O:38]
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc(-c2cccc3cc([C@H](C)Nc4nc(N)ncc4C(=O)O)n(-c4ccccc4)c(=O)c23)ccn1
Agent: CNC
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1cncnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-2-amino-4-((1-(8-(2-methoxypyridin-4-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)-pyrimidine-5-carboxylic acid (44 mg, 0.087 mmol) in anhydrous N,N-dimethylmethanamide (3 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (25 mg, 0.13 mmol) and hydroxybenzotriazole (18 mg, 0.13 mmol) were added and the resulting mixture was stirred at RT for 30 min. To this mixture, dimethylamine (2M in THF, 0.065 mL, 0.13 mmol) and N,N-diisopropylethylamine (0.040 mL, 0.19 mmol) were added and the reaction mixture was stirred at RT for 3 h. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford the product 112, (S)-2-amino-441-(8-(2-methoxypyridin-4-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)-N,N-dimethylpyrimidine-5-carboxamide. ESI-MS m/z: 533.8 [M−H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li+].CC([N-]C(C)C)C.[CH:16](=[O:18])[CH3:17].O>C1COCC1>[Cl:1][C:2]1[C:7]([CH:16]([OH:18])[CH3:17])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccccn1
Reactant: CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1cccnc1Cl
Temperature: -78 °C
Reaction time: 3 h
Yield: 38.1 %

Procedure:
A solution of 2-chloropyridine (I) (9.39 mL, 0.1 mol) in anhydrous THF (50 mL) was added slowly to a solution of LDA (2.0 M solution in THF/hexane/ethylbenzene, 50 mL, 0.1 mol) in THF (200 mL) stirred at −78° C. under nitrogen. The stirring was continued at −78° C. for an additional 3 h before adding acetaldehyde (6.17 mL, 0.110 mol). The solution was stirred at −78° C. for another 2 h before allowing the temperature to rise to −40° C. A solution of water (4 mL) in THF (40 mL) was added slowly to the solution. When the temperature reached −10° C., additional water (200 mL) was added to the solution. The solution was extracted with ethyl ether (3×100 mL). The combined organic phase was dried over MgSO4, filtered and evaporated under reduced pressure to get a brown viscous residue. The crude product was purified on a flash silica gel column (1:1 DCM:hexane→100% DCM) to produce 1-(2-chloropyridin-3-yl)ethanol (II) as a brown viscous oil (6 g, 38.1 mmol, 38% yield). 1H NMR (CDCl3) δ ppm 1.52 (d, J=6.41 Hz, 3 H), 2.51 (bs, 1 H), 5.24 (m, 1 H), 7.28 (m, 1 H), 7.97 (dd, J=7.72, 1.70, 1 H), 8.27 (dd, J=7.72, 1.79, 1 H).
Reaction SMILES: [Cl:1][C:2]([C:11]#[N:12])=[CH:3][S:4][C:5]([Cl:10])=[C:6]([Cl:9])[C:7]#[N:8].C(=O)([O-])[O-].[K+].[K+].S(Cl)([Cl:22])(=O)=O>C(Cl)Cl.ClC(Cl)C>[Cl:10][C:5]([S:4][C:3]([Cl:22])=[C:2]([Cl:1])[C:11]#[N:12])=[C:6]([Cl:9])[C:7]#[N:8]
Reactant: N#CC(Cl)=CSC(Cl)=C(Cl)C#N
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: N#CC(Cl)=C(Cl)SC(Cl)=C(Cl)C#N
Temperature: 70 °C
Reaction time: 12 h
Yield: 45 %

Procedure:
3.3 g of 1,2-dichloro-2-cyano-vinyl 2-chloro-2-cyano-vinyl sulphide were dissolved in 20 ml of methylene chloride, 2 g of potassium carbonate were added, and 2.15 g of sulphuryl chloride in 10 ml of dichloroethane were added dropwise at room temperature. The mixture was stirred at 70° C. for 12 hours and filtered, the filtrate was washed with water and concentrated and the resulting oil was chromatographed. 1.7 g of bis-(1,2-dichloro-2-cyano-vinyl) sulphide were obtained as an oil, which was identical to the product from Example 8.
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:8]=1[C:9]([O:11]C)=O)=[C:2]=[S:3].[CH3:19][C:20]1[N:21]=[CH:22][N:23]([CH2:25][CH2:26][CH2:27][NH2:28])[CH:24]=1>>[CH3:19][C:20]1[N:21]=[CH:22][N:23]([CH2:25][CH2:26][CH2:27][N:28]2[C:9](=[O:11])[C:8]3[CH:7]=[C:6]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[S:5][C:4]=3[NH:1][C:2]2=[S:3])[CH:24]=1
Reactant: Cc1cn(CCCN)cn1
Reactant: COC(=O)c1cc(-c2ccccc2)sc1N=C=S
Product: Cc1cn(CCCn2c(=S)[nH]c3sc(-c4ccccc4)cc3c2=O)cn1

Procedure:
The compound was synthesized starting from methyl 2-isothiocyanato-5-phenylthiophene-3-carboxylate (0.107 g. 0.39 mmol) and 3-(4-methyl-1H-imidazol-1-yl)propan-1-amine (9) (0.054 g, 0.39 mmol) as described above.
Reaction SMILES: O1CC[C@@H]([O:6][C:7](=[O:34])[NH:8][CH2:9][C@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]3[C:25]4[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=4)[N:19]=[C:18]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[OH:33])[N:17]=3)[CH2:11]2)C1.[ClH:35].[CH3:36][CH2:37][O:38][CH2:39][CH3:40]>C(Cl)Cl>[ClH:35].[O:38]1[CH2:39][CH2:40][C@@H:36]([N:8]([CH2:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]3[C:25]4[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=4)[N:19]=[C:18]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[OH:33])[N:17]=3)[CH2:11]2)[C:7](=[O:34])[OH:6])[CH2:37]1
Reactant: Cc1ccc2c(N3CCC[C@H](CNC(=O)O[C@@H]4CCOC4)C3)nc(-c3ccccc3O)nc2c1
Reactant: CCOCC
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc2c(N3CCC[C@@H](CN(C(=O)O)[C@@H]4CCOC4)C3)nc(-c3ccccc3O)nc2c1
Reaction time: 0.04 h

Procedure:
To a solution of (R)-tetrahydrofuran-3-yl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate (0.085 g, 0.18 mmol) in 9 mL CH2Cl2 was added dropwise a 2.0 M HCl solution in ether (0.09 mL, 0.18 mmol). Ether (20 mL) was then added, leading to the precipitation of (R)-tetrahydrofuran-3-yl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate hydrochloride which was filtered and dried (85 mg, 95%). LC/MS: m/z 463.5 (M+H)+ at 2.33 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: C[O:2][C:3](=[O:37])[CH:4]([CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)[N:5]([CH2:19][O:20][CH:21]([Si:23]([CH3:26])([CH3:25])[CH3:24])[CH3:22])[C:6]([O:8][CH:9]1[CH:16]2[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:18][CH:10]1[CH2:11]3)[CH2:15]2)=[O:7].[Li+].[OH-].O1CCOCC1.Cl>O>[CH:10]12[CH2:11][CH:12]3[CH2:13][CH:14]([CH2:15][CH:16]([CH2:17]3)[CH:9]1[O:8][C:6]([N:5]([CH2:19][O:20][CH:21]([Si:23]([CH3:25])([CH3:24])[CH3:26])[CH3:22])[CH:4]([C:3]([OH:37])=[O:2])[CH2:27][C:28]1[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][CH:29]=1)=[O:7])[CH2:18]2
Reactant: COC(=O)C(Cc1c[nH]c2ccccc12)N(COC(C)[Si](C)(C)C)C(=O)OC1C2CC3CC(C2)CC1C3
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(OCN(C(=O)OC1C2CC3CC(C2)CC1C3)C(Cc1c[nH]c2ccccc12)C(=O)O)[Si](C)(C)C
Temperature: 60 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
A mixture of N-[(2-adamantyloxy)carbonyl]-α-trimethylsilylethoxymethyl-DL-tryptophan methyl ester (4.5 g, 8.5 mmol), LiOH (0.22 g, 9.1 mmol), dioxane (90 mL), and water (30 mL) was stirred at 60° C. for 16 hours. After cooling, the reaction mixture was acidified to pH 4 with 1N hydrochloric acid and extracted with ethyl acetate. The organic extract was dried over Na2SO4 and then concentrated in vacuo. Trituration of the oily residue with diethyl ether gave the title compound as a white solid (4.0 g, 91.7%), mp 203° C. (dec.).
Reaction SMILES: [CH:1]1([CH2:9]Br)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.CC(C)([O-])C.[K+]>C(O)CCC>[CH:1]1([CH2:9][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: BrCC1C=CCCCCC1
Reactant: c1c[nH]cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCO
Product: C1=CC(Cn2ccnc2)CCCCC1

Procedure:
2-Cyclooctenylmethyl bromide (0.7 g; 0.0035 mole) as just made was added dropwise to a refluxing solution of imidazole (0.24 g; 0.0025 mole) and potassium tertiary butoxide (0.39 g; 0.0035 mole) in dry butanol under nitrogen. After addition the mixture was stirred under reflux for 1 hour. Pure product was obtained as described in Example 4, b.p. 108°-110°/0.02 mmHg.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[Cl:25]>>[Cl:18][C:19]1[CH:20]=[C:21]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([F:17])[CH:3]=2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(Cl)c(Cl)c4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, light yellow solid (63 mg, 69%), MS (ISP) m/z=363.5 [(M+H)+], mp 224° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 3,4-dichloro-phenylboronic acid (62.0 mg, 0.325 mmol).
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29]1(O)[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[CH3:20][CH:19]([CH3:21])[C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@H:2]([O:1][C:37]3[C:38]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:34]=[CH:35][CH:36]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:12]=1)=[O:22]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Reactant: Oc1cccc2ccccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3cccc4ccccc34)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.9 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 1-naphthol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (4.30 mg, 66.2% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.72 (d, 1H, J=8.5 Hz), 7.59 (d, 1H, J=8.5 Hz), 7.5 (m, 2H), 7.45-7.30 (m, 6H), 7.25 (m, 3H), 7.17 (apparent dd, 1H, J=2.6, 9.0 Hz), 7.01 (apparent d, 1H, J=2.6 Hz), 6.97 (apparent d, 1H, J=7.9 Hz), 5.46 (apparent dd, 1H, J=4.5, 8.1 Hz), 3.12 (m, 2H), 2.61 (m, 2H), 2.53 (apparent sept, partially hidden, 2H, J=7.9 Hz), 2.30-2.10 (m, 6H), 1.90 (m, 2H), 1.25 (d, 6H, J=7.3 Hz, overlapped); ESMS m/e: 507.2 (M+H)+.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[C:4]=1[C:10]1[NH:21][C:20]2[CH:19]=[C:18]3[C:14]([CH:15]=[N:16][NH:17]3)=[CH:13][C:12]=2[N:11]=1.Cl.[NH2:23][CH2:24][C@H:25]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([Br:35])[CH:28]=1)[OH:26].CN1CCOCC1>C(#N)C>[Br:35][C:29]1[CH:28]=[C:27]([C@H:25]([OH:26])[CH2:24][NH:23][C:3]2[CH:8]=[CH:7][NH:6][C:5](=[O:9])[C:4]=2[C:10]2[NH:21][C:20]3[CH:19]=[C:18]4[C:14]([CH:15]=[N:16][NH:17]4)=[CH:13][C:12]=3[N:11]=2)[CH:32]=[CH:31][C:30]=1[O:33][CH3:34]
Reactant: O=c1[nH]ccc(Cl)c1-c1nc2cc3cn[nH]c3cc2[nH]1
Reactant: COc1ccc([C@H](O)CN)cc1Br
Agent: Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Product: COc1ccc([C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4cn[nH]c4cc3[nH]2)cc1Br
Temperature: 80 °C
Yield: 63.8 %

Procedure:
The mixture of crude 4-chloro-3-(1,7-dihydro-1,2,5,7-tetraaza-s-indacen-6-yl)-1H-pyridin-2-one hydrochloric acid salt (80 mg, 0.25 mmol), (S)-2-amino-1-(3-bromo-4-methoxy-phenyl)-ethanol hydrochloric acid salt (105 mg, 0.37 mmol), N-methyl morpholine (0.5 ml, excess), and acetonitrile (15 mL) was heated to 80° C. overnight and cooled to room temperature. After concentration in vacuo, the residue was purified by prep. HPLC to yield the titled compound (79 mg, 66%). 1H NMR (400 MHz, CD3OD) δ 8.13 (s, 1H), 7.85 (s, 1H), 7.69 (narrow d, J=2.0 Hz, 1H), 7.59 (s, 1H), 7.40 (dd, J=2.0, 8.5 Hz, 1H), 7.29 (d, J=7.6 Hz, 1H), 6.96 (d, J=8.5 Hz, 1H), 6.22 (d, J=7.6 Hz, 1H), 4.93 (m, 1H), 3.80 (s, 3H), 3.66 (d, J=6.0 Hz, 2H). LCMS (t=1.39 min), [M+H]+ 495.
Reaction SMILES: C1(C[N:8]([CH2:23][C@@H:24]([C@H:26]2[CH2:31][CH2:30][C:29]3[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:28]=3[O:27]2)[OH:25])[CH2:9][C@@H:10]([C@@H:12]2[CH2:17][CH2:16][C:15]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:14]=3[O:13]2)[OH:11])C=CC=CC=1.C([O-])=O.[NH4+].O>CO.[Pd]>[NH:8]([CH2:23][C@@H:24]([C@H:26]1[CH2:31][CH2:30][C:29]2[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:28]=2[O:27]1)[OH:25])[CH2:9][C@@H:10]([C@@H:12]1[CH2:17][CH2:16][C:15]2[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:14]=2[O:13]1)[OH:11]
Reactant: O[C@@H](CN(Cc1ccccc1)C[C@H](O)[C@H]1CCc2cc(F)ccc2O1)[C@@H]1CCc2cc(F)ccc2O1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: O[C@@H](CNC[C@H](O)[C@H]1CCc2cc(F)ccc2O1)[C@@H]1CCc2cc(F)ccc2O1
Temperature: 65 °C
Reaction time: 11 h
Yield: 85.5 %

Procedure:
(±)[R*,S*,S*,S*]-α,α′-[(phenylmethyl)imino-bis (methylene)] bis [6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] (5.0 g; 0.0101 mol) was dissolved in methanol (343.9 g). Ammonium formate (4.8 g; 0.0761 mol) was added to the reaction mixture followed by catalytic Palladium on carbon 5 wt. % wet (contains ˜50% water) (0.5 g). The reaction mixture was heated at reflux (about 65° C.) under stirring for about 11 hours then cooled to 45° C. filtered on a celite pad, washing with methanol, and finally concentrated under vacuum. The crude residue (6.2 g) was diluted with 2-butanol (65.2 g) then a solution of aq. 30% sodium hydroxide (2.0 g) and water (29.8 g) was added under stirring. The resulting suspension was heated to 70±2° C. until complete dissolution obtaining a clear two-phase mixture. The aqueous layer was separated and the resulting organic phase was washed with aq. sodium hydrogen carbonate (1.7 g dissolved in 22.6 g of water) and then with water (2×21.5 g). Toluene (5.0 g) was also added to improve the aqueous-organic separation. The organic phase was concentrated two-times under reduced pressure while adding fresh 2-butanol (total 32.9 g) to the resulting residues. The final organic solution (about 60 ml) was further diluted with 2-butanol (9.5 g) heated to 85-90° C. until complete dissolution and then gradually cooled to 20° C. obtaining the product precipitation. The solid was isolated by filtration, washing with 2-butanol (3×2.7 g), and dried under vacuum at 60° C. to give the title compound as a white solid (3.5 g, 96.6% w/w assay (HPLC); 82.6% molar yield). Purity Profile (HPLC): Sum of Impurities=0.284% w/w; Max Single Impurity (“de-F” Nebivolol)=0.196% w/w.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[CH:8]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[O:7]C(C)C2.[CH3:23][C:24]([CH3:26])=[O:25].OS(O)(=O)=O.O=[Cr](=O)=O.Cl(O)(=O)(=O)=O>>[CH2:23]([C:9]1([CH:4]=[CH:3][C:2]([Cl:1])=[C:11]([Cl:12])[CH2:10]1)[C:8]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:7])[C:24]([CH3:26])=[O:25]
Reactant: CC1Cc2cc(Cl)c(Cl)cc2C(c2ccc([N+](=O)[O-])cc2)O1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(=O)CC1(C(=O)c2ccc([N+](=O)[O-])cc2)C=CC(Cl)=C(Cl)C1

Procedure:
4.75 g (14.0 mmoles) of the isochromane derivative prepared in Step A are oxidized according to the method of Example 1, Step B using Jones' reagent with the exception that instead of reacting the crude product with perchloric acid, the 1-acetonyl-3,4-dichloro-4'-nitrobenzophenone derivative (m.p.: 121°-122° C.) is isolated by chromatography. The solution of the above derivative in isopropanol is reacted with 98% hydrazine hydrate at 25° C. to obtain the monohydrazone derivative (m.p.: 167°-169° C.). The monohydrazone compound is reacted with methanol containing 15% hydrogen chloride, then, the hydrochloride of the title compound is treated with triethylamine to obtain the free base that is purified by recrystallization from hot dimethylformamide. M.p.: 231°-233° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[C:8](Cl)(=[O:11])[CH2:9][CH3:10].O>N1C=CC=CC=1>[C:8]([NH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1)(=[O:11])[CH2:9][CH3:10]
Reactant: Nc1nnc(S)s1
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCC(=O)Nc1nnc(S)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.1 %

Procedure:
To a suspension of 20 g of 2-amino-5-mercapto-1,3,4 -thiadiazole in 200 ml of pyridine was added 14.6 g of propionyl chloride with cooling over a 5 minute period. After stirring the reaction mixture for 4 hours at room temperature, water was added and the resulting solid collected by filtration to give 20.2 g of 2-propionamido-5-mercapto-1,3,4-thiadiazole, m.p. 234°-237° C.
Reaction SMILES: COC(=O)CC1C(C)=NN([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)C=1C.[C:23]([O:27][C:28](=[O:39])[CH2:29][C:30]1[C:31]([CH2:37][CH3:38])=[N:32][NH:33][C:34]=1[CH2:35][CH3:36])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28](=[O:39])[CH2:29][C:30]1[C:34]([CH2:35][CH3:36])=[N:33][N:32]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:31]=1[CH2:37][CH3:38])([CH3:25])([CH3:26])[CH3:24]
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc([N+](=O)[O-])cc2)c1C
Reactant: CCc1n[nH]c(CC)c1CC(=O)OC(C)(C)C
Product: CCc1nn(Cc2ccc([N+](=O)[O-])cc2)c(CC)c1CC(=O)OC(C)(C)C

Procedure:
[3,5-Diethyl-1-(4-nitro-benzyl)-1H-pyrazol-4-yl]-acetic acid tert-butyl ester was prepared according to the preparation of intermediate 1.1.2, using in the alkylation reaction (3,5-diethyl-1H-pyrazol-4-yl)-acetic acid tert-butyl ester (preparation according to WO2007/141267) instead of (3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH:27]1[C:32]#[N:33])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:28][CH:27]1[C:32]#[N:33])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: N#CC1CNCCN1C(=O)OCc1ccccc1
Product: N#CC1CN(Cc2cccc(-c3ccnc(Cl)n3)c2)CCN1C(=O)OCc1ccccc1

Procedure:
Intermediate 1 was coupled with 2-cyano-piperazine-1-carboxylic acid benzyl ester (generated according to literature procedure (ref 4)) following procedure B. LC-MS showed the product had the expected M+H+ of 448.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:16])[CH2:14]Br)=[C:8]([N+:17]([O-:19])=[O:18])[CH:7]=1)=[O:4].[CH3:20][NH:21][CH3:22]>C(O)C>[CH3:1][O:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:16])[CH2:14][N:21]([CH3:22])[CH3:20])=[C:8]([N+:17]([O-:19])=[O:18])[CH:7]=1)=[O:4]
Reactant: CNC
Reactant: COC(=O)Nc1ccc(NC(=O)CBr)c([N+](=O)[O-])c1
Solvent: CCO
Product: COC(=O)Nc1ccc(NC(=O)CN(C)C)c([N+](=O)[O-])c1

Procedure:
N-(4-methoxycarbonylamino-2-nitrophenyl)-2-bromoacetamide (25 g) in ethanol (250 ml) was treated with a solution of dimethylamine in ethanol (35.5 g of a 30% w/w solution) and the mixture refluxed for one hour. The ethanol was evaporated and the residual solid shaken with water and filtered to give N-(4-methoxycarbonylamino-2-nitrophenyl)-2-dimethylaminoacetamide (21.1 g), m.p. 186°-189° C.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O-]CC.[Na+].CS(O[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])(=O)=O>CCO>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: Cc1ccccc1CCOS(C)(=O)=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1C)C(=O)OCC
Reaction time: 0.5 h

Procedure:
33.9 mL (0.223 mol) of diethyl malonate were added, under a nitrogen atmosphere and at room temperature, to a solution of sodium ethoxide (prepared in situ by dissolving 2.6 g (0.0151 mol) of Na in 80 mL of absolute EtOH). After 30 min, 14.5 g (0.0677 mol) of 2-methylphenethyl alcohol methanesulphonate dissolved in 40 mL of abs. EtOH were added dropwise and the resulting solution was heated to reflux for 3 h. EtOH was removed in vacuo, the residue was taken up in water and extracted with Et2O. The organic phase was washed successively with 10% HCl and brine, dried and the solvent was removed in vacuo. The excess diethyl malonate was removed by distillation under reduced pressure. The resulting oil (15.6 g) was used without further purification.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C@@H:4](O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.N1C(C)=CC=CC=1C.[C:34]([O:38][C:39](=[O:42])[NH:40][NH2:41])([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl>[Br:1][CH2:2][CH2:3][C@H:4]([NH:41][NH:40][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:42])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCOC(=O)[C@H](O)CCBr
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)[C@H](CCBr)NNC(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 97 %

Procedure:
To a solution of ethyl (2R)-4-bromo-2-hydroxybutanoate (1.1 g, 5.2 mmol, prepared as described in J. Med. Chem. 2003, 46, 2057 or J. Am. Chem. Soc., 2004, 126, 12432 and Tetrahedron Letters 1997, 38, 4935-4938, in dry DCM (20 mL) at 0° C. was added Tf2O (1.62 g, 5.7 mmol) via syringe. After 5 min, 2,6-lutidine (0.67 g, 6.2 mmol) was added. After another 5 min, t-butylcarbazate (1.38 g, 10.4 mmol) in DCM (5 mL) was added. The solution was allowed to attain rt and stirred overnight. The solvent was evaporated and the residue was purified using flash chromatography (heptane/EtOAc 4:1, 3:1, 2:1) to give the slightly impure tert-butyl 2-[(1S)-3-bromo-1-(ethoxycarbonyl)propyl]hydrazinecarboxylate (1.65 g, 97%) as an oil.